The Pediatric Artificial Pancreas Automated Initialization Trial (PEDAP-AI): A Pilot Study of AI Advisor-Driven Pump Initiation and Parameter Adaptation in Young Children With Type 1 Diabetes
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Marc Breton

PEDAP-AI PROTOCOL V5.0 2024-02-14 
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Signature Page 
The Pediatric Artificial Pancreas Automated Initialization trial 
(PEDAP-AI): A Pilot Study of AI Advisor-Driven Pump Initiation 
and Parameter Adaptation in Young Children with Type 1 Diabetes  
Protocol Identifying Number: PEDAP-AI 
IDE Sponsor: University of Virginia 
Version Number: 5.0 
14FEBRUARY 2024 
 
JCHR Protocol Director/Principal Investigator (PD/PI) 
Name, degree 
John Lum, MS  
Signature/Date 
 
 
External Sponsor (IDE Holder) 
Name, degree 
Marc D. Breton, Ph.D.  
Signature/Date 
 
 
Protocol Chair/Coordinating Investigator 
Name, degree 
R. Paul Wadwa, M.D. 
Signature/Date 
 
 
Medical Monitor 
Name, degree 
Roy Beck, MD, Ph.D. 
Signature/Date 
 
 

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The Pediatric Artificial Pancreas Automated 
Initialization trial (PEDAP-AI): A Pilot Study of AI 
Advisor-Driven Pump Initiation and Parameter 
Adaptation in Young Children with Type 1 Diabetes  
 
IDE Sponsor  
University of Virginia 
Center for Diabetes Technology 
IDE# G230127 
 
Funded by: 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 
Protocol Chair 
R. Paul Wadwa, MD 
Barbara Davis Center 
University of Colorado 
 
Participating Institutions 
University of Virginia, Charlottesville, Virginia 
Barbara Davis Center, University of Colorado, Colorado 
Stanford University, California 
 
Coordinating Center 
Jaeb Center for Health Research 
 
 
Version Number: v5.0 
14 FEBRUARY 2024 

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KEY ROLES 
 
Sponsor Chair / IDE Chair 
Name, degree 
Marc D. Breton, Ph.D. 
Institution Name 
University of Virginia, Center for Diabetes Technology 
 
Protocol Chair/Coordinating Investigator 
Name, degree 
R. Paul Wadwa, MD 
Institution Name 
Barbara Davis Center, University of Colorado  
 
JCHR Protocol Director/Principal Investigator (PD/PI) 
Name, degree 
John Lum, MS 
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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VERSION HISTORY 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0  
J. Lum 
M. Breton, P. 
Wadwa 
25 APR 2023 
Initial protocol draft 
2.0 
D. Rojas 
J. Lum 
M. Breton, P. 
Wadwa 
15 MAY 2023 
Reorganize Chapter 4, add new section 4.2 
Add certificate of confidentiality language in 
section 10.3.2 
Address FDA questions during IDE review, 
including time period for pump training, 
requirement not to change pump settings 
without discussion with study team, and 
logistics associated with occasional stoppage 
of closed-loop delivery related to exogenous 
insulin delivery 
Fix typos, spacing errors 
3.0 
D. Rojas 
J. Lum 
M. Breton, P. 
Wadwa 
13 JUNE 2023 
Revisions to address IRB requests, including: 
• clarified language in exclusion criterion 8 
• minor edits, added footnotes to Table 1 
• clarified eConsent process in Section 2.1.1 
• specified timing of procedures at screening 
and pump initiation visits in Section 2.4 
• specified method of delivery for scale in 
Section 2.4.1 
• specified eConsent is repeated at 
rescreening in Section 2.5 
• removed reference to randomization in 
Section 7.3 
• added reference to study pump data 
collection in Section 9.1 
• specified device materials language in 
Section 10.3.1 
• indicated no genetic testing in Section 
10.3.2 
Minor clerical edits throughout 
Fix typos 
*4.0 
Z. Reed 
M. Breton, P. 
Wadwa 
28 AUG 2023 
Revisions to Statistical Considerations 
chapter: 
• Both primary safety outcomes 
(hypoglycemia and hyperglycemia) will be 
tested for non-inferiority 
• Restructured safety endpoints section to 
specify the pair of hierarchical CGM-
measured primary safety endpoints plus 
additional safety endpoints 
• Restructured efficacy endpoints to specify 
a set of hierarchical CGM-measured 
efficacy endpoints plus additional 
secondary and exploratory efficacy 
endpoints 

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VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
• Revised material describing analysis 
details for various outcomes 
• Added section on insulin metrics 
• Expanded description of comparison with 
PEDAP historical control 
Revised Endpoints row of Protocol 
Summary table to match Stats chapter 
changes. 
Revisions based on JCHR QA review 
5.0 
J. Lum 
M. Breton, P. 
Wadwa 
14 FEB 2024 
• Relaxed eligibility criteria to allow 
enrollment sooner after T1D diagnosis and 
allow current pump users 
• Corrected “Error” text in several TOC 
entries by fixing text style in section 6.2 
• Revised Protocol Overview section of 
Protocol Summary table to make 3 Day 
Visit procedures identical to subsequent 
visit procedures, consistent with remainder 
of document  
• Clarified insulin data needed for system 
initialization in section 3.2.1 
• Revised section 3.3.4 to allow off-cycle 
optimization of pump settings 
• Revised section 4.2.1 to describe use of 
either Dexcom G6 or G7 CGM 
components, making this section consistent 
with the rest of the document 
 
   *Version in effect at study initiation

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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................ 16 
1.1 Introduction ..................................................................................................................................... 16 
1.2 Rationale.......................................................................................................................................... 16 
1.3 Potential Risks and Benefits of the Investigational Device .............................................................. 16 
1.3.1 Known Potential Risks .............................................................................................................. 16 
1.3.1.1 Potential Risks and Benefits of the CLC System ............................................................... 16 
1.3.1.2 Risk of Hypoglycemia ....................................................................................................... 16 
1.3.1.3 Risk of Hyperglycemia...................................................................................................... 17 
1.3.1.4 Fingerstick Risks ............................................................................................................... 17 
1.3.1.5 Subcutaneous Catheter Risks (CGM) ................................................................................ 17 
1.3.1.6 Risk of Device Reuse ........................................................................................................ 17 
1.3.1.7 Other Risks........................................................................................................................ 17 
1.3.2 Known Potential Benefits .......................................................................................................... 18 
1.3.3 Risk Assessment ........................................................................................................................ 18 
1.4 General Considerations .................................................................................................................... 18 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING ............................................................................. 19 
2.1 Participant Recruitment and Enrollment .......................................................................................... 19 
2.1.1 Informed Consent and Authorization Procedures ...................................................................... 19 
2.2 Participant Inclusion Criteria ........................................................................................................... 19 
2.3 Participant Exclusion Criteria .......................................................................................................... 20 
2.4 Screening Procedures ...................................................................................................................... 20 
2.4.1 Data Collection and Testing ...................................................................................................... 21 
2.5 Screen Failures ................................................................................................................................ 21 
CHAPTER 3: MAIN PHASE ....................................................................................................................... 22 
3.1 Visit and Contact Schedule .............................................................................................................. 22 
3.1 Blood Glucose Testing, Ketone Testing, and Glucagon .................................................................. 22 
3.2 Study Pump Procedures and Training .............................................................................................. 22 
3.2.1 Determination of Initial of Pump Settings ................................................................................. 23 
3.2.2 t:connect Mobile App for Data Upload to Study Server ............................................................ 24 
3.2.4 Home Use of the Study System ................................................................................................. 24 
3.2.5 Study Device Download ............................................................................................................ 25 
3.2.6 Baseline HbA1c Determination ................................................................................................. 25 
3.3 Study Visits ..................................................................................................................................... 25 
3.3.1 3-Day Visit ................................................................................................................................ 25 

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3.3.2 Subsequent Scheduled Study Visits ........................................................................................... 25 
3.3.3 3-Day Post-Study Safety Contact .............................................................................................. 26 
3.3.4 Unscheduled Visits .................................................................................................................... 26 
CHAPTER 4: STUDY DEVICES .................................................................................................................. 27 
4.1 Description of the Investigational Device ........................................................................................ 27 
4.1.1 UVA Clinician Portal ................................................................................................................ 27 
4.1.2 Insulin Pump ............................................................................................................................. 27 
4.2 Components of the Investigational Device System .......................................................................... 27 
4.2.1 Continuous Glucose Monitoring ................................................................................................ 27 
4.2.2 Phone Running t:connect Mobile App ....................................................................................... 27 
4.2.3 Blood Glucose Meter and Strips ................................................................................................ 27 
4.2.3.1 Blood Glucose Meter Testing ............................................................................................ 27 
4.2.4 Ketone Meter and Strips ............................................................................................................ 28 
4.2.4.1 Blood Ketone Testing ....................................................................................................... 28 
4.2.5 Study Device Accountability Procedures................................................................................... 28 
4.3 Safety Measures .............................................................................................................................. 28 
4.3.1 CGM Calibration ....................................................................................................................... 28 
4.3.2 Pump Failure ............................................................................................................................. 28 
4.3.3 Hypoglycemia Threshold Alarm and Safety Protocol................................................................ 28 
4.3.4 Hyperglycemia Threshold Alarm and Safety Protocol .............................................................. 29 
4.4 Participant Access to Study Device at Study Closure ...................................................................... 29 
CHAPTER 5: TESTING PROCEDURES....................................................................................................... 30 
5.1 Laboratory Testing .......................................................................................................................... 30 
CHAPTER 6: UNANTICIPATED PROBLEM, ADVERSE EVENT, AND DEVICE ISSUE REPORTING ............ 31 
6.1 Unanticipated Problems ................................................................................................................... 31 
6.2 Adverse Events ................................................................................................................................ 31 
6.2.1 Definitions ................................................................................................................................. 31 
6.2.2 Reportable Adverse Events........................................................................................................ 32 
6.2.3 Hypoglycemic Events ................................................................................................................ 33 
6.2.4 Hyperglycemic/Ketotic Events .................................................................................................. 33 
6.2.5 Relationship of Adverse Event to Study Device or Study Procedure ......................................... 34 
6.2.6 Severity (Intensity) of Adverse Events ...................................................................................... 35 
6.2.7 Expectedness ............................................................................................................................. 35 
6.2.8 Coding of Adverse Events ......................................................................................................... 35 
6.2.9 Outcome of Adverse Events ...................................................................................................... 35 

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6.3 Reportable Device Issues ................................................................................................................. 36 
6.4 Timing of Event Reporting .............................................................................................................. 36 
6.5 Safety Oversight .............................................................................................................................. 37 
6.6 Stopping Criteria ............................................................................................................................. 37 
6.6.1 Participant Discontinuation of Study Device ............................................................................. 37 
6.6.2 Criteria for Suspending or Stopping Overall Study ................................................................... 38 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS ................................................................................. 39 
7.1 Drugs Used as Part of the Protocol .................................................................................................. 39 
7.2 Collection of Medical Conditions and Medications ......................................................................... 39 
7.3 Prohibited Medications, Devices, Treatments, and Procedures ....................................................... 39 
7.4 Precautionary Medications, Treatments, and Procedures ................................................................. 39 
7.5 Prophylactic Medications, Treatments, and Procedures ................................................................... 39 
7.6 Rescue Medications, Treatments, and Procedures ........................................................................... 39 
7.7 Participant Compensation ................................................................................................................ 39 
7.8 Participant Withdrawal .................................................................................................................... 40 
7.9 Confidentiality ................................................................................................................................. 40 
CHAPTER 8: STATISTICAL CONSIDERATIONS ........................................................................................ 41 
8.1 Statistical and Analytical Plans ........................................................................................................ 41 
8.2 Statistical Hypotheses ...................................................................................................................... 41 
8.3 Sample Size ..................................................................................................................................... 41 
8.4 Endpoints ......................................................................................................................................... 41 
8.4.1 Safety Endpoints ........................................................................................................................ 41 
8.4.2 Efficacy Endpoints .................................................................................................................... 42 
8.5 Analysis Datasets and Sensitivity Analyses ..................................................................................... 43 
8.6 CGM Metrics Calculations .............................................................................................................. 43 
8.7 Insulin Metrics Calculations ............................................................................................................ 43 
8.8 Analysis of the Hierarchical Endpoints ........................................................................................... 43 
8.9 Analysis of Secondary Endpoints .................................................................................................... 44 
8.10 Comparison with PEDAP Historical Control ................................................................................. 44 
8.11 Analysis of Exploratory Endpoints ................................................................................................ 45 
8.12 Additional Tabulations and Plots ................................................................................................... 45 
8.13 Safety Analyses ............................................................................................................................. 45 
8.14 Intervention Adherence ................................................................................................................. 45 
8.15 Protocol Adherence and Retention ................................................................................................ 45 
8.16 Baseline Descriptive Statistics ....................................................................................................... 46 
8.17 Device Issues ................................................................................................................................. 46 

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8.18 Planned Interim Analyses .............................................................................................................. 46 
8.19 Subgroup Analyses ........................................................................................................................ 46 
8.20 Missing Data.................................................................................................................................. 46 
8.21 Multiple Comparison/Multiplicity ................................................................................................. 46 
CHAPTER 9: DATA COLLECTION AND MONITORING............................................................................. 47 
9.1 Case Report Forms and Other Data Collection ................................................................................ 47 
9.2 Study Records Retention ................................................................................................................. 47 
9.3 Quality Assurance and Monitoring .................................................................................................. 47 
9.4 Protocol Deviations ......................................................................................................................... 48 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS........................................................... 49 
10.1 Ethical Standards ........................................................................................................................... 49 
10.2 Institutional Review Boards........................................................................................................... 49 
10.3 Informed Consent Process ............................................................................................................. 49 
10.3.1 Consent Procedures and Documentation ................................................................................. 49 
10.3.2 Participant and Data Confidentiality ........................................................................................ 49 
CHAPTER 11: REFERENCES ..................................................................................................................... 51 
 
 
 

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

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: The Pediatric Artificial Pancreas Automated Initialization trial (PEDAP-AI): A Pilot 
Study of AI Advisor-Driven Pump Initiation and Parameter Adaptation in Young Children with 
Type 1 Diabetes 
Protocol Version/Date: 5.0 / 14 February 2024 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, my 
duties include ensuring the safety of the study participants enrolled under my supervision and providing 
the Jaeb Center for Health Research, which serves as the Coordinating Center for the protocol, with 
complete and timely information, as outlined in the protocol. It is understood that all information 
pertaining to the study will be held strictly confidential and that this confidentiality requirement applies 
to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as required 
by the following (use applicable regulations depending on study location and sponsor requirements; 
examples follow): United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the sponsor and documented approval from the Institutional Review 
Board (IRB), or other approved Ethics Committee, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have completed 
Human Participants Protection Training and Good Clinical Practice Training. Further, I agree to ensure 
that all staff members involved in the conduct of this study are informed about their obligations in 
meeting the above commitments. 
 
Investigator’s Signature __________________________________ 
Date: _____ / _____ / _____ 
 
dd 
mmm 
yyyy 
Investigator’s Name: ____________________________________ 
Site Name/Number: _____________________________________ 
 

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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
The Pediatric Artificial Pancreas Automated Initialization trial (PEDAP-AI): A Pilot 
Study of AI Advisor-Driven Pump Initiation and Parameter Adaptation in Young Children 
with Type 1 Diabetes 
Précis 
A single-arm pilot study of AI Advisor-driven at-home closed loop system initiation and 
parameter adaptation in youth age 2 to <6 years old. 
Investigational Device 
Tandem t:slim X2 with Control-IQ and t:connect mobile application and Dexcom G6 or 
G7 system, connected to UVA cloud-based Physician Dashboard 
Objectives 
The objective of the study is to obtain safety data and exploratory glycemic control data 
with initiation and use of a closed loop control (CLC) system (t:slim X2 with Control-IQ 
Technology) in young children with initial selection of pump parameters and subsequent 
periodic parameter adjustment driven by an AI-based Advisor system over a 8-week 
period. 
Study Design 
In this single-arm intervention trial, all participants will use the study system (pump and 
CGM) in closed-loop mode for 8 weeks. 
Number of Sites 
~3 US clinical centers 
Endpoints 
Safety 
The key safety outcomes are adverse events related to hypoglycemia and hyperglycemia, 
CGM-measured time spent below 54mg/dL, and CGM-measured time spent above 
250mg/dL. CGM-measured endpoints will be tested against baseline for non-inferiority.  
Efficacy 
Glycemic outcomes including time in target range 70-180 mg/dL (TIR) and various other 
CGM measures of hypo- and hyperglycemia will be assessed and tested for superiority 
against baseline and a matched historical control population from the prior PEDAP study 
that did not involve the use of any AI-driven pump parameters. 
Population 
Key Inclusion Criteria 
1. 
Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least 1 
month 
2. 
Familiarity and use of a carbohydrate ratio for meal boluses 
3. 
Age ≥2 and <6 years old 
4. 
Using a Dexcom CGM at the time of enrollment, with use on at least 21 out of the 
prior 28 days 
5. 
Living with one or more parent/legal guardian knowledgeable about emergency 
procedures for severe hypoglycemia and able to contact emergency services and 
study staff. 
6. 
Parent/guardian has a phone that can run the Tandem t:connect Mobile App 
(typically Android 10 or above or iOS 15 or above) 
7. 
Willingness to use the t:connect Mobile App as needed during the study and ensure 
connectivity for a data upload at least once per day 
8. 
Investigator has confidence that the parent can successfully operate all study devices 
and is capable of adhering to the protocol 
9. 
Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, 
and to use no other insulin besides lispro (Humalog) or aspart (Novolog) during the 
study for participants using a study-provided Tandem pump during the study. 
10. Total daily insulin dose (TDD) at least 5 U/day 
11. Body weight at least 20 lbs 
12. Willingness not to start any new non-insulin glucose-lowering agent during the 
course of the trial 
13. Participant and parent(s)/guardian(s) willingness to participate in all training sessions 
as directed by study staff  
14. Parent/guardian proficient in reading and writing English 

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PARTICIPANT AREA 
DESCRIPTION 
15. Live in the United States, with no plans to move outside the United States during the 
study period 
Key Exclusion Criteria 
1. 
Concurrent use of any non-insulin glucose-lowering agent (including GLP-1 
agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas) 
2. 
Hemophilia or any other bleeding disorder 
3. 
History of >1 severe hypoglycemic event with seizure or loss of consciousness in the 
last 3 months 
4. 
History of >1 DKA event in the last 6 months not related to illness, infusion set 
failure, or initial diagnosis 
5. 
History of chronic renal disease or currently on hemodialysis 
6. 
History of adrenal insufficiency 
7. 
Hypothyroidism that is not adequately treated in the opinion of the investigator 
8. 
Use of oral or injectable steroids within the last 8 weeks  
9. 
Known, ongoing adhesive intolerance 
10. Plans to receive blood transfusions or erythropoietin injections during the course of 
the study 
11. A condition, which in the opinion of the investigator or designee, would put the 
participant or study at risk 
12. Participation in another pharmaceutical or device trial at the time of enrollment or 
during the study 
13. Having immediate family members employed by Tandem Diabetes Care, Inc. or 
Dexcom, Inc., or having a direct supervisor at place of employment who is also 
directly involved in conducting the clinical trial (as a study investigator, coordinator, 
etc.); or having a first-degree relative who is directly involved in conducting the 
clinical trial 
Sample Size 
Up to 45 screened participants with the goal of at least 30 participants completing the 
study pump use period 
Intervention 
t:slim X2 with Control-IQ Technology and t:connect mobile application with mobile bolus 
capabilities and Study CGM 
Participant Duration 
~8 weeks 
Study Duration (planned) 
~8 months from first enrollment until last participant visit 
Protocol Overview/Synopsis 
After consent is signed, eligibility will be assessed. Eligible participants will proceed to 
the main study described below. 
Initial pump parameter settings will be reviewed by clinical site staff after uploading 
baseline personal CGM and insulin data to a web-based AI-driven Advisor interface. The 
Advisor will suggest pump parameter settings that the study investigator may either accept 
unchanged or else override based on clinical judgment if there are any safety concerns. A 
study pump will be configured with the resulting parameter values, the participant will be 
provided with the study pump and study CGM and other supplies, and the participant will 
begin home use of the pump. 
Visits* will occur at 3 days and at 1, 2, 4, and 6 weeks, with each visit including site 
upload of pump/CGM data to the Advisor interface to obtain recommended adjustments to 
pump parameters. As before, the study investigator may either accept unchanged or else 
override based on clinical judgment if there are any safety concerns. 
A final study visit will occur at 8 weeks, at which time the study participant will be 
transitioned back to preferred post-study insulin therapy. A follow-up safety visit will 
occur 3 days after the final visit to confirm successful transition to post-study insulin 
therapy. 
* All study visits may be conducted either remotely via teleconference, or else in person at 
the clinical site 

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SCHEMATIC OF STUDY DESIGN 
 
Enrollment 
Closed-Loop Initiation 
3-Day Visit 
1 Week Visit 
2 Week Visit 
4 Week Visit 
6 Week Visit 
8 Week (Final) Visit 
Initial adjustment of AI-driven pump parameters  
AI-driven pump parameter adjustment 
AI-driven pump parameter adjustment 
AI-driven pump parameter adjustment 
AI-driven pump parameter adjustment 
3-Day Safety Contact 
Return of study supplies; transition to post-study 
insulin therapy 
Confirm successful transition to post-study 
insulin therapy 
Initial configuration of AI-driven pump parameters  

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
Table 1. Schedule of Study Visits and Procedures 
* All screening visit procedures must be completed within 28 days of eConsent. 
** All Pump initiation visit procedures must be completed within 10 days of screening visit procedure completion. 
 
Screening 
Visit* 
Baseline-
Pump 
Initiation** 
3d 
1w 
2w 
4w 
6w 
8w 
8w 
+3d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
Medical history/ 
height/weight 
X 
 
 
 
 
 
 
 
 
Central lab HbA1c 
 
X 
 
 
 
 
 
 
 
Study pump training 
 
X 
 
 
 
 
 
 
 
Upload device data from home 
 
 
X 
X 
X 
X 
X 
X 
 
Review diabetes management, 
AEs, and medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Manual pump parameter 
adjustment only if safety issue 
 
 
Any scheduled or unscheduled visit 
 
 
AI-driven pump parameter 
initiation/adjustment 
 
X 
X 
X 
X 
X 
X 
 
 

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Chapter 1: Background Information 
1 
1.1 Introduction 
2 
The Tandem X2 insulin pump with Control-IQ Technology is a third-generation closed-loop control (CLC) 
3 
system retaining the same control algorithm that was initially tested by UVA’s DiAs system and then 
4 
implemented in the inControl system (TypeZero Technologies, Inc.). 
5 
The system has received FDA approval for use in individuals ≥6 years old following a series of pivotal 
6 
trials that demonstrated the system’s safety and efficacy, first in participants ≥14 years old (1) then in 
7 
participants ≥6 years old (2), and finally in participants ≥2 years old (3).  
8 
Closed-Loop Control System 
9 
The Closed-Loop Control System contained in t-slim X2 with Control-IQ Technology is described in 
10 
Master File MAF-2032/A008. Control-IQ Technology is derived from inControl previously described in 
11 
IDE# G160097, G160181, G150240 and G140169/S010. The CLC is an “artificial pancreas” (AP) 
12 
application that uses advanced closed loop control algorithms to automatically manage blood glucose (BG) 
13 
levels for people with Type 1 Diabetes. The system modulates insulin to keep BG in a targeted range. The 
14 
system components include the t:slim X2 with Control-IQ Technology, t:connect Mobile App, and Dexcom 
15 
G6 or G7 system, connected to UVA cloud-based Physician Dashboard. 
16 
1.2 Rationale 
17 
The objective of this trial is to obtain safety data and exploratory glycemic control data with initiation and 
18 
use of a closed loop control (CLC) system (t:slim X2 with Control-IQ Technology) in young children with 
19 
initial selection of pump parameters and subsequent weekly parameter adjustment driven by an AI-based 
20 
Advisor system over a 8-week period. 
21 
1.3 Potential Risks and Benefits of the Investigational Device 
22 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are handled 
23 
to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are always a risk in participants 
24 
with type 1 diabetes and participants will be monitored for these events. 
25 
1.3.1 Known Potential Risks 
26 
1.3.1.1 Potential Risks and Benefits of the CLC System 
27 
Even though the study system has been tested prior to this study, there is still a risk that parts of the 
28 
system may not function properly. The following are possible reasons the system may deliver too much 
29 
insulin or incorrectly stop insulin delivery: 
30 
• CGM sensor reads higher or lower than the actual glucose level which increases risk for 
31 
hypoglycemia and hyperglycemia with automated insulin delivery system; 
32 
• Device malfunctions that could produce a suspension of insulin delivery or over delivery of 
33 
insulin. 
34 
1.3.1.2 Risk of Hypoglycemia 
35 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low blood 
36 
sugar (hypoglycemia). The frequency of hypoglycemia should be no more and possibly less than it would 
37 
be as part of daily living. Symptoms of hypoglycemia can include sweating, jitteriness, and not feeling well.  
38 
Just as at home, there is the possibility of fainting or seizures (convulsions) and that for a few days the 
39 

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participant may not be as aware of symptoms of hypoglycemia. A CGM functioning poorly and 
40 
significantly over-reading glucose values could lead to inappropriate insulin delivery. 
41 
1.3.1.3 Risk of Hyperglycemia 
42 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an extended 
43 
period or if the pump or infusion set is not working properly. A CGM functioning poorly and significantly 
44 
under-reading glucose values could lead to inappropriate suspension of insulin delivery. 
45 
1.3.1.4 Fingerstick Risks 
46 
At various times several drops of blood will be removed by fingerstick. This is a standard method used to 
47 
obtain blood for routine hospital laboratory tests. Pain is common at the time of lancing. In about 1 in 10 
48 
cases, a small amount of bleeding under the skin will produce a bruise. A small scar may persist for several 
49 
weeks. The risk of local infection is less than 1 in 1000. This should not be a significant contributor to risks 
50 
in this study as fingersticks are part of the usual care for people with diabetes. 
51 
1.3.1.5 Subcutaneous Catheter Risks (CGM) 
52 
Participants using the CGM will be at low risk for developing a local skin infection at the site of the sensor 
53 
needle placement. If a catheter is left under the skin for more than 24 hours, it is possible to get an infection 
54 
where it goes into the skin, with swelling, redness and pain. There may be bleeding where the catheter is 
55 
put in and bleeding under the skin causes a bruise (1 in 10 risk). 
56 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and leave a 
57 
small portion of the sensor under the skin that may cause redness, swelling or pain at the insertion site. The 
58 
participant should be further instructed to notify the study coordinator immediately if this occurs. 
59 
1.3.1.6 Risk of Device Reuse 
60 
The study CGM system is labeled for single use only. The sensor (the component of the system that enters 
61 
the skin) will be single use only. The receiver, if used, is a hand-held device. The transmitter and receiver 
62 
may be reused during the study after cleaning the device using a hospital-approved cleaning procedure. The 
63 
transmitter is attached to the sensor but does not enter the skin. Participants will be informed that FDA or 
64 
relevant national authorities have approved these devices for single use and that by using them among 
65 
multiple patients, bloodborne pathogens (i.e., Hepatitis B) may be spread through the use of multiple users. 
66 
The study insulin pump is labeled for single-patient use. During the study, this device may be reused after 
67 
cleaning adhering to a hospital-approved cleaning procedure. All infusion set equipment will be single 
68 
patient use only (infusion set insertion kits, tubing, cartridges etc.)  Participants will be informed that FDA 
69 
or relevant national authorities typically approve the insulin pump device for single use and that by using 
70 
them among multiple patients, bloodborne pathogens (i.e., Hepatitis B) may be spread through the use of 
71 
multiple users. 
72 
The study BG meter and blood ketone meter are labeled for single-patient use.  
73 
During the study, only one person can use each device as there are rare risks that bloodborne pathogens 
74 
(i.e., Hepatitis B) may be spread through the use of multiple users. 
75 
1.3.1.7 Other Risks 
76 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure the CGM, 
77 
or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion. If these reactions 
78 
occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be tried, sites will 
79 
be rotated frequently, and a mild topical steroid cream or other medication may be required. 
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Whenever the skin is broken there is the possibility of an infection. The CGM and pump infusion sites are 
81 
inserted under the skin. It is possible that any part that is inserted under the skin may cause an infection.  
82 
These occur very infrequently, but, if an infection was to occur, oral and/or topical antibiotics can be used.  
83 
The risk of skin problems could be greater if you use a sensor for longer than it is supposed to be used.  
84 
Therefore, participants (and parents) will be carefully instructed about proper use of the sensor. 
85 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be collected for the 
86 
study as measures of diabetes self-management behaviors. Some people may be uncomfortable with the 
87 
researchers' having such detailed information about their daily diabetes habits. 
88 
1.3.2 Known Potential Benefits 
89 
It is expected that this protocol will yield increased knowledge about the feasibility of using an AI-driven 
90 
algorithm to adjust pump therapy parameters for an automated closed-loop system to control the glucose 
91 
level. The individual participant may not benefit from study participation. 
92 
1.3.3 Risk Assessment 
93 
Based on the facts that (1) children with diabetes experience mild hypoglycemia and hyperglycemia 
94 
frequently as a consequence of the disease and its management, (2) the study intervention involves periodic 
95 
automated insulin dosing that may reduce the likelihood of hypoglycemia, and periodic automated 
96 
attenuation of insulin delivery that may reduce the likelihood of hyperglycemia, (3) if any, hypo and/or 
97 
hyperglycemia occur, mitigations are in place, and have been tested in prior studies using the investigational 
98 
device system in the home setting, that limit the likelihood of excessive insulin dosing or prolonged 
99 
withdrawal of insulin, and (4) rapid reversal of hypoglycemia and hyperglycemia can be achieved, it is the 
100 
assessment of the investigators that this protocol falls under DHHS 45 CFR 46.405 and 21 CFR 50.52 as a 
101 
clinical investigation involving greater than minimal risk but presenting the prospect of direct benefit to 
102 
individual subjects. In addition, it is the belief of the investigators that this study also presents prospect of 
103 
general benefit to others with diabetes. 
104 
1.4 General Considerations 
105 
The study is being conducted in compliance with the policies described in the study policies document, 
106 
with the ethical principles that have their origin in the Declaration of Helsinki, with the protocol described 
107 
herein, and with the standards of Good Clinical Practice (GCP). 
108 
The protocol is considered a significant risk device study, due to the fact that the closed loop system is 
109 
experimental in the population under study and the AI-driven pump parameter adjustment algorithm—
110 
though all adjustments are reviewed and approved by study physicians—is experimental. Therefore, an 
111 
investigational device exemption (IDE) from the U.S. Food and Drug Administration (FDA) is required to 
112 
conduct the study. 
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Chapter 2: Study Enrollment and Screening 
114 
2.1 Participant Recruitment and Enrollment 
115 
Enrollment will proceed with the goal of having 30 completing the study pump use period. A maximum of 
116 
45 individuals may be enrolled into screening for the study in order to achieve this goal. 
117 
Study participants will be recruited at ~3 clinical centers in the United States without regard to gender, race, 
118 
or ethnicity. There is no restriction on the number of participants to be enrolled by each clinical center 
119 
toward the overall recruitment goal. 
120 
The study team will make every effort to have the following minimum numbers of participants complete 
121 
the trial in the specified subgroups at the time of enrollment: 
122 
• 
At least 50% of the participants with most recent available HbA1c ≥ 7.5% 
123 
2.1.1 Informed Consent and Authorization Procedures 
124 
Potential eligibility may be assessed as part of a routine-care examination. Before completing any 
125 
procedures or collecting any data that are not part of usual care, written informed consent will be 
126 
obtained. 
127 
A parent/legal guardian (referred to subsequently as “parent”) will be provided with the Informed Consent 
128 
Form to read and will be given the opportunity to ask questions either via phone/videoconference or by 
129 
mail or email. If the parent is interested in the study, the investigator will schedule a virtual or in-person 
130 
visit to discuss study, and if the parent agrees to participation, the Informed Consent Form will be 
131 
electronically signed through the JCHR website. A copy of the electronically signed consent form can be 
132 
printed by the parent and another copy will be printed by the site to add to the participant’s study record. 
133 
This process is referred to as eConsent. 
134 
As part of the eConsent process, each parent will be asked to electronically sign an authorization for 
135 
release of the participant’s personal information (i.e., HIPAA Authorization). The investigator, or his or 
136 
her designee, will review the study-specific information that will be collected and to whom that 
137 
information will be disclosed. After speaking with the parent, questions will be answered about the details 
138 
regarding authorization. 
139 
A participant is considered enrolled when the eConsent has been signed by the parent and the 
140 
investigator. 
141 
The participants are not being asked to provide assent as (1) they will be less than 7 years of age, (2) it is 
142 
not expected that they would have the capacity to understand, and (3) their wear of the devices will be 
143 
similar to the wear of these devices outside of the study. 
144 
2.2 Participant Inclusion Criteria 
145 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate in the 
146 
study: 
147 
1. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least 1 month 
148 
2. Familiarity and use of a carbohydrate ratio for meal boluses 
149 
3. Age ≥2 and <6 years old 
150 
4. Using a Dexcom CGM at the time of enrollment, with use on at least 21 out of the prior 28 days 
151 
5. Living with one or more parent/legal guardian knowledgeable about emergency procedures for severe 
152 
hypoglycemia and able to contact emergency services and study staff 
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6. Parent/guardian has a phone that can run the Tandem t:connect Mobile App (typically Android 10 or 
154 
above or iOS 15 or above) 
155 
7. Willingness to use the t:connect Mobile App as needed during the study and ensure connectivity for a 
156 
data upload at least once per day 
157 
8. Investigator has confidence that the parent can successfully operate all study devices and is capable of 
158 
adhering to the protocol 
159 
9. Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, and to use no other 
160 
insulin besides lispro (Humalog) or aspart (Novolog) during the study for participants using a study-
161 
provided Tandem pump during the study 
162 
10. Total daily insulin dose (TDD) at least 5 U/day 
163 
11. Body weight at least 20 lbs 
164 
12. Willingness not to start any new non-insulin glucose-lowering agent during the course of the trial 
165 
13. Participant and parent(s)/guardian(s) willingness to participate in all training sessions as directed by 
166 
study staff  
167 
14. Parent/guardian proficient in reading and writing English 
168 
15. Live in the United States, with no plans to move outside the United States during the study period 
169 
2.3 Participant Exclusion Criteria 
170 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from study 
171 
participation: 
172 
1. Concurrent use of any non-insulin glucose-lowering agent (including GLP-1 agonists, Symlin, DPP-4 
173 
inhibitors, SGLT-2 inhibitors, sulfonylureas) 
174 
2. Hemophilia or any other bleeding disorder 
175 
3. History of >1 severe hypoglycemic event with seizure or loss of consciousness in the last 3 months 
176 
4. History of >1 DKA event in the last 6 months not related to illness, infusion set failure, or initial 
177 
diagnosis 
178 
5. History of chronic renal disease or currently on hemodialysis 
179 
6. History of adrenal insufficiency 
180 
7. Hypothyroidism that is not adequately treated in the opinion of the investigator 
181 
8. Use of oral or injectable steroids within the last 8 weeks  
182 
9. Known, ongoing adhesive intolerance 
183 
10. Plans to receive blood transfusions or erythropoietin injections during the course of the study 
184 
11. A condition, which in the opinion of the investigator or designee, would put the participant or study at 
185 
risk 
186 
12. Participation in another pharmaceutical or device trial at the time of enrollment or during the study 
187 
13. Having immediate family members employed by Tandem Diabetes Care, Inc. or Dexcom, Inc., or 
188 
having a direct supervisor at place of employment who is also directly involved in conducting the 
189 
clinical trial (as a study investigator, coordinator, etc.); or having a first-degree relative who is directly 
190 
involved in conducting the clinical trial 
191 
2.4 Screening Procedures 
192 
Potential participants will be evaluated for study eligibility through the elicitation of a medical history and 
193 
local laboratory testing as needed in the judgment of the investigator (as part of usual care). 
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The screening visit and subsequent scheduled study visits may be conducted virtually via videoconference 
195 
at the discretion of the study investigator, for example due to institutional restrictions or the participant or 
196 
investigator’s preference for a remote visit. Study staff will discuss the feasibility of conducting virtual 
197 
visits with each participant and provide support as needed to ensure adequate access. All screening 
198 
procedures must be completed within 28 days of participant enrollment (i.e., eConsent). All pump 
199 
initiation visit procedures must be completed within 10 days of completion of screening.  
200 
2.4.1 Data Collection and Testing 
201 
A history will be elicited from the parent and extracted from available medical records with respect to the 
202 
participant’s diabetes history, current diabetes management, other past and current medical problems, past 
203 
and current medications, and drug allergies.   
204 
The following procedures will be performed at the screening visit:  
205 
• 
Informed consent process 
206 
• 
Assessment of eligibility 
207 
• 
Contact information (retained at the clinical center and not entered into study database) 
208 
• 
Demographics (date of birth, sex, race and ethnicity) 
209 
• 
Measurement of height/weight 
210 
o If the visit is conducted virtually, a verbal report of the participant’s weight and verbal 
211 
report of height will be acceptable. A scale will be mailed to participants who do not 
212 
already have access to one. 
213 
• 
Determination of most recent HbA1c level from medical records or verbal report 
214 
Screening procedures will last approximately 1-2 hours. 
215 
2.5 Screen Failures 
216 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later date per 
217 
investigator discretion. They will be asked to complete eConsent again.  
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Chapter 3: Main Phase 
219 
3.1 Visit and Contact Schedule 
220 
Visits and contacts will be scheduled as outlined below: 
221 
Table 4-1. Study Visits 
222 
Target Day/Week 
Contact Type1 
Target/Allowable Window 
(around Target Day/Week) 
3 days 
VC/V 
± 1 day 
1 week 
VC/V 
± 2 days 
2 weeks 
VC/V 
± 2 days 
4 weeks 
VC/V 
± 4 days 
6 weeks 
VC/V 
± 4 days 
8 weeks 
VC/V 
± 4 days 
3-day post-study safety 
contact 
VC/P 
± 1 day 
1 Contact Types are defined as Clinic Visit (V), Videoconference (VC), or Phone call (P); Phone calls may be replaced by 
223 
Videoconferences or Clinic Visits and Videoconferences may be replaced by Clinic Visits at investigator discretion 
224 
 
225 
Additional office visits may occur as needed. 
226 
3.1 Blood Glucose Testing, Ketone Testing, and Glucagon 
227 
Participants will receive supplies, training, and instructions for blood glucose and ketone testing as 
228 
described in section 4.3. 
229 
Participants will be required to have glucagon at home. Participants who currently do not have one will be 
230 
given a prescription for glucagon (either emergency kit or nasal glucagon per investigator discretion for 
231 
participants over 4 years of age). 
232 
3.2 Study Pump Procedures and Training 
233 
The study pump, study CGM, study blood glucose and ketone meters and associated supplies will be 
234 
provided to participants within 3 days of completion of the Screening visit once eligibility to continue in 
235 
the study has been confirmed. Dispensation of supplies may occur either in-person at the clinic, or via 
236 
delivery by other means (personal delivery, overnight shipment, etc.). 
237 
Training on use of the study pump will be completed within 10 days of completion of the Screening visit, 
238 
and closed-loop system use will begin at that time. Pump training may be delivered in one or more 
239 
sessions (in-person or virtual), as needed. During the training window, participants will be permitted to 
240 
use the study CGM and to use the study pump in open-loop mode if desired by the investigator. 
241 
Parents of participants will receive study pump training by a qualified trainer and will be fully instructed 
242 
on the study insulin pump. The trainer will discuss topics such as: infusion site initiation, 
243 
cartridge/priming procedures, setting up the pump, charging the pump, navigation through menus, bolus 
244 
procedures including stopping a bolus, etc. The participating child will participate in training sessions to 
245 
the degree judged appropriate by the parent and trainer. 
246 
 
247 

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Parents will be instructed to change the study insulin pump infusion set at least once every 3 days or per 
248 
manufacturer guidelines, whichever is shorter. 
249 
 
250 
Parents will be trained to use the bolus calculator following the standard t:slim X2 training.  
251 
• 
The study team will assist the parent in study pump infusion site initiation and will start the 
252 
participant on the study pump.  
253 
• 
The parent will be supervised with the study pump during at least one meal or snack bolus to 
254 
ensure participant understanding of the pump features. 
255 
• 
The parent will be encouraged to review the literature provided with the pump and infusion sets 
256 
after the training is completed. 
257 
• 
The parent will be trained on severe hypoglycemia emergency procedures including removal of 
258 
the study pump and administration of glucagon. 
259 
Pump training specific to the Control-IQ Technology functions will include: 
260 
• 
How to turn on and off Control-IQ technology 
261 
• 
How to understand when Control-IQ is increasing or decreasing basal rates 
262 
• 
How to administer a meal or correction boluses 
263 
• 
What to do when exercising while using the system 
264 
• 
How to enable the sleep function and set the sleep schedule 
265 
• 
The parent will be assessed for understanding of the system interface and how to react to 
266 
safety/alert messages. 
267 
The parent will be given a User Guide as a reference. 
268 
3.2.1 Determination of Initial of Pump Settings 
269 
For participants currently using an insulin pump, the study investigator may choose to enter the existing 
270 
daily pump settings profiles directly into the web-based UVA Clinician Portal. 
271 
For participants not currently using an insulin pump or without an established daily pump settings profile, 
272 
initial pump settings will be determined by the study AI algorithm. This will be achieved by study staff 
273 
providing the following information to a web-based UVA Clinician Portal: 
274 
• 
The participant’s personal CGM data from approximately two weeks prior to initiating pump use 
275 
• 
Entering the participant’s average total daily insulin dose 
276 
• 
Body weight 
277 
The recommended pump settings will include daily profile values for basal rate, correction factor, 
278 
carbohydrate ratio, and sleep activity. 
279 
After the recommended settings are provided, they will be reviewed by a study physician. The study 
280 
physician may make necessary adjustments for safety prior to confirming that the values are successfully 
281 
entered into the study pump. Both the AI-recommended and approved settings will be recorded on the 
282 
Clinician Portal. 
283 
Parents will be instructed that any subsequent changes to the pump profile settings related to insulin 
284 
delivery must be discussed with the study team prior to implementation. 
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3.2.2 t:connect Mobile App for Data Upload to Study Server 
286 
The participant/parent will be expected to upload pump and CGM data at least once per day during the 
287 
course of the main phase of the study. This data upload will be achieved using the t:connect Mobile App, 
288 
which will be installed on the participant/parent’s personal phone. Participants/parents will be trained on 
289 
configuring the app to connect to a study-provided t:connect account and ensuring that pump data upload 
290 
to t:connect at least once per day. 
291 
Study data uploaded to the t:connect server will be periodically copied to the database of the study-
292 
specific Clinician Portal to support AI-driven settings adjustments during the course of the study. 
293 
3.2.3 System Use Guidelines 
294 
The participant/parent will be instructed to use the system in closed-loop mode except if insulin is 
295 
delivered by any means other than the study pump (e.g., injection of subcutaneous insulin via syringe in 
296 
the event of infusion site failure). 
297 
If insulin is delivered by any means other than the study pump, the parent will be instructed to turn off 
298 
Control-IQ for approximately four hours and notify study staff. In case of recurring instances of 
299 
exogenous insulin delivery, the study team will determine if there are any safety or study integrity 
300 
concerns to warrant withdrawal of the study participant. 
301 
The parent will also be instructed to contact study staff if the participating child has illness with an 
302 
elevated temperature >100.4 degrees Fahrenheit (>38.0 degrees Celsius), other periods of significant 
303 
illness, significant changes in physical activity level or food intake related to illness, or during periods of 
304 
use of medications such as epinephrine for the emergency treatment of a severe allergic reaction or 
305 
asthma attack, in addition to use of oral or injectable glucocorticoids, to determine if closed-loop use 
306 
should be temporarily discontinued. 
307 
Parents will be provided with sufficient supplies to last until the subsequent visit. 
308 
Parents will be provided with contact information and will be asked to call the study clinical staff for any 
309 
health-related issues and for technical issues with the system. Participants may use the study pump 
310 
without Control-IQ activated and study CGM during periods of component disconnections or technical 
311 
difficulties. Parents will also receive study staff contact information to ask any questions they may have 
312 
during the study. 
313 
Study staff will discuss with the parent that routine contact is required and will make arrangements with 
314 
the parent for the contacts. If the parent cannot be reached, the participant’s other contact methods will be 
315 
utilized, including the emergency contact. Parents who are not compliant with the arranged contacts on 
316 
two separate occasions may be discontinued at the discretion of the investigator.  
317 
Upon completion of the CGM and study pump training components, study staff will document, using a 
318 
checklist, that the parent is familiar with the functions/features/tasks addressed during the training. 
319 
Parents will be provided Hypoglycemia, Hyperglycemia and Ketone Guidelines (section 4.3) for when 
320 
their glucose levels are >300 mg/dL for more than 90 minutes or >400 mg/dL at any time or <70 mg/dL 
321 
or ketones ≥1.0 mmol/L. 
322 
Parents will be instructed that any changes to the pump profile settings related to insulin delivery must be 
323 
discussed with the study team prior to implementation. 
324 
3.2.4 Home Use of the Study System 
325 
After training on the study system has been completed, participants will proceed with home use (meaning 
326 
free-living use at school, home, etc.) of the study pump. 
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Parents may use available manufacturer-provided software and features of the study CGM related to 
328 
mobile data access or remote monitoring but will be instructed not to use any third-party components for 
329 
this purpose. 
330 
3.2.5 Study Device Download 
331 
Parents will be instructed to upload the study CGM and pump prior to each phone or videoconference 
332 
contact throughout the study. 
333 
3.2.6 Baseline HbA1c Determination 
334 
A capillary blood sample will be obtained for baseline HbA1c determination. Capillary collection supplies 
335 
will be provided to the participant in conjunction with the study pump training visit. This may occur either 
336 
in-person at the clinic, or via delivery by other means (personal delivery, overnight shipment, etc.).   
337 
3.3 Study Visits 
338 
3.3.1 3-Day Visit 
339 
Study staff will perform an in-clinic visit or videoconference with the parent within 3 (±1) days following 
340 
initiation of study pump use. The following will occur: 
341 
• 
Assessment of compliance with study device use by review of any available device data 
342 
• 
Assessment of adverse events, adverse device effects, and device issues 
343 
• 
Study staff will answer any questions related to device use  
344 
• 
Study staff will use the Clinician Portal to obtain updated pump settings to apply to the study 
345 
pump. As described above, the settings will be reviewed by a study physician prior to being 
346 
entered on the study pump. 
347 
3.3.2 Subsequent Scheduled Study Visits 
348 
The remaining scheduled study visits at 1, 2, 4, 6, and 8 weeks will occur either in-clinic or via 
349 
videoconference in accordance with the schedule and windows shown in Table 4-1 above. 
350 
Procedures for the scheduled visits will be identical to those described for the 3-Day Visit in section 3.3.1 
351 
above—including AI-driven pump settings adjustment—with the following visit-specific variations: 
352 
• 
8 Week visit: 
353 
o There will be no AI-driven study pump settings adjustment, and participants will be 
354 
switched to the post-study insulin pump or MDI therapy that is desired by the 
355 
participant’s parent/legal guardian. 
356 
 
For participants who were on MDI at study enrollment, the possibility of 
357 
switching to a commercially-available insulin pump after study completion 
358 
should be discussed within the first 1-2 weeks of study pump use, to allow time 
359 
for planning any required insurance- or prescription-related activities. The 
360 
primary diabetes care team (outside of the study period) should be involved in 
361 
this process.  
362 
o Study participants will return study devices as specified in section 4.4 below. 
363 

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3.3.3 3-Day Post-Study Safety Contact 
364 
Study staff will perform a phone call or videoconference with the parent within 3 (±1) days following the 
365 
8-week final visit. This visit may also be conducted in person at the clinical site. The following will 
366 
occur: 
367 
• 
Assessment of adverse events, adverse device effects, and device issues 
368 
• 
Confirmation that participant has successfully transitioned to the desired post-study insulin 
369 
therapy 
370 
3.3.4 Unscheduled Visits 
371 
Participants may have unscheduled visits during the study period if required for additional device training 
372 
or other unanticipated needs per the study investigator discretion. 
373 
During an unscheduled visit, the study investigator may elect to request an off-cycle optimization of pump 
374 
settings from the UVA Clinician Portal and update the participant’s pump settings accordingly. 
375 
 
376 

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Chapter 4: Study Devices 
377 
4.1 Description of the Investigational Device 
378 
The investigational components of the device system are the UVA Clinical Portal and insulin pump 
379 
described below. The hardware components described in section 4.2 are all individually FDA-approved or 
380 
-cleared commercial devices. 
381 
4.1.1 UVA Clinician Portal 
382 
The UVA Clinician Portal is an investigational software system that includes a front-end web site for 
383 
monitoring participant data and determining AI-recommended pump settings and back-end logic 
384 
responsible for suggesting pump settings based on data previously collected for the participant. Data from 
385 
t:connect are automatically transferred to the Portal on a recurring basis every few hours. 
386 
4.1.2 Insulin Pump 
387 
The study system will include an unmodified Tandem t:slim X2 with Control-IQ technology. This is an 
388 
FDA-approved device for ages 6 and older but is not approved for younger children at the time of this 
389 
protocol version. There are no changes to its hardware or firmware components. These study pumps will 
390 
be labeled as investigational devices.  
391 
4.2 Components of the Investigational Device System 
392 
4.2.1 Continuous Glucose Monitoring 
393 
The study CGM will include an unmodified Dexcom G6 or G7 transmitter and sensors. This is an FDA-
394 
approved device system for children as young as 2 years of age, with no changes to its hardware or 
395 
firmware components. The CGM sensor will be replaced at least once every ten days. Participants will be 
396 
permitted to switch between G6 and G7 components during the study if needed. 
397 
4.2.2 Phone Running t:connect Mobile App 
398 
Study data upload from pump and CGM will be achieved using the t:connect Mobile App, which will be 
399 
installed on the parent/participant’s personal phone during the study. This is a commercially-available, 
400 
FDA-cleared software app with no modifications. 
401 
4.2.3 Blood Glucose Meter and Strips 
402 
Blood glucose levels will be measured using the CONTOUR Next One meter and strips in accordance 
403 
with the manufacturer’s labeling. 
404 
4.2.3.1 Blood Glucose Meter Testing 
405 
• 
All study blood glucose meters will be QC tested with control solution prior to dispensation. A 
406 
tested meter will not be used in a study if it does not read within the target range at each 
407 
concentration per manufacturer labeling. The participant will be instructed to contact study staff 
408 
for a replacement of the meter and test strips if there is a suspicion that the meter is not reading 
409 
accurately at home. 
410 
• 
Participants will be instructed on when and how to perform blood glucose testing. 
411 
• 
Participants will be reminded to use the study blood glucose meter for all fingerstick blood 
412 
glucose measurements. 
413 

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• 
Participants will be given guidelines for treatment of low or high blood glucose 
414 
4.2.4 Ketone Meter and Strips 
415 
Blood ketone levels will be measured using the Abbott Precision Xtra meter and strips in accordance with 
416 
the manufacturer’s labeling. The blood glucose meter component of the Precision Xtra device will not be 
417 
used. 
418 
4.2.4.1 Blood Ketone Testing 
419 
• 
All study blood ketone meters will be QC tested with control solution prior to dispensation. A 
420 
tested meter will not be used in a study if it does not read within the target range at each 
421 
concentration per manufacturer labeling. The participant will be instructed to contact study staff 
422 
for a replacement of the meter and test strips if there is a suspicion that the meter is not reading 
423 
accurately at home. 
424 
• 
Participants will be instructed on when and how to perform blood ketone testing. 
425 
• 
Participants will be reminded to use the study blood ketone meter for all fingerstick blood ketone 
426 
measurements. 
427 
• 
Participants will be given guidelines for treatment of elevated blood ketones. 
428 
4.2.5 Study Device Accountability Procedures 
429 
Device accountability procedures will be detailed in the site procedures manual. 
430 
4.3 Safety Measures 
431 
4.3.1 CGM Calibration 
432 
Throughout the study, participants will be instructed to calibrate the study CGM in accordance with 
433 
manufacturer labelling. 
434 
4.3.2 Pump Failure 
435 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, Control-IQ or closed loop 
436 
will not operate to automatically adjust insulin. If the CGM is not connected, the system will revert to usual 
437 
function of the pump and deliver insulin with the insulin dosing parameters programmed in the system for 
438 
that individual. Resumption of closed-loop will occur automatically once CGM signal is available again. 
439 
If the study system is unable to activate Control-IQ for any reason, the pump will automatically revert to 
440 
preprogrammed basal insulin delivery without any need for instruction from the user. 
441 
If the pump detects a system error that does not allow it to operate, the Malfunction Alarm will display and 
442 
the participant will be instructed to contact Tandem Technical Support via the study team. 
443 
4.3.3 Hypoglycemia Threshold Alarm and Safety Protocol 
444 
During the course of the study, participants will be permitted to change the CGM low glucose threshold 
445 
alert setting on their device or mobile app, but will be instructed to choose a value no less than 70 mg/dL. 
446 
The t:slim X2 with Control-IQ system will issue a predictive hypoglycemia alert (Control-IQ Low Alert) 
447 
when the system predicts BG <70 mg/dL within the next 15 minutes (<80 mg/dL when exercise mode is 
448 
activated). 
449 

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If the participant receives a Control-IQ Low Alert, a message appears on the user interface (UI) that is 
450 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user in 5 
451 
minutes. This alert remains on the screen until acknowledged by the user. The user is prompted to test blood 
452 
sugar and treat with carbs. 
453 
4.3.4 Hyperglycemia Threshold Alarm and Safety Protocol 
454 
During the course of the study, participants will be permitted to change this setting, but will be instructed 
455 
to choose a value no greater than 300 mg/dL. 
456 
If a participant receives a CGM hyperglycemia threshold alarm or notes that the CGM glucose is above 
457 
the hyperglycemia threshold alarm value, confirmatory fingerstick testing will be performed if required 
458 
by CGM labelling. 
459 
If a participant’s CGM reading is >300 mg/dL for over 90 minutes or ≥400 mg/dL at any point, or if 
460 
CGM reading is >250 mg/dL more than 3 hours after a meal, the participant took correction insulin, and 
461 
CGM didn’t decrease by at least 50 mg/dL, the participant will be instructed to take the following steps: 
462 
• 
Inspect infusion site for problems. 
463 
• 
Perform a blood glucose meter check. 
464 
• 
If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
465 
• 
If the ketone level is ≥1.0 mmol /L, contact study staff for further instructions, which may include 
466 
replacing the insulin infusion set. 
467 
• 
If a participant administers correction insulin via insulin syringe, participants will be instructed to 
468 
turn Control-IQ off for approximately four hours and notify the study team. 
469 
4.4 Participant Access to Study Device at Study Closure 
470 
Participants will return all insulin pump, CGM, and related supplies at their final visit. Participant may 
471 
keep the study ketone meter and study glucometer and test strips if all study data have been downloaded 
472 
and these devices are not marked for investigational use only. 
473 

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Chapter 5: Testing Procedures 
474 
5.1 Laboratory Testing 
475 
1. HbA1c: 
476 
• 
Sample collected within 3 days of closed-loop initiation.  
477 
• 
Blood samples will be sent to the central laboratory for sample analysis using an NGSP 
478 
approved method. 
479 

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Chapter 6: Unanticipated Problem, Adverse Event, and 
480 
Device Issue Reporting 
481 
6.1 Unanticipated Problems 
482 
Site investigators will promptly report all potential unanticipated problems meeting the criteria below on 
483 
an eCRF. Sites overseen by the JCHR IRB must report Unanticipated Problems to the IRB within seven 
484 
(7) calendar days of recognition. For this protocol, an unanticipated problem is an incident, experience, or 
485 
outcome that meets all of the following criteria: 
486 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
487 
described in the protocol related documents, such as the IRB-approved research protocol and 
488 
informed consent document; and (b) the characteristics of the subject population being studied 
489 
• 
Related or possibly related to participation in the research (possibly related means there is a 
490 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
491 
procedures involved in the research) 
492 
• 
Suggests that the research places participants or others at a greater risk of harm than was 
493 
previously known or recognized (including physical, psychological, economic, or social harm) 
494 
The Sponsor also will report to the IRB all potential unanticipated problems not directly involving a 
495 
specific site such as unanticipated problems that occur study-wide or at another participating entity such 
496 
as a vendor. These instances must be reported to the JCHR IRB within seven (7) calendar days of 
497 
recognition. The Director of the JCHR Human Research Protection Program (HRPP) will report to the 
498 
appropriate regulatory authorities if the IRB determines that the event indeed meets the criteria of an 
499 
Unanticipated Problem requiring additional reporting to fulfill the reporting obligations of the HRPP. 
500 
6.2 Adverse Events 
501 
6.2.1 Definitions 
502 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) associated with 
503 
study procedures, the use of a device, biologic, or drug in humans, including any comparator used, 
504 
whether or not the event is considered related (i.e., irrespective of the relationship between the adverse 
505 
event and the device(s) under investigation). 
506 
To further clarify, an adverse event is any unintended disease or injury, or untoward clinically significant 
507 
clinical sign (including abnormal laboratory findings) in a research participant that manifests while in the 
508 
study if it was not present before enrolling in the study, or if it was present before enrolling, it has 
509 
increased in severity, frequency or type since enrolling in the study. For this purpose, a participant is 
510 
considered enrolled once the participant has signed the consent form. Reportable AEs for this protocol are 
511 
defined in section 6.2.2. 
512 
Serious Adverse Event (SAE): Any untoward medical occurrence that results in any of the following 
513 
outcomes: 
514 
• 
Death. 
515 
• 
A life-threatening adverse event; (a non-life-threatening event which, had it been more severe, 
516 
might have become life-threatening, is not necessarily considered a serious adverse event). 
517 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
518 
• 
A persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
519 
normal life functions. 
520 

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• 
A congenital anomaly or birth defect. 
521 
An important medical event that may not result in death, be life-threatening, or require hospitalization 
522 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
523 
patient or subject and may require medical and surgical intervention to prevent one of the outcomes listed 
524 
in this definition. Note: If either the Sponsor or investigator believes that the event is serious, the event 
525 
must be considered serious and evaluated by the Sponsor for expedited reporting. See 21 CFR 312 for 
526 
more information. 
527 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any life-
528 
threatening problem or death caused by, or associated with a device, if that effect, problem, or death was 
529 
not previously identified in nature, severity, or degree of incidence in the investigational plan or 
530 
application (including a supplementary plan or application), or any other unanticipated serious problem 
531 
associated with a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
532 
Adverse Device Effect (ADE): An adverse event related to the use of an investigational medical device. 
533 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
534 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
535 
device. This definition includes any event resulting from use error or from intentional misuse of the 
536 
investigational medical device. This includes comparator if the comparator is a medical device. (Note 
537 
that an Adverse Event CRF is to be completed in addition to a Device Deficiency or Issue CRF, unless 
538 
excluded from reporting as defined in section 6.3). 
539 
Comparator: Medical device, therapy (e.g., active treatment, normal clinical practice), placebo or no 
540 
treatment, used in the control group in a clinical investigation. (ISO 14155:2020) 
541 
Device Complaints and Malfunctions: A device complication or complaint is something that happens to a 
542 
device or related to device performance, whereas an adverse event happens to a participant. A device 
543 
complaint may occur independently from an AE, or along with an AE. An AE may occur without a device 
544 
complaint or there may be an AE related to a device complaint. A device malfunction is any failure of a 
545 
device to meet its performance specifications or otherwise perform as intended. Performance 
546 
specifications include all claims made in the labeling for the device. For cleared devices, the intended 
547 
performance of a device refers to the intended use for which the device is labeled or marketed (21 CFR 
548 
803.3). Note: for reporting purposes, sites will not be asked to distinguish between device complaints and 
549 
malfunctions. 
550 
Use Error: User action or lack of user action while using the medical device that leads to a different result 
551 
than that intended by the manufacturer or expected by the user. Includes the inability of the user to 
552 
complete a task. Use errors can result from a mismatch between the characteristics of the user, user 
553 
interface, task or use environment. Users might be aware or unaware that a use error has occurred. An 
554 
unexpected physiological response of the patient is not by itself considered a use error. A malfunction of a 
555 
medical device that causes an unexpected result is not considered a use error. (ISO 14155:2020) 
556 
6.2.2 Reportable Adverse Events 
557 
For this protocol, a reportable adverse event includes any untoward medical occurrence that meets one of 
558 
the following criteria: 
559 
1. An SAE as defined in section 6.2.1 
560 
2. An ADE, unless excluded from reporting in section 6.3 
561 
3. An AE as defined in section 6.2.1 occurring in association with a study procedure 
562 
4. An AE as defined in which leads to temporary or permanent discontinuation of a study device 
563 

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5. An AE as defined in section 6.2.1 that affects the participant’s ability to complete any study 
564 
procedures 
565 
6. An AE as defined in section 6.2.1 for which a visit is made to a hospital emergency department   
566 
7. Hypoglycemia meeting the reporting criteria in section 6.2.3 
567 
8. Hyperglycemia meeting the reporting criteria in section 6.2.4 
568 
9. An AE as defined in section 6.2.1 considered to be related to either ineffective insulin (e.g., 
569 
insulin exposed to high temperature that loses potency), signs or symptoms related to insulin 
570 
infusion, or changing of type of insulin related to an AE. 
571 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse events. 
572 
Skin reactions from sensor placement are only reportable if severe and/or required treatment. 
573 
All reportable AEs—whether volunteered by the participant, discovered by study personnel during 
574 
questioning, or detected through physical examination, laboratory test, or other means—will be reported 
575 
on an AE CRF online. Each AE CRF is reviewed by the Medical Monitor to assess safety and to verify 
576 
the coding and the reporting that is required. 
577 
6.2.3 Hypoglycemic Events 
578 
Hypoglycemia is only reportable as an adverse event when one of the following criteria is met: 
579 
• 
A hypoglycemic event occurred meeting the following definition of severe hypoglycemia:  the 
580 
event required assistance of another person due to altered consciousness, and required another 
581 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. This means 
582 
that the participant was impaired cognitively to the point that he/she was unable to treat 
583 
himself/herself, was unable to verbalize his/ her needs, was incoherent, disoriented, and/or 
584 
combative, or experienced seizure or loss of consciousness. These episodes may be associated 
585 
with sufficient neuroglycopenia to induce seizure or loss of consciousness. If glucose 
586 
measurements are not available during such an event, neurological recovery attributable to the 
587 
restoration of glucose to normal is considered sufficient evidence that the event was induced by a 
588 
low glucose concentration. 
589 
• 
Evaluation or treatment was obtained at a health care provider facility for an acute event 
590 
involving hypoglycemia, or the participant contacted the site and received guidance  following 
591 
the occurrence of an acute event involving hypoglycemia 
592 
• 
Hypoglycemia occurred that was associated with an ADE as defined in section 6.2.1  
593 
• 
Study device discontinued due to hypoglycemia 
594 
When a severe hypoglycemia event occurs (as defined above), a Hypoglycemia CRF should be completed 
595 
in addition to the Adverse Event CRF. Severe hypoglycemia events should be considered serious adverse 
596 
events with respect to reporting requirements. When a severe hypoglycemia event occurs during use of a 
597 
study device, it generally will be considered unrelated to the device (per section 6.2.1) if the device 
598 
functioned as intended and there does not appear to be a flaw in how the device is intended to function. 
599 
6.2.4 Hyperglycemic/Ketotic Events 
600 
Hyperglycemia or ketosis is only reportable as an adverse event when one of the following criteria is met: 
601 
• 
evaluation or treatment was obtained at a health care provider facility for an acute event involving 
602 
hyperglycemia or ketosis, or the participant contacted the site and received guidance on how to 
603 
manage the hyperglycemia/ketosis 
604 

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• 
the event involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) and 
605 
described below 
606 
o Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
607 
o Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
608 
o Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate (or CO2) <15; and 
609 
o Treatment provided in a health care facility 
610 
• 
Hyperglycemia occurred that was associated with an ADE as defined in section 6.2.1 
611 
• 
Study device discontinued due to hyperglycemia 
612 
When a hyperglycemia/ketotic event qualifies as an SAE as defined in section 6.2.1, a 
613 
Hyperglycemia/DKA CRF should be completed in addition to the Adverse Event CRF. Events meeting 
614 
DKA criteria should be considered serious adverse events with respect to reporting requirements. 
615 
Hyperglycemia events not meeting criteria  for DKA generally will not be considered serious adverse 
616 
events unless one of the SAE criteria in section 6.2.1 is met. 
617 
When a hyperglycemia/DKA event occurs during use of a study device, it generally will be considered 
618 
unrelated to the device (per section 6.2.1) if the device functioned as intended and there does not appear 
619 
to be a flaw in how the device is intended to function. 
620 
6.2.5 Relationship of Adverse Event to Study Device or Study Procedure 
621 
The site investigator will assess the relationship of any adverse event to be related or unrelated by 
622 
determining if there is a reasonable possibility that the adverse event may have been caused by the study 
623 
device or a study procedure. The Medical Monitor also will make this assessment, which may or may not 
624 
agree with that of the site investigator. Reporting requirements will be based on the Medical Monitor’s 
625 
assessment as the Sponsor’s representative. 
626 
To ensure consistency of adverse event causality assessments, investigators should apply the following 
627 
general guideline when determining whether an adverse event is related: 
628 
• 
Unrelated: The AE is clearly not related to a study device/procedure and a likely alternative 
629 
etiology exists such as an underlying disease, environmental or toxic factors or other therapy. 
630 
• 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after use of 
631 
study device/procedure and a more likely alternative etiology exists such as an underlying 
632 
disease, environmental or toxic factors, or other therapy.  
633 
• 
Possibly Related: The AE occurred in a reasonable time during or after use of study device or a 
634 
study procedure; but could be related to another factor such as an underlying disease, 
635 
environmental or toxic factors, or other therapy; and there is a possible, though weak, scientific 
636 
basis for establishing a causal association between the AE and the study device. 
637 
• 
Probably Related: The AE occurred in a reasonable time during or after use of study device or a 
638 
study procedure; is unlikely to be related to another factor such as an underlying disease, 
639 
environmental or toxic factors, or other therapy; and there is a plausible, though not strong, 
640 
scientific basis for establishing a causal association between the AE and the study device.  
641 
• 
Definitely Related: The AE occurred in a reasonable time during or after use of study device or a 
642 
study procedure; cannot be explained by another factor such as an underlying disease, 
643 
environmental or toxic factors, or therapy; and there is a strong scientific basis for establishing a 
644 
causal association between the AE and the study device. 
645 

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Events determined to be Possibly Related, Probably Related, or Definitely Related will be considered to 
646 
meet the reasonable possibility causality standard for relatedness and necessitate reporting as required 
647 
(see 21 CFR 312.32 for more information).  
648 
6.2.6 Severity (Intensity) of Adverse Events 
649 
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, or 
650 
(3) severe. A severity assessment is a clinical determination of the intensity of an event. Thus, a severe 
651 
adverse event is not necessarily serious. For example, itching for several days may be rated as severe, but 
652 
may not be clinically serious. 
653 
• 
MILD: Usually transient, requires no special treatment, and does not interfere with the 
654 
participant’s daily activities. 
655 
• 
MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
656 
participant and may interfere with daily activities, but is usually ameliorated by simple 
657 
therapeutic measures and participant is able to continue in study. 
658 
• 
SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may cause 
659 
discontinuation of study device, and generally requires systemic drug therapy or other treatment. 
660 
6.2.7 Expectedness 
661 
For a serious adverse event that is considered possibly related to study device/procedure, the Medical 
662 
Monitor will classify the event as unexpected if the nature, severity, or frequency of the event is not 
663 
consistent with the risk information previously described in the approved labelling of the Control-IQ 
664 
study pump. 
665 
6.2.8 Coding of Adverse Events 
666 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will enter a 
667 
preliminary MedDRA code which the Medical Monitor may accept or change (the Medical Monitor’s 
668 
MedDRA coding will be used for all reporting). The Medical Monitor will review the investigator’s 
669 
assessment of causality and may agree or disagree. Both the investigator’s and Medical Monitor’s 
670 
assessments will be recorded. The Medical Monitor will have the final say in determining the causality as 
671 
well as whether an event is classified as a serious adverse event and/or an unanticipated adverse device 
672 
effect. 
673 
6.2.9 Outcome of Adverse Events 
674 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
675 
• 
RECOVERED/RESOLVED (COMPLETE RECOVERY) – The participant recovered from the 
676 
AE/SAE without sequelae. Record the AE/SAE stop date. 
677 
• 
RECOVERED/RESOLVED WITH SEQUELAE – AE/SAE where the subject recuperated but 
678 
retained pathological conditions resulting from the prior disease or injury.. Record the 
679 
AE/SAE stop date. 
680 
• 
FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that was 
681 
the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time of death; 
682 
however, were not the cause of death, will be recorded as “resolved” at the time of death. 
683 
• 
ONGOING (NOT RECOVERED/NOT RESOLVED) – An ongoing AE/SAE is defined as an 
684 
ongoing event with an undetermined outcome. 
685 

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 
An ongoing outcome will require follow-up by the site in order to determine the final 
686 
outcome of the AE/SAE. 
687 
 
The outcome of an ongoing event at the time of death that was not the cause of death, will be 
688 
updated and recorded as “resolved” with the date of death recorded as the stop date. 
689 
• 
ONGOING (MEDICALLY STABLE) – AE/SAE is ongoing, but medically stable. For example, 
690 
a chronic condition where no further change is expected. 
691 
If any reported adverse events are ongoing when a participant completes the study (or withdraws), 
692 
adverse events classified as UADEs or related SAEs will be followed until they are either resolved, or 
693 
have no prospect of improvement or change, even after the participant has completed all applicable study 
694 
visits/contacts. For all other adverse events, data collection will end at the time the participant completes 
695 
the study. Note: participants should continue to receive appropriate medical care for an adverse event 
696 
after their participation in the study ends. 
697 
If a participant is lost to follow up and participant outcome cannot be determined, outcome classification 
698 
will be the last known outcome. 
699 
6.3 Reportable Device Issues 
700 
All UADEs and ADEs as defined in section 6.2.1 will be reported on both a Device Issue CRF and AE 
701 
CRF, except for skin reactions from CGM sensor placement or pump infusion set placement that do not 
702 
require pharmacologic treatment. 
703 
Device complaints and device malfunctions will be reported except in the following circumstances. These 
704 
occurrences are expected and will not be reported on a Device Issue CRF assuming criteria for a UADE 
705 
or ADE have not been met: 
706 
• 
CGM sensor lasting fewer days than expected per manufacturer 
707 
• 
CGM tape adherence issues 
708 
• 
Pump infusion set insertion lasting fewer days than expected per manufacturer  
709 
• 
Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
710 
• 
Intermittent device component disconnections/communication failures not requiring system 
711 
replacement or workaround/resolution not specified in user guide/manual. 
712 
• 
Device issues clearly addressed in the user guide manual that do not require additional 
713 
troubleshooting 
714 
Use error (as defined above) will only be reported on a device issue form if an Adverse Event results from 
715 
the error. In these cases, both a Device Issue and an Adverse Event form will be completed. 
716 
6.4 Timing of Event Reporting 
717 
SAEs possibly related to a study device or procedure and UADEs must be reported by the investigator to 
718 
the Sponsor within twenty-four (24) hours of the site becoming aware of the event. This can occur via 
719 
phone or email, or by completion of the AE CRF and Device Issue CRF if applicable. If the AE CRF is 
720 
not initially completed, it should be completed as soon as possible after there is sufficient information to 
721 
evaluate the event. All other reportable ADEs and other reportable AEs should be submitted by 
722 
completion on the respective CRF within seven (7) days of the site becoming aware of the event.  
723 
The Sponsor will notify all participating investigators of any adverse event that is serious, related, and 
724 
unexpected. Notification will be made within ten (10) working days after the Sponsor becomes aware of 
725 
the event. 
726 

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Each site principal investigator is responsible for reporting serious study-related adverse events and 
727 
abiding by any other reporting requirements specific to his/her Institutional Review Board or Ethics 
728 
Committee. Where the JCHR IRB is the overseeing IRB, sites must report all serious, related adverse 
729 
events within seven calendar days. 
730 
Upon receipt of a qualifying event, the Sponsor will investigate the event to determine if a UADE has 
731 
occurred, and if indicated, report the results of the investigation to all overseeing IRBs, and the FDA 
732 
within ten (10) working days of the Sponsor becoming aware of the UADE per 21CFR 812.46(b) (2). The 
733 
Sponsor in conjunction with the Medical Monitor must determine if the UADE presents an unreasonable 
734 
risk to participants. If so, the Sponsor must ensure that all investigations, or parts of investigations 
735 
presenting that risk, are terminated as soon as possible but no later than five (5) working days after the 
736 
Sponsor  makes this determination and no later than fifteen (15) working days after first receipt notice of 
737 
the UADE. The investigator(s) may then be required to provide approval or acknowledgment of receipt of 
738 
that notification, and must submit to their overseeing IRB as required.  
739 
The investigators are also required to report, without unjustified delay, all reportable device deficiencies 
740 
that could have led to a UADE, including device deficiencies, irrespective of whether an adverse event 
741 
occurred. 
742 
6.5 Safety Oversight 
743 
The study Medical Monitor will review all adverse events and adverse device events that are reported 
744 
during the study. SAEs typically will be reviewed within twenty-four (24) hours of reporting. Other AEs 
745 
typically will be reviewed on a weekly basis. Additionally, the Medical Monitor will review compiled 
746 
safety data at periodic intervals (generally timed to the review of compiled safety data by the DSMB). 
747 
The Protocol Chair/Coordinating Investigator will be informed of all cases of severe hypoglycemia and 
748 
DKA and the Medical Monitor’s assessment of relationship to the study device; and informed of all 
749 
reported device issues. 
750 
A Data and Safety Monitoring Board (DSMB) will be informed of all cases of severe hypoglycemia and 
751 
diabetic ketoacidosis irrespective of device relationship, all device-related SAEs, and all UADEs at the 
752 
time that they occur during the study and will review compiled safety data at periodic intervals. The 
753 
DSMB also will be informed of any ADEs not meeting criteria for a UADE if the Medical Monitor 
754 
requests the DSMB review. The DSMB can request modifications to the study protocol or suspension or 
755 
outright stoppage of the study if deemed necessary based on the totality of safety data available. Details 
756 
regarding DSMB review will be documented in a separate DSMB document. 
757 
6.6 Stopping Criteria 
758 
6.6.1 Participant Discontinuation of Study Device 
759 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA event (or a 
760 
malfunction that could have led to severe hypoglycemia or DKA), use of the study device will be 
761 
suspended while the problem is diagnosed. The UADE will be reported to the IRB, DSMB, and FDA. 
762 
After assessment of the problem and any correction, use of the study device will not be restarted until 
763 
approval is received from the IRB, DSMB, and FDA. 
764 
In the absence of a device malfunction, use of the study device by a participant will be discontinued if any 
765 
of the following occur and the participant will be withdrawn from the study:  
766 
• 
The investigator believes it is unsafe for the participant to continue on the intervention. This could 
767 
be due to the development of a new medical condition or worsening of an existing condition; or 
768 
participant behavior contrary to the indications for use of the device that imposes on the 
769 
participant’s safety 
770 

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• 
The participant requests that the treatment be stopped 
771 
• 
Two distinct episodes of DKA as defined in section 6.2.4 
772 
• 
Two distinct severe hypoglycemia events as defined in section 6.2.3 
773 
• 
One episode of DKA as defined in section 6.2.4 and one severe hypoglycemia event as defined in 
774 
section 6.2.3 
775 
Each DKA or severe hypoglycemia event will be reviewed by the Medical Monitor and by the DSMB 
776 
with respect to determination of cause and whether the occurrence of the event can be attributed to use of 
777 
the study device.  
778 
An additional requirement for continued study device use following a single DKA or severe 
779 
hypoglycemia event will be that the site investigator believes that the event is unlikely to recur and that it 
780 
is safe for the participant to continue to use the system. Additionally, if either the Medical Monitor or 
781 
DSMB determines that the occurrence of the event indicates that it is not safe for the participant to 
782 
continue to use the study device, use will be discontinued. 
783 
Even if the study device system is discontinued, the participant will be encouraged to remain in the study 
784 
through the final study visit. 
785 
6.6.2 Criteria for Suspending or Stopping Overall Study 
786 
In addition to the suspension of device use due to a UADE as described in section 6.2.1, study activities 
787 
could be similarly suspended if the Medical Monitor deems suspension of study activities or stoppage of 
788 
the study necessary based on the totality of safety data available or if the manufacturer of any constituent 
789 
study device requires stoppage of device use for safety reasons (e.g., product recall). The affected study 
790 
activities may resume if the underlying problem can be corrected by a protocol or system modification 
791 
that will not invalidate the results obtained prior to suspension. 
792 

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Chapter 7: Miscellaneous Considerations 
793 
7.1 Drugs Used as Part of the Protocol 
794 
Participants will use standard care lispro or aspart rapid-acting insulin prescribed by their personal 
795 
physician. 
796 
7.2 Collection of Medical Conditions and Medications 
797 
Pre-Existing Condition: Any medical condition that is either present at screening, a chronic disease, or a 
798 
prior condition that could impact the participant’s health during the course of the study (e.g., prior 
799 
myocardial infarction or stroke). 
800 
Medical Conditions During the Study: In addition to conditions meeting the reporting requirements for an 
801 
adverse event or device issue as described above, the following medical conditions should also be 
802 
reported: (1) new diagnosis of a chronic disease (i.e., not present at the time of enrollment), (2) worsening 
803 
of an existing condition, and (3) any medical condition that could affect the participant’s ability to carry 
804 
out any aspect of the protocol or could affect an outcome assessment. 
805 
Medications: All medication for the treatment of chronic pre-existing conditions, medical conditions 
806 
(including medical conditions that do not require recording), and/or adverse events that the participant is 
807 
currently taking at screening and during the course of the study should be recorded. Nutraceuticals and 
808 
preventative treatment also should be recorded. Medications only taken as needed either can be recorded 
809 
when prescribed or only recorded if used during the study. Glucagon for treatment of severe 
810 
hypoglycemia will only be recorded if used during the study. 
811 
7.3 Prohibited Medications, Devices, Treatments, and Procedures 
812 
Participants using an insulin not approved for the study pump at the time of enrollment will be asked to 
813 
contact their personal physician to change their prescribed personal insulin to lispro or aspart for the 
814 
duration of the trial. 
815 
Treatment with any non-insulin glucose-lowering agent (including GLP-1 agonists, Symlin, DPP-4 
816 
inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas and naturaceuticals) will not be permitted. 
817 
The body-worn study devices (t:slim X2 insulin pump, study CGM systems) must be removed before 
818 
Magnetic Resonance Imaging (MRI), Computed Tomography (CT) or diathermy treatment. Participants 
819 
may continue in the trial after temporarily discontinuing use if requiring one of the treatments above. 
820 
7.4 Precautionary Medications, Treatments, and Procedures 
821 
Not applicable. 
822 
7.5 Prophylactic Medications, Treatments, and Procedures 
823 
Not applicable. 
824 
7.6 Rescue Medications, Treatments, and Procedures 
825 
All participants will be required to have a commercially available standard care glucagon (or glucagon 
826 
analog) preparation for treatment as needed of severe hypoglycemia. 
827 
7.7 Participant Compensation 
828 
Participant compensation will be specified in the informed consent form. 
829 

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7.8 Participant Withdrawal 
830 
Participation in the study is voluntary, and a participant may withdraw at any time. For participants who 
831 
withdraw, their data will be used up until the time of withdrawal. 
832 
7.9 Confidentiality 
833 
For security and confidentiality purposes, participants will be assigned an identifier that will be used 
834 
instead of their name. Protected health information gathered for this study will be shared with the 
835 
coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified participant 
836 
information may also be provided to research sites involved in the study. 
837 

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Chapter 8: Statistical Considerations 
838 
8.1 Statistical and Analytical Plans 
839 
The approach to statistical analysis is summarized below. A detailed statistical analysis plan (SAP) will 
840 
be written and finalized prior to the start of the study. 
841 
8.2 Statistical Hypotheses 
842 
The primary outcomes for this study are safety outcomes: hypoglycemia and hyperglycemia measured by 
843 
adverse events and CGM. Statistical hypotheses are stated for the CGM-measured outcomes only. 
844 
CGM-measured percentage below 54 mg/dL and CGM-measured percentage above 250 mg/dL will be 
845 
tested for non-inferiority over an 8-week period.  
846 
The null/alternative hypotheses are: 
847 
Percentage below 54 mg/dL: 
848 
a. Null Hypothesis: The difference in mean CGM-measured % below 54 mg/dL between the 8 
849 
weeks follow-up and baseline is greater than or equal to +0.5% (non-inferiority). 
850 
b. Alternative Hypothesis: The difference in mean CGM-measured % below 54 mg/dL between the 
851 
8 weeks follow-up and baseline is less than +0.5%. 
852 
Percentage above 250 mg/dL: 
853 
a. Null Hypothesis: The difference in mean CGM-measured % above 250 mg/dL between the 8 
854 
weeks follow-up and baseline is greater than or equal to +3% (non-inferiority). 
855 
b. Alternative Hypothesis: The difference in mean CGM-measured % above 250 mg/dL between the 
856 
8 weeks follow-up and baseline is less than +3%. 
857 
8.3 Sample Size 
858 
The study has not been formally powered to test any a priori hypothesis. The goal is to have at least 30 
859 
participants complete the 8-week trial period. Some outcomes will be compared between these 
860 
participants and a sample of participants from the prior PEDAP study. 
861 
8.4 Endpoints 
862 
8.4.1 Safety Endpoints 
863 
• 
Severe Hypoglycemia (SH) events and SH event rate per 100 person-years 
864 
• 
Diabetic ketoacidosis (DKA) events and DKA event rate per 100 person-years 
865 
• 
Reportable hyperglycemia adverse events with or without ketosis 
866 
o Events related to the study device 
867 
o Events not related to the study device 
868 
• 
Reportable hypoglycemia adverse events that are not severe 
869 
• 
Number of calendar days with any ketone level ≥1.0 mmol/L 
870 
Hierarchical Safety Endpoints 
871 
• 
CGM-Measured 
872 
o % Time >250 mg/dL (non-inferiority) 
873 

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o % Time <54 mg/dL (non-inferiority) 
874 
Additional Safety Endpoints 
875 
• 
Other serious adverse events 
876 
• 
Any adverse event rate per 100 person-years 
877 
• 
Adverse device effects (ADE) 
878 
• 
Serious adverse device events (SADE) 
879 
• 
Unanticipated adverse device effects (UADE) 
880 
8.4.2 Efficacy Endpoints 
881 
Hierarchical Efficacy Endpoints (tested for superiority compared with baseline) 
882 
• 
CGM-Measured 
883 
o % Time in range 70–180 mg/dL 
884 
o Mean glucose 
885 
o % Time >250 mg/dL 
886 
o % Time <70 mg/dL 
887 
o % Time <54 mg/dL 
888 
Secondary Endpoints 
889 
• 
CGM-Measured 
890 
o % Time in range 70–140 mg/dL 
891 
o % Time >180 mg/dL 
892 
o % Time >300 mg/dL 
893 
o % Time <60 mg/dL 
894 
o Glucose standard deviation  
895 
o Glucose coefficient of variation 
896 
o High blood glucose index (HBGI) 
897 
o Low blood glucose index (LBGI) 
898 
o Weekly hyperglycemic event rate 
899 
o Weekly hypoglycemic event rate 
900 
o Binary 
901 
 
% Time in range 70–180 mg/dL improvement from baseline to 8 weeks ≥5% 
902 
 
% Time in range 70–180 mg/dL improvement from baseline to 8 weeks ≥10% 
903 
 
% Time in range 70–180 mg/dL >70% and % time <70 mg/dL <4% 
904 
• 
Insulin 
905 
o Total daily insulin (units/kg) 
906 
o Percentage of total insulin delivered via basal 
907 

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Exploratory Endpoints 
908 
• 
Insulin 
909 
o Total daily basal insulin (units/kg) 
910 
o Total daily bolus insulin (units/kg) 
911 
o Total daily manual bolus (units/kg) 
912 
o Total daily automated bolus (units/kg) 
913 
o Number of manual insulin doses per day 
914 
o Number of manual insulin doses with carb announcement per day 
915 
o Average daily profile basal rate divided by total daily insulin in percentage points 
916 
o Average carbohydrate ratio daily profile (C:I) multiplied by total daily insulin  
917 
o Average insulin sensitivity factor daily profile (G:I) multiplied by total daily insulin 
918 
8.5 Analysis Datasets and Sensitivity Analyses 
919 
To be included in included in analyses of CGM and insulin outcomes, participants must provide at least 
920 
168 hours of CGM data for each of the baseline and trial phase and spend at least 50% of the study period 
921 
in closed-loop mode. 
922 
All participants who enroll in the PEDAP-AI study will be included in the safety analyses of endpoints 
923 
that are not measured by CGM. Analyses will include all events that occur between enrollment and the 3-
924 
Day Post-Study Safety contact or the end of the 71st day after the date of the Closed Loop Initiation 
925 
visit—whichever is earlier. For participants who do not complete the study, the date of the final contact 
926 
will be used in place of the 3-Day Post-Study Safety contact date. 
927 
8.6 CGM Metrics Calculations 
928 
Baseline values for each CGM metric will be computed from the most recent 28 days of CGM data before 
929 
the Screening visit.  
930 
During the 8-week treatment period, CGM metrics will be calculated from the beginning of study pump 
931 
use until the end of the day before the final visit. 
932 
8.7 Insulin Metrics Calculations 
933 
Insulin metrics for comparisons between baseline and follow-up describe the seven days prior to the 
934 
visits. 
935 
Baseline insulin metrics will use data reported from the Diabetes Screening CRF. Insulin metrics at 8 
936 
weeks will be calculated using Tandem pump data. Insulin pump data on at least 5 of 7 days will be 
937 
required to calculate insulin metrics. Weight will only be recorded at the screening visit. All calculations 
938 
of units/kg will use this weight. 
939 
8.8 Analysis of the Hierarchical Endpoints  
940 
Summary statistics will be reported for the hierarchical endpoints at baseline and during follow-up as well 
941 
as for differences from baseline. 24-hr profile plots will be drawn for follow-up. Boxplots will be drawn 
942 
for baseline and follow-up. Scatter plots will be drawn for follow-up versus baseline. 95% confidence 
943 
intervals will be constructed for the change from baseline to 8 weeks. For % <54 mg/dL and % >250 
944 
mg/dL, tests of non-inferiority will be conducted using paired t-tests. The limits will be 0.5% for % <54 
945 

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mg/dL and 3% for % >250 mg/dL. If these outcomes are determined to be non-inferior, they will be 
946 
tested for superiority in a hierarchy with % 70–180 mg/dL, mean glucose, and % <70 mg/dL. Tests of 
947 
superiority will be two-sided paired t-tests. If the distribution of changes is skewed, then robust methods 
948 
will be used instead. 
949 
To preserve the overall type 1 error among the formal comparisons, a hierarchy will be used in the 
950 
following order: 
951 
• 
CGM % >250 mg/dL (non-inferiority; limit = 3%) 
952 
• 
CGM % <54 mg/dL (non-inferiority; limit = 0.5%) 
953 
• 
CGM % 70–180 mg/dL (superiority) 
954 
• 
Mean glucose (superiority) 
955 
• 
CGM % >250 mg/dL (superiority) 
956 
• 
CGM % <70 mg/dL (superiority) 
957 
• 
CGM % <54 mg/dL (superiority) 
958 
If any of these comparisons result in a p-value >0.05, then formal testing will stop and p-values will not 
959 
be generated for any subsequent tests on the list. Note that the point estimates and confidence intervals 
960 
will be generated for metrics regardless of statistical significance. 
961 
8.9 Analysis of Secondary Endpoints 
962 
Summary statistics will be reported for baseline, follow-up, and difference from baseline. For all 
963 
continuous outcomes, boxplots will be drawn for baseline and follow-up and scatter plots will be drawn 
964 
for follow-up versus baseline. 24-hr profile plots will be drawn for continuous CGM-measured endpoints 
965 
during follow-up. 
966 
Change over time will be compared with a paired t-test when the change appears approximately normal, 
967 
and using robust methods when the change is skewed. Ninety-five percent confidence intervals of the 
968 
changes from baseline will be derived from these tests. 
969 
For the binary outcome % time in range 70–180 mg/dL >70% and % time <70 mg/dL <4%, the 
970 
proportion will be compared between baseline and follow-up with Barnard’s exact test. A ninety-five 
971 
percent confidence interval of the change from baseline will be derived from this test. 
972 
8.10 Comparison with PEDAP Historical Control 
973 
Results from this PEDAP-AI study will be compared with those from a sample of participants from the 
974 
prior PEDAP study. For this analysis, participants from the prior PEDAP study will be limited to those 
975 
who were using MDI before initiating use of the study pump, and whose baseline HbA1c values are no 
976 
more than 0.2 percentage points outside of the range observed among the PEDAP-AI participants. These 
977 
comparisons will be restricted to a follow-up period of approximately two weeks. For PEDAP-AI 
978 
participants, this will be the period from the adjustment of pump settings at the 6-Week visit until the 
979 
beginning of the day of the 8-Week visit. For the PEDAP historical control group, the follow-up metrics 
980 
will be calculated from RCT study phase data for those who were assigned to the CLC group, and 
981 
Extension phase data for those who were assigned to the SC group. In either case, follow-up data will 
982 
come from the 14 days prior to the 56th day after the date of closed loop initiation. 
983 
Comparisons between the PEDAP-AI group and the PEDAP historical control group will be made for all 
984 
of the hierarchical and secondary efficacy endpoints listed in section 8.4.2. Continuous endpoints will be 
985 
compared between the PEDAP-AI and PEDAP cohorts using a linear model adjusting for the baseline 
986 

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value, age at initiation of closed loop use, and clinical center as fixed effects. Binary endpoints will be 
987 
compared using a logistic model that adjusts for the same effects. Summary statistics for baseline, follow-
988 
up, and change from baseline will be reported by study, along with the adjusted differences between the 
989 
studies and their 95% confidence intervals. Boxplots displaying baseline and follow-up for both groups 
990 
will be drawn for continuous outcomes. 
991 
8.11 Analysis of Exploratory Endpoints 
992 
No p-values will be calculated for exploratory analyses. Summary statistics for total daily basal insulin 
993 
and total daily bolus insulin will be tabulated for baseline, 8 weeks, and change from baseline to 8 weeks. 
994 
For all other outcomes, summary statistics will be tabulated for 8 weeks. Boxplots for the follow-up 
995 
period will be drawn for all outcomes. Boxplots for baseline will be given for total daily basal insulin and 
996 
total daily bolus insulin. Summary statistics for the final 2-week period will be displayed side-by-side 
997 
with those of the PEDAP historical control group. 
998 
8.12 Additional Tabulations and Plots 
999 
Summary statistics will be tabulated by daytime (6:00 am – 9:59 pm) and nighttime (10:00 pm – 5:59 am) 
1000 
during baseline and the 8 weeks of follow-up for each of the continuous CGM-measured outcomes listed 
1001 
in section 8.4.2. 
1002 
During the trial period, the closed-loop system will include a periodic parameter adjustment driven by an 
1003 
AI-based Advisor system. Tabulations, 24-hour profile plots, and boxplots of the continuous CGM-
1004 
measured outcomes listed in section 8.4.2 will be generated for each of the six adaptation periods and the 
1005 
two 4-week periods of the study. 
1006 
8.13 Safety Analyses 
1007 
Hierarchical safety endpoints will be analyzed according to the directions in section 8.8. All safety 
1008 
endpoints listed in section 8.4.1 will be summarized in tables. Details of each reportable adverse event 
1009 
will be provided in a listing. 
1010 
8.14 Intervention Adherence 
1011 
The following will be tabulated for the 8-week study period to assess intervention adherence: 
1012 
• 
Percent time of CGM sensor use 
1013 
• 
Percent time of closed-loop system use 
1014 
• 
Percent time in different operational modes 
1015 
• 
Percent of AI recommendations that are accepted 
1016 
8.15 Protocol Adherence and Retention 
1017 
The following tabulations and analyses will be performed to assess protocol adherence for the study: 
1018 
• 
Number of protocol and procedural deviations  
1019 
• 
Flowchart accounting for all enrolled participants 
1020 
• 
Flowchart of all participants at all scheduled visits and phone contacts after treatment initiation 
1021 
• 
Number of and reasons for unscheduled visits and phone calls 
1022 
• 
Number of participants who stopped treatment and reasons 
1023 

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8.16 Baseline Descriptive Statistics 
1024 
Baseline demographic and clinical characteristics of all participants included in the primary analysis will 
1025 
be summarized in a table with statistics appropriate to the distribution of each variable. 
1026 
8.17 Device Issues 
1027 
The following will be tabulated for the 8-week study period to assess device issues: 
1028 
• 
Device malfunctions requiring study team contact and other reported device issues 
1029 
• 
Rate of different failure events and alarms per 24 hours recorded by the Control-IQ system 
1030 
Details of device issues will be provided in a listing. 
1031 
8.18 Planned Interim Analyses 
1032 
No formal interim efficacy analyses are planned.  
1033 
The DSMB will review safety data at intervals, with no formal stopping rules. 
1034 
8.19 Subgroup Analyses 
1035 
With only 30 participants, the ability to evaluate subgroups is limited. However, percentage of time spent 
1036 
>250 mg/dL and % of time spent <54 mg/dL over 8 weeks will be explored separately in baseline HbA1c, 
1037 
race/ethnicity, and sex. No p-values will be calculated for these analyses. 
1038 
8.20 Missing Data 
1039 
All comparisons will be restricted to available cases. 
1040 
8.21 Multiple Comparison/Multiplicity 
1041 
For the baseline versus follow-up comparisons of the metrics mentioned in section 8.8, the overall type 1 
1042 
error will be preserved using the hierarchical procedure described above. For all other analyses, the false 
1043 
discovery rate will be controlled using the adaptive Benjamini-Hochberg procedure (4). 
1044 

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Chapter 9: Data Collection and Monitoring 
1045 
9.1 Case Report Forms and Other Data Collection 
1046 
The main study data are collected from the study pump downloads or on the electronic case report forms 
1047 
(CRFs). When data are directly collected in electronic CRFs in real time, this will be considered the 
1048 
source data. For any data points for which the eCRF is not considered source (e.g., lab results that are 
1049 
transcribed from a printed report into the eCRF), the original source documentation must be maintained in 
1050 
the participant’s study chart or medical record. This source must be readily verifiable against the values 
1051 
entered into eCRF. Even where all study data are directly entered into the eCRFs at office visits, evidence 
1052 
of interaction with a live subject must be recorded (e.g., office note, visit record, etc.). 
1053 
Electronic device data files are obtained from the study software and individual hardware components. 
1054 
These electronic device files are considered the primary source documentation. 
1055 
9.2 Study Records Retention 
1056 
Each participating site will maintain appropriate medical and research records for this trial, in compliance 
1057 
with ICH E6 and regulatory and institutional requirements for the protection of confidentiality of 
1058 
participants. 
1059 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
1060 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
1061 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
1062 
of the investigational product. These documents should be retained for a longer period, however, if 
1063 
required by local regulations. No records will be destroyed without the written consent of the sponsor. It 
1064 
is the responsibility of the sponsor to inform the investigator when these documents no longer need to be 
1065 
retained. 
1066 
9.3 Quality Assurance and Monitoring 
1067 
Designated JCHR personnel will be responsible for maintaining quality assurance (QA) and quality 
1068 
control (QC) systems to ensure that the clinical portion of the trial is conducted and data are generated, 
1069 
documented and reported in compliance with the protocol, Good Clinical Practice (GCP) and the 
1070 
applicable regulatory requirements, as well as to ensure that the rights and wellbeing of trial participants 
1071 
are protected and that the reported trial data are accurate, complete, and verifiable. Adverse events will be 
1072 
prioritized for monitoring. 
1073 
A risk-based monitoring plan will be developed and revised as needed during the study, consistent with 
1074 
FDA’s risk-based monitoring guidance, “Guidance for Industry Oversight of Clinical Investigations — A 
1075 
Risk-Based Approach to Monitoring” (August 2013). Study conduct and monitoring will conform with 21 
1076 
Code of Federal Regulations (CFR) 812. The monitoring plan details who will conduct the monitoring, at 
1077 
what frequency monitoring will be done, at what level of detail monitoring will be performed, and the 
1078 
distribution of monitoring reports. 
1079 
The data of most importance for monitoring at the site are participant eligibility and adverse events. 
1080 
Therefore, the monitoring plan will focus on these areas. As much as possible, remote monitoring will be 
1081 
performed in real-time with on-site monitoring performed to evaluate the verity and completeness of 
1082 
critical data and processes. Elements of the monitoring plan may include: 
1083 
• 
Qualification assessment, training, and certification for sites and site personnel 
1084 
• 
Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1085 

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• 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol review 
1086 
of entered data and edits, statistical monitoring, study closeout 
1087 
• 
On-site monitoring (site visits): source data verification, site visit report 
1088 
• 
Investigational Product accountability 
1089 
• 
Communications with site staff 
1090 
• 
Patient retention and visit completion 
1091 
• 
Quality control reports 
1092 
• 
Management of noncompliance 
1093 
• 
Documenting monitoring activities 
1094 
• 
Adverse event reporting and monitoring 
1095 
JCHR representatives or their designees may visit the study facilities at any time to maintain current and 
1096 
personal knowledge of the study through review of the records, comparison with source documents, 
1097 
observation and discussion of the conduct and progress of the study. Clinical sites will provide direct 
1098 
access to all trial-related facilities/equipment, source data/documents, and reports for the purpose of 
1099 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
1100 
9.4 Protocol Deviations 
1101 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1102 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the 
1103 
study site staff. A significant (or major) deviation is any deviation that departs from the established 
1104 
materials in such a way that it poses an increase in the risk to subjects, adversely affects the welfare, 
1105 
rights, or safety of the research subjects, or negatively influences the scientific study integrity. As a result 
1106 
of a significant deviation, a corrective and preventive action plan shall be developed by the site and 
1107 
implemented promptly. 
1108 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. Further details 
1109 
about the handling of protocol deviations will be included in the monitoring plan. 
1110 

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Chapter 10: Ethics/Protection of Human Participants 
1111 
10.1 Ethical Standards 
1112 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
1113 
Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
1114 
Part 56, and/or the ICH E6. 
1115 
10.2 Institutional Review Boards 
1116 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
1117 
submitted to the JCHR IRB for review and approval as the IRB of Record. Approval of both the protocol 
1118 
and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol 
1119 
will require review and approval by the IRB before the changes are implemented to the study. All changes 
1120 
to the consent form will be IRB approved; a determination will be made regarding whether previously 
1121 
consented participants need to be re-consented. 
1122 
10.3 Informed Consent Process 
1123 
10.3.1 Consent Procedures and Documentation 
1124 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
1125 
and continues throughout the individual’s study participation. Written IRB-approved consent materials 
1126 
and consent discussions must be in a language understandable to the participants and their parent(s). The 
1127 
commercial materials to support device usage is currently only available in English, as such only English 
1128 
proficient participants and LARs may enroll.  
1129 
Extensive discussion of risks and possible benefits of participation will be provided to the participants’ 
1130 
parent(s). Consent forms will be IRB-approved and the parent(s) of the participants will be asked to read 
1131 
and review the document. The investigator will explain the research study to the parent(s) and answer any 
1132 
questions that may arise. All parent(s) will receive a verbal explanation in terms suited to their 
1133 
comprehension of the purposes, procedures, and potential risks of the study and of the rights of research 
1134 
participants. Parent(s) will have the opportunity to carefully review the written consent form and ask 
1135 
questions prior to signing. 
1136 
The parent(s) should have the opportunity to discuss the study with their surrogates or think about it prior 
1137 
to agreeing to participate. The parent(s) will sign the informed consent document prior to any procedures 
1138 
being done specifically for the study. The parent(s) may withdraw consent at any time throughout the 
1139 
course of the trial. A copy of the informed consent document will be given to the parent(s) for their 
1140 
records. The rights and welfare of the participants will be protected by emphasizing that the quality of 
1141 
their medical care will not be adversely affected if they decline to participate in this study. 
1142 
10.3.2 Participant and Data Confidentiality 
1143 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
1144 
sponsor(s) and their agents in accordance with the specifications in the informed consent form. This 
1145 
confidentiality is extended to cover testing of biological samples in addition to the clinical information 
1146 
relating to participants. No genetic testing will be conducted. Therefore, the study protocol, 
1147 
documentation, data, and all other information generated will be held in strict confidence. No information 
1148 
concerning the study or the data will be released to any unauthorized third party without prior written 
1149 
approval of the sponsor. 
1150 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, regulatory 
1151 
agencies or company supplying study product may inspect all documents and records required to be 
1152 

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maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
1153 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
1154 
records. 
1155 
The study participant’s and their parent’s contact information will be securely stored at each clinical site 
1156 
for internal use during the study. At the end of the study, all records will continue to be kept in a secure 
1157 
location for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
1158 
requirements. 
1159 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
1160 
be transmitted to and stored at the Jaeb Center for Health Research (JCHR).  This will not include the 
1161 
participant’s or their parent’s contact or identifying information, unless otherwise specified in the 
1162 
informed consent form.  Rather, individual participants and their research data will be identified by a 
1163 
unique study identification number.  The study data entry and study management systems used by clinical 
1164 
sites and by JCHR research staff will be secured and password protected.  At the end of the study, all 
1165 
study databases will be de-identified and archived at the JCHR and the University of Virginia Center for 
1166 
Diabetes Technology. 
1167 
To further protect the privacy of study participants, a Certificate of Confidentiality will be obtained from 
1168 
the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This certificate protects 
1169 
identifiable research information from forced disclosure. It allows the investigator and others who have 
1170 
access to research records to refuse to disclose identifying information on research participation in any 
1171 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. 
1172 
By protecting researchers and institutions from being compelled to disclose information that would 
1173 
identify research participants, Certificates of Confidentiality help achieve the research objectives and 
1174 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1175 

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Chapter 11: References 
1176 
1. Brown S, Kovatchev B, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM, Levy CJ, 
1177 
Pinsker JE, Wadwa RP, Dassau E, Doyle FJ, Anderson SM, Church MM, Dadlani V, Ekhlaspour L, 
1178 
Forlenza GP, Isganaitis E, Lam DW, Kollman C, and Beck RW, for the iDCL Trial Research Group: 
1179 
Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J 
1180 
Med. 2019 Oct 31;381(18):1707-1717. doi: 10.1056/NEJMoa1907863. 
1181 
2. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L, Forlenza GP, Cengiz E, Schoelwer M, Ruedy KJ, 
1182 
Jost E, Carria L, Emory E, Hsu LJ, Oliveri M, Kollman CK, Dokken BB, Weinzimer SA, DeBoer MD, 
1183 
Buckingham BA, Cherñavvsky D, and Wadwa RP, for the iDCL Trial Research Group: A Randomized 
1184 
Trial of Closed-Loop Control in Children with Type 1 Diabetes. N Engl J Med. 2020 Aug 
1185 
27;383(9):836-845. doi: 10.1056/NEJMoa2004736. 
1186 
3. Wadwa RP, Reed ZW, Buckingham BA, DeBoer MD, Ekhlaspour L, Forlenza GP, Schoelwer M, Lum 
1187 
J, Kollman C, Beck RW, Breton MD; PEDAP Trial Study Group. Trial of Hybrid Closed-Loop Control 
1188 
in Young Children with Type 1 Diabetes. N Engl J Med. 2023 Mar 16;388(11):991-1001. doi: 
1189 
10.1056/NEJMoa2210834. PMID: 36920756. 
1190 
4. Benjamini Y, Hochberg Y. On the adaptive control of the false discovery rate in multiple testing with 
1191 
independent statistics. Journal of Educational and Behavioral Statistics. 2000;25(1):60-83. 
1192