Control-IQ 2.0 Feasibility Study #2: Use of Control-IQ Technology 2.0 in Adults, Children, and Preschoolers With Type 1 Diabetes
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Tandem Diabetes Care, Inc.

  
 
Signature Page 
Control-IQ 2.0 Feasibility Study #2: Use of Control-IQ 
Technology 2.0 in Adults, Children, and Preschoolers with 
Type 1 Diabetes 
Protocol Identifying Number: TP-0011713 
IDE Number: G220181 
IDE Sponsor: Tandem Diabetes Care, Inc. 
Version Number: v 3.0 
20 SEP 2022 
Medical Monitor and Protocol Chair 
Name, degree 
Title 
Jordan Pinsker, MD 
Vice President & Medical Director, Tandem Diabetes Care 
Signature/Date 
Sponsor Representative 
Name, degree 
Title 
Ravid Sasson-Katchalski, PhD 
Director, Clinical Affairs, Tandem Diabetes Care 
Signature/Date 
B1
Ravid 
Katchalski
Digitally signed by Ravid 
Katchalski 
Date: 2022.09.26 15:03:32 
-07'00'
Jordan Pinsker
Digitally signed by Jordan 
Pinsker 
Date: 2022.09.26 15:22:15 
-07'00'

 
 
 
Protocol Revision History 
Version 
Number 
Amendment 
Date 
Brief Description of Changes 
1.0 
16 MAY 2022 
Initial Version Submitted to FDA 
2.0 
27 JUL 2022 
Initial Version Approved by FDA 
3.0 
20 SEP 2022 
Updated for consistency between sections and figures: 
• Study schematic figure updated to note Sleep Activity is required 
• Synopsis and Section 3.4 updated to add day 1 contact to match 
tables 
• Section 2.3.1 and 3.3: Clarified pregnancy test is for females “of 
childbearing potential” 
• Section 3.3: Clarified target is 112.5 mg/dL to be consistent with 
rest of protocol 
• Section 3.:4 Corrected visit numbers 10 and 14, and updated 
reference to section 3.4.1 
Section 6.24: Clarified when a hyperglycemia/ketotic event 
qualifies as an AE, or as a SAE, an adverse event form should be 
completed. 
 
 
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TABLE OF CONTENTS 
SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE .............................................................. 8 
CHAPTER 1: BACKGROUND INFORMATION .............................................................................................. 15 
1.1 Introduction ........................................................................................................................................ 15 
1.1.1 Disease Background ..................................................................................................................... 15 
1.1.2 Tandem X2 Insulin Pump with Control-IQ Technology ............................................................. 15 
1.2 Rationale ............................................................................................................................................. 15 
1.3 Potential Risks and Benefits ............................................................................................................... 15 
1.3.1 Known Potential Risks ................................................................................................................. 16 
1.3.1.1 Blood Draw .......................................................................................................................... 16 
1.3.1.2 CGM and Pump Catheter Risks ........................................................................................... 16 
1.3.1.3 Hypoglycemia ...................................................................................................................... 16 
1.3.1.4 Risk of Hyperglycemia ........................................................................................................ 16 
1.3.1.5 Risk of Device Reuse ........................................................................................................... 16 
1.3.1.6 Potential Risks of the CLC System ..................................................................................... 16 
1.3.1.7 Other Risks .......................................................................................................................... 17 
1.3.2 Benefits ........................................................................................................................................ 17 
1.3.3 Risk Assessment ........................................................................................................................... 17 
1.4 General Considerations ...................................................................................................................... 17 
CHAPTER 2: STUDY ENROLLMENT AND LEAD-IN PERIOD ...................................................................... 18 
2.1 Participant Recruitment and Enrollment ............................................................................................ 18 
2.1.1 Informed Consent and Authorization Procedures ........................................................................ 18 
2.2 Participant Eligibility Criteria ............................................................................................................ 19 
2.2.1 Inclusion Criteria .......................................................................................................................... 19 
2.2.2 Exclusion Criteria ......................................................................................................................... 19 
2.3 Visit 1: Screening Visit ...................................................................................................................... 20 
2.3.1 Data Collection and Testing ......................................................................................................... 20 
2.4 Screen Failures ................................................................................................................................... 21 
CHAPTER 3: DEVICE TRAINING AND STUDY VISITS ................................................................................ 22 
3.1 Visit 2: Control-IQ 1.5 Training Visit ................................................................................................ 22 
3.1.1 Training on System Use ............................................................................................................... 22 
3.1.2 Training on Management of Hypoglycemia ................................................................................ 23 
3.1.3 Training on Management of Hyperglycemia ............................................................................... 23 
3.2 Visits 3, 4 and 5: Control-IQ 1.5 follow up contacts ......................................................................... 24 
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3.3 Visit 6: Control-IQ 2.0 Training Visit ................................................................................................ 24 
3.4 Study Contacts in the Treatment Period with Control-IQ 2.0 Technology ........................................ 25 
3.4.1 Procedures at all Study Visits ...................................................................................................... 26 
3.5 Unscheduled Visits ............................................................................................................................. 27 
3.6 Late Bolus Meal Challenges............................................................................................................... 27 
3.7 Adjustments in Insulin Pump Settings ............................................................................................... 27 
3.8 Early Discontinuation of Study Device .............................................................................................. 27 
3.9 Remote Monitoring ............................................................................................................................ 27 
CHAPTER 4: STUDY DEVICES AND DRUGS ................................................................................................ 28 
4.1 Study Devices ..................................................................................................................................... 28 
4.1.1 Insulin Pump ................................................................................................................................ 28 
4.1.2 Continuous Glucose Monitoring .................................................................................................. 28 
4.1.3 Blood Glucose Meter ................................................................................................................... 28 
4.1.4 Ketone Meter ................................................................................................................................ 28 
4.2 Study Device and Drug Accountability Procedures ........................................................................... 28 
4.3 Participant Access to Study Device at Study Closure ........................................................................ 28 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES .................................................................. 29 
5.1 General Challenge Guidelines ............................................................................................................ 29 
5.1.1 Late Bolus Meal Challenges ........................................................................................................ 29 
5.2 Laboratory Testing ............................................................................................................................. 30 
5.2.1 HbA1c .......................................................................................................................................... 30 
5.2.2 Urine Pregnancy ........................................................................................................................... 30 
5.2.3 Patient Reported Outcomes .......................................................................................................... 30 
CHAPTER 6: UNANTICIPATED PROBLEM, ADVERSE EVENT, AND DEVICE ISSUE REPORTING ............. 32 
6.1 Unanticipated Problems ..................................................................................................................... 32 
6.2 Adverse Events ................................................................................................................................... 32 
6.2.1 Definitions .................................................................................................................................... 32 
6.2.2 Reportable Adverse Events .......................................................................................................... 33 
6.2.3 Hypoglycemic Events .................................................................................................................. 34 
6.2.4 Hyperglycemic/Ketotic Events .................................................................................................... 34 
6.2.5 Relationship of Adverse Event to Study Investigational Device ................................................. 35 
6.2.6 Severity (Intensity) of Adverse Events ........................................................................................ 35 
6.2.7 Expectedness ................................................................................................................................ 36 
6.2.8 Coding of Adverse Events ........................................................................................................... 36 
6.2.9 Outcome of Adverse Events ......................................................................................................... 36 
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6.3 Reportable Device Issues ................................................................................................................... 36 
6.4 Timing of Event Reporting................................................................................................................. 37 
6.5 Safety Oversight ................................................................................................................................. 37 
6.6 Stopping Criteria ................................................................................................................................ 38 
6.6.1 Participant Discontinuation of Study Device ............................................................................... 38 
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 Rescue Medications, Treatments, and Procedures ............................................................................. 39 
7.5 Pregnancy Reporting .......................................................................................................................... 39 
7.6 Participant Compensation................................................................................................................... 39 
7.7 Participant Withdrawal ....................................................................................................................... 39 
CHAPTER 8: STATISTICAL CONSIDERATIONS .......................................................................................... 40 
8.1 General Statistical Considerations...................................................................................................... 40 
8.2 Statistical Hypotheses......................................................................................................................... 40 
8.3 Sample Size ........................................................................................................................................ 40 
8.4 Outcome Measures ............................................................................................................................. 40 
8.5 Analysis Datasets ............................................................................................................................... 41 
8.6 Analysis of Endpoints ........................................................................................................................ 41 
8.6.1 Analysis of the Safety Event Endpoints ....................................................................................... 41 
8.6.2 Analysis of Other Safety Endpoints ............................................................................................. 42 
8.6.3 Analysis of CGM Endpoints ........................................................................................................ 42 
8.6.4 Analysis of Late Bolus Meal Challenges ..................................................................................... 42 
8.6.4.1 Late Bolus Meal Challenge Safety and CGM Subgroup Analysis ...................................... 42 
8.6.4.2 Time to Intervention Analysis ............................................................................................. 43 
8.6.4.3 Number of interventions analysis ........................................................................................ 43 
8.7 Intervention Adherence ...................................................................................................................... 43 
8.8 Protocol Adherence and Retention ..................................................................................................... 44 
8.9 Baseline Descriptive Statistics ........................................................................................................... 44 
8.10 Additional Tabulations and Analyses............................................................................................... 44 
8.11 Device Issues .................................................................................................................................... 44 
8.12 Planned Interim Analyses ................................................................................................................. 44 
8.13 Subgroup Analyses ........................................................................................................................... 45 
8.14 Multiple Comparison/Multiplicity ................................................................................................... 45 
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8.15 Handling of Missing Data ................................................................................................................ 45 
8.16 General Statistical Considerations.................................................................................................... 45 
CHAPTER 9: DATA COLLECTION AND MONITORING............................................................................... 46 
9.1 Case Report Forms and Other Data Collection .................................................................................. 46 
9.2 Study Records Retention .................................................................................................................... 46 
9.3 Quality Assurance and Monitoring .................................................................................................... 46 
9.4 Protocol Deviations ............................................................................................................................ 47 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 48 
10.1 Ethical Standard ............................................................................................................................... 48 
10.2 Institutional Review Boards ............................................................................................................. 48 
10.3 Informed Consent Process ................................................................................................................ 48 
10.3.1 Consent Procedures and Documentation ................................................................................... 48 
10.3.2 Participant and Data Confidentiality .......................................................................................... 48 
10.3.3 Future Use of Stored Specimens and Data ................................................................................. 49 
CHAPTER 11: REFERENCES ....................................................................................................................... 50 
 
 
 
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1 
LIST OF ABBREVIATIONS 
 
 
ABBREVIATION 
DEFINITION 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AID 
Automated Insulin Dosing 
BGM 
Blood Glucose Meter 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGM 
Continuous Glucose Monitoring  
CLC 
Closed-Loop Control 
DCCT 
Diabetes Control & Complications Trial 
DKA 
Diabetic Ketoacidosis 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICF 
Informed consent form 
ICH 
International Conference of Harmonisation 
IDE  
Investigational Device Exemption 
IRB 
Institutional Review Board 
RBM 
Risk-Based Monitoring 
SAE 
Serious Adverse Event 
T1D 
Type 1 Diabetes 
UADE 
Unanticipated Adverse Device Effect 
 
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Site Principal Investigator Statement of Compliance 
Protocol Identifying Number: 
TP-0011713 
Protocol Name: 
Control-IQ 2.0 Feasibility Study #2: Use of Control-IQ 
Technology 2.0 in Adults, Children, and Preschoolers 
with Type 1 Diabetes 
Protocol Version / Date: 
3.0 / 20 SEP 2022 
 
The Principal Investigators (undersigned) hereby declare that they have read this protocol and 
agree to its contents. 
This trial will be carried out in accordance with the principles of Good Clinical Practice (GCP) 
and as required by the following, as applicable: United States (US) Code of Federal Regulations 
(CFR) (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812). 
By written consent to this protocol, the investigators agree to the above and to fully co-operate 
with all monitoring and audits in relation to this trial by allowing direct access to all 
documentation, including source data, by authorized individuals representing Tandem Diabetes 
Care, Inc., IRBs and/or by the US Federal, State and local regulatory authorities. 
 
Investigator Name: ___________________________________________ 
 
Investigator Signature: ________________________________________ 
 
Date (DD/MMM/YYYY): ______________________________________ 
 
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PROTOCOL SUMMARY 
Study Sponsor 
Tandem Diabetes Care, Inc. 
Protocol Number 
TP-0011713 
Protocol Title 
Control-IQ 2.0 Feasibility Study #2: Use of Control-IQ Technology 2.0 in Adults, Children, 
and Preschoolers with Type 1 Diabetes 
Précis 
This feasibility study is a prospective, randomized, two-period crossover multi-center study 
of 2 weeks of home use of Control-IQ 1.5 technology (run-in period), followed by 2 weeks 
of home use of Control-IQ 2.0 technology at one target, followed by 2 weeks of home use of 
Control-IQ 2.0 at another target. This automated insulin dosing (AID) system will be 
evaluated in multiple age groups, with late bolus meal challenges. 
Products 
t:slim X2 insulin pump with Control-IQ technology 1.5 (Run-In Period) 
t:slim X2 insulin pump with Control-IQ technology 2.0 (Treatment Periods) 
Objectives 
The objectives of the study are to assess safety of and explore glycemic outcomes with 
Control-IQ technology 2.0 in adults, children and preschoolers with type 1 diabetes using 
different targets and after late bolus meal challenges. 
Number of Sites 
Up to 6 clinical sites in the US. 
Study Design 
Randomized sequence, prospective safety study 
Number of Participants 
Up to 100 participants signing consent to use the study devices, so that at least 72 complete 
the study (at least 30 participants age 14+, at least 30 participants age 6-13, and at least 12 
participants age 2-5), plus local contacts for adult participants.  
Enrollment goal is at least 50% of all participants in each age group have an HbA1c at 
baseline of ≥ 7.5%.                                                                                                                         
Participant Population: 
Eligibility to enroll in the study will be assessed based on the following inclusion 
criteria: 
1. 
Age 2 to ≤ 81 years 
2. 
Diagnosis of type 1 diabetes for at least 1 year, or at least 6 months for age 2-5 
years at enrollment 
3. 
Prior Dexcom CGM user, with at least 11 of the prior 14 days of CGM use 
available for download at the screening visit to confirm eligibility 
4. 
Total Daily Insulin Dose (TDD) at least 2 units/day 
5. 
Weight ≥ 20 lbs 
6. 
HbA1c ≤ 10.5% 
7. 
For participants <18 years old, living with one or more parent/legal guardian 
knowledgeable about emergency procedures for severe hypoglycemia, present 
with the participant during and for 5 hours (3 hours for participants age 2-5) after 
the meal challenges, and willing to use the Dexcom Follow app (with push 
notifications turned on) for the duration of the study.  
8. 
For participants ≥18 years old, availability of a local contact who has access to the 
study participant, knows their whereabouts, can be available to assist during the 
late bolus meal challenges, agrees to be promptly available if contacted by study 
staff, and willing to use the Dexcom Follow app (with push notifications turned 
on) for the duration of the study. If the participant lives alone, the local contact 
must live within 30 minutes and have access to the subject overnight.  
9. 
Investigator has confidence that the participant and/or parent/guardian can 
successfully operate all study devices and is capable of adhering to the protocol. 
10. Willing to use only aspart (novolog) or lispro (humalog) insulin with the study 
devices, with no use of long-acting basal insulin injections, or inhaled insulin with 
the study devices. 
11. Have current glucagon product to treat severe hypoglycemia (injectable or nasal) 
at home (site will provide prescription if they do not have one) 
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12. Willing and able to perform the study late bolus meal challenges. 
Eligibility to enroll in the study will be assessed based on the following exclusion 
criteria:  
1. 
More than 1 episode of diabetic ketoacidosis (DKA) in the past 6 months 
2. 
More than 1 episode of severe hypoglycemia (needing assistance) in the past 6 
months 
3. 
Inpatient psychiatric treatment in the past 6 months  
4. 
For Female: Currently pregnant or planning to become pregnant during the time 
period of study participation 
a. 
A negative pregnancy test will be required for all females of child-
bearing potential 
b. 
Counseling on appropriate birth control options will be provided to all 
females of child-bearing potential 
5. 
Concurrent use of any non-insulin glucose-lowering agent, other than metformin 
(for example, GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, 
sulfonylureas). 
6. 
Hemophilia or any other bleeding disorder 
7. 
Hemoglobinopathy 
8. 
History of heart, liver, lung or kidney disease determined by investigator to 
interfere with the study 
9. 
History of allergic reaction to Humalog or Novolog 
10. Use of any medications determined by investigator to interfere with study 
11. Significant chronic kidney disease (which could impact CGM accuracy in 
investigator’s judgment) or hemodialysis 
12. Concurrent use of any medication that could interfere with the study CGM, such as 
hydroxyurea 
13. History of adrenal insufficiency 
14. History of abnormal TSH consistent with hypothyroidism or hyperthyroidism that 
is not appropriately treated 
15. History of gastroparesis 
16. A condition, which in the opinion of the investigator or designee, would put the 
participant or study at risk 
17. Participation in another pharmaceutical or device trial at the time of enrollment or 
anticipated for during the time period of study participation 
18. Employed by, or having immediate family members employed by Tandem 
Diabetes Care, 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 
                                                    
Participant Duration 
Approximately 6-12 weeks 
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1 
Study Endpoints 
The adult, pediatric and preschool populations will be combined for the analysis of primary 
and secondary endpoints. Separate analyses also will be performed for the adult, pediatric 
and preschool cohorts for the primary and secondary endpoints. CGM data collected during 
the challenge periods will not contribute to overall analysis of CGM metrics. The three study 
time periods are the Run-In period with Control-IQ technology 1.5, treatment period with 
Control-IQ technology 2.0 at the standard target, and treatment period with Control-IQ 
technology 2.0 at the lower target, where the order of treatment periods will be randomized. 
Primary Endpoints: 
1. 
Severe hypoglycemia (with cognitive impairment such that assistance of another 
individual is needed for treatment) during study compared with data on severe 
hypoglycemic events reported by T1D Exchange clinic registry over a 3-month 
time period 
2. 
Diabetic ketoacidosis during study compared with data on DKA events reported by 
T1D Exchange clinic registry over a 3-month time period 
3. 
Number of unanticipated adverse device effects 
4. 
Number of other serious device-related adverse events 
Secondary Endpoints: 
1. 
All device-related adverse events 
2. 
CGM hypoglycemia outcomes, compared between the three study time periods  
a. 
Overall % time <54 mg/dL 
b. 
Overall % time <70 mg/dL 
3. 
Times in ranges-overall (70-180 mg/dL, >180 mg/dL, >250 mg/dL, 70-140 
mg/dL) compared between the three study time periods 
4. 
Mean glucose compared between the three study time periods 
5. 
Overall variability (CV and SD) compared between the three study time periods 
6. 
Secondary endpoints 2 – 5 compared during daytime and nighttime, across the 
three study time periods  
7. 
Secondary endpoints 2 - 5 as well as adverse events, during the study meal 
challenge periods, for late bolus feature use compared to normal bolus in the meal 
challenges. 
8. 
Time to intervention for hypo- or hyperglycemia during the study meal challenge 
periods, for late bolus feature use compared to normal bolus in the meal 
challenges. 
9. 
Number of interventions for hypo- or hyperglycemia during the study meal 
challenge periods for late bolus feature use compared to normal bolus in the meal 
challenges. 
10. Subgroup Analysis for all metrics by age cohort, baseline HbA1c cohort, and 
target activity use (standard target, lower target, sleep activity, exercise activity) 
Protocol Overview/Synopsis 
After consent is signed, eligibility will be assessed.  
 
Run-In Period: 
Participants will return to clinic to undergo device training with the study CGM and a 
Control-IQ technology 1.5 pump. Training for both devices may be combined, or depending 
on comfort level of investigator and participant, participants may return for a second session 
to complete device training and begin the Control-IQ 1.5 run in period. The run-in period 
will end after 2 weeks of Control-IQ technology 1.5 use. 
Participants will have a phone follow up phone call at 1 day, 3 days and 1 week after starting 
Control-IQ technology 1.5 use, and will return to clinic at two weeks to commence Control-
IQ technology 2.0 training. 
 
Treatment Periods: 
Participants will then use the study pump with Control-IQ technology 2.0 for 4 weeks during 
the study period (2 weeks with a lower target of 90-130 mg/dL, and 2 weeks with a standard 
target of 112.5-160 mg/dL, in random order). Participants will have a follow up contact at 1 
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day, 3 days and 1 week into Control-IQ 2.0 use, a follow-up visit at 2 weeks to switch 
targets, a follow up contact 3 days later and 1 week after switching targets, and a follow up 
visit at 4 weeks to end the study. 
Participants will use the t:slim X2 insulin pump with Control-IQ technology 2.0 turned on. It 
is acceptable to use manual mode when there is a loss of CGM data. 
Each participant will perform 2 late bolus meal challenges in each two-week period, 
contacting the study clinical site before and after each challenge. 
An assessment of adverse events, using open ended questions to capture hyperglycemic and 
hypoglycemic events, and their underlying cause and relationship to the study device or 
other parts of the system (such as the infusion set), will occur at all visits/contacts. 
Study Safety Plan:  
Participants will be given a blood glucose and ketone meter to use throughout the study, and 
will be trained on their use by qualified staff.  
BGM readings will be performed in accordance with the participant instruction sheet and per 
CGM manufacturer instructions. 
Ketone readings will be performed per the participant instruction sheet. 
Site investigators may adjust insulin delivery profile settings as needed throughout the study 
in accordance with their clinical practice. 
Real-time CGM alerts will be sent to study staff providers (MD, DO, NP, PA) for the first 
ten 6-13 year old participants to begin use of the lower target (90-130 mg/dL) for the first 
week of Control-IQ 2.0 use at that target. In addition, real-time CGM alerts will be sent to 
study staff providers for all 2-5 year old participants throughout their use of Control-IQ 2.0 
technology (all 4 weeks). 
 
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SCHEMATIC OF STUDY DESIGN 
 
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SCHEDULE OF STUDY VISITS AND PROCEDURES 
1Late meal bolus challenges will occur throughout Control-IQ 2.0 use in the treatment period, with 2 challenges in each 2 week period. 
2Pregnancy test at Control-IQ 1.5 device training does not need to be repeated if screening and Control-IQ 1.5 training visits are performed on the 
same day. 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UV 
 
 
Run-In Period 
Treatment Period 
 
Screening 
Visit 
Control-IQ 
1.5 Training 
Visit 
Control-IQ 1.5 Run-In 
Period 
Control-
IQ 2.0 
Training 
Control-IQ 2.0 Treatment 
Period 1 
Control-IQ 2.0 Treatment 
Period 2 
 
 
 
Up to 2 
weeks after 
screening 
1d 
3d 
1w 
2w 
1d 
3d 
1w 
2w 
1d 
3d 
1w 
2w 
(Final  
Visit) 
UV 
Visit (V) or Contact (C) 
V 
V 
C 
C 
C 
V 
C 
C 
C 
V 
C 
C 
C 
V 
V/C 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, 
blood pressure and pulse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbAlc (POC or local lab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females 
of child-bearing potential) 
X 
X2 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Questionnaires 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Assessment of Device Use 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study system training 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Late Meal Bolus Challenges1 
 
 
 
 
 
 
 
X 
 
X 
 
AE/Device Issue Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Upload and Review Study 
Device Data 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Chapter 1: Background Information 
1 
1.1 Introduction 
2 
1.1.1 Disease Background 
3 
Type 1 diabetes affects 1.25 million people in the United States. Approximately 70% of individuals with 
4 
type 1 diabetes report poor metabolic control, and do not meet the American Diabetes Association’s 
5 
recommended goal of hemoglobin A1c (HbA1c) level of 7.0%. These findings indicate the need for better 
6 
approaches to type 1 diabetes management. 
7 
1.1.2 Tandem X2 Insulin Pump with Control-IQ Technology 
8 
The Tandem X2 insulin pump with Control-IQ technology is an FDA-approved closed-loop control 
9 
(CLC) system based on the control algorithm developed and initially tested in the University of 
10 
Virginia’s DiAs system and then implemented in the inControl system (TypeZero, Technologies, Inc.). 
11 
Use of the Control-IQ system has been extensively tested in adults and children with type 1 diabetes 
12 
(T1D), demonstrating its efficacy and safety when used with insulin lispro (Humalog) or insulin aspart 
13 
(Novolog).1,2 The system is currently approved for ages 6 years and older and its use in younger children 
14 
is currently being studied (clinical trials.gov NCT04796779). There are over 150,000 users of the 
15 
system since it became commercially available in 2020. A recent evaluation of real-world use of the 
16 
system in 9,451 users age >6 years with at least 12 months of system use found results comparable to 
17 
those found in the randomized trials.3  
18 
Since the initial approval of the system, modifications have been made in the software, which is referred 
19 
to as version 1.5. These modifications include modest usability improvements and other enhancements 
20 
intended to further reduce risk. The Control-IQ 1.5 system also allows for a wider range of inputs to 
21 
weight and total daily insulin, allowing it to be used by a broader group of individuals with diabetes, and 
22 
has been evaluated in numerous clinical trials (NCT04796779, NCT05111301, NCT05403502). 
23 
Control-IQ technology 2.0 incorporates all the changes in version 1.5, and adds several new features 
24 
intended to improve time-in-range with no significant increase in hypoglycemia. These changes also 
25 
include features to improve safety around exercise, and to make bolusing for meals safer. Control-IQ 
26 
technology 2.0 was recently studied in 30 adults and adolescents age 14+, with over 20,000 hours of use, 
27 
and showed improvements in time in range without increases in hypoglycemia (NCT05014789).  
28 
1.2 Rationale 
29 
The objective of this randomized, prospective, two-period crossover study conducted in three age cohorts 
30 
is to assess safety and explore glycemic outcomes associated with use of Control-IQ technology 2.0 
31 
including Adults and Adolescents age 14+ years old, children age 6-13 years old, and preschool children 
32 
age 2-5 years old. Participants will evaluate Control-IQ 2.0 technology using different glycemic targets, 
33 
as well as perform late bolus meal challenges.  
34 
1.3 Potential Risks and Benefits 
35 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are 
36 
handled to minimize this risk. Hypoglycemia, hyperglycemia and ketone formation are always a risk in 
37 
participants with type 1 diabetes and participants will be monitored for these events. 
38 
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1.3.1 Known Potential Risks 
39 
1.3.1.1 Blood Draw 
40 
A venipuncture and/or fingerstick will be performed to obtain blood for HbA1c measurement. 
41 
Venipuncture can cause common reactions like pain, bruising, or redness at the sampling site. 
42 
Less common reactions include bleeding from the sampling site, formation of a small blood clot or 
43 
swelling of the vein and surrounding tissues, and fainting. A fingerstick frequently causes transient pain 
44 
and there may be a small, localized bruise, which may be followed by a small scar that may persist for 
45 
several weeks. The risk of local infection is less than 1 in 1000 with either venipuncture or fingerstick. 
46 
1.3.1.2 CGM and Pump Catheter Risks 
47 
There is a small risk of bleeding where the sensor or infusion set is inserted. There is a small risk for 
48 
developing a local skin infection at the site of CGM sensor placement of pump infusion set placement. 
49 
This may be associated with swelling, redness and pain; and may require antibiotic therapy. Rarely, a 
50 
CGM sensor may break and leave a small portion of the sensor under the skin that may cause redness, 
51 
swelling or pain at the insertion site. 
52 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure the 
53 
CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion. If these 
54 
reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be 
55 
tried, sites will be rotated frequently, and a mild topical steroid cream or other medication may be 
56 
required.  
57 
1.3.1.3 Hypoglycemia 
58 
As with any person having type 1 diabetes and using insulin, there is always a risk of having 
59 
hypoglycemia. The frequency of hypoglycemia should be no more and possibly less than it would be 
60 
as part of daily living. Symptoms of hypoglycemia can include sweating, jitteriness, and not feeling well. 
61 
There is the possibility of fainting or seizures (convulsions) and that for a few days the participant may 
62 
not be as aware of symptoms of hypoglycemia. A CGM functioning poorly and significantly over-
63 
reading glucose values could lead to inappropriate insulin delivery. The study meal challenges, requiring 
64 
boluses to be delivered late, could increase the risk of hypoglycemia. 
65 
1.3.1.4 Risk of Hyperglycemia 
66 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
67 
extended period or if the pump or infusion set is not working properly. A CGM functioning poorly 
68 
and significantly under-reading glucose values could lead to inappropriate suspension of insulin delivery. 
69 
The study meal challenges, requiring boluses to be delivered late, could increase the risk of 
70 
hyperglycemia. 
71 
1.3.1.5 Risk of Device Reuse 
72 
All devices will be used by a single study participant only. There will be no device reuse. 
73 
1.3.1.6 Potential Risks of the CLC System 
74 
Even though the study system has been tested prior to this study, there is still a risk that parts of the 
75 
system may not function properly. The following are possible reasons the system may deliver too much 
76 
insulin or incorrectly stop insulin delivery: 
77 
• 
CGM sensor reads higher or lower than the actual glucose level which increases risk for 
78 
hypoglycemia and hyperglycemia with automated insulin delivery system; 
79 

 
 
• 
Device malfunctions that could produce a suspension of insulin delivery or over delivery of insulin. 
80 
1.3.1.7 Other Risks 
81 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be collected for the 
82 
study. The downloaded data from the participant’s home devices at the screening visit may include data 
83 
from the period beyond the last 2 weeks prior to screening. Some people may be uncomfortable with the 
84 
researchers' having such detailed information about their daily diabetes habits. 
85 
1.3.2 Benefits 
86 
Participants may achieve better glucose control than they are currently achieving using their home insulin 
87 
pump.  
88 
The individual participant may not benefit from study participation. 
89 
1.3.3 Risk Assessment 
90 
Based on the facts that (1) individuals with diabetes experience mild hypoglycemia and hyperglycemia 
91 
frequently as a consequence of the disease and its management, (2),  mitigations are in place, and have 
92 
been tested in prior studies using the investigational device system in the home setting, that limit the 
93 
likelihood of excessive insulin dosing or prolonged withdrawal of insulin, and (3) rapid reversal of 
94 
hypoglycemia and hyperglycemia can be achieved, it is the assessment of the Sponsor that this protocol is 
95 
an investigation involving a minor increase over minimal risk. In addition, it is the belief of the Sponsor 
96 
that this study also presents prospect of direct benefit to the participants and general benefit to others with 
97 
diabetes. 
98 
1.4 General Considerations 
99 
The study is being conducted in compliance with the ethical principles that have their origin in the 
100 
Declaration of Helsinki, with the protocol described herein, and with the standards of Good Clinical 
101 
Practice (GCP). 
102 
In accordance with 21 CFR 812.66, the protocol is considered a significant risk device study, due to the 
103 
fact that the intervention is investigational. Therefore, an investigational device exemption (IDE) from the 
104 
U.S. Food and Drug Administration (FDA) is required to conduct the study. 
105 
 
106 
B17

 
Chapter 2: Study Enrollment and Lead-in Period 
107 
2.1 Participant Recruitment and Enrollment 
108 
Enrollment will proceed with the goal of having up to 100 subjects screened, so that at least 72 complete 
109 
closed loop use (at least 30 participants age 14+, at least 30 participants age 6-13, and at least 12 
110 
participants age 2-5), plus local contacts for adult participants. 
111 
Enrollment will be staged, so that at least ten 6-13 year olds will complete the trial before enrolling any 2-
112 
5 year olds. A trial level safety review with the study coordinating center, sponsor and the site primary 
113 
investigators will be performed, summarizing the data after the first ten 6-13 year olds who complete this 
114 
trial. Criteria to begin enrolling 2-5 years will include 1) No UADE’s affecting participant safety, 2) 
115 
Study Stopping Criteria have not been met overall (total AE’s related to DKA or severe hypoglycemia), 
116 
3) No safety concerns from all parties and approval from all parties to continue the study. This review 
117 
will be documented in the trial master file. 
118 
An enrollment goal is to have at least 50% of all participants in each age group have an HbA1c at baseline 
119 
of ≥ 7.5%, and to have at least 6 participants age 14-17 years old. 
120 
Study participants will be recruited from up to 6 clinical centers in the United States without regard to 
121 
gender, race, or ethnicity. There is no restriction on the number of participants to be enrolled by each site 
122 
toward the overall recruitment goal.          
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 or electronic informed consent 
126 
will be obtained. 
127 
For potential study participants, the study protocol will be discussed with the potential study participant 
128 
by study staff. The potential study participant will be given the Informed Consent Form to read. Potential 
129 
study participants will be encouraged to discuss the study with family members and their personal 
130 
physicians(s) before deciding whether to participate in the study.  
131 
For participants less than 18 years of age, a parent/legal guardian will be provided with the Informed 
132 
Consent Form to read and will be given the opportunity to ask questions. Assent will be obtained from 
133 
subjects 7 to <18 years of age. A legally authorized representative (parent/guardian) must sign the consent 
134 
form for all participants less than 18 years of age, and agree to the CGM monitoring requirements of the 
135 
study. 
136 
A copy of the consent/assent form will be provided to the participant and if the participant is a minor, 
137 
his/her parent/guardian, and another copy will be added to the participant’s study record. 
138 
As part of the informed consent process, each participant will be asked to sign an authorization for 
139 
release of personal information. The investigator, or his or her designee, will review the study-specific 
140 
information that will be collected and to whom that information will be disclosed. After speaking with 
141 
the participant and/or parent/guardian, questions will be answered about the details regarding 
142 
authorization. 
143 
A local contact is required for all participants > 18 years of age. Each local contact must sign the local 
144 
contact consent form, and agree to the CGM monitoring requirements of the study. 
145 
A participant is considered enrolled when the informed consent form has been signed. 
146 
B18

 
2.2 Participant Eligibility Criteria 
147 
2.2.1 Inclusion Criteria 
148 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate in the 
149 
study. 
150 
1. Age 2 to ≤ 81 years 
151 
2. Diagnosis of type 1 diabetes for at least 1 year, or at least 6 months for age 2-5 years at 
152 
enrollment 
153 
3. Prior Dexcom CGM user, with at least 11 of the prior 14 days of CGM use available for 
154 
download at the screening visit to confirm eligibility 
155 
4. Total Daily Insulin Dose (TDD) at least 2 units/day 
156 
5. Weight ≥ 20 lbs 
157 
6. HbA1c < 10.5% 
158 
7. For participants <18 years old, living with one or more parent/legal guardian knowledgeable 
159 
about emergency procedures for severe hypoglycemia, present with the participant during and for 
160 
5 hours (3 hours for participants age 2-5) after the meal challenges, and willing to use the 
161 
Dexcom Follow app (with push notifications turned on) for the duration of the study. 
162 
 
163 
8. For participants ≥18 years old, availability of a local contact who has access to the study 
164 
participant, knows their whereabouts, can be available to assist during the late bolus meal 
165 
challenges, agrees to be promptly available if contacted by study staff, and willing to use the 
166 
Dexcom Follow app (with push notifications turned on) for the duration of the study. If the 
167 
participant lives alone, the local contact must live within 30 minutes and have access to the 
168 
subject overnight.  
169 
 
170 
9. Investigator has confidence that the participant and/or parent/guardian can successfully operate 
171 
all study devices and is capable of adhering to the protocol. 
172 
10. Willing to use only aspart (novolog) or lispro (humalog) insulin with the study devices, with no 
173 
use of long-acting basal insulin injections, or inhaled insulin with the study devices. 
174 
11. Have current glucagon product to treat severe hypoglycemia (injectable or nasal) at home (will 
175 
provide prescription if they do not have one). 
176 
12. Willing and able to perform the study late bolus meal challenges. 
177 
2.2.2 Exclusion Criteria 
178 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from study 
179 
participation. 
180 
1. More than 1 episode of diabetic ketoacidosis (DKA) in the past 6 months 
181 
2. More than 1 episode of severe hypoglycemia (needing assistance) in the past 6 months 
182 
3. Inpatient psychiatric treatment in the past 6 months 
183 
4. For Female: Currently pregnant or planning to become pregnant during the time period of study 
184 
participation 
185 
• 
A negative pregnancy test will be required for all females of child-bearing potential  
186 
B19

 
• 
Counseling on appropriate birth control options will be provided to all females of child-
187 
bearing potential 
188 
5. Concurrent use of any non-insulin glucose-lowering agent, other than metformin (for example, 
189 
GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas). 
190 
6. Hemophilia or any other bleeding disorder 
191 
7. Hemoglobinopathy 
192 
8. History of heart, liver, lung or kidney disease determined by investigator to interfere with the 
193 
study 
194 
9. History of allergic reaction to Humalog or Novolog 
195 
10. Use of any medications determined by investigator to interfere with study 
196 
11. Significant chronic kidney disease (which could impact CGM accuracy in investigator’s 
197 
judgment) or hemodialysis 
198 
12. Concurrent use of any medication that could interfere with the study CGM, such as hydroxyurea 
199 
13. History of adrenal insufficiency 
200 
14. History of abnormal TSH consistent with hypothyroidism or hyperthyroidism that is not 
201 
appropriately treated 
202 
15. History of gastroparesis 
203 
16. A condition, which in the opinion of the investigator or designee, would put the participant or 
204 
study at risk 
205 
17. Participation in another pharmaceutical or device trial at the time of enrollment or anticipated for 
206 
during the time period of study participation 
207 
18. Employed by, or having immediate family members employed by Tandem Diabetes Care, Inc., or 
208 
having a direct supervisor at place of employment who is also directly involved in conducting the 
209 
clinical trial (as a study investigator, coordinator, etc.); or having a first-degree relative who is 
210 
directly involved in conducting the clinical trial 
211 
2.3 Visit 1: Screening Visit 
212 
After informed consent has been signed, a potential participant will be evaluated for study eligibility 
213 
through the elicitation of a medical history, performance of a physical examination by study personnel 
214 
and local laboratory testing if needed to screen for exclusionary medical conditions. 
215 
2.3.1 Data Collection and Testing 
216 
A standard physical exam (including vital signs and height and weight measurements) will be performed 
217 
by the study investigator or designee (a physician, fellow, nurse practitioner or a physician assistant). 
218 
Height, weight and vital signs may be recorded by appropriately delegated office staff. 
219 
The following procedures will be performed/data collected/eligibility criteria checked and documented: 
220 
• 
Inclusion and exclusion criteria assessed 
221 
• 
Demographics (age or year and month of birth for preschool participants, sex, race and ethnicity and 
222 
socioeconomic information ) 
223 
• 
Subject initials to verify eCRF entry is associated with the correct individual  
224 
B20

 
• 
Contact information (retained at the site and not entered into study database) 
225 
• 
Medical history 
226 
• 
Concomitant medications 
227 
• 
Physical examination to include: 
228 
 
Weight, height 
229 
 
Vital signs including measurement of blood pressure and pulse 
230 
• 
Blood draw (venipuncture or fingerstick) for local HbA1c measurement 
231 
• 
Urine pregnancy test for all females of childbearing potential who are premenopausal and not 
232 
surgically sterile 
233 
• 
Current device download, to include insulin pump and CGM device data, for up to the last two weeks 
234 
of data if available 
235 
Screening procedures will last approximately 1-2 hours. The screening visit must occur in clinic and 
236 
cannot be performed remotely. 
237 
2.4 Screen Failures 
238 
Individuals who do not initially meet study eligibility requirements may be rescreened one more time at a 
239 
later date per investigator discretion. 
240 
 
241 
B21

 
Chapter 3: Device Training and Study Visits 
242 
3.1 Visit 2: Control-IQ 1.5 Training Visit 
243 
After screening, participants will have a clinic visit at which they will undergo CGM and Control-IQ 1.5 
244 
technology pump device training.  
245 
The device training visit should be completed within 2 weeks of screening, and may be performed the 
246 
same day as the screening visit. If not completed within 2 weeks of screening, re-review of screening 
247 
results by the investigator should be performed, who may ask for repeated testing as per investigator 
248 
judgement. The device training visit may be extended over the course of more than 1 session if needed. 
249 
The device training visit must occur in clinic and cannot be performed remotely. 
250 
A urine pregnancy test for all females of childbearing potential (postmenarchal) who are premenopausal 
251 
and not surgically sterile will be completed. 
252 
Participants will receive supplies for blood glucose and ketone testing. Quality Control (QC) testing will 
253 
be performed on the meters before they are dispensed. 
254 
All participants will use study supplied Control-IQ technology 1.5 pumps during the study run-in phase, 
255 
even if they are current Control-IQ technology users. Pump settings may be transferred over from the 
256 
participant’s prior pump, or for current multiple daily injection users, can be started per the guidance on 
257 
the device training checklist. 
258 
3.1.1 Training on System Use 
259 
All participants will receive study system training from qualified staff, to include CGM and Control-IQ 
260 
training. 
261 
At a minimum training will include the following: 
262 
• 
Calibration of the CGM in accordance with manufacturer labeling 
263 
• 
Procedures for treating severe hypoglycemia 
264 
• 
Procedures for identifying potential infusion set failure and steps to take including the checking of the 
265 
blood ketone level and changing the infusion set 
266 
• 
Use of the security PIN on the insulin pump will be required for anyone who is not entirely 
267 
responsible for their own diabetes care, to include all 2-5 year olds, and those 6 years of age or older 
268 
who may be only partially responsible for their own diabetes management. 
269 
The participant will be given a User Guide as a reference as well as Hypoglycemia and Hyperglycemia 
270 
Treatment Guidelines as part of the Study Participant Instruction Sheet. The device training checklist for 
271 
CGM and the Control-IQ 1.5 pump will be completed by qualified study staff. 
272 
Participants will be instructed to download the study device prior to each phone contact or office visit. 
273 
The participant will be instructed to use the system in closed-loop mode except 1) when no calibrated 
274 
CGM sensor is available or 2) if insulin is delivered by any means other than the study pump (e.g. 
275 
injection of subcutaneous insulin via syringe in the event of infusion site failure). If insulin is delivered 
276 
by any means other than the study pump, participant will be instructed to turn off Control-IQ for the next 
277 
four hour and until CGM glucose is < 180 mg/dL. 
278 
The participant will also be instructed to contact study staff during periods of illness with an elevated 
279 
temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant illness, or during 
280 
periods of use of medications such as epinephrine for the emergency treatment of a severe allergic 
281 
reaction or asthma attack. Participants will contact study staff if treatment with oral or injectable 
282 
B22

 
glucocorticoids is needed to determine if and for how long closed-loop use should be temporarily 
283 
discontinued. Given the short period of use of each aspect of the system, participants may be asked to end 
284 
participation in the study if the investigator judges Control-IQ technology use must be stopped for more 
285 
than a few days. 
286 
Participants will be provided with contact information and will be asked to call the study clinical staff 
287 
for any health-related issues and for technical issues with the system. Participants may use the study 
288 
pump without Control-IQ activated and study CGM during periods of component disconnections or 
289 
technical difficulties. 
290 
Participants may use available manufacturer-provided CGM software and features of the study CGM 
291 
related to mobile data access or remote monitoring, but will be instructed not to use any third-party 
292 
components for this purpose. The t:connect mobile app from Tandem Diabetes Care will not be 
293 
available for use during the trial, and will not pair to the study pumps. 
294 
Study staff will discuss with the participant that routine contact is required as per the study visit schedule 
295 
and will make arrangements with the participant for the contacts.  
296 
Participants may complete the device training visit in more than 1 session if necessary. 
297 
3.1.2 Training on Management of Hypoglycemia 
298 
The t:slim X2 with Control-IQ system will issue a predictive hypoglycemia alert (Control-IQ Low Alert) 
299 
when the system predicts BG <70 mg/dL within the next 15 minutes (<80 mg/dL when exercise mode is 
300 
activated). Participants will be permitted to change the CGM low glucose threshold alert setting on their 
301 
device (or Dexcom mobile app), but will be instructed to choose a value no less than 70 mg/dL. 
302 
If the participant receives a Control-IQ Low Alert, a message appears on the user interface that is 
303 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user in 5 
304 
minutes. This alert remains on the screen until acknowledged by the participant. The user is prompted 
305 
to test blood glucose and treat with carbohydrate. 
306 
The participant (and /or parent/guardian) will be instructed that if severe hypoglycemia occurs, the study 
307 
pump’s insulin delivery should be suspended and glucagon administered if the participant is unable to 
308 
consume carbohydrate. 
309 
Participants will be required to have a home glucagon emergency kit. Participants who currently do not 
310 
have one will be given a prescription for the glucagon emergency kit. 
311 
3.1.3 Training on Management of Hyperglycemia 
312 
The t:slim X2 with Control-IQ system will issue a predictive hyperglycemia alert (Control-IQ High Alert) 
313 
when the system has increased insulin delivery, but detects a CGM value above 200 mg/dL and does not 
314 
predict the value will decrease in the next 30 minutes. During the course of the study, participants will be 
315 
permitted to change the CGM high glucose threshold alert setting on their device or mobile app, but will 
316 
be instructed to choose a value no greater than 300 mg/dL. 
317 
If the participant receives a Control-IQ High Alert, a prompt appears on the user interface to check the 
318 
site for occlusion and test blood glucose. 
319 
If a participant’s CGM reading is >300 mg/dL for more than 60 minutes or is ≥400 mg/dL at any point, 
320 
the participant will be instructed to take the following steps: 
321 
• 
Perform a blood glucose meter check. 
322 
• 
If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
323 
B23

 
• 
If the ketone level is ≥ 0.6 mmol/L (or ≥ 2.5 mmol\L at any time), take correction insulin, change 
324 
insulin (pump) infusion site and contact study staff. Continue to monitor their glucose and blood 
325 
ketone levels until they return to normoglycemia and ketones are < 0.6 mmol/l. 
326 
 
If ketones are <0.6 mmol/l, participants will be advised to continue to monitor their glucose 
327 
until it returns to normoglycemia and to repeat the ketone measurement in 90 minutes if 
328 
necessary 
329 
• 
If correction insulin is administered via insulin syringe, turn Control-IQ off for four hours and until 
330 
glucose level has returned to <180 mg/dL. 
331 
3.2 Visits 3, 4 and 5: Control-IQ 1.5 follow up contacts 
332 
Following the Control-IQ 1.5 Training Visit, participants will use the study Control-IQ 1.5 pump and 
333 
study CGM for ~2 weeks during the study Run-In Period. A contact will occur at 1 day (+12 hours), 3 
334 
days (1 day) to review adverse events as well as discuss infusion set care, and another phone call at 7 
335 
days (2 days). Participants will then return to clinic in approximately 2 weeks (3 days). 
336 
3.3 Visit 6: Control-IQ 2.0 Training Visit 
337 
After participants complete the run-in, they will return for the Control-IQ 2.0 training visit, and switch to 
338 
the Control-IQ 2.0 study pump after training by qualified staff.  
339 
Control-IQ 2.0 allow for selection of different glycemic targets, as well as toggling autoboluses in 
340 
standard and exercise activity. The late bolus feature will also be available. 
341 
Participants will be randomized to use either a daytime 30-min predictive glucose target of 90-130 mg/dL 
342 
or 112.5 to 160 mg/dL for the first two-week period, then switch to the other target after 2 weeks.  
343 
In the training visit, participants will: 
344 
1) Select the appropriate target in clinic on their study pump per the randomization, and will be 
345 
instructed by study staff to use the assigned glycemic target during each two week period.  
346 
2) Be instructed that autoboluses will default to on during normal activity, and off during exercise 
347 
activity.  
348 
3) Be reminded again that use of the security PIN on the insulin pump will be required for anyone 
349 
who is not entirely responsible for their own diabetes care, to include all 2-5 year olds, and those 
350 
6 years of age or older who may be only partially responsible for their own diabetes management. 
351 
4) Be instructed that sleep activity will be required during Control-IQ 2.0 use. A sleep schedule 
352 
should be programmed into the pump for use each night. Participants will be instructed to disable 
353 
sleep or adjust the schedule on the nights of the late bolus meal challenges, then re-enable sleep 
354 
activity as soon as the challenges are over, so it is used the rest of the night. 
355 
5) Review prior training guidelines from the Control-IQ technology 1.5 training visit, and be taught 
356 
how the new features are different in Control-IQ technology 2.0. 
357 
6) Review the study meal late bolus challenges, to be performed twice in each two week period. 
358 
Participants may also use late bolus as desired outside of the challenges. 
359 
The participant will be given a User Guide as a reference as well as review the Hypoglycemia and 
360 
Hyperglycemia Treatment Guidelines as part of the Study Participant Instruction Sheet. The study device 
361 
training form will be completed. 
362 
Participants will be instructed to download the study device prior to each phone contact or office visit. 
363 
B24

 
Participants may use available manufacturer-provided CGM software and features of the study CGM 
364 
related to mobile data access or remote monitoring, but will be instructed not to use any third-party 
365 
components for this purpose. The t:connect mobile app from Tandem Diabetes Care will not be 
366 
available for use during the trial, and will not pair to the study pump. 
367 
The device training checklist for the Control-IQ 2.0 pump will be completed by qualified study staff. 
368 
A urine pregnancy test for all females of childbearing potential who are premenopausal and not surgically 
369 
sterile will be performed. 
370 
Study staff will discuss with the participant that routine contact is required as per the study visit schedule 
371 
and will make arrangements with the participant for the contacts.  
372 
Clinical staff will verify with participants at each contact that the correct glycemic targets are being used. 
373 
Contacts for the study meal challenges will occur throughout the study Treatment Period. 
374 
Baseline INSPIRE questionnaire for pediatric participants age 8-17, for adult participants age 18+, and 
375 
for parents of pediatric participants age 2-17 will be completed. 
376 
3.4 Study Contacts in the Treatment Period with Control-IQ 2.0 Technology 
377 
Participants will have a phone (or video-conference) follow-up visit at 1 day, 3 days and 1 week, a clinic 
378 
follow-up visit at 2 weeks, a phone follow-up visit at 3 days and 1 week after switching glycemic targets, 
379 
and a final clinic visit at 2 weeks after switching glycemic targets, within the windows specified below. 
380 
TARGET DAY/WEEK 
VISIT OR 
PHONE 
TARGET WINDOW (AROUND 
TARGET DAY/WEEK) 
Visit 6: Control-IQ 2.0 Training Visit 
V 
2 weeks (3 days) after Visit 2 
Visit 7: 1 days after visit 6 
P 
+12 hours 
Visit 8: 3 days after visit 6 
P 
+1 day 
Visit 9: 1 week after visit 6 
P 
+2 days 
Visit 10: 2 weeks after visit 6 (switch targets) 
V 
+3 days 
Visit 11: 1 day after visit 10 
P 
+12 hours 
Visit 12: 3 days after visit 10 
P 
+1 days 
Visit 13: 1 week after visit 10 
P 
+2 days 
Visit14: 2 weeks after visit 10 
V 
+3 days 
If necessary, visits should be completed out-of-window rather than missed. A visit is not considered 
381 
missed until the next visit/phone window opens.  
382 
The goal will be for all participants to complete all scheduled visits. However, participants who 
383 
(because of unforeseen circumstances or due to changes in contact precautions that may be needed 
384 
during the evolving COVID-19 pandemic) are unable or unwilling to return for all follow-up visits 
385 
will be permitted to return for key visits only (Visits 1, 2 and 6) as an alternative to withdrawal from the 
386 
study. Remote (phone) visits will still be performed as scheduled. When a participant is placed into this 
387 
status, remote visits for visits 10 and 14 will not be recorded as protocol deviations. 
388 
Additional phone and office visits may occur as needed. 
389 
For the in clinic visits at the end of each two week treatment period, if a clinical site believes these visits 
390 
need to be performed remotely, the following approvals must be obtained prior to conducting the visit 
391 
remotely: 
392 
5

 
• 
Sponsor approval for the reason the visit cannot be performed in person 
393 
• 
Investigator approval at the site level for the reason the visit cannot be performed in person 
394 
In addition, all study procedures listed in section 3.4.1 are to be completed, including upload of the study 
395 
device and review of the device data. If the final visit is performed remotely, participant will mail in their 
396 
study devices, and investigators will remotely supervise transition back to their home diabetes treatment 
397 
plan. 
398 
3.4.1 Procedures at all Study Visits 
399 
The following procedures will be performed at each visit, unless otherwise specified: 
400 
• 
Review of study device data 
401 
• 
Assessment of compliance with study device use by review of any available device data 
402 
• 
Assessment of device issues that have occurred 
403 
• 
Assessment of adverse events, using open ended questions to capture hyperglycemic and 
404 
hypoglycemic events, and their underlying cause and relationship to the study device or other parts of 
405 
the system (such as the infusion set). 
406 
• 
Review of ongoing study late bolus meal challenges when in the treatment period 
407 
• 
Baseline INSPIRE questionnaire for pediatric participants age 8-17, for adult participants age 18+, 
408 
and for parents of pediatric participants age 2-17 will be completed at visit 6 
409 
• 
Post Assessment INSPIRE questionnaire for pediatric participants age 8-17, for adult participants age 
410 
18+, and for parents of pediatric participants age 2-17 will be completed at visits 10 and 14 
411 
• 
SUS Scale will be completed at visits 10 and 14 
412 
• 
Study Specific Questionnaire will be completed at visits 10 and 14 
413 
At the final visit (or at subject withdrawal), the study staff will then supervise the participants transition 
414 
back to their standard of care therapy as follows: 
415 
• 
Study staff will re-evaluate the subject’s baseline therapy doses, noting changes in basal rates, 
416 
carbohydrate ratios, and correction factors in use at the end of the trial. For prior CSII users, the 
417 
study investigator will supervise and confirm the entry of settings in the insulin delivery profile of 
418 
the participant’s home pump at the end of the study. 
419 
• 
For those subjects using basal insulin, doses will be adjusted to best match the current daily 
420 
insulin requirements from CSII use, typically = (total daily dose + 20%)/2, with further 
421 
modification as per clinical site usual practice.  
422 
• 
Participants must have two CGM or fingerstick BG values, separated by at least 15 minutes, that 
423 
must be above 80 mg/dL prior to discharge from the clinic for the final visit. In addition, CGM 
424 
trend arrow must not be going down at the time of discharge. 
425 
• 
Study staff will confirm subjects have carbohydrates on hand for their drive back home, and 
426 
instruct subjects to check their glucose levels when they arrive at home, prior to bedtime, and at 
427 
least one time overnight on the first night to monitor for hypoglycemia, reminding subjects that 
428 
insulin on board can be active for the next few hours even after stopping their pump. 
429 
B26

 
3.5 Unscheduled Visits 
430 
Participants may have unscheduled visits during the study period if required for additional device training 
431 
or other unanticipated needs per the study investigator discretion. 
432 
3.6 Late Bolus Meal Challenges 
433 
Participants will complete two late bolus meal challenges during each two week treatment period. 
434 
Procedures are described in section 5.1. 
435 
3.7 Adjustments in Insulin Pump Settings 
436 
Insulin and glucose data from the screening visit, as well as follow up visits, will be reviewed and the site 
437 
investigator may adjust insulin delivery profile settings as needed in accordance with their clinical 
438 
practice. 
439 
3.8 Early Discontinuation of Study Device 
440 
If the participant cannot be reached for scheduled study contacts, the participant’s other contact methods 
441 
will be utilized. Participants who are not compliant with the arranged contacts on two separate occasions 
442 
may be discontinued at the discretion of the investigator. Participants who discontinue the study device 
443 
prior to the final visit, either by choice or by investigator decision, will be asked to come for an end of 
444 
study visit and then will be dropped from the study.  
445 
3.9 Remote Monitoring 
446 
Real-time CGM alerts will be sent to study staff providers (MD, DO, NP, PA) for the first ten 6-13 year 
447 
old participants to begin use of the lower target (90-130 mg/dL) for the first week of Control-IQ 2.0 use at 
448 
that target. This requirement will only be removed for future participants in this age group after the first 
449 
ten participants finish the first week of use of the lower target, and no safety concerns arise, where: 
450 
1) No severe hypoglycemia events related to algorithm delivered automated insulin dosing occur 
451 
that required study staff intervention because the participant was not aware/treating 
452 
appropriately. 
453 
2) No severe hyperglycemic events related to algorithm delivered automated insulin dosing 
454 
occurred that required study staff intervention because the participant was not aware/treating 
455 
appropriately.  
456 
In addition, real-time CGM alerts will be sent to study staff providers (MD, DO, NP, PA) for all 2-5 year 
457 
old participants throughout their use of Control-IQ 2.0 technology (all 4 weeks). 
458 
B27

 
Chapter 4: Study Devices and Drugs 
459 
4.1 Study Devices 
460 
4.1.1 Insulin Pump 
461 
For the run in period, participants will use a study provided Tandem t:slim X2 with Control-IQ 1.5 
462 
technology (Investigational Device). For the treatment period, participants will use a study provided 
463 
Tandem t:slim X2 with Control-IQ 2.0 technology (Investigational Device). 
464 
4.1.2 Continuous Glucose Monitoring 
465 
The study CGM is the commercial version of the Dexcom G6, which includes a transmitter and sensors. 
466 
The CGM sensor will be replaced at least once every 10 days. 
467 
4.1.3 Blood Glucose Meter 
468 
The study blood glucose meter is the Contour® NEXT (Ascencia Diabetes Care). 
469 
Blood glucose levels will be measured using the study’s blood glucose meter (glucometer) and the 
470 
CGM device will be calibrated if needed using the study glucometer and strips in accordance with the 
471 
manufacturer’s labeling. 
472 
4.1.4 Ketone Meter 
473 
The study blood ketone meter is the Precision Xtra Blood Glucose and Ketone Monitoring System 
474 
(Abbott Diabetes Care). 
475 
Blood ketone levels will be measured when needed to evaluate prolonged hyperglycemia. The blood 
476 
glucose meter component of the Precision Xtra device will not be used. 
477 
4.2 Study Device and Drug Accountability Procedures 
478 
Device accountability and inventory will be documented to include detailed inventory records of the study 
479 
CGM supplies, and Tandem insulin pump system. 
480 
4.3 Participant Access to Study Device at Study Closure 
481 
Participant will return all investigational study devices and supplies (insulin pump, CGM and related 
482 
supplies) at study closure. Participant may keep the study ketone meter and study glucometer if these 
483 
devices are not marked for investigational use only. 
484 
B28

 
Chapter 5: Testing Procedures and Questionnaires 
485 
5.1 General Challenge Guidelines 
486 
All study participants will complete two late bolus meal challenges during each two week treatment 
487 
period. Participants will be instructed to wait at least 48 hours after switching targets in the treatment 
488 
period to perform the next set of challenges. 
489 
A minimum of 48 hours will occur between all challenges for each participant.  
490 
A paper logbook will be provided to participants that includes a page to record details about each 
491 
challenge and procedural instructions about how participants will conduct these challenges. This material 
492 
will be reviewed with each participant, and will be used for source verification for the eCRF database. 
493 
Before starting each challenge, participants (or parent/guardian if the participant is < 18 years of age) 
494 
must assure the participant has a working CGM and Control-IQ is active. For pediatric participants, the 
495 
participant’s parent or guardian must remain with the child at all times and monitor CGM readings 
496 
frequently during and through meal completion plus 5 hours (3 hours for participants age 2-5). Snacks 
497 
and glucagon must be available for use during and after each challenge. 
498 
Participants will be instructed to communicate with study staff within one day prior to each challenge to 
499 
review procedures and to have a contact with study staff no more than 1 day after the completion of each 
500 
challenge. The participant or parent/guardian must have an on-call phone number for the study team prior 
501 
to initiation of each challenge. 
502 
Hyperglycemia and Hypoglycemia treatment guidelines (sections 3.1.3 and 3.1.2) remain in effect for the 
503 
challenges, and will be reviewed with participants prior to each challenge.  
504 
Site staff will directly contact the participant if they do not receive a follow up contact from participants 
505 
when 24 hours have passed since the time of completion of the planned challenge. 
506 
5.1.1 Late Bolus Meal Challenges 
507 
All challenges will be performed with the last meal of the day (dinner) and participants will be instructed 
508 
not to snack after dinner on days they are performing meal challenges, unless it is to treat hypoglycemia. 
509 
Participants will also be instructed not to use sleep activity for at least 5 hours (3 hours for participants 
510 
age 2-5) once starting the meal challenge. Participants will be reminded to disable sleep activity if it is 
511 
inadvertently activated during the challenge, and to re-enable it at the end of the challenge. 
512 
Time zero (start of the challenge) is at the first bite of food for the study meal. 
513 
During each two week treatment period with Control-IQ technology 2.0 use, the two meal challenges will 
514 
consist of: 
515 
• 
Full bolus for the given carbohydrates and calculated correction, given 45 minutes after 
516 
starting the meal, based on calculated bolus dose using the bolus calculator (with full amount 
517 
of carbohydrates entered). 
518 
• 
Full bolus for the given carbohydrates and calculated correction, given 45 minutes after 
519 
starting the meal, based on calculated bolus dose using the bolus calculator (with full amount 
520 
of carbohydrates entered) AND enabling the late bolus feature to 45 minutes later. 
521 
For each meal challenge, participants will: 
522 
1. Be in a fasting state for two hours prior to consuming the last meal of the day, with the last 
523 
manual insulin bolus more than two hours prior to the meal.   
524 
B29

 
 
2. For participants age 6+, only begin the meal challenge if CGM glucose is between 70 mg/dL and 
525 
200 mg/dL, and CGM trend arrow is not down.   
526 
For participants age 2-5, only begin the meal challenge if CGM glucose is between 70 mg/dL and 
527 
250 mg/dL, and CGM trend arrow is not down.   
528 
Subjects with hyperglycemia > 200mg/dL will reschedule their challenge for another time. If < 
529 
70 mg/dL, carbohydrate treatment can be given, after which the meal challenge can continue. 
530 
3. Pediatric participants age 2-5 should have a meal with at least 20 grams of carbohydrates. 
531 
Participants age 6-13 should have a meal with at least 35 grams of carbohydrates. All other 
532 
participants should have at least 50 grams of carbohydrates for the study meal challenges. Each 
533 
participant should use the same meal for all of their meal challenges in the study. Participants 
534 
will be encouraged to use the same frozen entrée of their choice for consistency. 
535 
4. Do their best to complete the meal within 30 minutes of starting to eat. 
536 
5. Write down the start and end time of eating the meal, as well as the meal content (to include 
537 
amount of carbohydrate, protein and fat) on the study provided logbook. 
538 
6. Bolus for the meal 45 minutes after starting to eat, entering the full carbohydrate amount and 
539 
using the recommended dose from the bolus calculator. For one of the two challenges during a 
540 
single treatment period, use the bolus calculator but do not change the bolus time. For the other 
541 
challenge during the same treatment period, use the bolus calculator but change the bolus time to 
542 
45 minutes late. 
543 
7. Not give an additional bolus during 5 hours (3 hours for participants age 2-5) after the start of 
544 
meal challenge (i.e., after start of meal), unless BG is above 300 mg/dL for more than 1 hour, or 
545 
symptoms of hyperglycemia develop. 
546 
8. Not take additional carbohydrates during 5 hours (3 hours for participants age 2-5) after the start 
547 
of meal challenge (i.e., after start of meal), unless BG is < 70 mg/dL, or symptoms of 
548 
hypoglycemia develop. 
549 
9. Not exercise for 5 hours (3 hours for participants age 2-5) after the meal challenge begins. 
550 
10. Make sure sleep activity is not active for the 5 hours (3 hours for participants age 2-5) after the 
551 
meal challenge begins (start of meal). 
552 
11. Notify the site within 24 hours after completion of each meal challenge. 
553 
5.2 Laboratory Testing 
554 
5.2.1 HbA1c 
555 
HbA1c measurement will be performed locally at the Screening visit. 
556 
5.2.2 Urine Pregnancy 
557 
Urine pregnancy testing performed locally at clinical site for females of child-bearing potential at the 
558 
screening visit, at the start of study device use (for both device training visits), and anytime pregnancy is 
559 
suspected. 
560 
5.2.3 Patient Reported Outcomes 
561 
The following patient reported outcomes/questionnaires and study specific outcomes will be assessed 
562 
during the trial as per the study visit schedule. 
563 
B30

 
INSPIRE Survey 
564 
The INSPIRE (Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations) survey was 
565 
developed to assess various aspects of a user’s experience regarding automated insulin delivery for both 
566 
patients and family members. The surveys include various topics important to patients with type 1 
567 
diabetes and their family members based upon >200 hours of qualitative interviews and focus groups. The 
568 
adult survey includes 31 items; the adolescent survey includes 28 items; and the parent survey includes 30 
569 
items. Response options for all surveys include a 5-point Likert scale from strongly agree to strongly 
570 
disagree, along with an N/A option. 
571 
Administration time is approximately 5 minutes. 
572 
System Usability Scale (SUS) 
573 
The System Usability Scale (SUS) is a 10-item questionnaire that measures the overall usability of a 
574 
system. It is a valid and reliable measure of the perceived usability of a system and is technology-
575 
agnostic. The questionnaire presents statements with five response options (anchoring the options from 
576 
strongly disagree to strongly agree) and asks users to rate their agreement to the statements. User scores 
577 
are transformed into a composite score, from 0 to 100, and this score is taken as an overall measure of the 
578 
system’s usability; higher scores indicate better perceived usability. 
579 
Administration time is approximately 5 minutes. 
580 
Study Specific Questionnaire 
581 
A study-specific questionnaire will be used to assess experiences and views around the different target 
582 
ranges, late bolus challenges, freedom to eat and adjust meals, and general thoughts about the trial.  
583 
Administration time is approximately 5 minutes. 
584 
B31

 
Chapter 6: Unanticipated Problem, Adverse Event, and 
585 
Device Issue Reporting 
586 
6.1 Unanticipated Problems 
587 
Site investigators will promptly report to the Coordinating Center and Sponsor on an eCRF all 
588 
unanticipated problems meeting the criteria below. For this protocol, an unanticipated problem is an 
589 
incident, experience, or outcome that meets all of the following criteria: 
590 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
591 
described in the protocol related documents, such as the IRB-approved research protocol and 
592 
informed consent document; and (b) the characteristics of the subject population being studied 
593 
• 
Related or possibly related to participation in the research (possibly related means there is a 
594 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
595 
procedures involved in the research) 
596 
• 
Suggests that the research places participants or others at a greater risk of harm than was previously 
597 
known or recognized (including physical, psychological, economic, or social harm) 
598 
The Coordinating Center will report to the IRB all unanticipated problems not directly involving a 
599 
specific site such as unanticipated problems that occur at another participating entity such as a pharmacy 
600 
or laboratory. These instances must be reported to the study IRB within seven calendar days of 
601 
recognition. The Sponsor will report to the appropriate regulatory authorities if the IRB determines that 
602 
the event indeed meets the criteria of an Unanticipated Problem requiring additional reporting. 
603 
6.2 Adverse Events 
604 
6.2.1 Definitions 
605 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) associated with 
606 
study procedures, the use of a device, biologic in a study participant, including any comparator used, 
607 
irrespective of the relationship between the adverse event and the device(s) under investigation (referred 
608 
to as Adverse Reaction when caused by a drug). 
609 
Serious Adverse Event (SAE): Any untoward medical occurrence that meets at least one of the following: 
610 
• 
Results in death. 
611 
• 
Is life-threatening; (a non-life-threatening event which, had it been more severe, might have become 
612 
life-threatening, is not necessarily considered a serious adverse event). 
613 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
614 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the ability 
615 
to conduct normal life functions (sight threatening). 
616 
• 
Is a congenital anomaly or birth defect. 
617 
• 
Is considered a significant medical event by the investigator based on medical judgment (e.g., may 
618 
jeopardize the participant or may require medical/surgical intervention to prevent one of the outcomes 
619 
listed above). 
620 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any 
621 
life -threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
622 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
623 
B32

 
application (including a supplementary plan or application), or any other unanticipated serious problem 
624 
associated with a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
625 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the device 
626 
may have caused or to which the device may have contributed (Note that an Adverse Event Form is to be 
627 
completed in addition to a Device Issues Form, unless excluded from reporting as defined in section 
628 
6.2.2). 
629 
Comparator: Medical device, therapy (e.g. active treatment, normal clinical practice), placebo or no 
630 
treatment, used in the control group in a clinical investigation. (ISO 14155:2020) 
631 
Device Complaints and Malfunctions: A device malfunction or complaint is something that happens 
632 
to a device or related to device performance, whereas an adverse event happens to a participant. A device 
633 
complaint may occur independently from an AE, or along with an AE. An AE may occur without a 
634 
device complaint or there may be an AE related to a device complaint. A device malfunction is any 
635 
failure of a device to meet its performance specifications or otherwise perform as intended. 
636 
Performance specifications include all claims made in the labeling for the device. The intended 
637 
performance of a device refers to the intended use for which the device is labeled or marketed. 
638 
(21 CFR 803.3). Note: for reporting purposes, sites will not be asked to distinguish between device 
639 
complaints and malfunctions. 
640 
Use Error: User action or lack of user action while using the medical device (3.34) that leads to a 
641 
different result than that intended by the manufacturer or expected by the user. Includes the inability of 
642 
the user to complete a task. Use errors can result from a mismatch between the characteristics of the user, 
643 
user interface, task or use environment. Users might be aware or unaware that a use error has occurred. 
644 
An unexpected physiological response of the patient is not by itself considered a use error. A malfunction 
645 
of a medical device that causes an unexpected result is not considered a use error. (ISO 14155:2020) 
646 
6.2.2 Reportable Adverse Events 
647 
A reportable adverse event includes all events meeting the definition of an adverse event, except for the 
648 
following: 
649 
• 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
650 
events unless associated with an Adverse Device Effect or discontinuation of the study device.  
651 
• 
Skin reactions from sensor or pump infusion set placement are only reportable if severe and/or 
652 
required treatment. 
653 
B33

 
All reportable AEs—whether volunteered by the participant, discovered by study personnel during 
654 
questioning, or detected through physical examination, laboratory test, or other means—will be reported 
655 
on an AE form online. Each AE form is reviewed by the Medical Monitor to assess safety and to verify 
656 
the coding and the reporting that is required. 
657 
6.2.3 Hypoglycemic Events 
658 
Hypoglycemia is only reportable as an adverse event when one of the following criteria is met: 
659 
• 
a hypoglycemic event occurred meeting the following definition of severe hypoglycemia: the event 
660 
required assistance of another person due to altered consciousness, and required another person to 
661 
actively administer carbohydrate, glucagon, or other resuscitative actions. This means that the 
662 
participant was impaired cognitively to the point that he/she was unable to treat himself/herself, was 
663 
unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced 
664 
seizure or loss of consciousness. These episodes may be associated with sufficient neuroglycopenia to 
665 
induce seizure or loss of consciousness. If glucose measurements are not available during such an 
666 
event, neurological recovery attributable to the restoration of glucose to normal is considered 
667 
sufficient evidence that the event was induced by a low glucose concentration. 
668 
• 
evaluation or treatment was obtained at a health care provider facility for an acute event involving 
669 
hypoglycemia, or the participant contacted the site and received guidance following the occurrence of 
670 
an acute event involving hypoglycemia 
671 
When a severe hypoglycemia event occurs (as defined above), an Adverse Event Form should be 
672 
completed. Severe hypoglycemia events should be considered to be serious adverse events with respect to 
673 
reporting requirements. When a severe hypoglycemia event occurs during use of a study device, it 
674 
generally will be considered to be unrelated to the device (per section 6.2.5) if the device functioned as 
675 
intended and there does not appear to be a flaw in how the device is intended to function. 
676 
6.2.4 Hyperglycemic/Ketotic Events 
677 
Hyperglycemia is only reportable as an adverse event when one of the following criteria is met:   
678 
• 
the event involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) and 
679 
described below 
680 
• 
evaluation or treatment was obtained at a health care provider facility for an acute event involving 
681 
hyperglycemia or ketosis, or the participant contacted the site and received guidance on how to 
682 
manage the hyperglycemia/ketosis 
683 
• 
blood ketone level ≥1.0 mmol/L, even if there was no communication with a health care provider at 
684 
the time of the event 
685 
Hyperglycemic events are classified as DKA if all of the following are present, or judged likely to have 
686 
been present based on available data: 
687 
• 
Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
688 
• 
Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
689 
• 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate (or CO2) <15; and 
690 
• 
Treatment provided in a health care facility 
691 
When a hyperglycemia/ketotic event qualifies as an AE, or as a SAE as defined in section 6.2.1, an 
692 
Adverse Event Form should be completed. Events meeting DKA criteria should be considered to be 
693 
serious adverse events with respect to reporting requirements. Hyperglycemia events not meeting criteria 
694 
B34

 
 
for DKA generally will not be considered as serious adverse events unless one of the SAE criteria in 
695 
section 6.2.1 is met. 
696 
When a hyperglycemia/DKA event occurs during use of a study device, it generally will be considered to 
697 
be unrelated to the device (per section 6.2.5) if the device functioned as intended and there does not 
698 
appear to be a flaw in how the device is intended to function. 
699 
6.2.5 Relationship of Adverse Event to Study Investigational Device 
700 
The study investigator will assess the relationship of any adverse event to the study device or study drug. 
701 
The Medical Monitor also will make this assessment, which may or may not agree with that of the study 
702 
investigator. Reporting requirements will be based on the Medical Monitor’s assessment. 
703 
To ensure consistency of adverse event causality assessments, investigators should apply the following 
704 
general guidelines when determining whether an adverse event is related to a study device or study drug: 
705 
Unrelated: The AE is clearly not related to a study drug/device and a likely alternative etiology exists 
706 
such as an underlying disease, environmental or toxic factors or other therapy. 
707 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after use of study 
708 
drug/device and a more likely alternative etiology exists such as an underlying disease, environmental or 
709 
toxic factors, or other therapy.  
710 
Possibly Related: The AE occurred in a reasonable time during or after use of study drug/device; but 
711 
could be related to another factor such as an underlying disease, environmental or toxic factors, or other 
712 
therapy; and there is a possible, though weak, scientific basis for establishing a causal association 
713 
between the AE and the study drug/device. 
714 
Probably Related: The AE occurred in a reasonable time during or after use of study drug/device; is 
715 
unlikely to be related to another factor such as an underlying disease, environmental or toxic factors, or 
716 
other therapy; and there is a plausible, though not strong, scientific basis for establishing a causal 
717 
association between the AE and the study drug/device.  
718 
Definitely Related: The AE occurred in a reasonable time during or after use of study drug/device; 
719 
cannot be explained by another factor such as an underlying disease, environmental or toxic factors, or 
720 
therapy; and there is a strong scientific basis for establishing a causal association between the AE and the 
721 
study drug/device.  
722 
Events determined to be Possibly Related, Probably Related, or Definitely Related will be considered 
723 
‘Related’ with respect to any required IRB and FDA reporting. 
724 
6.2.6 Severity (Intensity) of Adverse Events 
725 
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, 
726 
or (3) severe. A severity assessment is a clinical determination of the intensity of an event. Thus, a severe 
727 
adverse event is not necessarily serious. For example, itching for several days may be rated as severe, but 
728 
may not be clinically serious. 
729 
MILD: Usually transient, requires no special treatment, and does not interfere with the participant’s daily 
730 
activities. 
731 
MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the participant 
732 
and may interfere with daily activities, but is usually ameliorated by simple therapeutic measures and 
733 
participant is able to continue in study. 
734 
SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may cause 
735 
discontinuation of study device, and generally requires systemic drug therapy or other treatment. 
736 
B35

 
 
6.2.7 Expectedness 
737 
For a serious adverse event that is considered possibly related to study device, the Medical Monitor will 
738 
classify the event as unexpected if the nature, severity, or frequency of the event is not consistent with the 
739 
risk information previously described in the protocol, labeling, or Investigator Brochure. 
740 
6.2.8 Coding of Adverse Events 
741 
Adverse events will be coded using the MedDRA dictionary. 
742 
6.2.9 Outcome of Adverse Events 
743 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
744 
• 
RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae. Record 
745 
the AE/SAE stop date. 
746 
• 
RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized without 
747 
change in the event anticipated. Record the AE/SAE stop date. 
748 
• 
FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that was the 
749 
cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time of death; 
750 
however, were not the cause of death, will be recorded as “resolved” at the time of death. 
751 
• 
NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as the event 
752 
was ongoing with an undetermined outcome. 
753 
An ongoing outcome will require follow-up by the site in order to determine the final outcome 
754 
of the AE/SAE. The outcome of an ongoing event at the time of death that was not the cause of 
755 
death, will be updated and recorded as “resolved” with the date of death recorded as the stop 
756 
date. 
757 
• 
UNKNOWN – An unknown outcome is defined as an inability to access the participant or the 
758 
participant’s records to determine the outcome (for example, a participant that was lost to follow-up). 
759 
If any reported adverse events are ongoing when a participant completes the study (or withdraws), 
760 
adverse events classified as UADEs or related SAEs or SUSARs will be followed until they are either 
761 
resolved, or have no prospect of improvement or change, even after the participant has completed all 
762 
applicable study visits/contacts. For all other adverse events, data collection will end at the time the 
763 
participant completes the study. Note: participants should continue to receive appropriate medical care 
764 
for an adverse event after their participation in the study ends. 
765 
6.3 Reportable Device Issues 
766 
All UADEs and ADEs as defined in section 6.2.1 will be reported as both ‘device issues’ and adverse 
767 
events, except for skin reactions from CGM sensor placement or pump infusion set placement that do not 
768 
require pharmacologic treatment. 
769 
Device issues will be reported except in the following circumstances. These occurrences are expected and 
770 
will not be reported on a Device Issue Form assuming criteria for a UADE or ADE have not been met: 
771 
• 
CGM sensor lasting fewer days than expected per manufacturer 
772 
• 
CGM tape adherence issues 
773 
• 
Pump infusion set insertion lasting fewer days than expected per manufacturer 
774 
• 
Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
775 
B36

 
• 
Intermittent device component disconnections/communication failures not requiring system 
776 
replacement or workaround/resolution not specified in user guide/manual. 
777 
• 
Device issues clearly addressed in the user guide manual that do not require additional 
778 
troubleshooting 
779 
6.4 Timing of Event Reporting 
780 
SAEs possibly related to a study device, study drug, or study participation and UADEs must be reported 
781 
by the site to the Sponsor within 1 working day of the site becoming aware of the event. This can occur 
782 
via phone or email, or by completion of the appropriate eCRFs as applicable. If the form(s) are not 
783 
initially completed, they should be competed as soon as possible after there is sufficient information to 
784 
evaluate the event. All other reportable ADEs and other reportable AEs should be submitted by 
785 
completion on the eCRF(s) within 7 days of the site becoming aware of the event.  
786 
The Sponsor will notify all participating investigators of any adverse event that is serious, related, and 
787 
unexpected. Notification will be made within 10 working days after the Sponsor becomes aware of the 
788 
event. 
789 
Each principal investigator is responsible for reporting serious study-related adverse events and abiding 
790 
by any other reporting requirements specific to his/her Institutional Review Board or Ethics Committee.  
791 
Upon receipt of a qualifying event, the Sponsor will investigate the event to determine if a UADE has 
792 
occurred, and if indicated, report the results of the investigation to all overseeing IRBs, and the FDA 
793 
within 10 working days of the Sponsor becoming aware of the UADE per 21CFR 812.46(b). The Sponsor 
794 
must determine if the UADE presents an unreasonable risk to participants. If so, the Sponsor must ensure 
795 
that all investigations, or parts of investigations presenting that risk, are terminated as soon as possible but 
796 
no later than 5 working days after the Sponsor makes this determination and no later than 15 working 
797 
days after first receipt notice of the UADE. 
798 
The investigators are also required to report, without unjustified delay, all device complaints and 
799 
malfunctions that could have led to a UADE, including device complaints and malfunctions, irrespective 
800 
of whether an adverse event occurred. 
801 
6.5 Safety Oversight 
802 
The study Sponsor’s Medical Director will serve as Medical Monitor, and will review all reported adverse 
803 
events, including all cases of severe hypoglycemia and DKA, and adverse device effects that are reported 
804 
during the study. SAEs typically will be reviewed within 1 working day of reporting. Other AEs typically 
805 
will be reviewed on a weekly basis.  
806 
The Medical Monitor will determine if the events require expedited reporting to FDA, IRB and/or all 
807 
participating sites. In addition, the Medical Monitor will confirm the MedDRA code assigned and 
808 
adjudicate events as specified in the safety management plan for relatedness to the study procedure and 
809 
investigational device, assess seriousness and severity, and determine if the event the event is anticipated 
810 
or unanticipated. Both the investigator’s and Medical Monitor’s assessments will be recorded, however, 
811 
the adjudication decision of the Medical Monitor will be used for the final classification of events, 
812 
including relatedness to the study procedures and/or the investigational device, for the determination of 
813 
safety endpoints and for all regulatory reports, product labeling, and publications or presentations. 
814 
B37

 
 
6.6 Stopping Criteria 
815 
6.6.1 Participant Discontinuation of Study Device 
816 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA event 
817 
(or a malfunction that could have led to severe hypoglycemia or DKA), use of the study device will be 
818 
suspended for that participant while the problem is diagnosed. The UADE will be reported to the IRB and 
819 
FDA. After assessment of the problem and any correction, use of the study device will not be restarted 
820 
until approval is received from the IRB and FDA. 
821 
In the absence of a device malfunction, use of the study device by a participant will be discontinued if 
822 
any of the following occur:  
823 
• 
The investigator believes it is unsafe for the participant to continue on the intervention. This could be 
824 
due to the development of a new medical condition or worsening of an existing condition; or 
825 
participant behavior contrary to the indications for use of the device that imposes on the participant’s 
826 
safety 
827 
• 
The participant requests that the treatment be stopped 
828 
• 
Participant pregnancy 
829 
• 
One distinct episodes of DKA in the study treatment period as defined in section 6.2.4 
830 
• 
One distinct severe hypoglycemia events in the study treatment period as defined in section 6.2.3 
831 
Each DKA or severe hypoglycemia event will be reviewed by the Medical Monitor with respect to 
832 
determination of cause and whether the occurrence of the event can be attributed to use of the study 
833 
device or study drug.  
834 
6.6.2 Criteria for Suspending or Stopping Overall Study 
835 
In addition to the suspension of device use due to a UADE as described in section 6.6.1, study activities 
836 
could be similarly suspended if the manufacturer of any constituent study device requires stoppage of 
837 
device use for safety reasons (e.g. product recall). The affected study activities may resume if the 
838 
underlying problem can be corrected by a protocol or system modification that will not invalidate the 
839 
results obtained prior to suspension. 
840 
Closed-loop system use will also be suspended if there are five or more cases of severe hypoglycemia or 
841 
five or more cases of DKA across the entire study in participants who have initiated Control-IQ 
842 
technology 2.0 use. The IRBs and FDA will be notified. After assessment of the problem and any 
843 
corrections are implemented, use of the closed-loop system may be restarted if approval is received from 
844 
the IRBs and FDA. 
845 
 
846 
B38

 
Chapter 7: Miscellaneous Considerations 
847 
7.1 Drugs Used as Part of the Protocol 
848 
Subjects will use their own Humalog (insulin lispro) or Novolog (insulin aspart) during the Run In and 
849 
Treatment Period with the study devices. 
850 
7.2 Collection of Medical Conditions and Medications 
851 
Pre-Existing Conditions: Any medical condition that is either present at screening, a chronic disease, 
852 
or a prior condition that could impact the participant’s health during the course of the study (e.g., prior 
853 
myocardial infarction or stroke) will be recorded. 
854 
Medical Conditions Developing During the Study: Medical conditions developing during the study will 
855 
be reviewed by the investigator for their relationship to the study device. 
856 
Medications: All medications in use at the time of screening or added during the course of the study will 
857 
be recorded. Nutraceuticals and preventative treatment also will be recorded. Medications only taken as 
858 
needed either can be recorded when prescribed or only recorded if used during the study. Glucagon for 
859 
treatment of severe hypoglycemia will only be recorded if used during the study. 
860 
7.3 Prohibited Medications, Devices, Treatments, and Procedures 
861 
Treatment with any insulin other than Humalog or Novolog insulin with the study pumps is not permitted. 
862 
Treatment with a non-insulin glucose -lowering agent, other than metformin, is not permitted, including 
863 
GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas. 
864 
The investigational study devices (t:slim X2 insulin pump with Control-IQ technology 1.5 or 2.0) and 
865 
study sensor and transmitter (Dexcom CGM sensor and transmitter) must be removed before magnetic 
866 
resonance imaging (MRI), computed tomography (CT) or diathermy treatment. Participants may continue 
867 
in the trial after temporarily discontinuing use if requiring one of the above. 
868 
7.4 Rescue Medications, Treatments, and Procedures 
869 
Each participant will be required to have a glucagon preparation for rescue therapy for severe 
870 
hypoglycemia. 
871 
7.5 Pregnancy Reporting 
872 
If pregnancy occurs, the participant will be discontinued from the study. The occurrence of pregnancy 
873 
will be reported to the Coordinating Center within seven days and to the IRB as an Unanticipated 
874 
Problem within seven calendar days. 
875 
7.6 Participant Compensation 
876 
Participant compensation will be specified in the informed consent form. 
877 
7.7 Participant Withdrawal 
878 
Participation in the study is voluntary, and a participant may withdraw at any time. For participants who 
879 
withdraw, their data will be used up until the time of withdrawal. 
880 
 
881 
B39

 
 
Chapter 8: Statistical Considerations 
882 
8.1 General Statistical Considerations 
883 
Summary statistics will be generated for all relevant variables. In the comparison of continuous variables, 
884 
distributions will be tested for the normality assumption. If standard parametric techniques are found to be 
885 
inadequate, an appropriate non-parametric technique will be used. Categorical variables will be presented 
886 
using frequencies and percentages and compared using differences in proportions unless stated otherwise. 
887 
For safety/adverse event reporting, both the number of overall events and the number of subjects 
888 
experiencing that event will be tabulated. No corrections will be made for multiple testing procedures. All 
889 
analyses will be conducted using SAS® version 9.4 or higher. Although this study features a crossover 
890 
design, it will be assumed for the exploratory purposes of this analysis that there are no residual period 
891 
effects and no carryover effects present. The correlated nature of data collected by the same subject across 
892 
multiple conditions will be accounted for in the statistical modeling, such as using a paired t-test for 
893 
comparing continuous outcomes. 
894 
8.2 Statistical Hypotheses 
895 
The primary objective of the study is assessment of safety. Therefore, there are no formal statistical 
896 
hypotheses associated with any of the endpoints. Safety endpoints for SH and DKA will be compared to 
897 
historical published data. Efficacy endpoints will be compared across study periods with the run-in period 
898 
designated as the comparator study period. P-values for differences between study periods on both safety 
899 
and efficacy endpoints will be calculated, however, will not be used for formal statistical inference due to 
900 
the exploratory nature of the study objectives and the lack of correction for multiple testing. 
901 
8.3 Sample Size 
902 
The sample size of at least 30 adults and adolescents age 14+ years old, 30 children age  6-13 years old, 
903 
and 12 preschool participants age 2-5 years of age who will complete the trial was selected to have a 
904 
reasonable time period of use in each age cohort to establish safety, with each subject completing 2 weeks 
905 
of Control-IQ 1.5 technology use, 2 weeks of Control-IQ 2.0 technology use with the target of 112.5 to 
906 
160 mg/dL, and 2 weeks of Control-IQ 2.0 technology use with the target of 90-130 mg/dL. The choice of 
907 
sample size is not based on statistical principles. In addition, the sample size assures a reasonable number 
908 
of late bolus meal challenges completed.  
909 
There is a further enrollment goal of at least half of all participants in each age group have an HbA1c at 
910 
baseline of ≥ 7.5%, and have at least 6 participants age 14-17. 
911 
8.4 Outcome Measures 
912 
Primary Endpoints 
913 
1. Severe hypoglycemia (with cognitive impairment such that assistance of another individual is needed 
914 
for treatment) during study compared with data on severe hypoglycemic events reported by T1D 
915 
Exchange clinic registry over a 3-month time period 
916 
2. Diabetic ketoacidosis during study compared with data on DKA events  
917 
3. Number of unanticipated adverse device effects 
918 
4. Number of other serious device-related adverse events 
919 
Secondary Endpoints  
920 
1. All device-related adverse events 
921 
B40

 
 
2. CGM hypoglycemia outcomes, compared between the three study time periods 
922 
a. Overall % time <54 mg/dL 
923 
b. Overall % time <70 mg/dL 
924 
3. Times in ranges-overall (70-180 mg/dL, >180 mg/dL, >250 mg/dL, 70-140 mg/dL) compared 
925 
between the three study time periods 
926 
4. Mean glucose compared between the three study time periods. 
927 
5. Overall variability (CV and SD) compared between the three study time periods 
928 
6. Secondary endpoints 2 - 5 compared during daytime and nighttime, across the three study time 
929 
periods 
930 
7. Secondary endpoints 2 - 5 as well as adverse events, during the study meal challenge periods, for 
931 
late bolus feature use compared to normal bolus in the meal challenges. 
932 
8. Time to intervention for hypo- or hyperglycemia during the study meal challenge periods, for late 
933 
bolus feature use compared to normal bolus in the meal challenges. 
934 
9. Number of interventions for hypo- or hyperglycemia during the study meal challenge periods for 
935 
late bolus feature use compared to normal bolus in the meal challenges. 
936 
10. Subgroup Analysis for all metrics by age cohort, baseline HbA1c cohort (HbA1c at baseline of ≥ 
937 
7.5%, yes/no), and target activity use (standard target, lower target, sleep activity, exercise 
938 
activity). 
939 
 
940 
8.5 Analysis Datasets  
941 
Safety analysis set: All participants who initiate the Treatment Period and use the study device at least 
942 
one time (including training).  
943 
CGM analysis set: Any member of the Safety Analysis Set who has at least 24 hours of CGM data during 
944 
either Treatment Period. CGM data occurring within the meal challenge windows (from time of start of 
945 
meal up to 5 hours afterwards [3 hours for age 2-5]) will not be used to determine whether a subject is 
946 
included in CGM analysis set or not. 
947 
Late bolus meal challenge set: Any member of the Safety Analysis Set who has at least 24 hours of CGM 
948 
data during the Treatment Period, and who has at least 3 hours of CGM data for at least one meal 
949 
challenge. 
950 
8.6 Analysis of Endpoints 
951 
8.6.1 Analysis of the Safety Event Endpoints 
952 
Safety events (not including CGM defined events defined in sections 6.2.2, 6.2.3, and 6.2.4) will be based 
953 
on Safety analysis set, and tabulated for each primary endpoint as the number of events per participant, 
954 
the number of participants with ≥ 1 event, and the rate of events per 100 person-years. A 95% confidence 
955 
interval will be calculated for the rate of events per 100 person-years. 
956 
Since study eligibility excluded participants with 2 or more severe hypoglycemia or DKA events in the 
957 
prior 6 months, an unbiased comparison of the event rate during the Treatment Period with the pre-study 
958 
event rate is not possible. Therefore, the severe hypoglycemia and DKA event rates will be compared 
959 
with the T1D Exchange data,4 which reported the frequency of 1 or more severe hypoglycemia and DKA 
960 
events in the prior 3 months. The proportion of participants with events during the Treatment Period (each 
961 
B41

 
period separately) will be compared with the run-in period as well as with the T1D Exchange frequency. 
962 
Differences in proportions across the three study periods (two active treatments and the run in) will be 
963 
estimated in a pairwise fashion, and statistical significance will be assessed using a normal approximation 
964 
to a binomial distribution. 
965 
8.6.2 Analysis of Other Safety Endpoints 
966 
Safety summaries will be based on Safety analysis set. All adverse events reported over the course of the 
967 
study will be summarized by study period for run-in and both treatment periods separately and overall. 
968 
Adverse events will be tabulated by System Organ Class and Preferred Term based on MedDRA version 
969 
22.0. Adverse events will also be summarized by seriousness, severity, and relationship to study 
970 
procedures and the investigational device. Except where indicated, a subject reporting the same adverse 
971 
event more than once will be counted once when calculating the number and percent of subjects with that 
972 
particular event. 
973 
Adverse events leading to death or to discontinuation from the study will be listed separately. A listing of 
974 
all adverse events will be provided. 
975 
8.6.3 Analysis of CGM Endpoints 
976 
CGM metrics will be assessed in CGM analysis set, and computed for the Run-In and both Treatment 
977 
Periods separately. CGM metrics will be computed per subject over 24 hours, during daytime (6am-
978 
11:59pm), and during nighttime (12am-5:59am), as well as by age cohort (adults/adolescents, children 6 – 
979 
13, and preschool), baseline HbA1c cohort (HbA1c at baseline of ≥ 7.5%,yes/no), and target activity use 
980 
as specified by the device (standard target, lower target, sleep activity, and exercise activity). 
981 
The main statistical comparison will be made between the three 2-week periods (Run In, Treatment 
982 
Period at standard target, Treatment Period at lower target). The comparison will be pairwise – Run-in vs 
983 
standard targe, Ru-in vs lower target, and standard vs lower target. The percent time in glycemic ranges 
984 
will be calculated as the number of measurements in the specified range divided by the total number of 
985 
measurements for which it can be determined whether or not the measurement was in specified range. 
986 
The “Low” and “High” CGM readings will be included in all analyses. Percent time will be compared 
987 
using a paired t-test assuming sufficient normality assumptions hold, otherwise an appropriate non-
988 
parametric method will be utilized.  
989 
8.6.4 Analysis of Late Bolus Meal Challenges 
990 
All analyses in section 8.6.4 will be conducted in the late bolus meal challenge analysis set. Data included 
991 
in these analyses will be restricted to data during the meal challenge window (start of meal through 5 
992 
hours from meal imitation [3 hours for age 2-5]). The subgroups assessed will be the same as sections 
993 
8.6.1 – 8.6.3 (age cohort, baseline HbA1c cohort (HbA1c at baseline of ≥ 7.5%. yes/no), etc.) 
994 
8.6.4.1 Late Bolus Meal Challenge Safety and CGM Subgroup Analysis 
995 
Two challenges are expected per subjects per treatment period for a total of four challenges, therefore 
996 
agreement of outcomes will need to be assessed. For continuous outcomes, two sets of Pearson’s 
997 
correlation coefficients will be calculated to measure concordance: one restricted to each treatment period 
998 
(higher range target and lower range target), and a single coefficient for all four challenges. For 
999 
categorical outcomes, a Cohen’s kappa statistic for agreement or a similarly appropriate statistic will be 
1000 
calculated and presented to describe agreement/dependence of outcomes by individual subjects. Results 
1001 
will be compared by treatment period and across treatment periods. 
1002 
The analyses described in sections 8.6.1, 8.6.2, and 8.6.3 will be repeated for subjects included in the late 
1003 
bolus meal challenge set. For the CGM outcomes, the mean of the CGM metrics for the two late meal 
1004 
B42

 
bolus challenges within study period will be used to account for within-subject non-independence (i.e. 
1005 
one data value per subject per study period).  
1006 
8.6.4.2  Time to Intervention Analysis 
1007 
Time to intervention for both hypo- or hyperglycemia during the study meal challenge periods will be 
1008 
summarized. Time to intervention is defined as the time (in minutes) from start of meal until the first 
1009 
treatment is given as defined in Section 6.2. If multiple interventions are needed to treat hypo- or 
1010 
hyperglycemia during the meal challenge, only time to the earliest intervention will be summarized. The 
1011 
results will be presented using general summary statistics, as well as utilizing Kaplan-Meier time-to-event 
1012 
analysis where subjects who complete the meal challenge without requiring any intervention will be right-
1013 
censored. A cox proportional hazards model will be fit comparing time to intervention between the two 
1014 
active treatment periods. A p-value from the log-rank test will be used to evaluate whether there is 
1015 
evidence of a difference between the two target ranges with respect to time to intervention. Results will be 
1016 
compared by treatment period and across treatment periods. 
1017 
8.6.4.3 Number of interventions analysis 
1018 
Number of interventions for hypo- or hyperglycemia during the study meal challenge periods will be 
1019 
summarized both overall and by type. The results will be presented using general summary statistics. 
1020 
Type of intervention may include timing of intervention (during meal, less than one hour after starting 
1021 
meal, greater than one hour after meal start), the number of carbs administered (grouped in increments of 
1022 
10 grams), and the timing of carb administration (less than 15 minutes per administration vs 15 minutes 
1023 
or more). The categories and groupings utilized for intervention type will be expanded or decreased based 
1024 
on the types of interventions that actually occur in the study. Results will be compared by treatment 
1025 
period and across treatment periods. 
1026 
Type of intervention will be reviewed and assessed by the study Medical Monitor prior to analysis to 
1027 
define the logic that can be applied across all subjects (e.g., an intervention that occurred more than 15 
1028 
minutes after the previous intervention will count as new intervention). Different logic may be applied to 
1029 
different age cohorts. This logic will be fully detailed in the final clinical study report.  
1030 
8.7 Intervention Adherence 
1031 
The following tabulations will be performed: 
1032 
• 
Sensor use – percent time of use as a function of overall treatment period 
1033 
• 
Sensor use is defined as percent of time CGM is recorded as active (to include warmup) vs total 
1034 
study time. 
1035 
• 
Closed loop system use – percent time of use as a function of overall treatment period 
1036 
• 
Closed loop system use is defined as percent of time closed-loop is recorded as active (to include 
1037 
pinning in sensor warmup) vs total study time. 
1038 
• 
Percent time in different operational modes as a function of overall treatment period 
1039 
• 
The investigational device allows for the following operational modes: standard target, lower 
1040 
target, sleep activity, and exercise activity. 
1041 
For intervention adherence, overall treatment period is calculated from the start of the treatment period to 
1042 
the end of the treatment period where any gaps in CGM data are ignored.  
1043 
B43

 
1 
8.8 Protocol Adherence and Retention 
1044 
The following tabulations and analyses will be performed to assess protocol adherence for the study: 
1045 
• 
Number of protocol deviations by site and by type, and number of unique subjects with each type of 
1046 
protocol deviation  
1047 
• 
Disposition summary (e.g., chart, table) accounting for all enrolled participants at each scheduled visit 
1048 
• 
Number of and reasons for unscheduled visits and phone calls 
1049 
• 
Number of participants who were enrolled but did not enter the Treatment Period and reasons 
1050 
• 
Number of participants who stopped treatment and reasons 
1051 
8.9 Baseline Descriptive Statistics 
1052 
Baseline demographic and clinical characteristics of the cohort of participants who initiate the Treatment 
1053 
Period will be summarized in a table using summary statistics appropriate to the distribution of each 
1054 
variable. Descriptive statistics will be displayed by treatment group for the following: 
1055 
• 
Age 
1056 
• 
Sex 
1057 
• 
Race 
1058 
• 
Ethnicity 
1059 
• 
Socio-economic factors (income, education, and/or insurance status) 
1060 
• 
Diabetes duration 
1061 
• 
HbA1c 
1062 
• 
BMI 
1063 
• 
Total daily insulin 
1064 
• 
Prior severe hypoglycemia and DKA events in the last 6 months 
1065 
8.10 Additional Tabulations and Analyses 
1066 
The following data will be tabulated at baseline, for the run-in period, and for the two treatment periods. 
1067 
• 
Insulin metrics (units/kg): total daily insulin, total daily basal insulin, total daily bolus insulin (plus 
1068 
total daily manual bolus, total daily automated bolus) 
1069 
8.11 Device Issues 
1070 
The following tabulations will be performed with respect to device issues: 
1071 
• 
Number of device issues by type, and number of unique subjects with each type of device issue 
1072 
8.12 Planned Interim Analyses 
1073 
No formal interim analyses are planned. 
1074 
B44

 
1 
8.13 Subgroup Analyses 
1075 
Results will be tabulated according to age cohort, baseline HbA1c category, and target activity use 
1076 
(standard target, lower target, sleep activity, exercise activity). There is an enrollment goal of at least half 
1077 
of all participants in each age group have an HbA1c at baseline of ≥ 7.5%, and all participants meeting 
1078 
that criteria will be analyzed as a subgroup. 
1079 
8.14 Multiple Comparison/Multiplicity 
1080 
There are no adjustments performed for multiple comparisons.  
1081 
8.15 Handling of Missing Data 
1082 
All practical monitoring and follow-up steps will be taken to ensure complete and accurate data 
1083 
collection. All analyses will be based on available data only; no imputation for missing data is planned.  
1084 
8.16 General Statistical Considerations 
1085 
Up to six sites in the US will enroll subjects into the study. For the purposes of statistical analyses and   
1086 
data summaries, data from all study centers will be pooled. Not official assessment of poolability will be 
1087 
performed.  
1088 
Unless otherwise specified, continuous variables will be summarizing using count, mean, median, 
1089 
standard deviation, and range. 95% confidence intervals, and/or first and third quartile may be presented 
1090 
were appropriate. Categorical variables will be summarized using count and percent of each level of 
1091 
categorical variable. Any statistical testing will be performed at a two-sided significance level of 5% with 
1092 
no adjustment for multiple testing. If the observed data are found not to follow a normal distribution, non-
1093 
parametric methods may be employed (such as Wilcoxon rank sum test as appropriate).  
1094 
The statistical software package SAS® 9.3 or later will be used for all data derivations, summaries, 
1095 
listings, and statistical analyses. Additional statistical software may be used for graphics or validation 
1096 
purposes as appropriate.
1097 
B45

 
Chapter 9: Data Collection and Monitoring 
1098 
9.1 Case Report Forms and Other Data Collection 
1099 
The main study data are collected on electronic case report forms (eCRFs). When data are directly 
1100 
collected in electronic case report forms, this will be considered the source data. For any data points 
1101 
for which the eCRF is not considered source (e.g. lab results that are transcribed from a printed report 
1102 
into the eCRF, data collected in the electronic medical record, study specific source worksheets, etc.), the 
1103 
original source documentation will be maintained in the participant’s study chart or medical record. This 
1104 
source must be readily verifiable against the values entered into eCRF.  
1105 
Electronic device data files are obtained from the study software and individual hardware components. 
1106 
These electronic device files are considered the primary source documentation. 
1107 
9.2 Study Records Retention 
1108 
Each participating site will maintain appropriate medical and research records for this trial, in 
1109 
compliance with GCP and regulatory and institutional requirements for the protection of confidentiality of 
1110 
participants. 
1111 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
1112 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
1113 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
1114 
of the investigational product. These documents should be retained for a longer period, however, 
1115 
if required by local regulations. No records will be destroyed without the written consent of the sponsor, 
1116 
if applicable. It is the responsibility of the sponsor to inform the investigator when these documents no 
1117 
longer need to be retained. 
1118 
9.3 Quality Assurance and Monitoring 
1119 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1120 
assurance (QA) and QC systems to ensure that the clinical portion of the trial is conducted and data are 
1121 
generated, documented and reported in compliance with the protocol, GCP and the applicable regulatory 
1122 
requirements, as well as to ensure that the rights and wellbeing of trial participants are protected and that 
1123 
the reported trial data are accurate, complete, and verifiable. Adverse events will be prioritized for 
1124 
monitoring. 
1125 
A monitoring plan will be developed and revised as needed during the course of the study. Study conduct 
1126 
and monitoring will conform with 21 Code of Federal Regulations (CFR) 812. This plan will describe in 
1127 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
1128 
monitoring will be performed, and the distribution of monitoring reports. 
1129 
The data of most importance for monitoring at the site are participant eligibility and adverse events. 
1130 
Therefore, the monitoring plan will focus on these areas. As much as possible, remote monitoring will be 
1131 
performed in real-time with on-site monitoring performed to evaluate the verity and completeness of 
1132 
the key site data. Elements of the monitoring may include: 
1133 
B46

 
• 
Qualification assessment, training, and certification for sites and site personnel 
1134 
• 
Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1135 
• 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol review of 
1136 
entered data and edits, statistical monitoring, study closeout 
1137 
• 
On-site monitoring (site visits): source data verification, site visit report 
1138 
• 
Agent/Device accountability 
1139 
• 
Communications with site staff 
1140 
• 
Patient retention and visit completion 
1141 
• 
Quality control reports 
1142 
• 
Management of noncompliance 
1143 
• 
Documenting monitoring activities 
1144 
• 
Adverse event reporting and monitoring 
1145 
Coordinating Center representatives or their designees may visit the study facilities at any time in order 
1146 
to maintain current and personal knowledge of the study through review of the records, comparison 
1147 
with source documents, observation and discussion of the conduct and progress of the study. 
1148 
The investigational site will provide direct access to all trial related source data/documents, and reports 
1149 
for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
1150 
authorities. 
1151 
9.4 Protocol Deviations 
1152 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1153 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the 
1154 
study site staff. A significant (or major) deviation is any deviation that departs from the established 
1155 
materials in such a way that it poses an increase in the risk to subjects, adversely affects the welfare, 
1156 
rights, or safety of the research subjects, or negatively influences the scientific study integrity. As a 
1157 
result of a significant deviation, a corrective and preventive action plan shall be developed by the site 
1158 
and implemented promptly. 
1159 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. Further details 
1160 
about the handling of protocol deviations will be included in the monitoring plan. 
1161 
 
1162 
B47

 
Chapter 10: Ethics/Protection of Human Participants 
1163 
10.1 Ethical Standard 
1164 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
1165 
Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
1166 
Part 56, and/or the ICH E6. 
1167 
10.2 Institutional Review Boards 
1168 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
1169 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
1170 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
1171 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
1172 
will be IRB approved; a determination will be made regarding whether previously consented participants 
1173 
need to be re-consented. 
1174 
10.3 Informed Consent Process 
1175 
10.3.1 Consent Procedures and Documentation 
1176 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
1177 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
1178 
benefits of participation will be provided to the participants and their families. Consent forms will be 
1179 
IRB-approved and the participant will be asked to read and review the document. The investigator will 
1180 
explain the research study to the participant and answer any questions that may arise. All participants 
1181 
will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, 
1182 
and potential risks of the study and of their rights as research participants. Participants will have the 
1183 
opportunity to carefully review the written consent form and ask questions prior to signing. 
1184 
The participants should have the opportunity to discuss the study with their surrogates or think about 
1185 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
1186 
procedures being done specifically for the study. The participants may withdraw consent at any time 
1187 
throughout the course of the trial. A copy of the informed consent document will be given to the 
1188 
participants for their records. The rights and welfare of the participants will be protected by emphasizing 
1189 
to them that the quality of their medical care will not be adversely affected if they decline to participate 
1190 
in this study. 
1191 
10.3.2 Participant and Data Confidentiality 
1192 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
1193 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
1194 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
1195 
documentation, data, and all other information generated will be held in strict confidence. No information 
1196 
concerning the study or the data will be released to any unauthorized third party without prior written 
1197 
approval of the sponsor. 
1198 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, regulatory 
1199 
agencies or company supplying study product may inspect all documents and records required to be 
1200 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
1201 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
1202 
records. 
1203 
B48

 
The study participant’s contact information will be securely stored at each clinical site for internal use 
1204 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
1205 
long a period as dictated by the reviewing IRB, institutional policies, sponsor requirements, and 
1206 
applicable regulations. 
1207 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
1208 
be transmitted to and stored at the Coordinating Center. This will not include the participant’s contact or 
1209 
identifying information, unless otherwise specified in the informed consent form. Rather, individual 
1210 
participants and their research data will be identified by a unique study identification number. The study 
1211 
data entry and study management systems used by clinical sites and by the Coordinating Center research 
1212 
staff will be secured and password protected. At the end of the study, all study databases will be de-
1213 
identified and archived at the Coordinating Center. 
1214 
10.3.3 Future Use of Stored Specimens and Data 
1215 
Data collected for this study will be analyzed and stored at the Coordinating Center. After the study is 
1216 
completed, a dataset will be provided to the study Sponsor. 
1217 
No biologic specimens will be stored. 
1218 
 
1219 
B49

 
Chapter 11: References 
1220 
 
1221 
1. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM, 
1222 
Levy CJ, Pinsker JE, Wadwa RP, Dassau E, Doyle FJ 3rd, Anderson SM, Church MM, 
1223 
Dadlani V, Ekhlaspour L, Forlenza GP, Isganaitis E, Lam DW, Kollman C, Beck RW; iDCL 
1224 
Trial Research Group.  Six-month randomized, multicenter trial of closed-loop control in 
1225 
type 1 diabetes. N Engl J Med. 2019; 381:1707-1717. 
1226 
2. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L, Forlenza GP, Cengiz E, Schoelwer M, 
1227 
Ruedy KJ, Jost E, Carria L, Emory E, Hsu LJ, Oliveri M, Kollman CC, Dokken BB, 
1228 
Weinzimer SA, DeBoer MD, Buckingham BA, Cherñavvsky D, Wadwa RP; iDCL Trial 
1229 
Research Group. A randomized trial of closed-loop control in children with type 1 diabetes. 
1230 
N Engl J Med. 2020; 383:836-845. 
1231 
3. Breton M, Kovatchev B. One year real-world use of the Control-IQ advanced hybrid closed 
1232 
loop technology. Diabetes Technol Ther. 2021;23:601-608. 
1233 
4. Foster et al. State of type 1 diabetes management and outcomes from the T1D Exchange in 
1234 
2016-2018. Diabetes Technol Ther. 2019; 21:66-72. 
1235 
 
1236 
B50