An Extension 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 
2 
A Pivotal Study of t:slim X2 with Control-IQ  
3 
Technology - Extension Study 
4 
Protocol Chair 
5 
Sue Brown, MD 
6 
University of Virginia 
7 
Center for Diabetes Technology 
8 
Participating Institutions 
9 
University of Virginia, Charlottesville, Virginia 
10 
Harvard University and the Joslin Diabetes Center, Massachusetts 
11 
Sansum Diabetes Research Institute, Santa Barbara, California 
12 
Mount Sinai School of Medicine, New York City 
13 
Mayo Clinic, Rochester, Minnesota 
14 
Barbara Davis Center, University of Colorado, Colorado 
15 
Stanford University, California 
16 
Coordinating Center 
17 
Jaeb Center for Health Research, Tampa, FL 
18 
Version Number: v6.1 
19 
11 SEP 2019 
20 
 
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KEY ROLES 
22 
 
Protocol Chair/Director 
 
Name, degree 
Sue A. Brown, MD 
Institution Name 
University of Virginia, Center for Diabetes Technology 
 
JCHR Coordinating Center Director 
 
Name, degree 
John Lum, M.S. 
Institution Name 
Jaeb Center for Health Research 
 
Medical Monitor 
 
Name, degree 
Roy Beck, M.D., Ph.D. 
Institution Name 
Jaeb Center for Health Research 
 
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TABLE OF CONTENTS 
24 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 15 
25 
1.1 Introduction ....................................................................................................................................... 15 
26 
1.2 Rationale ............................................................................................................................................ 18 
27 
1.3 Potential Risks and Benefits of the Investigational Device ............................................................... 18 
28 
1.3.1 Known Potential Risks ................................................................................................................ 18 
29 
1.3.1.1 Venipuncture Risks ............................................................................................................. 18 
30 
1.3.1.2 Fingerstick Risks ................................................................................................................. 18 
31 
1.3.1.3 Subcutaneous Catheter Risks (CGM) ................................................................................. 18 
32 
1.3.1.4 Risk of Hypoglycemia ........................................................................................................ 18 
33 
1.3.1.5 Risk of Hyperglycemia ....................................................................................................... 19 
34 
1.3.1.6 Risk of Device Reuse .......................................................................................................... 19 
35 
1.3.1.7 Questionnaire ...................................................................................................................... 19 
36 
1.3.1.8 Other Risks .......................................................................................................................... 19 
37 
1.3.2 Known Potential Benefits ............................................................................................................ 20 
38 
1.3.3 Risk Assessment .......................................................................................................................... 20 
39 
1.4 General Considerations...................................................................................................................... 20 
40 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 22 
41 
2.1 Participant Recruitment and Enrollment ........................................................................................... 22 
42 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 22 
43 
2.2 Participant Inclusion Criteria ............................................................................................................. 22 
44 
2.3 Participant Exclusion Criteria ............................................................................................................ 23 
45 
2.4 Screening Procedures ........................................................................................................................ 23 
46 
2.4.1 .  Assessment of Successful Completion of Original RCT .......................................................... 23 
47 
2.4.2 .  Data Collection and Testing ..................................................................................................... 24 
48 
CHAPTER 3: STUDY PROCEDURES ............................................................................................................ 25 
49 
3.1 Treatment Assignment ....................................................................................................................... 25 
50 
3.1.1 Randomization ............................................................................................................................. 25 
51 
3.2 Training for the Group Switching from SAP in the Original RCT to CLC (Control-IQ System)..... 25 
52 
3.2.1 Control-IQ System Training Details ........................................................................................... 26 
53 
3.2.2 System Initiation and Home Use ................................................................................................. 27 
54 
3.3 Training for the Group Switching from CLC in the Original RCT to PLGS (Basal-IQ System) ..... 27 
55 
3.3.1 Basal-IQ System Training Details ............................................................................................... 27 
56 
3.3.2 System Initiation and Home Use ................................................................................................. 28 
57 
3.4 Training for Group Continuing CLC Use After Using CLC in the Original Study .......................... 29 
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3.5 Blood Glucose and Ketone Testing ................................................................................................... 29 
59 
3.6 Menstrual Cycle Data Collection ...................................................................................................... 29 
60 
3.7 Optimization of Insulin Pump Settings.............................................................................................. 29 
61 
3.8 Phone Contacts and Study Visits ....................................................................................................... 29 
62 
3.8.1 1- and 2-Week Phone Contacts ................................................................................................... 30 
63 
3.8.2 Data Uploads ............................................................................................................................... 30 
64 
3.8.3 13-Week Visit .............................................................................................................................. 30 
65 
3.8.4 26-Week Visit and Subsequent Visits Every 13 Weeks .............................................................. 31 
66 
3.8.5 Final Visit .................................................................................................................................... 31 
67 
3.9 Early Termination Visit (If Applicable) ............................................................................................ 32 
68 
3.10 Unscheduled Visits .......................................................................................................................... 32 
69 
3.11 Participant Access to Study Device at Study Closure ..................................................................... 32 
70 
CHAPTER 4: STUDY DEVICES .................................................................................................................... 33 
71 
4.1 Description of the Investigational Device ......................................................................................... 33 
72 
4.1.1 Insulin Pump ................................................................................................................................ 33 
73 
4.1.2 Continuous Glucose Monitoring ................................................................................................. 33 
74 
4.1.3 Blood Glucose Meter and Strips .................................................................................................. 33 
75 
4.1.4 Ketone Meter and Strips .............................................................................................................. 33 
76 
4.1.5 Study Device Accountability Procedures .................................................................................... 33 
77 
4.1.6 Blood Glucose Meter Testing ...................................................................................................... 33 
78 
4.1.7 Blood Ketone Testing .................................................................................................................. 33 
79 
4.2 Safety Measures ................................................................................................................................. 34 
80 
4.2.1 CGM Calibration ......................................................................................................................... 34 
81 
4.2.2 Control-IQ System Failure .......................................................................................................... 34 
82 
4.2.3 Hypoglycemia Threshold Alert and Safety Protocol ................................................................... 34 
83 
4.2.4 Hyperglycemia Threshold Alert and Safety Protocol .................................................................. 34 
84 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 36 
85 
5.1 Laboratory Testing ............................................................................................................................ 36 
86 
5.2 Questionnaires ................................................................................................................................... 36 
87 
CHAPTER 6: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES .............................................. 40 
88 
6.1 Adverse Events .................................................................................................................................. 40 
89 
6.1.1 Definitions ................................................................................................................................... 40 
90 
6.1.2 Reportable Adverse Events ......................................................................................................... 41 
91 
6.1.2.1 Hypoglycemic Events ......................................................................................................... 41 
92 
6.1.2.2 Hyperglycemic/Ketotic Events ........................................................................................... 41 
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6.1.3 Relationship of Adverse Event to Study Device ......................................................................... 42 
94 
6.1.4 Intensity of Adverse Events......................................................................................................... 42 
95 
6.1.5 Coding of Adverse Events ........................................................................................................... 43 
96 
6.1.6 Outcome of Adverse Events ........................................................................................................ 43 
97 
6.2 Reportable Device Issues ................................................................................................................... 44 
98 
6.3 Pregnancy Reporting ......................................................................................................................... 44 
99 
6.4 Timing of Event Reporting ................................................................................................................ 44 
100 
6.5 Stopping Criteria ............................................................................................................................... 45 
101 
6.5.1 Participant Discontinuation of Study Device .............................................................................. 45 
102 
6.5.2 Criteria for Suspending or Stopping Overall Study ..................................................................... 45 
103 
6.6 Independent Safety Oversight ........................................................................................................... 45 
104 
6.7 Risks .................................................................................................................................................. 46 
105 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS ................................................................................... 47 
106 
7.1 Drugs Used as Part of the Protocol .................................................................................................... 47 
107 
7.2 Prohibited Medications, Treatments, and Procedures ....................................................................... 47 
108 
7.3 Participant Compensation .................................................................................................................. 47 
109 
7.4 Participant Withdrawal ...................................................................................................................... 47 
110 
7.5 Confidentiality ................................................................................................................................... 47 
111 
CHAPTER 8: STATISTICAL CONSIDERATION ........................................................................................... 48 
112 
8.1 Objectives .......................................................................................................................................... 48 
113 
8.2 Sample Size ....................................................................................................................................... 48 
114 
8.3 Outcome Measures ............................................................................................................................ 48 
115 
8.4 Objective 1 Analyses ......................................................................................................................... 51 
116 
8.4.1 Principles of Analyses ................................................................................................................. 51 
117 
8.4.2 Analytic Methods ........................................................................................................................ 51 
118 
8.4.3 Subgroup Analyses ...................................................................................................................... 52 
119 
8.5 Safety Analyses ................................................................................................................................. 52 
120 
8.6 Device Issues ..................................................................................................................................... 53 
121 
8.7 Protocol Adherence ........................................................................................................................... 53 
122 
8.8 Other Tabulations .............................................................................................................................. 54 
123 
8.9 Planned Interim Analyses .................................................................................................................. 54 
124 
8.10 Objective 2 Analyses ....................................................................................................................... 54 
125 
8.11 Objective 3 Analyses ....................................................................................................................... 55 
126 
CHAPTER 9: DATA COLLECTION AND MONITORING .............................................................................. 56 
127 
9.1 Case Report Forms and Device Data ................................................................................................. 56 
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9.2 Study Records Retention ................................................................................................................... 56 
129 
9.3 Quality Assurance and Monitoring .................................................................................................... 56 
130 
9.4 Protocol Deviations ........................................................................................................................... 57 
131 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 58 
132 
10.1 Ethical Standard ............................................................................................................................... 58 
133 
10.2 Institutional Review Boards ............................................................................................................ 58 
134 
10.3 Informed Consent Process ............................................................................................................... 58 
135 
10.3.1 Consent Procedures and Documentation ................................................................................... 58 
136 
10.3.2 Participant and Data Confidentiality ......................................................................................... 58 
137 
CHAPTER 11: REFERENCES ....................................................................................................................... 60 
138 
 
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LIST OF ABBREVIATIONS 
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ABBREVIATION 
DEFINITION 
AP 
Artificial Pancreas 
BG 
Blood Glucose 
BT/BTLE 
Bluetooth, Bluetooth low energy 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CLC 
Closed-Loop Control 
DiAs 
 
Diabetes Assistant 
DKA 
Diabetic Ketoacidosis 
EC 
European Commission 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
 
Hemoglobin A1c 
iDCL 
International Diabetes Closed Loop 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
JDRF 
Juvenile Diabetes Research Foundation 
PLGS 
Predictive Low Glucose Suspend 
POC 
Point-of-Care 
QA 
Quality Assurance 
QC 
Quality Control 
RBM 
Risk-Based Monitoring 
SAP 
Sensor-Augmented Pump 
SD 
Standard Deviation 
TDD 
Total Daily Dose 
UI 
User Interface 
UVA 
University of Virginia 
 
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Signature Page 
144 
The International Diabetes Closed Loop (iDCL) trial: Clinical 
145 
Acceptance of the Artificial Pancreas 
146 
A Pivotal Study of t:slim X2 with Control-IQ  
147 
Technology - Extension Study 
148 
Protocol Identifying Number: DCLP3 
149 
IND/IDE Sponsor: University of Virginia 
150 
Version Number: v.6.1 
151 
11 SEP 2019 
152 
 
153 
 
154 
 
155 
 
156 
 
JCHR Principal Investigator 
 
Name, degree 
John W. Lum, M.S. 
 
Signature / Date 
 
 
 
 
Protocol Chair/Director 
 
Name, degree 
Sue A. Brown, MD 
Signature / Date 
 
 
 
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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
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Protocol Title: The International Diabetes Closed Loop (iDCL) trial: Clinical Acceptance of 
159 
the Artificial Pancreas - A Pivotal Study of t:slim X2 with Control-IQ Technology – 
160 
Extension Study 
161 
Protocol Version/Date: v6.1/11 SEP 2019 
162 
I have read the protocol specified above.  In my formal capacity as a Site Principal Investigator, 
163 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
164 
providing the Jaeb Center for Health Research, which serves as the Coordinating Center for the 
165 
protocol, with complete and timely information, as outlined in the protocol.  It is understood that 
166 
all information pertaining to the study will be held strictly confidential and that this 
167 
confidentiality requirement applies to all study staff at this site. 
168 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
169 
required by the following: United States (US) Code of Federal Regulations (CFR) applicable to 
170 
clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 
171 
CFR Part 812). 
172 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
173 
will take place without prior agreement from the sponsor and documented approval from the 
174 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
175 
to eliminate an immediate hazard(s) to the trial participants. 
176 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
177 
completed Human Participants Protection Training and Good Clinical Practice Training.  
178 
Further, I agree to ensure that all staff members involved in the conduct of this study are 
179 
informed about their obligations in meeting the above commitments. 
180 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
181 
 
dd 
mmm 
yyyy 
182 
Investigator’s Name: ____________________________________ 
183 
Site Name/Number: _____________________________________ 
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PROTOCOL SUMMARY 
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PARTICIPANT AREA 
DESCRIPTION 
Title 
The International Diabetes Closed Loop (iDCL) Trial: Pivotal Trial of 
t:slim X2 with Control-IQ Technology - Extension Study 
Précis 
An extension study for participants who completed a prior 6-month 
randomized controlled trial (RCT) of a closed loop system (Control-IQ) 
vs. sensor-augmented pump (SAP). 
Investigational Device 
t:slim X2 with Control-IQ and Dexcom G6 system 
Objectives 
The objectives of the study are 
(1) Among individuals who used CLC in the original RCT, to 
compare continued use of CLC (t:slim X2 with Control-IQ 
Technology) for 3 months versus switching to a Predictive 
Low-Glucose Suspend (PLGS) system (t:slim X2 with Basal-IQ 
Technology) for 3 months. 
(2) Among individuals who used SAP in the original RCT, to 
obtain additional safety data by initiating use of the Control-IQ 
system for 3 months. 
(3) For all participants, use of the CLC system between the end of 
3-month period and the point that the system becomes 
commercially available in order to gather additional safety data 
Study Design 
Objective 1: RCT with 1:1 randomization to intervention with CLC vs. 
PLGS for 3 months.  
Objective 2: Observational study of initiation and use of CLC for 3 
months. 
Objective 3: Observational study of initiation and use of CLC for 3 
months following use of PLGS for 3 months; use of CLC by all 
participants between end of 3-month period and the point that the system 
becomes commercially available in order to gather additional safety data. 
Number of Sites 
Seven US clinical sites 
Primary Endpoint 
Objective 1: The primary efficacy outcome for the RCT is time in target 
range 70-180 mg/dL measured by CGM in CLC group vs. PLGS group 
over 3 months. Safety outcomes also will be assessed 
Objective 2: The primary outcome is safety outcomes.  Efficacy also will 
be assessed as a pre-post within participant analysis 
Objective 3: The primary outcome is safety outcomes.  Efficacy also will 
be assessed as a pre-post within participant analysis 
Population 
Key Inclusion Criteria 
 Successfully completed the original 6-month RCT within the prior 
14 days 
Key Exclusion Criteria  
 Use of any non-insulin glucose-lowering agents except metformin 
Sample Size 
Sample size is based on the number in the original RCT who successfully 
complete six months and sign consent to participate in this study (up to 
approximately 168 total). 
Treatment Groups 
Objective 1 
 Group 1: t:slim X2 with Control-IQ Technology and Study CGM 
 Group 2: t:slim X2 with Basal-IQ Technology and Study CGM 
 
Participant Duration 
3 months 

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PARTICIPANT AREA 
DESCRIPTION 
Protocol Overview/Synopsis 
Eligible participants in the original RCT who agree to be part of the 
Extension Study will sign the informed consent form. 
 Participants assigned to the original RCT SAP group will initiate 
use of the CLC system for 3 months.  
 Participants assigned to the original RCT CLC group will be 
randomly assigned 1:1 to either continue CLC or switch to PLGS 
for 3 months. 
 After 3 months, all participants will be given the opportunity to use 
the CLC system until the point that the system becomes 
commercially available 
 
 
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Figure 1: Study Design - Participants entering Extension Study after having completed preceding 6-
188 
month RCT. Participants in the original RCT SAP Group will use CLC in the first 3 months of the 
189 
Extension Study while participants in the original RCT CLC Group will be randomly assigned 1:1 
190 
to either continue CLC or switch to PLGS. After 3 months, all participants will be given the 
191 
opportunity to use CLC until the point that the CLC system becomes commercially available.
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SCHEMATICS OF STUDY DESIGN 
193 
 
194 
Figure 2: Schematic of Eligibility Assessment/Enrollment 
195 
 
196 
 
197 
Figure 3. Schematic of Study Design 
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Table 1. Schedule of Study Visits and Procedures 
199 
 
0 Weeks 
1w 
2w 
13w
26w, then 
every 13 
weeks 
until end 
Final 
Visit 
Visit (V) or Phone (P) 
V 
P1 
P1 
V 
V 
V 
Comment 
Screen/Enroll and Rand/Assign 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
HbA1c (DCA Vantage or similar point of care device, or local lab) 
X2 
 
 
X 
X 
X 
HbA1c (Central lab) 
X2 
 
 
X 
 
 
Pregnancy test (females of child-bearing potential) 
X 
 
 
X 
X 
 
Device Data download(s) 
 
X 
X 
X 
X 
X 
Review diabetes management and AEs 
 
X 
X 
X 
X 
X 
Questionnaires as defined in section 5.2 
X2 
 
 
X 
X3 
X 
Follow-up Phone Call  
 
 
 
 
 
P 
1 Only performed for those participants who switched from SAP in the original 6-month RCT to CLC in the Extension Study, or from CLC in the 
200 
original RCT to PLGS in the Extension Study 
201 
2 Will use results obtained at Final Visit of preceding 6-month RCT 
202 
3 26-Week visit only 
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Chapter 1: Background Information 
204 
1.1 Introduction 
205 
The Tandem X2 insulin pump with Control-IQ Technology is a third-generation closed-loop 
206 
control (CLC) system retaining the same control algorithm that was initially tested by University 
207 
of Virginia’s (UVA) diabetes assistant (DiAs) system and then implemented in the inControl 
208 
system. DiAs is described in 13 IDEs (see IDEs 1-12 and 14 in the list below) and inControl is 
209 
described in IDEs G160097, G160181, G150240, G140169/S010. For complete algorithmic and 
210 
clinical background, we refer to these IDEs and to a number of scientific publications that 
211 
describe glycemic control outcomes and clinical impressions from the use of these systems (see 
212 
list of 25 peer-reviewed papers and scientific presentations under Bibliography). Overall, this 
213 
control algorithm has been implemented in two mobile platforms (DiAs and inControl) and has 
214 
been tested in 30 clinical trials by 450 adults and children with type 1 diabetes for over 280,000 
215 
hours of use to date in the U.S. and overseas.  
216 
As described in the Background, this project is a result from a sequence of clinical trials that 
217 
have tested extensively the control system and in several centers in the U.S. and overseas. The 
218 
following 18 IDEs reflect this progress: 
219 
1. IDE #G110095: Feasibility study of closed loop control in type 1 diabetes using heart rate 
220 
monitoring as an exercise marker, approved 10/08/2011; 
221 
2. IDE #G120032: Early feasibility (pilot) study of outpatient control-to-range; 3/2/2012; 
222 
3. IDE #G120210: Early feasibility study 2 of outpatient control-to-range; 10/12/2012; 
223 
4. IDE #G130118: DiAs control-to-range nocturnal closed-loop camp study; 6/19/2013;  
224 
5. IDE #G130121: Optimizing closed-loop control of type 1 diabetes mellitus in adolescents; 
225 
6/19/2013; 
226 
6. IDE# G130142:  Closed loop control in adolescents using heart rate as exercise indicator; 
227 
7/16/13; 
228 
7. IDE #G130143: Early feasibility study of adaptive advisory/automated (AAA) control of 
229 
type 1 diabetes; 7/19/2013; 
230 
8. IDE #G140066:  Full day and night closed-loop with DiAs platform; 5/9/14. 
231 
9. IDE #G140068: Unified Safety System (USS) Virginia Closed Loop versus sensor 
232 
augmented pump therapy overnight in type 1 diabetes; 5/14/2014; 
233 
10. IDE #G140089: Outpatient control-to-range: Safety and efficacy with day-and-night in-home 
234 
use; 6/6/2014; 
235 
11. IDE #G140169: Unified Safety System (USS) Virginia Closed-Loop versus Sensor 
236 
Augmented Pump (SAP) therapy for hypoglycemia reduction in type 1 diabetes; 10/3/2014. 
237 
12. IDE #G150221: Reducing risks and improving glucose control during extended exercise in 
238 
youth with T1DM: The AP Ski Camp; 11/09/2015;  
239 
13. IDE #G150240: Project Nightlight: Efficacy and system acceptance of dinner/night vs. 24 hr 
240 
closed loop control; 11/12/2015; 
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14. IDE #G160047: Closed-loop in young children 5-8 years old using DiAs platform; 
242 
03/29/2016;  
243 
15. IDE #G160097: Clinical Acceptance of the Artificial Pancreas: the International Diabetes 
244 
Closed-Loop (iDCL) Trial/Research Site Training Protocol; 06/03/16. 
245 
16. IDE#G160181: PROTOCOL 1 for “Clinical Acceptance of the Artificial Pancreas: The 
246 
International Diabetes Closed Loop (iDCL) Trial; 09/21/16 
247 
17. IDE#G170255: Protocol 3 for “Pilot Trial of t:slim X2 with Control-IQ 
248 
Technology”;11/16/17 and IDE#G170255/S001 Protocol 3 for “Training Study of t:slim X2 
249 
with Control-IQ Technology”; 11/16/17 
250 
18. IDE#G170267: “Real-Time Monitoring and Glucose Control During Winter-Sport Exercise 
251 
in Youth with Type 1 Diabetes: The AP Ski Camp Continued”; 11/21/17 
252 
We further reference pre-submission Q170885 and our discussion with FDA on July 18, 2017 
253 
regarding the structure of studies intended to test inControl implemented on t:slim X2. Based on 
254 
the input provided by the Agency, we initially defined a series of three studies leading to a future 
255 
pivotal trial of this system (36-48 hr Pilot Study, 2 week at home Training Study, followed by 
256 
the Pivotal Trial). Since the time of the initial discussion, we have concluded a successful Pilot 
257 
of 5 Adult (December 2017) and a Ski Camp with 12 Teenagers (January 2018) on the System. 
258 
We have also received approval for the use of this system in a long-term home study (Project 
259 
Nightlight/G#150240/S008). The Project Nightlight Study will now replace the previous 
260 
Training Study as noted in Figure 4. 
261 
 
262 
Figure 4: Sequence of planned studies leading to this pivotal trial of the 
263 
Tandem X2 insulin pump with Control-IQ Technology 
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A successful pilot of 5 Adults (mean age 52.8 yrs; 3F/2M, mean A1c 6.5%) with Type 1 
265 
Diabetes was completed in December 2017. In this pilot study, the system was challenged with 
266 
a variety of scenarios including: Pump disconnection, CGM sensor removal without stopping 
267 
session, CGM sensor change, Basal Rate change, Cartridge Change, Extended Bolus, Calibration 
268 
at non-ideal conditions, Stopping Control-IQ, Reset Sleep Time, Restaurant Meals and Exercise 
269 
(treadmill/walk). The study demonstrated excellent connectivity with 98% time in closed-loop 
270 
control and 94% time CGM is available during 196 hours of use. 
271 
Table 2. Pilot Study results based on time in closed-loop 
272 
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% 
Closed-Loop Control System 
273 
The Closed-Loop Control System contained in t-slim X2 with Control-IQ Technology is 
274 
described in Master File MAF-2032/A008. Control-IQ Technology is derived from inControl 
275 
previously described in IDE# G160097, G160181, G150240 and G140169/S010. The CLC is 
276 
an “artificial pancreas” (AP) application that uses advanced closed loop control algorithms to 
277 
automatically manage blood glucose levels for people with Type 1 Diabetes. The system 
278 
modulates insulin to keep blood glucose in a targeted range. The system components include 
279 
the t:slim X2 with Control-IQ Technology and the Dexcom CGM G6. 
280 
 
281 
Figure 5. t:slim X2 with Control-IQ and Dexcom G6 system 
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1.2 Rationale 
283 
The main objective of the study is to compare continued use of CLC (t:slim X2 with Control-IQ 
284 
Technology) for 3 months versus switching to a Predictive Low-Glucose Suspend (PLGS) 
285 
system (t:slim X2 with Basal-IQ Technology) for 3 months following 6 months of Control-IQ 
286 
use in a preceding study, in a parallel group RCT design. 
287 
Another objective is to obtain additional safety data from the Control-IQ system in a large 
288 
population. 
289 
1.3 Potential Risks and Benefits of the Investigational Device 
290 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data 
291 
are handled to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are 
292 
always a risk in participants with type 1 diabetes and participants will be monitored for this. 
293 
1.3.1 Known Potential Risks 
294 
1.3.1.1 Venipuncture Risks 
295 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws 
296 
can cause some common reactions like pain, bruising, or redness at the sampling site.  Less 
297 
common reactions include bleeding from the sampling site, formation of a small blood clot or 
298 
swelling of the vein and surrounding tissues, and fainting. 
299 
1.3.1.2 Fingerstick Risks 
300 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
301 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital 
302 
laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount 
303 
of bleeding under the skin will produce a bruise.  A small scar may persist for several weeks.  
304 
The risk of local infection is less than 1 in 1000.  This should not be a significant contributor to 
305 
risks in this study as fingersticks are part of the usual care for people with diabetes. 
306 
1.3.1.3 Subcutaneous Catheter Risks (CGM) 
307 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
308 
the sensor needle placement.  If a catheter is left under the skin for more than 24 hours it is 
309 
possible to get an infection where it goes into the skin, with swelling, redness and pain.  There 
310 
may be bleeding where the catheter is put in and bleeding under the skin causes a bruise (1 in 10 
311 
risk). 
312 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
313 
leave a small portion of the sensor under the skin that may cause redness, swelling or pain at the 
314 
insertion site.  The participant should be further instructed to notify the study coordinator 
315 
immediately if this occurs. 
316 
1.3.1.4 Risk of Hypoglycemia 
317 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a 
318 
low blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and 
319 

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possibly less than it would be as part of daily living.  Symptoms of hypoglycemia can include 
320 
sweating, jitteriness, and not feeling well.  Just as at home, there is the possibility of fainting or 
321 
seizures (convulsions) and that for a few days the participant may not be as aware of symptoms 
322 
of hypoglycemia.  A CGM functioning poorly and significantly over-reading glucose values 
323 
could lead to inappropriate insulin delivery. 
324 
1.3.1.5 Risk of Hyperglycemia 
325 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
326 
extended period or if the pump or infusion set is not working properly.  A CGM functioning 
327 
poorly and significantly under-reading glucose values could lead to inappropriate suspension of 
328 
insulin delivery. 
329 
1.3.1.6 Risk of Device Reuse 
330 
The study CGM system is labeled for single use only. The sensor (the component of the system 
331 
that enters the skin) will be single use only. The transmitter and receiver may be reused during 
332 
the study after cleaning the device using a hospital-approved cleaning procedure. The transmitter 
333 
is attached to the sensor but does not enter the skin and the receiver is a hand held device. 
334 
Participants will be informed that FDA or relevant national authorities have approved these 
335 
devices for single use and that by using them among multiple patients, bloodborne pathogens 
336 
(i.e. Hepatitis B) may be spread through the use of multiple users. 
337 
The study insulin pumps are labeled for single-patient use. During the study, this device may be 
338 
reused after cleaning adhering to a hospital-approved cleaning procedure. All infusion set 
339 
equipment will be single patient use only (infusion set insertion kits, tubing, cartridges etc.)  
340 
Participants will be informed that FDA or relevant national authorities typically approve the 
341 
insulin pump device for single use and that by using them among multiple patients, bloodborne 
342 
pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
343 
The study blood glucose meter and blood ketone meter are labeled for single-patient use. 
344 
During the study, only one person can use each device as there are rare risks that bloodborne 
345 
pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
346 
1.3.1.7 Questionnaire 
347 
As part of the study, participants will complete questionnaires which include questions about 
348 
their private attitudes, feelings and behavior related to the investigational equipment as well as 
349 
managing diabetes.  It is possible that some people may find these questionnaires to be mildly 
350 
upsetting. Similar questionnaires have been used in previous research and these types of 
351 
reactions have been uncommon. 
352 
1.3.1.8 Other Risks 
353 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
354 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
355 
If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
356 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
357 
medication may be required. 
358 

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Whenever the skin is broken there is the possibility of an infection.  The CGM and pump 
359 
infusion sites are inserted under the skin.  It is possible that any part that is inserted under the 
360 
skin may cause an infection.  These occur very infrequently, but, if an infection was to occur, 
361 
oral and/or topical antibiotics can be used.  The risk of skin problems could be greater if you use 
362 
a sensor for longer than it is supposed to be used.  Therefore, participants will be carefully 
363 
instructed about proper use of the sensor. 
364 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be 
365 
collected for the study as measures of diabetes self-management behaviors.  Some people 
366 
may be uncomfortable with the researchers' having such detailed information about their daily 
367 
diabetes habits. 
368 
1.3.2 Known Potential Benefits 
369 
One purpose of this research is to reduce the frequency of hypoglycemia and severe 
370 
hypoglycemic events. Hypoglycemia is the number one fear of many individuals and families 
371 
with someone who has type 1 diabetes and this fear often prevents optimal glycemic control. 
372 
It is expected that this protocol will yield increased knowledge about using an automated 
373 
closed-loop to control the glucose level and is intended to develop data to support a future 
374 
PMA-application. The individual participant may not benefit from study participation. 
375 
1.3.3 Risk Assessment 
376 
Based on the facts that (1) adults and adolescents with diabetes experience mild hypoglycemia 
377 
and hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
378 
intervention involves periodic automated insulin dosing that may increase the likelihood of 
379 
hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the 
380 
likelihood of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies 
381 
using the investigational device system in the home setting, that limit the likelihood of excessive 
382 
insulin dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and 
383 
hyperglycemia can be achieved, it is the assessment of the investigators that this protocol falls 
384 
under DHHS 46.405 which is a minor increase over minimal risk. In addition, it is the belief of 
385 
the investigators that this study also presents prospect of direct benefit to the participants and 
386 
general benefit to others with diabetes. 
387 
1.4 General Considerations 
388 
The study is being conducted in compliance with the policies described in the study policies 
389 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
390 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
391 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
392 
considered the source data. 
393 
There is no restriction on the number of participants to be enrolled by each site toward the 
394 
overall recruitment goal. 
395 

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The protocol is considered a significant risk device study, due to the fact that the closed loop 
396 
system is experimental.  Therefore, an investigational device exemption (IDE) from the U.S. 
397 
Food and Drug Administration (FDA) is required to conduct the study.
398 

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Chapter 2: Study Enrollment and Screening 
399 
2.1 Participant Recruitment and Enrollment 
400 
Enrollment will include only those individuals who successfully completed the original 6-month 
401 
RCT comparing the CLC system to SAP, with a maximum of 168 participants. 
402 
Study participants will participate at the same 7 clinical centers in the United States who 
403 
participated in the preceding study without regard to gender, race, or ethnicity.  Recruitment per 
404 
site will be based on the number at the site that successfully completed the original RCT. 
405 
2.1.1 Informed Consent and Authorization Procedures 
406 
Before completing any procedures or collecting any data that are specific for the study, written 
407 
informed consent will be obtained. 
408 
For potential study participants ≥18 years old, the study protocol will be discussed with the 
409 
potential study participant by study staff.  The potential study participant will be given the 
410 
Informed Consent Form to read.  Potential study participants will be encouraged to discuss the 
411 
study with family members and their personal physicians(s) before deciding whether to 
412 
participate in the study. 
413 
For potential participants under 18 years of age, a parent/legal guardian (referred to subsequently 
414 
as “parent”) will be provided with the Informed Consent Form to read and will be given the 
415 
opportunity to ask questions.  Potential participants meeting the IRB’s minimum age of assent 
416 
will be given a Child Assent Form to read and discuss with his/her parents and study personnel.  
417 
If the parent and child agree to participate, the Informed Consent Form and Child Assent Form 
418 
will be signed.  A copy of the consent form will be provided to the participant and his/her parent 
419 
and another copy will be added to the participant’s study record. 
420 
As part of the informed consent process, each participant will be asked to sign an authorization 
421 
for release of personal information.  The investigator, or his or her designee, will review the 
422 
study-specific information that will be collected and to whom that information will be disclosed.  
423 
After speaking with the participant, questions will be answered about the details regarding 
424 
authorization. 
425 
A participant is considered enrolled when the informed consent form has been signed. 
426 
2.2 Participant Inclusion Criteria 
427 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
428 
in the study. 
429 
1. Successful completion of the original 6-month RCT within the prior 14 days 
430 
2. For females, not currently known to be pregnant 
431 
If female and sexually active, must agree to use a form of contraception to prevent pregnancy 
432 
while a participant in the study.  A negative urine pregnancy test will be required for all 
433 
females of child-bearing potential. Participants who become pregnant will be discontinued 
434 

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from the study. Also, participants who during the study develop and express the intention to 
435 
become pregnant within the timespan of the study will be discontinued. 
436 
3. For participants <18 years old, living with one or more parent/legal guardian knowledgeable 
437 
about emergency procedures for severe hypoglycemia and able to contact the participant in 
438 
case of an emergency. 
439 
4. Willingness to not use a personal CGM for the duration of the study 
440 
5. Investigator has confidence that the participant can successfully operate all study devices and 
441 
is capable of adhering to the protocol 
442 
6. Willingness to use only lispro (Humalog) or aspart (Novolog), and to use no other insulin 
443 
during the study. 
444 
7. Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
445 
trial (see section 2.3) 
446 
2.3 Participant Exclusion Criteria 
447 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from 
448 
study participation. 
449 
1. Concurrent use of any non-insulin glucose-lowering agent other than metformin (including 
450 
GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas). 
451 
2. Hemophilia or any other bleeding disorder 
452 
3. A condition, which in the opinion of the investigator or designee, would put the participant or 
453 
study at risk 
454 
4. Participation in another pharmaceutical or device trial at the time of enrollment or during the 
455 
study 
456 
5. Employed by, or having immediate family members employed by Tandem Diabetes Care, 
457 
Inc., Dexcom, Inc., or TypeZero Technologies, LLC, or having a direct supervisor at place of 
458 
employment who is also directly involved in conducting the clinical trial (as a study 
459 
investigator, coordinator, etc.); or having a first-degree relative who is directly involved in 
460 
conducting the clinical trial 
461 
2.4 Screening Procedures 
462 
2.4.1 .  Assessment of Successful Completion of Original RCT 
463 
A determination will be made as to whether the participant meets criteria for having successfully 
464 
completed the original RCT. Successful completion is defined as having participated in the 
465 
study’s 26-week visit and having completed the following associated study visit procedures 
466 
within the prior 14 days: 
467 
 Local HbA1c determination and collection of blood sample for central laboratory HbA1c 
468 
determination 
469 
 Completion of study questionnaires 
470 

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2.4.2 .  Data Collection and Testing 
471 
For participants who satisfy the completion criteria above, the remaining inclusion and exclusion 
472 
criteria will be reviewed and documented to verify the participant’s eligibility for the Extension 
473 
Study. A urine pregnancy test will be performed for all women of child-bearing potential. 
474 
The following information obtained during the original RCT will be captured/reviewed and 
475 
updated if necessary:  
476 
 Medical history 
477 
 Concomitant medications 
478 
Data obtained during the 26-week visit of the original RCT will be considered baseline data for 
479 
the Extension study, including: 
480 
 HbA1c as described above 
481 
 Weight (and height if <21 years of age) 
482 
Screening procedures may last approximately 15 minutes. 
483 

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Chapter 3: Study Procedures 
484 
3.1 Treatment Assignment 
485 
Treatment assignment will occur on the same day as the Screening visit. 
486 
 Participants who were assigned to the SAP group in the original RCT will be assigned to 
487 
use CLC during the extension study 
488 
 Participants who were assigned to the CLC group in the original RCT will receive a 
489 
randomized treatment assignment as detailed below 
490 
3.1.1 Randomization 
491 
Participants who were assigned to the CLC group in the original RCT will be randomly assigned 
492 
to one of two treatment groups in a 1:1 ratio: 
493 
1. CLC Group 
494 
2. PLGS Group 
495 
The participant’s randomization group assignment is determined by completing a Randomization 
496 
case report form on the study website. The randomization list will use a permuted block design, 
497 
stratified by clinical center. 
498 
The participant will be included in the data analysis regardless of whether or not the protocol 
499 
for the assigned randomization group is followed.  Thus, the investigator must not randomize a 
500 
participant until he/she is convinced that the participant/parent will accept assignment to either 
501 
of the two groups. 
502 
It was decided that it was more important to stratify randomization by site than by factors such 
503 
as baseline time in range, HbA1c, or device use since these factors will be easier to adjust for in 
504 
analysis than will site in view of the relatively small number at each site. 
505 
3.2 Training for the Group Switching from SAP in the Original RCT to CLC 
506 
(Control-IQ System) 
507 
Participants who were assigned to the SAP group in the original RCT will use CLC during the 
508 
extension study. These participants will receive study system training on the Control-IQ system. 
509 
This training sessions can occur on the same day or extend to up to one additional day if needed 
510 
within 1-7 days from assignment; participants will not take the study system home until training 
511 
has been completed. 
512 
For participants <18 years old, the parent/guardian will be trained on severe hypoglycemia 
513 
emergency procedures including removal of the study pump and administration of glucagon. 
514 
The parent/guardian will be asked to attend any/all of the other training procedures. 
515 

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3.2.1 Control-IQ System Training Details 
516 
Participants will receive system training by a qualified trainer. The study system includes the 
517 
Tandem t:slim X2 with Control-IQ technology and associated Dexcom G6 CGM. 
518 
CGM training may include any of the following refresher topics as needed: 
519 
 The participant will be instructed and supervised on how to insert the sensor and transmitter. 
520 
 The participant will learn how to calibrate the CGM unit 
521 
 The participant will learn how to access the CGM trace via the t:slim X2 with Control-IQ 
522 
user interface 
523 
 Participants will be asked to perform fingerstick blood glucose measurements in accordance 
524 
with the labeling of the study CGM device 
525 
Pump training may include any of the following refresher topics as needed: 
526 
 The participant will be fully instructed on the study insulin pump. A qualified system trainer 
527 
will conduct the training and in particular discuss differences from their home pump in 
528 
important aspects such as calculation of insulin on board and correction boluses. Additional 
529 
topics not limited to but may include: infusion site initiation, cartridge/priming procedures, 
530 
setting up the pump, charging the pump, navigation through menus, bolus procedures 
531 
including stopping a bolus, etc. 
532 
 The study team will assist the participant in study pump infusion site initiation and will start 
533 
the participant on the study pump. The study pump will be programmed with the 
534 
participant’s usual basal rates and pump parameters. The participant’s current pump will be 
535 
removed. 
536 
 The participant will be supervised with the study pump during at least one meal or snack 
537 
bolus to ensure participant understanding of the pump features. 
538 
 The participant will be encouraged to review the literature provided with the pump and 
539 
infusion sets after the training is completed. 
540 
Pump training specific to the Control-IQ Technology functions will include: 
541 
 How to turn on and off Control-IQ technology. 
542 
 How to understand when Control-IQ is increasing or decreasing basal rates. 
543 
 How to administer a meal or correction bolus on the t:slim X2 with Control-IQ system 
544 
 What to do when exercising while using the system 
545 
 How to enable the sleep function and set the sleep schedule 
546 
 The participant will be assessed for understanding of the system interface and how to react to 
547 
safety/alert messages. 
548 
 The participant will be given a User Guide as a reference. 
549 

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Upon completion of Control-IQ training, study staff will document, using a checklist, that the 
550 
participant is familiar with the function/feature and/or capable of performing each of the tasks 
551 
specified. 
552 
3.2.2 System Initiation and Home Use 
553 
After training on the study system has been completed, participants will proceed with home use 
554 
(meaning free-living use at work, home, etc.) of the Control-IQ system. 
555 
Participants will be instructed to use the system in closed-loop mode except 1) when no 
556 
calibrated CGM sensor is available or 2) if insulin is delivered by any means other than the 
557 
study pump (e.g. injection of subcutaneous insulin via syringe in the event of infusion site 
558 
failure). If insulin is delivered by any means other than the study pump, participant will be 
559 
instructed to turn off Control-IQ for approximately four hours. 
560 
Participants will also be instructed to contact study staff during periods of illness with an 
561 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
562 
illness, or during periods of use of medications such as epinephrine for the emergency treatment 
563 
of a severe allergic reaction or asthma attack in addition to use of oral or injectable 
564 
glucocorticoids to determine if Control-IQ use should be temporarily discontinued. 
565 
Participants may use available manufacturer-provided software and features of the study CGM 
566 
related to mobile data access or remote monitoring, but will be instructed not to use any third-
567 
party components for this purpose. 
568 
3.3 Training for the Group Switching from CLC in the Original RCT to 
569 
PLGS (Basal-IQ System) 
570 
The participants who used CLC in the original RCT and who are assigned to the PLGS (Basal-
571 
IQ) group during the extension study will receive study system training on the Basal-IQ system. 
572 
This training sessions can occur on the same day or extend to up to one additional day if needed 
573 
within 1-7 days from assignment; participants will not take the study system home until training 
574 
has been completed. 
575 
For participants <18 years old, the parent/guardian will be trained on severe hypoglycemia 
576 
emergency procedures including removal of the study pump and administration of glucagon. 
577 
The parent/guardian will be asked to attend any/all of the other training procedures. 
578 
3.3.1 Basal-IQ System Training Details 
579 
Participants will receive system training by a qualified trainer. The study system includes the 
580 
Tandem t:slim X2 with Basal-IQ technology and associated Dexcom G6 CGM. 
581 
CGM training may include any of the following refresher topics as needed: 
582 
 The participant will be instructed and supervised on how to insert the sensor and transmitter. 
583 
 The participant will learn how to calibrate the CGM unit 
584 

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 The participant will learn how to access the CGM trace via the t:slim X2 with Basal-IQ user 
585 
interface 
586 
 Participants will be asked to perform fingerstick blood glucose measurements in accordance 
587 
with the labeling of the study CGM device 
588 
Pump training may include any of the following refresher topics as needed: 
589 
 The participant will be fully instructed on the study insulin pump. A qualified system trainer 
590 
will conduct the training and in particular discuss differences from their home pump in 
591 
important aspects such as calculation of insulin on board and correction boluses. Additional 
592 
topics not limited to but may include: infusion site initiation, cartridge/priming procedures, 
593 
setting up the pump, charging the pump, navigation through menus, bolus procedures 
594 
including stopping a bolus, etc. 
595 
 The study team will assist the participant in study pump infusion site initiation and will start 
596 
the participant on the study pump. The study pump will be programmed with the 
597 
participant’s usual basal rates and pump parameters. The participant’s current pump will be 
598 
removed. 
599 
 The participant will be supervised with the study pump during at least one meal or snack 
600 
bolus to ensure participant understanding of the pump features. 
601 
The participant will be encouraged to review the literature provided with the pump and infusion 
602 
sets after the training is completed. 
603 
Pump training specific to the Basal-IQ Technology functions will include: 
604 
 How to turn on and off Basal-IQ technology. 
605 
 How to understand when Basal-IQ has suspended basal insulin delivery. 
606 
 What to do when exercising while using the system 
607 
 The participant will be assessed for understanding of the system interface and how to react to 
608 
safety/alert messages. 
609 
 The participant will be given a User Guide as a reference. 
610 
Upon completion of Basal-IQ training, study staff will document, using a checklist, that the 
611 
participant is familiar with the function/feature and/or capable of performing each of the tasks 
612 
specified. 
613 
3.3.2 System Initiation and Home Use 
614 
After training on the study system has been completed, participants will proceed with home use 
615 
(meaning free-living use at work, home, etc.) of the Basal-IQ system. 
616 
Participants will be instructed to use the system in accordance with the user documentation 
617 
provided by study staff. 
618 

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Participants may use available manufacturer-provided software and features of the study CGM 
619 
related to mobile data access or remote monitoring, but will be instructed not to use any third-
620 
party components for this purpose. 
621 
3.4 Training for Group Continuing CLC Use After Using CLC in the Original 
622 
Study 
623 
No additional system training is required for these participants. However, at the discretion of the 
624 
investigator, refresher training may be provided using a subset of the topics described in section 
625 
3.2.1 above. 
626 
3.5 Blood Glucose and Ketone Testing 
627 
Participants will receive supplies for blood glucose and ketone testing as needed and will be 
628 
provided Hypoglycemia, Hyperglycemia and Ketone Guidelines as detailed in section 4.2. 
629 
Participants will be required to have a home glucagon emergency kit. Participants who currently 
630 
do not have one will be given a prescription for the glucagon emergency kit. 
631 
3.6 Menstrual Cycle Data Collection 
632 
Participants who consent to participate in the collection of menstrual cycle data will be asked to 
633 
install a Menstrual Cycle tracking app on their personal phones. 
634 
These participants will be given instructions on how to use the app to collect the desired 
635 
menstrual cycle data information and will use the app to collect these data on an ongoing basis 
636 
until the study Final Visit. The data collected will include details about contraception method 
637 
and menses dates. 
638 
3.7 Optimization of Insulin Pump Settings 
639 
Data-driven optimization of pump settings will occur at the following times: 
640 
 Screening 
641 
 At the 1- and 2-Week phone contacts for those participants participating in the 
642 
Extension Phase who switched from SAP to CLC or from CLC to PLGS 
643 
 If the study participant contacts the study physician due to concerns about their pump 
644 
settings due to recurring hypo- or hyperglycemia. 
645 
Data will be obtained from CGM and/or pump downloads at the visit. Adjustments to pump 
646 
settings (basal rates, correction factor, insulin-to-carbohydrate ratio, etc.) will be made in 
647 
response to major trends observed in the CGM data, with flexibility for clinicians to adhere to 
648 
guidelines and practices established at each individual practice rather than a fixed set of 
649 
heuristics for all sites. 
650 
3.8 Phone Contacts and Study Visits 
651 
Participants will be provided with contact information and will be asked to call the study 
652 
clinical staff for any health related issues and for technical issues with study system components. 
653 
Participants will be provided with sufficient study supplies to last until the 13-Week visit.   
654 

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3.8.1 1- and 2-Week Phone Contacts 
655 
For those participants who switched from SAP in the original RCT to CLC in the Extension 
656 
Study, or from CLC in the original RCT to PLGS in the Extension Study, study staff will 
657 
perform a phone call with the participant within 7 (±3) days and at 14 (±3) days following group 
658 
assignment. 
659 
If the participant cannot be reached, the participant’s other contact methods will be utilized, 
660 
including the emergency contact.   
661 
The following will occur during each contact: 
662 
 Review of available CGM and/or system data to identify any safety issues associated 
663 
with insulin pump settings and current diabetes management approach 
664 
 Assessment of adverse events, adverse device effects, and device issues 
665 
 Optimization of pump settings, if indicated 
666 
At investigator discretion, either phone contact may be replaced by a clinic visit. Additional 
667 
phone contacts or clinic visits may be performed as needed.  
668 
3.8.2 Data Uploads 
669 
Participants will be instructed to upload data from their study insulin pump prior to the 1- and 2- 
670 
week phone contacts (if applicable) and at least every 4 weeks for the remainder of the study.  
671 
Participants will be provided with any software and hardware needed to perform these data 
672 
uploads. 
673 
If participating in the menstrual cycle data collection aspect of the study, participants may 
674 
periodically be asked to transmit the collected data to the clinical site using the export 
675 
functionality of the phone app that was used. 
676 
3.8.3 13-Week Visit 
677 
All participants will return to the clinic for a 13-Week (±7 days) clinic visit during which the 
678 
following will occur: 
679 
 HbA1c determination using the DCA Vantage or similar point of care device 
680 
 Collection of a blood sample to send to the central laboratory for HbA1c determination 
681 
 Completion of questionnaires  
682 
 Urine pregnancy test for all women of child-bearing potential 
683 
 Weight measurement  
684 
 Assessment of adverse events, adverse device effects, and device issues 
685 
 Download of device data (study system or personal pump and study CGM, study BG meter, 
686 
study ketone meter) 
687 

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688 
All participants will be offered the opportunity to continue in the study, using the CLC system 
689 
until such time that the system becomes commercially available. 
690 
 Participants who do not wish to continue in the study will transition back to personal insulin 
691 
pump, or to resumption of MDI. The 13-Week visit will serve as the final study visit for 
692 
these participants. 
693 
 Participants who agree to continue in the study will be provided with sufficient study 
694 
supplies to last until the 26-Week visit 
695 
 Participants who had been randomized to PLGS for the preceding 13-week period will be 
696 
given a CLC pump and will receive refresher training on the CLC system at the 
697 
discretion of the investigator, using a subset of the topics described in section 3.2.1 
698 
above. 
699 
3.8.4 26-Week Visit and Subsequent Visits Every 13 Weeks 
700 
Until the point that the CLC system is commercially available (but not longer than 15 months 
701 
after study enrollment), participants will return to the clinic for a visit every 13 weeks (±7 days), 
702 
beginning with a 26-Week visit (±7 days), during which the following will occur: 
703 
 HbA1c determination using the DCA Vantage or similar point of care device 
704 
 Completion of questionnaire (26-Week visit only) 
705 
 Urine pregnancy test for all women of child-bearing potential 
706 
 Weight measurement  
707 
 Assessment of adverse events, adverse device effects, and device issues 
708 
 Download of device data (study system or personal pump and study CGM, study BG meter, 
709 
study ketone meter) 
710 
3.8.5 Final Visit 
711 
When the CLC system becomes commercially available from the manufacturer (or 15 months 
712 
has elapsed since enrollment), participants will return to the clinic within a 6-week period for a 
713 
final study visit. The 6-week transition period is intended to provide an opportunity for the 
714 
participant to complete the logistics of obtaining the system commercially (insurance, etc.). The 
715 
following will occur during the final visit: 
716 
 HbA1c determination using the DCA Vantage or similar point of care device (skipped if the 
717 
prior 13-Week clinic visit occurred in the preceding 2-week period) 
718 
 Completion of questionnaires  
719 
 Weight measurement (skipped if the prior 13-Week clinic visit occurred in the preceding 2-
720 
week period) 
721 
 Assessment of adverse events, adverse device effects, and device issues 
722 

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 Download of device data (study system or personal pump and study CGM, study BG meter, 
723 
study ketone meter) 
724 
 If participating in the menstrual cycle data collection aspect of the study, participants will 
725 
transmit the collected data to the clinical site using the export functionality of the phone app 
726 
that was used 
727 
 Transition back to personal insulin pump, or to resumption of MDI; insulin parameters will 
728 
be assessed by a qualified clinical study team member (e.g. MD, NP, CDE) 
729 
 Follow-up phone call with the participant within 7 (±3) days of transitioning back to personal 
730 
insulin treatment regimen to assess safety of the treatment transition; will be instructed to 
731 
also continue usual clinical care with their personal health care team 
732 
 
733 
3.9 Early Termination Visit (If Applicable) 
734 
Participants will be asked to come for an end of study visit in the event of withdrawal or early 
735 
termination. 
736 
3.10 Unscheduled Visits 
737 
Participants may have unscheduled visits during the study period if required for additional device 
738 
training or other unanticipated needs per the study investigator discretion. 
739 
3.11 Participant Access to Study Device at Study Closure 
740 
Participant will return all investigational study devices and supplies (insulin pump, CGM and 
741 
related supplies) at study closure.  Participant may keep the study ketone meter and study 
742 
glucometer if these devices are not marked for investigational use only. 
743 

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Chapter 4: Study Devices 
744 
4.1 Description of the Investigational Device 
745 
4.1.1 Insulin Pump 
746 
The study system will include the Tandem t:slim X2 with Control-IQ technology. 
747 
4.1.2 Continuous Glucose Monitoring 
748 
The study CGM will include the FDA-approved Dexcom G6 transmitter and sensors. The CGM 
749 
sensor will be replaced at least once every 10 days. 
750 
4.1.3 Blood Glucose Meter and Strips 
751 
Blood glucose levels will be measured using the study-assigned blood glucose meter 
752 
(glucometer) and the CGM device will be calibrated if needed using the study glucometer 
753 
and strips in accordance with the manufacturer’s labeling. 
754 
4.1.4 Ketone Meter and Strips 
755 
Blood ketone levels will be measured using the Abbott Precision Xtra meter and strips in 
756 
accordance with the manufacturer’s labeling.  The blood glucose meter component of the 
757 
Precision Xtra device will not be used. 
758 
4.1.5 Study Device Accountability Procedures 
759 
Device accountability procedures will be detailed in the site procedures manual. 
760 
4.1.6 Blood Glucose Meter Testing 
761 
 Participants will be provided with instructions to perform QC testing per manufacturer 
762 
guidelines. 
763 
 All study blood glucose meters will be QC tested with at least two different concentrations of 
764 
control solution if available during all office visits.  A tested meter will not be used in a study 
765 
if it does not read within the target range at each concentration per manufacturer labeling.  
766 
The participant will be instructed to contact study staff for a replacement of the meter, test 
767 
strips, and control solution if a meter fails QC testing at home. 
768 
 Participants will be reminded to use the study blood glucose meter for all fingerstick blood 
769 
glucose measurements. 
770 
 Participants will be asked to perform fingerstick blood glucose measurements in accordance 
771 
with the labelling of the study CGM device. 
772 
4.1.7 Blood Ketone Testing 
773 
 Participants to perform QC testing at home per manufacturer guidelines. 
774 
 All study blood ketone meters will be QC tested with at least two different concentrations of 
775 
control solution if available during all office visits.  A tested meter will not be used in a study 
776 
if it does not read within the target range at each concentration per manufacturer labeling.  
777 

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The participant will be instructed to contact study staff for a replacement of the meter, test 
778 
strips, and control solution if a meter fails QC testing at home. 
779 
 Participants will be instructed on how to perform blood ketone testing. 
780 
 Participants will be given guidelines for treatment of elevated blood ketones. 
781 
4.2 Safety Measures 
782 
4.2.1 CGM Calibration 
783 
Throughout the study, participants will be instructed to calibrate the study CGM in accordance 
784 
with manufacturer labelling. 
785 
4.2.2 Control-IQ System Failure 
786 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, Control-IQ or 
787 
closed loop will not operate to automatically adjust insulin. If the CGM is not connected, the 
788 
system will revert to usual function of the pump and deliver insulin with the insulin dosing 
789 
parameters programmed in the system for that individual. Resumption of Closed-Loop will 
790 
occur automatically once CGM signal is available again. 
791 
If the study system is unable to activate Control-IQ for any reason, the pump will automatically 
792 
revert to preprogrammed basal insulin delivery without any need for instruction from the user. 
793 
If the t:slim X2 detects a system error that does not allow the pump to operate, the Malfunction 
794 
Alarm will display and the participant will be instructed to contact Tandem Technical Support 
795 
via the study team. 
796 
4.2.3 Hypoglycemia Threshold Alert and Safety Protocol 
797 
During the course of the study, participants will be permitted to change the CGM low glucose 
798 
threshold alert setting on their device or mobile app, but will be instructed to choose a value no 
799 
less than 60 mg/dL. 
800 
The t:slim X2 with Control-IQ system will issue a predictive hypoglycemia alert (Control-IQ 
801 
Low Alert) when the system predicts BG <70 mg/dL within the next 15 minutes (<80 mg/dL 
802 
when exercise mode is activated). 
803 
If the participant receives a Control-IQ Low Alert, a message appears on the user interface (UI) 
804 
that is accompanied by vibration followed by vibrations and/or sound if not acknowledged by the 
805 
user in 5 minutes.  This alert remains on the screen until acknowledged by the user. The user is 
806 
prompted to test blood sugar and treat with carbs. 
807 
4.2.4 Hyperglycemia Threshold Alert and Safety Protocol 
808 
During the course of the study, participants will be permitted to change the CGM high glucose 
809 
threshold alert setting on their device or mobile app, but will be instructed to choose a value no 
810 
greater than 300 mg/dL. 
811 

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The t:slim X2 with Control-IQ system will issue a predictive hyperglycemia alert (Control-IQ 
812 
High Alert) when the system has increased insulin delivery, but detects a CGM value above 200 
813 
mg/dL and does not predict the value will decrease in the next 30 minutes. 
814 
If the participant receives a Control-IQ High Alert, a message appears on the UI that is 
815 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user 
816 
in 5 minutes. This alert remains on the screen until acknowledged by the user. The user is 
817 
prompted to check the site for occlusion and test blood glucose. 
818 
If a participant’s CGM reading is >300 mg/dL for over 2 hours or ≥400 mg/dL at any point, the 
819 
participant will be instructed to take the following steps: 
820 
 Perform a blood glucose meter check. 
821 
 If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
822 
 If the ketone level is >0.6 mmol/L, take correction insulin, change insulin (pump) infusion 
823 
site and contact study staff. 
824 
 If a participant administers correction insulin via insulin syringe, participants will be 
825 
instructed to turn Control-IQ off for approximately four hours. 
826 

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Chapter 5: Testing Procedures and Questionnaires 
827 
5.1 Laboratory Testing 
828 
1. HbA1c: 
829 
 Performed locally at the 13-week visit and at subsequent study visits at 13-week intervals 
830 
using the DCA Vantage or similar point of care device 
831 
 A blood sample will be obtained and sent to central lab for HbA1c assessment at the 13-
832 
week visit. 
833 
2. Urine Pregnancy: 
834 
 A urine pregnancy test will be performed locally for females of child-bearing potential at 
835 
the Screening visit. The test will be repeated at the 13-week visit for participants 
836 
continuing in the study, and will be repeated at subsequent clinic visits at 13-week 
837 
intervals. A test will also be done anytime pregnancy is suspected. 
838 
5.2 Questionnaires 
839 
Questionnaires, described briefly below, are completed at various clinic visits detailed below.  
840 
The procedures for administration are described in the study procedures manual. 
841 
The following questionnaire will be completed at the Screening visit: 
842 
 Technology Expectations Survey (only for participants who had been assigned to SAP during 
843 
the original 6-month RCT) 
844 
The following questionnaires will be completed at the 13-week Visit: 
845 
 Clarke’s Hypoglycemia Awareness Scale 
846 
 Fear of Hypoglycemia Survey (HFS-II) 
847 
 Hyperglycemia Avoidance Scale 
848 
 Hypoglycemia Confidence Scale 
849 
 Diabetes Distress Scale 
850 
 INSPIRE Survey 
851 
 Technology Acceptance Survey 
852 
 System Usability Scale (SUS) 
853 
 
854 
The following questionnaires will be completed at the 26-week Visit: 
855 
 Control-IQ Patient-Reported Outcomes Questionnaire 
856 
 
857 
The following questionnaire will be completed at the final clinic visit: 
858 

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 System Usability Scale (SUS) 
859 
 Control-IQ Patient-Reported Outcomes Questionnaire 
860 
 
861 
Clarke’s Hypoglycemia Awareness Scale 
862 
The scale (28) comprises eight questions characterizing the participant's exposure to episodes 
863 
of moderate and severe hypoglycemia. It also examines the glycemic threshold for, and 
864 
symptomatic responses to hypoglycemia. A score of four or more on a scale of 0 to 7 implies 
865 
impaired awareness of hypoglycemia.  
866 
Administration time is approximately 5 minutes. 
867 
Hypoglycemia Fear Survey (HFS-II)/Low Blood Sugar Survey 
868 
The Hypoglycemia Fear Survey-II (29) was developed to measure behaviors and worries related 
869 
to fear of hypoglycemia in adults with type 1 diabetes. It is composed of 2 subscales, the 
870 
Behavior (HFS-B) and Worry (HFS-W). HFS-B items describe behaviors in which patients may 
871 
engage to avoid hypoglycemic episodes and/or their negative consequences (e.g., keeping blood 
872 
glucose levels above150 mg/dL, making sure other people are around, and limiting exercise or 
873 
physical activity). HFS-W items describe specific concerns that patients may have about their 
874 
hypoglycemic episodes (e.g., being alone, episodes occurring during sleep, or having an 
875 
accident). 
876 
Administration time is approximately 10 minutes. 
877 
Hyperglycemia Avoidance Survey (HAS)/High Blood Sugar Survey 
878 
The HAS (30) reliably quantifies affective and behavioral aspects of hyperglycemia avoidance 
879 
and is used to assess the extent of potentially problematic avoidant attitudes and behaviors 
880 
regarding hyperglycemia in people with Type 1 diabetes (T1D). 
881 
Administration time is approximately 10 minutes. 
882 
Hypoglycemia Confidence Scale 
883 
The HCS (31) is a 9-item self-report scale that examines the degree to which people with 
884 
diabetes feel able, secure, and comfortable regarding their ability to stay safe from 
885 
hypoglycemic-related problems. It has been validated for use in adults with type 1 diabetes and 
886 
insulin-using type 2 diabetes. 
887 
Administration time is approximately 5 minutes. 
888 
Diabetes Distress Scale 
889 
The Diabetes Distress Scale (32) is a measure of diabetes-related emotional distress and consists 
890 
of a scale of 28 items. These include 7 items from each of four domains central to diabetes-
891 

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related emotional distress. Patients rate the degree to which each item is currently problematic 
892 
for them on a 6-point Likert scale, from 1 (no problem) to 6 (serious problem). 
893 
Administration time is approximately 10 minutes. 
894 
Technology Expectation and Technology Acceptance Surveys 
895 
The Technology Expectation and Technology Acceptance Surveys were developed for a Bionic 
896 
Pancreas camp study (33). The 38 items in the Questionnaire were based on interviews 
897 
conducted with individuals who had participated in previous Bionic Pancreas trials about their 
898 
experience regarding the Bionic Pancreas. It was subsequently adapted to assess these same 
899 
measures for the inControl closed-loop system. It assesses both positive and negative 
900 
experiences with CLC, including blood glucose management, device burden, and overall 
901 
satisfaction. Items were rated on a 5-point scale. 
902 
Administration time is approximately 10 minutes. 
903 
INSPIRE Survey 
904 
The INSPIRE (Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations) 
905 
survey was developed to assess various aspects of a user’s experience regarding automated 
906 
insulin delivery for both patients and family members. The surveys include various topics 
907 
important to patients with type 1 diabetes and their family members based upon >200 hours 
908 
of qualitative interviews and focus groups. The adult survey includes 31 items; the adolescent 
909 
survey includes 28 items; and the parent survey includes 30 items. Response options for all 
910 
surveys include a 5-point Likert scale from strongly agree to strongly disagree, along with an 
911 
N/A option. 
912 
Administration time is approximately 5 minutes. 
913 
System Usability Scale (SUS) 
914 
The System Usability Scale (SUS) is a 10-item questionnaire that measures the overall 
915 
usability of a system. It is a valid and reliable measure of the perceived usability of a system 
916 
and is technology-agnostic. The questionnaire presents statements with five response options 
917 
(anchoring the options from strongly disagree to strongly agree) and asks users to rate their 
918 
agreement to the statements.  User scores are transformed into a composite score, from 0 to 100, 
919 
and this score is taken as an overall measure of the system’s usability; higher scores indicate 
920 
better perceived usability. 
921 
Administration time is approximately 5 minutes. 
922 
 
923 
 
 
924 

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Control-IQ Patient-Reported Outcomes Questionnaire 
925 
This is a 10-item questionnaire that solicits information about frequency of use of the Control-IQ 
926 
closed-loop feature, satisfaction with and trust in the system, impact on aspects of living with 
927 
diabetes, and likelihood of recommending the system to others. 
928 
Administration time is approximately 5 minutes. 
929 

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Chapter 6: Adverse Events, Device Issues, and Stopping Rules 
930 
6.1 Adverse Events 
931 
6.1.1 Definitions 
932 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
933 
relationship between the adverse event and the device(s) under investigation (see section 6.1.2 
934 
for reportable adverse events for this protocol). 
935 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
936 
 Results in death. 
937 
 Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
938 
become life-threatening, is not necessarily considered a serious adverse event). 
939 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
940 
 Results in persistent or significant disability/incapacity or substantial disruption of the ability 
941 
to conduct normal life functions (sight threatening). 
942 
 Is a congenital anomaly or birth defect. 
943 
 Is considered a significant medical event by the investigator based on medical judgment (e.g., 
944 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
945 
the outcomes listed above). 
946 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
947 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
948 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
949 
investigational plan or application (including a supplementary plan or application), or any other 
950 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
951 
welfare of participants (21 CFR 812.3(s)). 
952 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
953 
the device may have caused or to which the device may have contributed (Note that an Adverse 
954 
Event Form is to be completed in addition to a Device Deficiency or Issue Form, unless excluded 
955 
from reporting as defined in section 6.2). 
956 
Device Complaints and Malfunctions: A device complication or complaint is something that 
957 
happens to a device or related to device performance, whereas an adverse event happens to a 
958 
participant.  A device complaint may occur independently from an AE, or along with an AE.  
959 
An AE may occur without a device complaint or there may be an AE related to a device 
960 
complaint.  A device malfunction is any failure of a device to meet its performance specifications 
961 
or otherwise perform as intended.  Performance specifications include all claims made in the 
962 
labeling for the device.  The intended performance of a device refers to the intended use for 
963 
which the device is labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, sites 
964 
will not be asked to distinguish between device complaints and malfunctions. 
965 

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6.1.2 Reportable Adverse Events 
966 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
967 
meets one of the following criteria: 
968 
1. An SAE 
969 
2. An ADE as defined in section 6.1.1, unless excluded from reporting in section 6.2 
970 
3. An AE as defined in section 6.1.1 occurring in association with a study procedure 
971 
4. An AE as defined in section 6.1.1 which leads to discontinuation of  a study device  for 2 or 
972 
more hours 
973 
5. Hypoglycemia meeting the definition of severe hypoglycemia as defined below  
974 
6. Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, a hyperglycemia or 
975 
ketosis event meeting the criteria defined below 
976 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
977 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor placement 
978 
are only reportable if severe and/or required treatment. 
979 
Pregnancy occurring during the study will be reported as an AE (see section 6.3). 
980 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
981 
during questioning, or detected through physical examination, laboratory test, or other means—
982 
will be reported on an AE form online.  Each AE form is reviewed by the Medical Monitor to 
983 
assess safety and to verify the coding and the reporting that is required. 
984 
6.1.2.1 Hypoglycemic Events 
985 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
986 
event when the following definition for severe hypoglycemia is met:  the event required 
987 
assistance of another person due to altered consciousness, and required another person to actively 
988 
administer carbohydrate, glucagon, or other resuscitative actions.  This means that the participant 
989 
was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable 
990 
to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure 
991 
or loss of consciousness.  These episodes may be associated with sufficient neuroglycopenia to 
992 
induce seizure or loss of consciousness.  If plasma glucose measurements are not available 
993 
during such an event, neurological recovery attributable to the restoration of plasma glucose to 
994 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
995 
concentration. 
996 
6.1.2.2 Hyperglycemic/Ketotic Events 
997 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
998 
event when one of the following 4 criteria is met:  
999 
 the event involved DKA, as defined by the Diabetes Control and Complications Trial 
1000 
(DCCT) and described below 
1001 

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 evaluation or treatment was obtained at a health care provider facility for an acute event 
1002 
involving hyperglycemia or ketosis 
1003 
 blood ketone level ≥1.0 mmol/L and communication occurred with a health care provider 
1004 
at the time of the event 
1005 
 blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
1006 
provider 
1007 
Hyperglycemic events are classified as DKA if the following are present: 
1008 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
1009 
 Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
1010 
 Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1011 
 Treatment provided in a health care facility 
1012 
6.1.3 Relationship of Adverse Event to Study Device 
1013 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1014 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1015 
by the study device. 
1016 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1017 
following general guideline when determining whether an adverse event is related: 
1018 
Yes 
1019 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1020 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
1021 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
1022 
of response to the study intervention; and/or the adverse event abates or resolves upon 
1023 
discontinuation of the study intervention or dose reduction and, if applicable, reappears upon 
1024 
re-challenge. 
1025 
No 
1026 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
1027 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1028 
medication); and/or the adverse event has no plausible temporal relationship to study 
1029 
intervention. 
1030 
6.1.4 Intensity of Adverse Events 
1031 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or 
1032 
(3) severe.  It is emphasized that the term severe is a measure of intensity: thus a severe adverse 
1033 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
1034 
but may not be clinically serious. 
1035 

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 MILD: Usually transient, requires no special treatment, and does not interfere with the 
1036 
participant’s daily activities. 
1037 
 MODERATE: Usually causes a low level of inconvenience or concern to the participant and 
1038 
may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
1039 
 SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic 
1040 
drug therapy or other treatment. 
1041 
6.1.5 Coding of Adverse Events 
1042 
Adverse events will be coded using the MedDRA dictionary.  The Medical Monitor will review 
1043 
the investigator’s assessment of causality and may agree or disagree.  Both the investigator’s and 
1044 
Medical Monitor’s assessments will be recorded.  The Medical Monitor will have the final say in 
1045 
determining the causality. 
1046 
6.1.6 Outcome of Adverse Events 
1047 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1048 
 RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae.  
1049 
Record the AE/SAE stop date. 
1050 
 RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
1051 
without change in the event anticipated.  Record the AE/SAE stop date. 
1052 
 FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event that 
1053 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the time 
1054 
of death; however, were not the cause of death, will be recorded as “resolved” at the time of 
1055 
death. 
1056 
 NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as 
1057 
the event was ongoing with an undetermined outcome. 
1058 
 An ongoing outcome will require follow-up by the site in order to determine the final 
1059 
outcome of the AE/SAE. 
1060 
 The outcome of an ongoing event at the time of death that was not the cause of death, 
1061 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1062 
date. 
1063 
 UNKNOWN – An unknown outcome is defined as an inability to access the participant or 
1064 
the participant’s records to determine the outcome (for example, a participant that was lost to 
1065 
follow-up). 
1066 
 If any reported adverse events are ongoing when a participant completes the study (or 
1067 
withdraws), adverse events classified UADEs will be followed until they are either resolved, 
1068 
or have no prospect of improvement or change, even after the subject has completed all 
1069 
applicable study visits/contacts. For all other adverse events, data collection will end at the 
1070 
time the participant completes the study. Note: participants should continue to receive 
1071 
appropriate medical care for an adverse event after their participation in the study ends.  
1072 

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6.2 Reportable Device Issues 
1073 
All UADEs and ADEs as defined in section 6.1.1 will be reported on both a device issue form 
1074 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1075 
placement that do not require pharmacologic treatment. 
1076 
Device complaints and device malfunctions will be reported except in the following 
1077 
circumstances. These occurrences are expected and will not be reported on a Device Issue Form 
1078 
assuming criteria for a UADE or ADE have not been met: 
1079 
 CGM sensors lasting fewer than the number of days expected per CGM labeling 
1080 
 CGM tape adherence issues 
1081 
 Pump infusion set occlusion (including tubing and cartridge) not leading to ketosis ≥0.6 
1082 
mmol/L or in the absence of checking for blood ketones, blood glucose >350 mg/dL; and not 
1083 
requiring an intervention other than replacing the tubing and/or cartridge 
1084 
 Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
1085 
 Intermittent device component disconnections/communication failures not leading to 
1086 
requiring system replacement or workaround/resolution not specified in user guide/manual 
1087 
 Device issues clearly addressed in the user guide manual that do not require additional 
1088 
troubleshooting 
1089 
6.3 Pregnancy Reporting 
1090 
If pregnancy occurs, the participant will be discontinued from the study.  The occurrence of 
1091 
pregnancy will be reported on an AE Form. 
1092 
6.4 Timing of Event Reporting 
1093 
SAEs possibly related to a study device or study participation and UADEs must be reported to 
1094 
the Coordinating Center within 24 hours of the site becoming aware of the event.  This can occur 
1095 
via phone or email, or by completion of the online serious adverse event form and device issue 
1096 
form if applicable. If the form is not initially completed, it should be competed as soon as 
1097 
possible after there is sufficient information to evaluate the event.  All other reportable ADEs 
1098 
and other reportable AEs should be submitted by completion on the online form within 7 days of 
1099 
the site becoming aware of the event. 
1100 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1101 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
1102 
Center becomes aware of the event. 
1103 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1104 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1105 
Ethics Committee. 
1106 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report 
1107 
the results of the investigation to the sites’ IRBs, and the FDA within 10 working days of the 
1108 
Sponsor becoming aware of the UADE per 21CFR 812.46(b) (2). The Medical Monitor must 
1109 

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determine if the UADE presents an unreasonable risk to participants. If so, the Medical Monitor 
1110 
must ensure that all investigations, or parts of investigations presenting that risk, are terminated 
1111 
as soon as possible but no later than 5 working days after the Medical Monitor makes this 
1112 
determination and no later than 15 working days after first receipt notice of the UADE. 
1113 
In the case of a device system component malfunction (e.g. pump, CGM, control algorithm), 
1114 
information will be forwarded to the responsible company by the site personnel, to be handled 
1115 
by its complaint management system. 
1116 
6.5 Stopping Criteria 
1117 
6.5.1 Participant Discontinuation of Study Device 
1118 
Rules for discontinuing study device use are described below. 
1119 
 The investigator believes it is unsafe for the participant to continue on the intervention.  This 
1120 
could be due to the development of a new medical condition or worsening of an existing 
1121 
condition; or participant behavior contrary to the indications for use of the device that 
1122 
imposes on the participant’s safety 
1123 
 The participant requests that the treatment be stopped 
1124 
 Participant pregnancy 
1125 
 Two distinct episodes of DKA 
1126 
 Two distinct severe hypoglycemia events as defined in section 6.1.2.1 
1127 
Even if the study device system is discontinued, the participant will be encouraged to remain in 
1128 
the study through the final study visit. 
1129 
6.5.2 Criteria for Suspending or Stopping Overall Study 
1130 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
1131 
hyperglycemia event (as defined in section 6.1.2), use of the study device system will be 
1132 
suspended while the problem is diagnosed. 
1133 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1134 
study device requires stoppage of device use for safety reasons (e.g. product recall).  The 
1135 
affected study activities may resume if the underlying problem can be corrected by a protocol or 
1136 
system modification that will not invalidate the results obtained prior to suspension. 
1137 
The study Medical Monitor will review all adverse events and adverse device events that are 
1138 
reported during the study and will review compiled safety data at periodic intervals (generally 
1139 
timed to the review of compiled safety data by the DSMB). The Medical Monitor may request 
1140 
suspension of study activities or stoppage of the study if deemed necessary based on the totality 
1141 
of safety data available. 
1142 
6.6 Independent Safety Oversight 
1143 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data at periodic 
1144 
intervals (typically every 6 months). In addition, the DSMB will review all DKA and severe 
1145 

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hypoglycemia irrespective of relatedness to study device use, and all serious events (including 
1146 
UADEs) related to study device use at the time of occurrence. The DSMB also will be informed 
1147 
of any ADEs not meeting criteria for a UADE if the Medical Monitor requests the DSMB 
1148 
review.   The DSMB can request modifications to the study protocol or suspension or outright 
1149 
stoppage of the study if deemed necessary based on the totality of safety data available. Details 
1150 
regarding DSMB review will be documented in a separate DSMB document. 
1151 
6.7 Risks 
1152 
The potential risks associated with use of the study device are described in section 1.3. 
1153 
Additional risks are minor and/or infrequent and include: 
1154 
 Pain, bruising, redness, or infection from blood draws 
1155 
 Loss of confidentiality 
1156 
 Stress from completing quality of life questionnaires 
1157 

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Chapter 7: Miscellaneous Considerations 
1158 
7.1 Drugs Used as Part of the Protocol 
1159 
Participants will use either lispro or aspart insulin prescribed by their personal physician. 
1160 
7.2 Prohibited Medications, Treatments, and Procedures 
1161 
Participants using glulisine at the time of enrollment will be asked to contact their personal 
1162 
physician to change their prescribed personal insulin to lispro or aspart for the duration of the 
1163 
trial. This should not occur, since participants were required to use either lispro or aspast insulin 
1164 
during the preceding 6-month RCT. 
1165 
Treatment with any non-insulin glucose-lowering agent (including GLP-1 agonists, Symlin, 
1166 
DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas and naturaceuticals) will not be 
1167 
permitted. 
1168 
The investigational study devices (insulin pump, study CGM systems) must be removed before 
1169 
Magnetic Resonance Imaging (MRI), Computed Tomography (CT) or diathermy treatment. 
1170 
Participants may continue in the trial after temporarily discontinuing use if requiring one of the 
1171 
treatments above. 
1172 
7.3 Participant Compensation 
1173 
Participant compensation will be specified in the informed consent form. 
1174 
A maximum of $200 will be paid for completing the entire study. Participants will be paid $100 
1175 
for completing the screening visit and $100 for completing the 13-week visit.  No additional 
1176 
payments will be provided for the subsequent clinic visits at 13-week intervals following the 13-
1177 
week visit, or for unplanned visits to the research site. 
1178 
 Screening Visit: $100 
1179 
 13-week Visit:  $100 
1180 
7.4 Participant Withdrawal 
1181 
Participation in the study is voluntary, and a participant may withdraw at any time.  
1182 
For participants who withdraw, their data will be used up until the time of withdrawal. 
1183 
7.5 Confidentiality 
1184 
For security and confidentiality purposes, participants will be assigned an identifier that will 
1185 
be used instead of their name.  Protected health information gathered for this study will be 
1186 
shared with the coordinating center, the Jaeb Center for Health Research in Tampa, FL.  
1187 
De-identified participant information may also be provided to research sites involved in the 
1188 
study. De-identified participant information may also be provided to Tandem for system 
1189 
evaluation purposes. 
1190 

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Chapter 8: Statistical Consideration 
1191 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1192 
analysis plan will be written and finalized prior to the first tabulation of data (i.e., for DSMB 
1193 
review).  
1194 
8.1 Objectives 
1195 
There are three objectives for this study: 
1196 
 Objective 1: Among individuals who used CLC in the Main RCT, to compare continued 
1197 
use of CLC (t:slim X2 with Control-IQ Technology) for 3 months versus switching to a 
1198 
Predictive Low-Glucose Suspend (PLGS) system (t:slim X2 with Basal-IQ Technology) 
1199 
for 3 months. 
1200 
o RCT with 1:1 randomization to intervention with CLC vs. PLGS for 3 months. 
1201 
All analyses (treatment group comparisons) will be considered 
1202 
exploratory/hypothesis-generating. Consequently, there will not be an attempt to 
1203 
adjust for multiplicity. Time-in-range 70-180 mg/dL will be considered the 
1204 
primary exploratory outcome. 
1205 
 Objective 2: Among individuals who used SAP in the Main RCT, to obtain additional 
1206 
safety data by initiating use of the Control-IQ system for 3 months. 
1207 
o Observational study of initiation and use of CLC for 3 months. Safety outcomes 
1208 
will be tabulated and certain exploratory analyses will be conducted, analyzing 
1209 
metrics as change from baseline (using SAP) to study period (using CLC).  
1210 
 Objective 3: To obtain additional safety data by continuing use of the Control-IQ system 
1211 
until it becomes commercially available 
1212 
o Observational study of initiation and use of CLC for 3 months following use of 
1213 
PLGS for 3 months. Safety outcomes will be tabulated and certain exploratory 
1214 
analyses will be conducted, analyzing metrics as change from baseline (using 
1215 
PLGS) to study period (using CLC).  
1216 
8.2 Sample Size  
1217 
The sample size for Objectives 1 and 2 will depend on how many subjects will complete the 
1218 
prior 6-month Original RCT and consent to participate in the extension. However, it is expected 
1219 
that about 100 subjects will be enrolled and randomized for Objective 1 and 50 subjects enrolled 
1220 
for Objective 2.  
1221 
As the sample size for objective 1 is determined by the preceding RCT and a variance estimate 
1222 
for both the group continuing CLC and the group switching to PLGS is not known (no prior data 
1223 
available to estimate), a power calculation has not been performed.   
1224 
8.3 Outcome Measures 
1225 
 CGM Metrics 
1226 
 Overall Control and Hyperglycemia 
1227 

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o CGM-measured % in range 70-180 mg/dL.  
1228 
o CGM-measured % above 180 mg/dL  
1229 
o CGM-measured mean glucose  
1230 
o % >250 mg/dL 
1231 
o % >300 mg/dL  
1232 
o high blood glucose index 
1233 
o % in range 70-140 mg/dL 
1234 
 
1235 
 Hypoglycemia 
1236 
o % below 70 mg/dL 
1237 
o % below 54 mg/dL 
1238 
o % <60 mg/dL 
1239 
o low blood glucose index 
1240 
o hypoglycemia events (defined as at least 15 consecutive minutes <70 mg/dL) 
1241 
 
1242 
 Glucose variability 
1243 
o Coefficient of variation (CV) 
1244 
o Standard deviation (SD) 
1245 
 
1246 
The last 3 months of the Original RCT Study will be used to calculate baseline CGM metrics for 
1247 
the extension study.  CGM data starting from randomization into the extension through the 3 
1248 
month visit will be included in the calculation of each CGM metric. Each metric will be 
1249 
calculated giving equal weight to each CGM reading for each participant.  CGM metrics will be 
1250 
computed overall and all for daytime (6am-12mn) and nighttime (12mn-6am) by time of day.   
1251 
 
1252 
HbA1c 
1253 
 HbA1c at 13 weeks 
1254 
 HbA1c <7.0% at 13 weeks 
1255 
 HbA1c <7.5% at 13 weeks 
1256 
 HbA1c improvement from baseline to 13 weeks >0.5% 
1257 
 HbA1c improvement from baseline to 13 weeks >1.0% 
1258 
 HbA1c relative improvement from baseline to 13 weeks >10% 
1259 
 HbA1c improvement from baseline to 13 weeks >1.0% or HbA1c <7.0% at 13 weeks 
1260 

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Questionnaires: 
1261 
 Fear of Hypoglycemia Survey (HFS-II) – total score and 3 subscales: 
1262 
 Behavior (avoid) 
1263 
 Behavior (maintain high BG) 
1264 
 Worry 
1265 
 Hyperglycemia Avoidance Scale – total score and 4 subscales: 
1266 
 Immediate action 
1267 
 Worry 
1268 
 Low BG preference 
1269 
 Avoid extremes 
1270 
 Diabetes Distress Scale – total score and 4 subscales: 
1271 
 Emotional burden 
1272 
 Physician-related distress 
1273 
 Regimen-related distress 
1274 
 Interpersonal distress 
1275 
 Hypoglycemia Confidence Scale – total score 
1276 
 Clarke Hypoglycemia Awareness Scores 
1277 
 INSPIRE survey scores 
1278 
 System Usability Scale (SUS) 
1279 
 Technology Acceptance Survey  
1280 
 Control-IQ Patient-Reported Outcomes Questionnaire 
1281 
 
1282 
Other 
1283 
 Insulin 
1284 
 Total daily insulin (units/kg) 
1285 
 Basal: bolus insulin ratio 
1286 
 Weight and Body Mass Index (BMI) 
1287 
 
1288 

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8.4 Objective 1 Analyses 
1289 
8.4.1 Principles of Analyses 
1290 
All analyses comparing the CLC arm with PLGS arm will follow the intention-to-treat (ITT) 
1291 
principle with each participant analyzed according to the treatment assigned by randomization. 
1292 
Safety outcomes will be reported for all enrolled participants. 
1293 
If more than 5% of participants have fewer than 50% of post-randomization CGM data, 
1294 
the analyses will be replicated excluding such participants. In addition, analyses will be 
1295 
replicated including only those participants from the CLC and PLGS groups who used the 
1296 
system for >80% overall. 
1297 
The analyses described below include a pre-specified list of covariates.  As an additional 
1298 
sensitivity analysis, any baseline demographic or clinical characteristics observed to be 
1299 
imbalanced between treatment groups will be added as covariates to the analyses. The 
1300 
determination of a meaningful baseline imbalance will be based on clinical judgement and not a 
1301 
p-value. 
1302 
With respect to missing data, it is worth emphasizing that any statistical method for handling 
1303 
missing data makes a number of untestable assumptions.  The goal will be to minimize the 
1304 
amount of missing data in this study so that results and conclusions will not be sensitive to which 
1305 
statistical method is used. To that end, sensitivity analyses will be performed to explore whether 
1306 
results are similar for when using different methods.  The following methods will be applied: 
1307 
 Direct likelihood (analysis described below) 
1308 
 Rubin’s multiple imputation  
1309 
 Available cases only  
1310 
 
1311 
8.4.2 Analytic Methods 
1312 
CGM Metrics 
1313 
Summary statistics (mean ± SD or median (quartiles)) will be reported for each CGM metric and 
1314 
for differences from pre-randomization by treatment group. 
1315 
The analyses will be done using direct likelihood. A longitudinal linear regression model will be 
1316 
fit with the metric at baseline and follow-up as the dependent variable. This model will adjust for 
1317 
age as fixed effect and site as a random effect. The analyses will report the point estimate, 95% 
1318 
confidence interval and p-value for the treatment group difference at follow-up. Residual values 
1319 
will be examined for an approximate normal distribution. If residuals are highly skewed, then a 
1320 
transformation or robust statistical method (e.g., non-parametric or MM estimation) will be used 
1321 
instead.  
1322 
HbA1c  
1323 
Summary statistics (mean ± SD or n(%)) will be reported for the central lab HbA1c (continuous 
1324 
variable) at 13-weeks and for differences from randomization by treatment group. A longitudinal 
1325 

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model will be fit using values at randomization and 13 weeks adjusting for age as fixed effect 
1326 
and site as a random effect.  Missing data will be handled by direct likelihood in this longitudinal 
1327 
model. This model implicitly adjusts for baseline HbA1c by forcing the treatment groups to have 
1328 
the same mean value at baseline.  Local HbA1c values measured at the site will be included as an 
1329 
auxiliary variable (analogous to imputing any missing lab values).  Regression diagnostics will 
1330 
be employed as described earlier. 
1331 
For the binary HbA1c outcomes listed above, risk-adjusted percentages by treatment group will 
1332 
be computed from a logistic regression model.  The logistic regression will adjust for the same 
1333 
factors mentioned above for the analysis with HbA1c as a continuous factor. 
1334 
Questionnaires and Other Outcomes 
1335 
For questionnaires, insulin, weight, and BMI metrics comparisons between treatment arms will 
1336 
be made using similar methods as described above for the continuous HbA1c analysis. 
1337 
 
1338 
8.4.3 Subgroup Analyses 
1339 
In exploratory analyses, outcomes for which analyses suggest a treatment group difference will 
1340 
be assessed separately in various subgroups and for continuous variables according to the 
1341 
baseline value as defined below. Tests for interaction with treatment group will be performed 
1342 
and further explored if an interaction will be found in the first place. For continuous variables, 
1343 
results will be displayed in subgroups based on cutpoints although the analysis will utilize the 
1344 
variable as continuous. If there is insufficient sample size in a given subgroup, the cutpoints for 
1345 
continuous measures may be adjusted per the observed distribution of values. Cutpoint selection 
1346 
for display purposes will be made masked to the outcome data. 
1347 
 Baseline HbA1c  
1348 
 Baseline CGM time spent <70 mg/dL 
1349 
 Baseline CGM time spent >180 mg/dL 
1350 
 Baseline CGM time 70-180 mg/dL 
1351 
 Age 
1352 
 Sex 
1353 
 Race 
1354 
 Clinical site 
1355 
 Body mass index 
1356 
 Income, education, and/or insurance status 
1357 
 Baseline scores for quality of life, hypoglycemia awareness and fear questionnaires 
1358 
 
1359 
8.5 Safety Analyses 
1360 
The following will be summarized and tabulated by treatment group: 
1361 
 Severe hypoglycemia  
1362 
 Diabetic ketoacidosis  
1363 

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 Ketone events defined as a calendar day with ketone level >1.0 mmol/L 
1364 
 CGM-measured hypoglycemic events (defined as at least 15 consecutive minutes <54 
1365 
mg/dL) 
1366 
 CGM-measured hyperglycemic events (defined as at least 120 consecutive minutes 
1367 
>300 mg/dL) 
1368 
 Worsening of HbA1c from randomization to 13 weeks by >0.5% 
1369 
 Serious adverse events with a possible or greater relationship to a study device 
1370 
(including anticipated and unanticipated adverse device effects) 
1371 
 Other serious adverse events not related to a study device 
1372 
 Adverse device effects (ADE) that do not meet criteria for SAE 
1373 
 
1374 
 For the following, mean ± SD or summary statistics appropriate to the distribution will be 
1375 
tabulated by treatment group: 
1376 
 Number of SH events and SH event rate per 100 person-years 
1377 
 Number of DKA events and DKA event rate per 100 person-years 
1378 
 Any adverse event rate per 100 person-years.  
1379 
If there are at least 10 events across both treatment arms, the numbers will be compared between 
1380 
the two treatment arms using a robust Poisson regression and the percentage of subjects with at 
1381 
least one event will be compared using logistic regression. The regression will adjust for site as 
1382 
random effect. The amount of follow up will be included as an offset covariate to compare the 
1383 
rates. 
1384 
 
1385 
8.6 Device Issues 
1386 
Reported device issues will be tabulated by treatment group.  
1387 
 
1388 
8.7 Protocol Adherence  
1389 
The following tabulations and analyses will be performed by treatment group to assess protocol 
1390 
adherence for the study: 
1391 
 Listing of all protocol deviations 
1392 
 Tabulation of protocol-specified visits and phone contacts completed in window, out 
1393 
of window and missed for each visit/phone contact 
1394 
 Flow chart accounting for all enrolled participants  
1395 
 Flow chart of all randomized participants at all scheduled visits and phone contacts to 
1396 
assess visit, and phone completion, and study completion rates 
1397 

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 Number of and reasons for unscheduled visits and phone calls 
1398 
 Number of participants who stopped treatment (CLC or PLGS) and reasons 
1399 
 
1400 
8.8 Other Tabulations 
1401 
Baseline demographic and clinical characteristics will be tabulated by treatment group. 
1402 
Individual listings of key data for each participant will be created. 
1403 
The following tabulations and analyses will be performed by treatment group: 
1404 
 Sensor performance metrics (difference, absolute relative difference, and 
1405 
International Organization for Standardization criteria)  
1406 
 Sensor use –percent time of use overall and by month 
1407 
 The daily frequency of downloaded BGM use - overall and by month 
1408 
 % time CGM data were available to the system – overall and by month 
1409 
 % time in different operational modes - overall and by month  
1410 
 Rate of different failure events and alarms per 24 recorded by the system – overall 
1411 
and by month Among women who consent to collection of the menstrual information, 
1412 
an analysis that compares outcomes at different times during the menstrual cycle will 
1413 
be performed overall and by contraception type for selected CGM and insulin 
1414 
metrics. 
1415 
 
1416 
8.9 Planned Interim Analyses 
1417 
No interim efficacy analysis is planned. 
1418 
The DSMB will review safety data at intervals, with no formal stopping rules other than the 
1419 
guidelines provided in the participant-level and study-level stopping criteria (as defined in 
1420 
section 6.5 of the protocol). 
1421 
 
1422 
8.10 Objective 2 Analyses  
1423 
All enrolled subjects will be included in the analyses.  Although the primary objective is the 
1424 
collection of safety data, analyses will be conducted for the outcomes listed above for Objective 
1425 
1 comparing baseline to follow up using paired t-tests unless the data are highly skewed in which 
1426 
case a transformation or a robust statistical method will be used instead. 
1427 
Safety outcomes will be tabulated.  Device issues, protocol adherence, and the other variables 
1428 
listed above for tabulation will be described or summarized as indicated. 
1429 
 
1430 

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8.11 Objective 3 Analyses  
1431 
All enrolled subjects will be included in the analyses.  Although the primary objective is the 
1432 
collection of safety data, analyses will be conducted for the outcomes listed above for Objective 
1433 
1 comparing 3 months of PLGS baseline to 3 months of CLC follow up using paired t-tests 
1434 
unless the data are highly skewed in which case a transformation or a robust statistical method 
1435 
will be used instead. 
1436 
Safety outcomes will be tabulated.  Device issues, protocol adherence, and the other variables 
1437 
listed above for tabulation will be described or summarized as indicated. 
1438 
 
1439 

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Chapter 9: Data Collection and Monitoring 
1440 
9.1 Case Report Forms and Device Data 
1441 
The main study data are collected through a combination of electronic case report forms 
1442 
(CRFs) and electronic device data files obtained from the study software and individual 
1443 
hardware components.  These electronic device files and electronic CRFs from the study 
1444 
website are considered the primary source documentation. 
1445 
When data are directly collected in electronic case report forms, this will be considered the 
1446 
source data.  Each participating site will maintain appropriate medical and research records for 
1447 
this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
1448 
protection of confidentiality of participants. 
1449 
9.2 Study Records Retention 
1450 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1451 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1452 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1453 
discontinuation of clinical development of the investigational product.  These documents should 
1454 
be retained for a longer period, however, if required by local regulations.  No records will be 
1455 
destroyed without the written consent of the sponsor, if applicable.  It is the responsibility of the 
1456 
sponsor to inform the investigator when these documents no longer need to be retained. 
1457 
9.3 Quality Assurance and Monitoring 
1458 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1459 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1460 
conducted and data are generated, documented and reported in compliance with the protocol, 
1461 
Good Clinical Practice (GCP) and the applicable regulatory requirements.  Adverse events will 
1462 
be prioritized for monitoring. 
1463 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1464 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1465 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1466 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. 
1467 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1468 
events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1469 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1470 
verity and completeness of the key site data.  Elements of the RBM may include: 
1471 
 Qualification assessment, training, and certification for sites and site personnel 
1472 
 Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1473 
 Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1474 
review of entered data and edits, statistical monitoring, study closeout 
1475 
 On-site monitoring (site visits): source data verification, site visit report 
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 Agent/Device accountability 
1477 
 Communications with site staff 
1478 
 Patient retention and visit completion 
1479 
 Quality control reports 
1480 
 Management of noncompliance 
1481 
 Documenting monitoring activities 
1482 
 Adverse event reporting and monitoring 
1483 
Coordinating Center representatives or their designees may visit the study facilities at any time 
1484 
in order to maintain current and personal knowledge of the study through review of the records, 
1485 
comparison with source documents, observation and discussion of the conduct and progress of 
1486 
the study. 
1487 
9.4 Protocol Deviations 
1488 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1489 
requirements.  The noncompliance may be either on the part of the participant, the investigator, 
1490 
or the study site staff.  As a result of deviations, corrective actions are to be developed by the site 
1491 
and implemented promptly.                                                                                                                                       
1492 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
1493 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1494 

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Chapter 10: Ethics/Protection of Human Participants 
1495 
10.1 Ethical Standard 
1496 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1497 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1498 
21 CFR Part 56, and/or the ICH E6. 
1499 
10.2 Institutional Review Boards 
1500 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1501 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1502 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1503 
require review and approval by the IRB before the changes are implemented to the study.  All 
1504 
changes to the consent form will be IRB approved; a determination will be made regarding 
1505 
whether previously consented participants need to be re-consented. 
1506 
10.3 Informed Consent Process 
1507 
10.3.1 Consent Procedures and Documentation 
1508 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1509 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1510 
risks and possible benefits of participation will be provided to the participants and their families.  
1511 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
1512 
document.  The investigator will explain the research study to the participant and answer any 
1513 
questions that may arise.  All participants will receive a verbal explanation in terms suited to 
1514 
their comprehension of the purposes, procedures, and potential risks of the study and of their 
1515 
rights as research participants.  Participants will have the opportunity to carefully review the 
1516 
written consent form and ask questions prior to signing. 
1517 
The participants should have the opportunity to discuss the study with their surrogates or think 
1518 
about it prior to agreeing to participate.  The participant will sign the informed consent document 
1519 
prior to any procedures being done specifically for the study.  The participants may withdraw 
1520 
consent at any time throughout the course of the trial.  A copy of the informed consent document 
1521 
will be given to the participants for their records.  The rights and welfare of the participants will 
1522 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1523 
affected if they decline to participate in this study. 
1524 
10.3.2 Participant and Data Confidentiality 
1525 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
1526 
device company supplying study product may inspect all documents and records required to be 
1527 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
1528 
hospital) for the participants in this study.  The clinical study site will permit access to such 
1529 
records. 
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The study participant’s contact information will be securely stored at each clinical site for 
1531 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1532 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
1533 
Study participant research data, which is for purposes of statistical analysis and scientific 
1534 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research and the 
1535 
University of Virginia Center for Diabetes Technology.  This will not include the participant’s 
1536 
contact or identifying information.  Rather, individual participants and their research data will be 
1537 
identified by a unique study identification number.  The study data entry and study management 
1538 
systems used by clinical sites and by Jaeb research staff will be secured and password protected.  
1539 
At the end of the study, all study databases will be de-identified and archived at Jaeb Center for 
1540 
Health Research and the University of Virginia Center for Diabetes Technology. Permission to 
1541 
transmit data will be included in the informed consent. 
1542 

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Chapter 11: References 
1543 
1. Kovatchev, B.P., Breton, M.D., Keith-Hynes, P.T., Patek, S.D. The Diabetes Assistant 
1544 
(DiAs) – Unified platform for monitoring and control of blood glucose levels in diabetic 
1545 
patients; PCT/US12/43910, 2012. 
1546 
2. Keith Hynes, P., Guerlain, S., Mize, L.B., Hughes Karvetski, C., Khan, M., McElwee 
1547 
Malloy, M. & Kovatchev, B.P. DiAs user interface: A patient-centric interface for mobile 
1548 
artificial pancreas systems. J Diabetes Sci Technol, 7, 1416–1426 (2013). PMID: 24351168 
1549 
3. Place, J., Robert, A., Ben Brahim, N., Keith Hynes, P., Farret, A., Pelletier, M.J., 
1550 
Buckingham, B., Breton, M., Kovatchev, B.P. & Renard, E. DiAs web monitoring: A 
1551 
real-time remote monitoring system designed for artificial pancreas outpatient trials. J 
1552 
Diabetes Sci Technol, 7, 1427–1435. (2013). PMID: 24351169 
1553 
4. Keith-Hynes, P., Mize, B., Robert, A., Place, J. The Diabetes Assistant: A smartphone-based 
1554 
system for real-time control of blood glucose. Electronics 2014, 3, 609-623; 
1555 
doi:10.3390/electronics3040609 
1556 
5. Kovatchev, B.P., Renard, E., Cobelli, C., Zisser, H., Keith-Hynes, P., Anderson, S.M. 
1557 
Brown, S.A. Chernavvsky, D.R., Breton, M.D., Farret, A., Pelletier, M.J., Place, J., 
1558 
Bruttomesso, D., Del Favero, S., Visentin, R., Filippi, A., Scotton, R., Avogaro, A. & Doyle 
1559 
III, F.J. Feasibility of outpatient fully integrated closed-loop control: First studies of wearable 
1560 
artificial pancreas. Diabetes Care, 36, 1851-1858 doi: 10.2337/dc12-1965 (2013). PMID: 
1561 
23801798, PMCID: PMC3687268 
1562 
6. Kovatchev, B.P., Renard, E., Cobelli, C., Zisser, H., Keith-Hynes, P., Anderson, S.M., 
1563 
Brown, S.A., Chernavvsky, D.R., Breton, M.D., Mize, L.B., Farret, A., Place, J., 
1564 
Bruttomesso, D., Del Favero, S., Boscari, F., Galasso, S., Avogaro, A., Magni, L., Di Palma, 
1565 
F., Toffanin, C., Messori, M., Dassay, E., Doyle, F. III. Safety of outpatient closed-loop 
1566 
control: First randomized crossover trials of a wearable artificial pancreas. Diabetes Care, 
1567 
37, 1789-1796 doi: 10.2337/dc13-2076 (2014). PMID: 24929429, PMCID: PMC4067397 
1568 
7. DeSalvo, D., Keith-Hynes, P., Peyser, T., Place, J., Caswell, K., Wilson, D., Harris, B., 
1569 
Clinton, P., Kovatchev, B.P., Buckingham, B.A. Remote glucose monitoring in camp setting 
1570 
reduces the risk of prolonged nocturnal hypoglycemia. Diabetes Technol Ther, 16, 1-7 
1571 
doi:10.1089/dia.2013.0139 (2013). PMID: 24168317 
1572 
8. Ly, T.T., Breton, M.D., Keith-Hynes, P., De Salvo, D., Clinton, P., Benassi, K., Mize, L.B., 
1573 
Chernavvsky, D.R., Place, J., Wilson, D.M., Kovatchev, B.P., Buckingham, B.A. Overnight 
1574 
glucose control with an automated, unified safety system in children and adolescents with 
1575 
type 1 diabetes at diabetes camp. Diabetes Care, 37, doi: 10.2337/dc14-0147 (2014). PMID: 
1576 
24879841, PMCID: PMC4179507 
1577 
9. Kropff, J., Del Favero, S., Place, J., Toffanin, C., Visentin, R., Monaro, M., Messori, M., 
1578 
Di Palma, F., Lanzola, G., Farret, A., Boscari, F., Galasso, S., Magni, P., Avogaro, A., 
1579 
Keith-Hynes, P., Kovatchev, B.P., Bruttomesso, D., Cobelli, C.,  DeVries, J.H., Renard, E., 
1580 
Magni, L., for the AP@home consortium. 2 month evening and night closed-loop glucose 
1581 
control in patients with Type 1 Diabetes under free-living conditions: A randomised 
1582 
crossover trial. Lancet Diabetes Endocrinol, 3(12):939-47 dx.doi.org/10.1016/S2213-
1583 
8587(15)00335-6 (2015). 
1584 

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10. Renard, E et al. Reduction of hyper- and hypoglycemia during two months with a wearable 
1585 
artificial pancreas from dinner to breakfast in patients with type 1 diabetes. 2015-A-3083-
1586 
Diabetes. American Diabetes Association 75th Scientific Sessions, Boston, MA, poster 
1587 
940-P. 
1588 
11. Anderson, S et al. First New Year’s Night on closed-loop control (CLC) at home: Case 
1589 
reports from a multi-center international trial of long-term 24/7 CLC. 2015-A-4763-Diabetes. 
1590 
American Diabetes Association 75th Scientific Sessions, Boston, MA, presentation 223–OR. 
1591 
12. Kovatchev BP. JDRF Multi-Center 6-Month Trial of 24/7 Closed-Loop Control. Advanced 
1592 
Technologies and Treatments for Diabetes (ATTD), Plenary Session, Milan, Italy, 2016. 
1593 
13. Kovatchev, B.P. Closed-loop control modalities in type 1 diabetes: Efficacy and system 
1594 
acceptance. Advanced Technologies and Treatments for Diabetes (ATTD), Paris, France, 
1595 
2015. 
1596 
14. Del Favero S. A multicenter randomized cross-over Italian pediatric summer camp: AP vs 
1597 
SAP in 5-8 year old children. Advanced Technologies and Treatments for Diabetes (ATTD), 
1598 
Plenary Session, Milan, Italy, 2016. 
1599 
15. Cherñavvsky, D. et al. Closed-loop control during extended winter-sport exercise in youth 
1600 
with T1DM: Results from the first AP ski camp. ATTD Data Club Session, Milan, (2016). 
1601 
16. Chernavvsky, D.R., DeBoer, M.D., Keith-Hynes, P., Mize, B., McElwee, M., Demartini, S., 
1602 
Dunsmore, S.F., Wakeman, C., Kovatchev, B.P., Breton, M.D. Use of an artificial pancreas 
1603 
among adolescents for a missed snack bolus and an underestimated meal bolus. Pediatric 
1604 
Diabetes, doi:10.1111/pedi.12230 (2014). PMID: 25348683 
1605 
17. Brown, S.A., Kovatchev, B.P., Breton, M.D., Anderson, S.M., Keith-Hynes, P., Patek, S.D., 
1606 
Jiang, B., Ben Brahim, N., Vereshchetin, P., Bruttomesso, D., Avogaro, A., Del Favero, S., 
1607 
Boscari, F., Galasso, S., Visentin, R., Monaro, M., Cobelli, C. Multinight “bedside” 
1608 
closed-loop control for patients with type 1 diabetes. Diabetes Technol Ther 17(3), 
1609 
doi:10.1089/dia.2014.0259 (2015). PMID: 25594434, PMCID: PMC4346235 
1610 
18. Kovatchev BP, Tamborlane WV, Cefalu WT, Cobelli C. The Artificial Pancreas in 2016: 
1611 
A Digital Treatment Ecosystem for Diabetes. Diabetes Care 2016; 39:1123-27. PMID: 
1612 
27330124 
1613 
19. Del Favero S, Boscari F, Messori M, Rabbone I, Bonfanti R, Sabbion A, IaFusco D, 
1614 
Schiaffini R, Visentin R, Calore R, Moncada YL, Galasso S, Galderisi A, Vallone V, Di 
1615 
Palma F, Losiouk E1, Lanzola G1, Tinti D, Rigamonti A, Marigliano M, Zanfardino A, 
1616 
Rapini N, Avogaro A, Chernavvsky D, Magni L, Cobelli C, Bruttomesso D. Randomized 
1617 
Summer Camp Crossover Trial in 5- to 9-Year-Old Children: Outpatient Wearable Artificial 
1618 
Pancreas Is Feasible and Safe. Diabetes Care. 2016;39:1180-5. PMID: 27208335 
1619 
20. Renard E, Farret A, Kropff J, Bruttomesso D, Messori M, Place J, Visentin R, Calore R, 
1620 
Toffanin C, Di Palma F, Lanzola G, Galasso S, Avogaro A, Keith-Hynes P, Kovatchev BP, 
1621 
Del Favero S., Cobelli C, Magni L, DeVries HJ. AP@home Consortium. Day and night 
1622 
closed loop glucose control in patients with type 1 diabetes under free-living conditions: 
1623 
comparison of a single-arm, 1-month experience to results of a previously reported feasibility 
1624 
study of evening and night at home. Diabetes Care 2016; 39:1151-60. PMID: 27208331 
1625 

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21. Anderson SM, Raghinaru D, Pinsker JE, Boscari F, Renard E, Buckingham BA, Nimri R, 
1626 
Doyle FJ III, Brown SA, Keith-Hynes P, Breton MD, Chernavvsky D, Bevier WC, Bradley 
1627 
PK, Bruttomesso D, Del Favero S, Calore R, Cobelli C, Avogaro A, Farret A, Place J, Ly TT, 
1628 
Shanmugham S, Phillip M, Dassau E, Dasanayake IS, Kollman C, Lum JW, Beck RW, and 
1629 
Kovatchev BP. Multinational home use of closed-loop control is safe and effective. 
1630 
Diabetes Care 2016; 39:1143-1150. PMID: 27208316 
1631 
22. DeBoer MD, Cherñavvsky DR, Topchyan K, Kovatchev BP, Francis GL, Breton MD. Heart 
1632 
rate informed artificial pancreas system enhances glycemic control during exercise in 
1633 
adolescents with T1D. Pediatr Diabetes. 2016; doi: 10.1111/pedi.12454. PMID: 27734563 
1634 
23. Kovatchev BP, Cheng P, Anderson SM, Pinsker JE, Boscari F, Buckingham BA, Doyle FJ. 
1635 
III, Hood KK, Brown SA. Breton MD, Chernavvsky DR, Bevier WC, Bradley PK, 
1636 
Bruttomesso D, Del Favero S, Calore R, Cobelli C, Avogaro A, Ly TT, Shanmugham S, 
1637 
Dassau E, Kollman C, Lum JW, Beck RW, for the Control to Range Study Group. Feasibility 
1638 
of Long-Term Closed-Loop Control: A Multicenter 6-Month Trial of 24/7 Automated Insulin 
1639 
Delivery. Diabetes Technol Ther 2017; 19: 18-24. doi:10.1089/dia.2016.0333. PMID: 
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27982707 
1641 
24. DeBoer MD, Breton MD, Wakeman CA, Schertz EM, Emory EG, Robic JL, Kollar LL, 
1642 
Kovatchev BP, Chernavvsky DR. Performance of an Artificial Pancreas System for Young 
1643 
Children with Type 1 Diabetes. Diabetes Technol Ther 2017; 19, DOI: 
1644 
10.1089/dia.2016.0424. PMID: 28426239 
1645 
25. Breton MD, Cherñavvsky DR, Forlenza GP, DeBoer MD, Robic J, Wadwa RP, Messer LH,  
1646 
Kovatchev BP, Maahs DM. Closed Loop Control During Intense Prolonged Outdoor 
1647 
Exercise in Adolescents With Type 1 Diabetes: The Artificial Pancreas Ski Study. Diabetes 
1648 
Care 2017 Aug; dc170883. https://doi.org/10.2337/dc17-0883 
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26. Gonder-Frederick L, Shepard J, Vajda K, Wakeman C, McElwee M, Kovatchev B: 
1650 
Personality traits and BG profile improvements with continuous glucose monitoring use. 
1651 
Diabetes 61 (Suppl 1):808-P, 2012 
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27. Jackson DN, Ashton MC, Tomes JL: The six-factor model of personality: Facets from the 
1653 
Big Five. Personality & Individual Differences 21:391-402, 1996 
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28. Clarke WL, Cox DJ, Gonder-Frederick L, Julian D, Schlundt D, Polonsky W: Reduced 
1655 
Awareness of Hypoglycemia in Adults With IDDM: A prospective study of hypoglycemic 
1656 
frequency and associated symptoms. Diabetes Care 18:517-522, 1995 
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29. Gonder-Frederick LA, Schmidt KM, Vajda KA, Greear ML, Singh H, Shepard JA, Cox DJ: 
1658 
Psychometric properties of the hypoglycemia fear survey-ii for adults with type 1 diabetes. 
1659 
Diabetes Care 34:801-806, 2011 
1660 
30. Singh H, Gonder-Frederick L, Schmidt K, Ford D, Vajda K, Hawley J, Cox DJ: Assessing 
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Hyperglycemia Avoidance in People with type 1 Diabetes. Diabetes Management 4:263-271, 
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2014 
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31. Polonsky WH, Fisher L, Hessler D, Edelman SV. Investigating Hypoglycemic Confidence in 
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Type 1 and Type 2 Diabetes. Diabetes Technol Ther. 2017;19(2):131-6. 
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32. Polonsky WH, Fisher L, Earles J, Dudl RJ, Lees J, Mullan J, Jackson RA: Assessing 
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psychosocial distress in diabetes: development of the diabetes distress scale. Diabetes Care 
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28:626-631, 2005 
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33. Weissberg-Benchell J, Hessler D, Polonsky WH, Fisher L: Psychosocial Impact of the Bionic 
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Pancreas During Summer Camp. J Diabetes Sci Technol, 2016 
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