A Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy (2IQP)
Phase: NA
Conditions: Type 2 Diabetes Treated With Insulin
Sponsor: Tandem Diabetes Care, Inc.

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Signature Page 
A Randomized Trial Evaluating the Efficacy and Safety of 
Control-IQ Technology in Adults with Type 2 Diabetes Using 
Basal-Bolus Insulin Therapy (2IQP) 
Protocol Identifying Number: TP-0013437 
IND/IDE Sponsor: Tandem Diabetes Care, Inc. 
Version Number: v. 8.0 
October 31, 2023 
JCHR Protocol Director 
Name, degree 
John Lum, MS / Jaeb Center for Health Research 
Signature/Date 
 
Sponsor 
Tandem Diabetes Care, Inc. 
Name, degree 
Jordan Pinsker, M.D. 
Signature/Date 
Protocol Chair 
Name, degree 
Yogish Kudva, M.D. / Mayo Clinic 
Signature/Date 
Medical Monitor 
Name, degree 
Roy Beck, MD, Ph.D. / Jaeb Center for Health Research 
Signature/Date 
 
John Lum
I am digitally signing this document
2023-11-13 09:17-05:00
Roy Beck
I am digitally signing this document
2023-11-13 16:07-05:00
Jordan 
Pinsker
Digitally signed by Jordan 
Pinsker 
Date: 2023.11.13 13:58:42 
-08'00'
November 14, 2023

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A Randomized Trial Evaluating the Efficacy and Safety of 
Control-IQ Technology in Adults with Type 2 Diabetes Using 
Basal-Bolus Insulin Therapy (2IQP) 
Protocol Identifying Number: TP-0013437 
IDE Sponsor: Tandem Diabetes Care, Inc. 
Version Number: 8.0 
 October 31, 2023

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VERSION HISTORY 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
J. Lum, R. Beck., N.
Mba-Oduwusi, J.
Pinsker, R. Sasson-
Katchalski
J. Pinsker
December 7, 
2022 
Original version 
2.0 
J. Lum, R. Beck., N.
Mba-Oduwusi, J.
Pinsker, R. Sasson-
Katchalski
J. Pinsker
January 6, 
2023 
Incorporates FDA feedback on version 1.0: 
(content-related changes are listed below by 
protocol section and are also reflected in the 
Protocol Summary and the Schedule of 
Visits and Procedures table)  
Section 1.5.1.2: Added potential risks of CGM 
Section 2.1:  
•
The maximum number that can be randomized by any site is 66 (20% of 330).
•
Added maximum of 30 participants randomized from Canada
•
Increased minimum recruitment goal to 30% of a minority race or ethnicity; 20% using an
SGLT2 inhibitor, 20% using a GLP-1 receptor agonist, and 10% using both; 15% with
TDI>100 units/day and attempt to enrich cohort with participants with TDI >200 units;
25% using a form of fixed dosing to calculate meal boluses (e.g., fixed dose at meal or
fixed dose for small/medium/large meal [i.e., dose not determined by carbohydrate
counting]). Changed HbA1c goal to be maximum of 25% with HbA1c <8% (based on
screening  HbA1c or HbA1c available within the last 30 days) and maximum of 10% with
screening HbA1c <7%
Section 2.2.1:The following changes were made in the inclusion criteria 
•
Added requirement that type 2 diabetes was diagnosed at least 6 months prior to screening
•
Modified insulin use requirement to be: Using basal-bolus insulin therapy with at least one
injection containing rapid-acting insulin per day or an insulin pump for at least 3 months
prior to enrollment, with no major modification to insulin regime in the last 3 months
•
Dropped requirement of TDI < 250 units
•
Added: If using noninsulin glucose-lowering medications (such as GLP-1 receptor agonist,
SGLT2 inhibitor, or other) or weight-reduction medications, dose has been stable for the 3
months prior to screening; and participant is willing to not change the dose unless required
for safety purposes
•
Added: Participant willing to not initiate use of any new glucose-lowering medications
during the trial
•
Dropped requirement for HbA1c 7.0% to 11.9%
Section 2.2.3: The eligibility for the exercise challenges was changed to be the following: All 
participants will have a screening EKG or review of an EKG completed in the 12 months prior 
to screening. To participate in the exercise challenges, a participant must have either no history 
of a cardiovascular event in the year prior to screening  and no EKG abnormalities associated 
with increased risk during exercise.   
Section 2.3.1: The following changes were made in the screening data collection and testing: 
•
HHS and hospitalization for SH, DKA, HHS added to medical history information
•
Blood draw for central lab HbA1c deleted
•
Added EKG for all participants unless performed in the prior 12 months
Section 4.4: information added about IRB-approved handouts for training 
Section 4.6: need for AID group to have care partner trained in treatment of hypoglycemia present 

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during exercise challenges 
Section 4.6.2: Added that sleep activity will be enabled during normal sleep time for all users unless 
a safety concern arises as judged by the investigator 
Section 5.2. Changed the training/check-in contact with the AID group participants to be 3 ±1 days 
to conform current practices 
Section 5.2.1: 
•
Added that site investigators may adjust insulin delivery profile settings only for safety
concerns and the reasons will be documented on CRF
•
Deleted recording of non-severe hypoglycemia treatments at each visit (correction of
protocol)
Section 5.3: Added that at final visit when transitioning back to pre-study insulin delivery method, 
participants must have two CGM or fingerstick blood glucose values, separated by at least 15 
minutes, that are above 80 mg/dL prior to discharge from the clinic. 
Section 5.4: Regarding glucose-lowering or weight reduction medications, add the following: The 
only changes of glucose-lowering or weight-reduction medications permitted will be a 
reduction in dose for safety reasons, or an adjustment to an equivalent dose of a different 
formulation if participant’s insurance coverage changes. No increased doses or initiation of a 
new glucose-lowering or weight-reduction medication will be permitted.  
Section 6.1: Challenges 
•
Plan for exercise and meal challenges modified to require the 3 challenges of each type to
be on consecutive days and to have about 25% of each type of challenge within the
following 4 periods timed from randomization: 1-2 weeks, 3-4 weeks, 5-6 weeks, 7-8
weeks.
•
Added need for trained care partner to be present during exercise challenges
Section 6.2 Meal Challenges: 
•
Added that CGM trend error must not be rapidly rising at the start of the challenge
•
Added information about the need to reschedule a challenge
Section 6.3 Exercise Challenges: 
•
Added that exercise mode will be active during exercise challenges, with the timing of
activation determined by investigator and participant
•
Added if CGM glucose is <120 mg/dL at start of session, carbohydrate can be taken and
exercise should not begin until glucose is ≥120 mg/dL
•
Added that the participant will be asked to record whether the prior insulin meal bolus was
intentionally reduced in preparation for exercise
•
Added information about the need to reschedule a challenge
Section 9.5: Added that cases of HHS will have expedited reporting to DSMB in addition to SH and 
DKA 
Section 9.6.2: Added that the DSMB will be immediately notified of all adverse events related to 
SH, DKA, or HHS, as well as any recurrence of these events across participants or study sites. 
Section 10.1: added that only insulin approved for the study pump can be used by the AID group 
Section 10.3: added that dose increases in glucose-lowering or weight-reduction medications in use 
at the time of randomization are not permitted 
Section 11.1: Added reference to section 11.15 regarding single-arm analyses to be performed for 
the AID group. 
Section 11.2: Statistical hypotheses added for the secondary endpoints 
Section 11.4.2: Clarification added that statistical testing is for superiority 
Section 11.5.1: Clarified the criteria for inclusion in the per-protocol analysis and added ‘no major 

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protocol deviation’. 
Section 11.7.1: Added that CGM metrics during and following the challenges will be reported 
separately as described in section 11.15.3 and an overall analysis within the AID group will be 
performed for all CGM data including the challenge data as described in section 11.15.2. 
Section 11.7.1: Definitions and statistical methods added for CGM-measured prolonged 
hyperglycemia events and CGM-measured hypoglycemia events. 
Section 11.12: Added the following subgroup analyses 
•
Total daily insulin (<100 units versus ≥100 units)
•
C-peptide level
•
Baseline scores on the Subjective Numeracy Scale
Section 11.14. Added the following exploratory treatment group comparisons 
•
Separate sub-analyses for participants negative for GAD antibodies (if GAD antibodies are
present in ≥5% of participants)
•
Efficacy and safety outcomes in participants with TDI ≥100 units
Section 11.15.1. Added the following tabulations for the AID group 
•
Frequency of use of sleep mode and exploratory outcomes for times with versus without
sleep mode
•
Frequency of use of exercise mode
Section 11.15.2. Added an additional analysis in which CGM metrics will be computed over the 
entire 13 weeks of the trial (including the challenge periods) and statistically compared with 
baseline metrics 
3.0 
J. Lum, J. Pinsker,
D. Raghinaru
J. Pinsker
January 16, 
2023 
Insulin will now be provided to study 
participants using the study device (changes 
to Protocol Summary, Table 1, Potential 
Risks, Eligibility Criteria, study pump 
training, Chapter 7, Chapter 10); 
clarification of capture of hypoglycemia in 
last 3 months via participant survey 
(changes to Protocol Summary, Table 1, 
Screening and Visit procedures, 
Questionnaires section); 
Added sub-analysis of > 150, > 200 units 
TDI (changes to Chapter 11, Statistical 
Considerations) 
4.0 
N Mba-Oduwusi, 
J. Lum
February 16, 
2023 
IRB edits and criteria of no plan to become 
pregnant adjusted from 2 months to study 
period. 
Inserted AE, SAR, SUSAR in section 9.2 
per Novo Nordisk request. 
5.0 
N. Mba-Oduwusi
J. Pinsker
March 09, 
2023 
Corrected line 371 to indicate use of HbA1c 
within a 30-day timeframe (not 91 days). 
Clarified Schedule of Study Visits and 
Procedures to indicate that the central 
HbA1c is required at randomization, 
irrespective of whether this visit occurs at 
the same time as screening. 
Clarified Schedule of Study Visits and 
Procedures to indicate that height and 
weight will be done at randomization, 4 
week visit, 8 week visit (if done in person), 
and 13 week visit, while physical 
examination is only required at screening. 

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6.0 
J. Lum
J. Pinsker
August 03, 
2023 
Removed erroneous reference to “semi-
structured interviews.” Resolved conflicting 
statement about allowable meals for 
challenges. Clarified study insulin is 
branded as NovoRapid in Canada. Clarified 
definition of individuals permitted to 
perform physical exams. Resolved other 
minor conflicting statements. 
7.0 
J. Lum
J. Pinsker
October 02, 
2023 
Changed study goal to maximum percent of 
participants with A1c ≤8.0 to 60%. This 
version was approved by FDA but never 
submitted to IRB or used clinically. 
8.0 
J. Lum
J. Pinsker
October 31, 
2023 
Revised section 10.6 to indicate that 
glucagon will be offered to exercise 
challenge participants by study staff. 

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KEY ROLES 
Protocol Chair 
Name, degree 
Yogish Kudva, M.D. 
Institution Name 
Mayo Clinic 
JCHR Coordinating Center Director 
Name, degree 
John Lum, MS 
Institution Name 
Jaeb Center for Health Research 
Medical Monitor 
Name, degree 
Roy Beck, M.D., Ph.D. 
Institution Name 
Jaeb Center for Health Research 
Sponsor 
Name, degree 
Jordan Pinsker, M.D. 
Institution Name 
Tandem Diabetes Care, Inc. 
12400 High Bluff Drive 
San Diego, CA 92130 

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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 27 
1.1 Disease Background .......................................................................................................................... 27 
1.2 Device Background ........................................................................................................................... 27 
1.3 Control-IQ Use in Type 2 Diabetes ................................................................................................... 27 
1.4 Rationale and Objectives ................................................................................................................... 28 
1.5 Potential Risks and Benefits of the Investigational Device ............................................................... 29 
1.5.1 Known Potential Risks ................................................................................................................ 29 
1.5.1.1 Potential Risks of the AID System ..................................................................................... 29 
1.5.1.1 Potential Risks of Using Insulin Aspart .............................................................................. 29 
1.5.1.2 Potential Risks of CGM ...................................................................................................... 29 
1.5.1.3 Risk of Hypoglycemia ........................................................................................................ 29 
1.5.1.4 Risk of Hyperglycemia ....................................................................................................... 30 
1.5.1.5 Fingerstick Risks ................................................................................................................. 30 
1.5.1.6 Venipuncture Risks ............................................................................................................. 30 
1.5.1.7 Subcutaneous Catheter Risks .............................................................................................. 30 
1.5.1.8 Risk of Exercise .................................................................................................................. 30 
1.5.1.9 Risk of Device Reuse .......................................................................................................... 31 
1.5.1.10 Questionnaires ................................................................................................................... 31 
1.5.1.11 Other Risks ........................................................................................................................ 31 
1.5.2 Known Potential Benefits ............................................................................................................ 31 
1.5.3 Risk Assessment .......................................................................................................................... 31 
1.6 General Considerations...................................................................................................................... 32 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 33 
2.1 Participant Recruitment and Enrollment ........................................................................................... 33 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 34 
2.2 Participant Eligibility Criteria ........................................................................................................... 34 
2.2.1 Participant Inclusion Criteria ....................................................................................................... 34 
2.2.2 Participant Exclusion Criteria ...................................................................................................... 35 
2.2.3 Eligibility for Exercise Challenges .............................................................................................. 36 
2.3 Screening Procedures ........................................................................................................................ 36 
2.3.1 Data Collection and Testing ........................................................................................................ 36 
2.4 Screen Failures .................................................................................................................................. 37 
CHAPTER 3: CGM RUN-IN ........................................................................................................................ 38 
3.1 CGM Run-in Overview ..................................................................................................................... 38 

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3.2 Initiation of CGM .............................................................................................................................. 38 
3.2.1 CGM Training ............................................................................................................................. 38 
3.3 Assessment of Successful Completion of the CGM Run-in Phase ................................................... 39 
CHAPTER 4: RANDOMIZATION VISIT ....................................................................................................... 40 
4.1 Overview ........................................................................................................................................... 40 
4.2 Testing and Procedures ...................................................................................................................... 40 
4.3 Randomization ................................................................................................................................... 40 
4.4 Instructions for Both Groups ............................................................................................................. 41 
4.5 Instructions for the Control Group .................................................................................................... 41 
4.6 Instructions for the AID Group ......................................................................................................... 41 
4.6.1 Study Pump Training ................................................................................................................... 42 
4.6.1.1 Initiation of Pump by MDI Participants .............................................................................. 42 
4.6.2 Training on Using the Pump with Control-IQ Technology ......................................................... 43 
4.6.3 System Use Guidelines ................................................................................................................ 43 
4.6.4 Hyperglycemia and Ketosis Detection and Management ............................................................ 43 
CHAPTER 5: RCT ....................................................................................................................................... 45 
5.1 Overview ........................................................................................................................................... 45 
5.2 Follow-up Visits and Contacts .......................................................................................................... 45 
5.2.1 Contact and Visit Procedures ...................................................................................................... 45 
5.3 Transition to Pre-study Insulin Therapy ............................................................................................ 46 
5.3.1 3-Day Post-Study or Discontinuation of AID System Contact ................................................... 46 
5.4 Safety Visits Following Changes in Glucose-Lowering or Weight-Reduction Medications ............ 46 
5.5 Early Termination Visit ..................................................................................................................... 46 
CHAPTER 6: EXERCISE AND MEAL CHALLENGES ................................................................................... 48 
6.1 Overview ........................................................................................................................................... 48 
6.2 Meal Challenges ................................................................................................................................ 48 
6.3 Exercise Challenges ........................................................................................................................... 49 
6.4 Meal and Exercise Challenge Follow-Up .......................................................................................... 50 
CHAPTER 7: STUDY DEVICES AND STUDY INSULIN ................................................................................. 51 
7.1 Description of the Investigational Device ......................................................................................... 51 
7.1.1 Insulin Pump ................................................................................................................................ 51 
7.1.2 Continuous Glucose Monitoring ................................................................................................. 51 
7.1.3 Blood Glucose Meter and Strips .................................................................................................. 51 
7.1.4 Ketone Meter ............................................................................................................................... 51 
7.2 Description of Study-Provided Insulin .............................................................................................. 51 

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7.3 Study Device Accountability Procedures .......................................................................................... 52 
7.4 Participant Access to Study Device at Study Closure ....................................................................... 52 
CHAPTER 8: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 53 
8.1 Laboratory Testing ............................................................................................................................ 53 
8.2 Physical Examination ........................................................................................................................ 53 
8.3 Questionnaires ................................................................................................................................... 53 
8.3.1 Baseline Surveys ......................................................................................................................... 53 
8.3.2 Patient-reported Outcome Surveys .............................................................................................. 54 
CHAPTER 9: UNANTICIPATED PROBLEM, ADVERSE EVENT, AND DEVICE ISSUE REPORTING ............ 55 
9.1 Unanticipated Problems ..................................................................................................................... 55 
9.2 Adverse Events .................................................................................................................................. 55 
9.2.1 Definitions ................................................................................................................................... 55 
9.2.2 Reportable Adverse Events ......................................................................................................... 57 
9.2.3 Hypoglycemic Events .................................................................................................................. 58 
9.2.4 Hyperglycemic/Ketotic Events .................................................................................................... 58 
9.2.5 Relationship of Adverse Event to Study Investigational Device or Study 
Procedure .............................................................................................................................................. 59 
9.2.6 Severity (Intensity) of Adverse Events ........................................................................................ 60 
9.2.7 Expectedness ............................................................................................................................... 60 
9.2.8 Coding of Adverse Events ........................................................................................................... 60 
9.2.9 Outcome of Adverse Events ........................................................................................................ 61 
9.3 Reportable Device Issues ................................................................................................................... 61 
9.4 Timing of Event Reporting ................................................................................................................ 62 
9.5 Safety Oversight ................................................................................................................................ 63 
9.6 Stopping Criteria ............................................................................................................................... 63 
9.6.1 Participant Discontinuation of Study Device .............................................................................. 63 
9.6.2 Criteria for Suspending or Stopping Overall Study ..................................................................... 64 
CHAPTER 10: MISCELLANEOUS CONSIDERATIONS ................................................................................. 65 
10.1 Drugs Used as Part of the Protocol .................................................................................................. 65 
10.2 Collection of Medical Conditions and Medications ........................................................................ 65 
10.3 Prohibited Medications, Devices, Treatments, and Procedures ....................................................... 65 
10.4 Precautionary Medications, Treatments, and Procedures ................................................................ 65 
10.5 Prophylactic Medications, Treatments, and Procedures .................................................................. 66 
10.6 Rescue Medications, Treatments, and Procedures .......................................................................... 66 
10.7 Pregnancy Reporting ....................................................................................................................... 66 
10.8 Participant Compensation ................................................................................................................ 66 

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10.9 Participant Withdrawal .................................................................................................................... 66 
10.10 Confidentiality ............................................................................................................................... 66 
CHAPTER 11: STATISTICAL CONSIDERATIONS ........................................................................................ 67 
11.1 Statistical and Analytical Plans ....................................................................................................... 67 
11.2 Statistical Hypotheses ...................................................................................................................... 67 
11.3 Sample Size ..................................................................................................................................... 67 
11.4 Efficacy Outcome Measures ............................................................................................................ 67 
11.4.1 Primary Efficacy Endpoint ........................................................................................................ 67 
11.4.2 Secondary Efficacy Endpoints Included in Hierarchical Analysis ............................................ 68 
11.4.3 Other Secondary Efficacy Endpoints ........................................................................................ 68 
11.4.4 Safety Endpoints ........................................................................................................................ 69 
11.5 Analysis Datasets and Sensitivity Analyses .................................................................................... 69 
11.5.1 Per Protocol Analyses................................................................................................................ 69 
11.5.2 Other Sensitivity Analyses ........................................................................................................ 70 
11.6 Analysis of the Primary Efficacy Endpoint: HbA1c ....................................................................... 70 
11.7 Analysis of Secondary Endpoints .................................................................................................... 71 
11.7.1 CGM Metrics ............................................................................................................................. 71 
11.7.2 Binary Outcomes ....................................................................................................................... 71 
11.8 Questionnaires and Other Outcomes Analyses ................................................................................ 71 
11.9 Safety Analyses ............................................................................................................................... 72 
11.9.1 Safety Tabulations Specific to the AID Group .......................................................................... 72 
11.11 Planned Interim Analyses .............................................................................................................. 72 
11.12 Subgroup Analyses ........................................................................................................................ 73 
11.13 Multiple Comparison/Multiplicity ................................................................................................. 73 
11.14 Exploratory Treatment Group Comparisons ................................................................................. 74 
11.15 Additional Analyses and Tabulations for the Single-Arm AID Group ......................................... 74 
11.15.1 Tabulations Specific to the AID Group ................................................................................... 74 
11.15.2 Analyses of Complete CGM Data Set ..................................................................................... 74 
11.15.3 Analysis of Data from Meal and Exercise Challenges ............................................................ 74 
CHAPTER 12: DATA COLLECTION AND MONITORING ............................................................................ 75 
12.1 Case Report Forms and Other Data Collection ............................................................................... 75 
12.2 Study Records Retention ................................................................................................................. 75 
12.3 Quality Assurance and Monitoring .................................................................................................. 75 
12.4 Protocol Deviations ......................................................................................................................... 76 
CHAPTER 13: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 77 

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13.1 Ethical Standard ............................................................................................................................... 77 
13.2 Institutional Review Boards ............................................................................................................ 77 
13.3 Informed Consent Process ............................................................................................................... 77 
13.3.1 Consent Procedures and Documentation ................................................................................... 77 
13.3.2 Participant and Data Confidentiality ......................................................................................... 77 
CHAPTER 14: REFERENCES ....................................................................................................................... 79 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADE 
Adverse Device Event 
AE 
Adverse Event 
AID 
Automated Insulin Dosing 
AUC 
(Glucose) Area under the curve 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGM 
Continuous Glucose Monitoring 
CRF 
Case Report Form 
Control-IQ System 
t:slim X2 insulin pump with Control-IQ technology 
CSII 
Continuous Subcutaneous Insulin Infusion 
DCA2000 
Siemens/Bayer DCA 2000+ Hematology Analyzer 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EKG 
Electrocardiogram 
FDA 
United States Food and Drug Administration 
GAD 
Glutamic Acid Decarboxylase 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCL 
Hybrid Closed-loop 
HHS 
Hyperosmolar Hyperglycemic Syndrome 
HRPP 
Human Research Protection Program 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
MDI 
Multiple Daily Injections of insulin 
POC 
Point-Of-Care 

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ABBREVIATION 
DEFINITION 
PRO 
Patient-reported Outcomes 
RBM 
Risk-based Monitoring 
SAE 
Serious Adverse Event 
TDD 
Total Daily Dose 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
RCT 
Randomized Control Trial 
SAR 
Serious Adverse Reaction 
SC 
Standard of Care 
SD 
Standard Deviation 
SUS 
System Usability Scale 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2D 
Type 2 diabetes 
TDD 
Total Daily Dose of insulin 
TIR 
Time in range 
UADE 
Unexpected Adverse Device Event 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: A Randomized Trial Evaluating the Efficacy and Safety of Control-IQ 
Technology in Adults with Type 2 Diabetes Using Basal-Bolus Insulin Therapy (2IQP) 
Protocol Version/Date: 8.0/October 31, 2023 
I have read the protocol specified above.  In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
providing the Jaeb Center for Health Research, which serves as the Coordinating Center for the 
protocol, with complete and timely information, as outlined in the protocol.  It is understood that 
all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with the principles of Good Clinical Practice (GCP) 
and as required by the following (use applicable regulations depending on study location and 
sponsor requirements; examples follow): United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 
312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training.  
Further, I agree to ensure that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments. 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
dd 
mmm 
yyyy 
Investigator’s Name: ____________________________________ 
Site Name/Number: _____________________________________ 

A RANDOMIZED TRIAL EVALUATING CONTROL-IQ TECHNOLOGY IN ADULTS WITH TYPE 2
DIABETES USING BASAL-BOLUS INSULIN THERAPY 
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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
A Randomized Trial Evaluating the Efficacy and Safety of Control-IQ 
Technology in Adults with Type 2 Diabetes Using Basal-Bolus Insulin 
Therapy 
Précis 
A randomized controlled trial (RCT) will evaluate 13 weeks of home use of the 
t:slim X2 insulin pump with Control-IQ technology in adults with type 2 
diabetes age 18 and older using basal-bolus insulin therapy compared with 
continuation of pre-study insulin delivery plus continuous glucose monitoring 
(CGM). Exercise and meal-related challenges will be performed by all 
participants in the Control-IQ group unless there is a cardiac contraindication 
or other safety concern. 
Investigational Device 
t:slim X2 insulin pump with Control-IQ technology v1.5 (Control-IQ System) 
Objectives 
•
To assess the safety of use of Control-IQ technology in adults with type 2
diabetes using basal-bolus insulin therapy
•
To assess the efficacy of use of Control-IQ technology in adults with type
2 diabetes using basal-bolus insulin therapy
•
To assess user satisfaction and quality of life with use of Control-IQ
technology in adults with type 2 diabetes using basal-bolus insulin therapy
Study Design 
RCT 
Number of Sites 
~20-25 clinical centers in the U.S. and Canada 
Key RCT Endpoints 
Key Effectiveness Endpoints 
These endpoints will be tested in the following hierarchy to control for the type 
1 error 
•
HbA1c (primary)
•
Time in range 70-180 mg/dL
•
Mean glucose
•
Time >180 mg/dL
•
Time >250 mg/dL
•
Prolonged hyperglycemia events (>90 minutes >300 mg/dL within a
120-minute period)
•
Time <70 mg/dL
•
Time <54 mg/dL
•
CGM-measured hypoglycemia events (15 or more consecutive
minutes <54 mg/dL)
•
Coefficient of variation
Calculation of CGM metrics for the treatment group comparison will exclude 
the challenges and the 24-hour period following the end of the challenge 
Key Safety Endpoints: 
•
Severe hypoglycemia
•
Diabetic ketoacidosis
•
Hyperosmolar hyperglycemic syndrome
•
Other serious adverse events

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PARTICIPANT AREA 
DESCRIPTION 
•
Unanticipated adverse device effects
•
Hypoglycemia and prolonged hyperglycemia endpoints listed as
effectiveness endpoints
•
Infusion set failures
•
Other device malfunctions/device issues
Other Endpoints 
•
% time in closed loop
•
Total daily insulin delivery
•
Weight change
•
Change in lipid levels
•
Cardiovascular events
•
Patient-reported outcome (PRO) measures
o
Diabetes Distress Scale
o
Diabetes Impact and Device Satisfaction Scale
o
PROMIS (Sleep Related Impairment Questionnaire)
o
DAWN-Impact of Diabetes Profiles
o
HFS I and II
o
EQ5D
o
Study-specific survey
o
System Usability Scale (SUS)
•
Frequency of non-severe hypoglycemia
Exploratory analyses will evaluate endpoints in subgroups based on diabetic 
medication use, body mass index, baseline HbA1c 
Eligibility Criteria 
Inclusion Criteria 
1.
Age ≥18 years old at time of screening
2.
Currently resides in the U.S. or Canada with the ability to complete in-
person study visits at one of the participating clinical sites
3.
Clinical diagnosis, based on investigator assessment, of type 2 diabetes of
at least 6 months duration at time of screening.
4.
Using basal-bolus insulin therapy with at least one injection containing
rapid-acting insulin per day or an insulin pump for at least 3 months prior
to enrollment, with no major modification to insulin regime in the last 3
months
•
Mixed insulin with a rapid component is acceptable
5.
If using noninsulin glucose-lowering medications (such as GLP-1 receptor
agonist, SGLT2 inhibitor, or other) or weight-reduction medications, dose
has been stable for the 3 months prior to screening; and participant is
willing to not change the dose unless required for safety purposes
6.
Participant willing to not initiate use of any new glucose-lowering
medications during the trial
7.
Willing to use an approved insulin while using the study pump if assigned
to the AID group
8.
Willing to not use concentrated insulin above U-100 or inhaled insulin
while using the study pump

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PARTICIPANT AREA 
DESCRIPTION 
9.
Willing to participate in the study meal and exercise challenges if assigned
to the AID group, and have a care partner, trained in hypoglycemia
treatment guidelines, to include glucagon use, present during and
immediately after the exercise challenges.
10. Has the ability to read and understand written English
11. Investigator believes that the participant has the cognitive capacity to
provide informed consent
12. Investigator believes that the participant can successfully and safely
operate all study devices and is capable of adhering to the protocol and
completing the study
13. No medical, psychiatric, or other conditions, or medications being taken
that in the investigator’s judgement would be a safety concern for
participation in the study
•
This includes considering the potential impact of medical conditions
known to be present including cardiovascular, liver, kidney disease,
thyroid disease, adrenal disease, malignancies, vision difficulties,
active proliferative retinopathy, and other medical conditions;
psychiatric conditions including eating disorders; drug or alcohol
abuse.
14. Participants capable of becoming pregnant must meet one of the following
criteria:
a. has a negative urine pregnancy test and agrees to use one of the
accepted contraceptive regimens throughout the entire duration of
the trial from screening until last follow-up visit. The following
contraceptive measures are considered adequate:
i.
Combined estrogen and progestogen containing
hormonal contraception associated with inhibition of
ovulation (oral, intravaginal, transdermal)
ii.
Progestogen-only hormonal contraception associated
with inhibition of ovulation (oral, injectable,
implantable)
iii.
Placement of an intrauterine device or intrauterine
hormone-releasing system
iv.
Bilateral tubal occlusion
v.
Barrier methods of contraception (condom or occlusive
cap with spermicidal foam/gel/film/cream/suppository).
vi.
Has a vasectomized or sterile partner (where partner is
sole partner of subject) and where vasectomy has been
confirmed by medical assessment
vii.
Exercises true sexual abstinence. Sexual abstinence is
defined as refraining from heterosexual intercourse
during the entire period of risk associated with the study
treatments. The reliability of sexual abstinence needs to
be evaluated in relation to the duration of the clinical
trial and the preferred and usual lifestyle of the subject.
or 
b.
Participant is of non-childbearing potential due to
menopause with at least one year since last menses or a medical

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PARTICIPANT AREA 
DESCRIPTION 
condition confirmed by the investigator 
Exclusion Criteria 
1.
Current use of hybrid closed-loop system
2.
Current use of systemic glucocorticoids or anticipated use of
glucocorticoids during the RCT (topical or inhaled -ie, non-systemic is
acceptable).
3.
Current use of sulfonylurea or meglitinide medications
4.
Current use of hydroxyurea
5.
Tape allergy or skin condition that will preclude use of the study pump or
CGM
6.
Presence of a hemoglobinopathy or other condition that is expected to
affect the measurement of HbA1c
7.
Pregnant (positive urine hCG), breast feeding, plan to become pregnant
during the study period, or sexually active without use of accepted
contraceptive measures
8.
Current participation in another diabetes-related interventional clinical
trial
9.
Anticipated change of residency or travel for more than 7 days at a time
during the study that may, per investigator judgment, interfere with the
completion of study visits, contacts, or procedures
10. Immediate family member (spouse, biological or legal guardian, child,
sibling, parent) who is an investigative site personnel directly affiliated
with this study or who is an employee of Tandem Diabetes Care, Inc.
Eligibility for Exercise Challenges 
All participants will have a screening EKG or review of an EKG completed in 
the 12 months prior to screening. 
To participate in the exercise challenge, a participant must not have a history 
of a cardiovascular event in the year prior to screening and/or EKG 
abnormalities associated with increased risk during exercise.  
Sample Size 
A maximum of 450 individuals may be enrolled (consented for screening) in 
order to achieve the goal of 330 randomized participants. 
This equates with a maximum of 220 using the AID system for 13 weeks and 
110 using pre-study basal-bolus insulin delivery method plus the study CGM. 
Assuming 10% drop out rate in each group, there will be 200 using the system 
for 13 weeks.  
Approximate Study Goals 
-
Minimum 25% MDI users
-
Minimum 30% of a minority race or ethnicity
-
Minimum 10% older than 50 years old
-
Minimum 20% using an SGLT2 inhibitor,20% using a GLP-1 receptor
agonist, and a minimum of 10% using both
-
Minimum of 15% with TDI> 100 units/day and attempt to enrich
cohort with participants with TDI >200 units

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PARTICIPANT AREA 
DESCRIPTION 
-
Minimum of 25% using a form of fixed dosing to calculate meal
boluses (e.g., fixed dose at meal or fixed dose for small/medium/large
meal [i.e., dose not determined by carbohydrate counting])
-
Maximum of 60% with HbA1c <8% (based on screening  HbA1c or
HbA1c available within the last 30 days) and maximum of 10% with
screening HbA1c <7%
Treatment Groups 
Random assignment 2:1 to an intervention group or control group: 
•
Intervention group: t:slim X2 insulin pump with Control-IQ
technology and Dexcom G6 CGM
•
Control group: Continuation of pre-study basal-bolus insulin delivery
method, plus use of study CGM (Dexcom G6)
Participant Duration 
~13-17 weeks, depending on duration of run-in phase 
Study Duration (planned) 
~9 months from first enrollment until last participant visit (assuming 4-month 
recruitment period; study duration will be extended as needed to complete 
recruitment) 
Protocol Overview/Synopsis 
Screening Visit 
•
Informed consent obtained and participant screened for eligibility. Testing
for eligibility assessment and baseline will include:
o
Medical history, including total daily insulin dose, prior severe
hypoglycemia,  diabetic ketoacidosis (DKA), hyperosmolar
hyperglycemic syndrome (HHS), and hospitalizations for these
events.
o
HbA1c with point-of-care device or local lab, unless available
from the prior 30 days
o
Focused physical exam, including height and weight to compute
body mass index (BMI) and blood pressure
o
Urine pregnancy test for participants capable of becoming
pregnant
o
EKG unless performed within 12 months prior to screening
o
Subjective Numeracy Scale
o
Patient-reported outcome (PRO) surveys (see section 8.3),
including frequency of non-severe hypoglycemia during the prior
3 months
CGM Run-in 
•
Eligible participants will be started on the study CGM, if applicable
•
Experienced current users of the study CGM with at least 85% of available
readings from prior 14 days will skip the CGM Run-In
•
Otherwise, participants will use CGM for a minimum of 21 days
o
Training provided to use the CGM in conjunction with basal-
bolus insulin therapy
o
Participants expected to use the CGM until return for post- run-in
clinic visit.
o
At investigator discretion, contacts may occur with participant
during run-in phase for further training on use of CGM

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PARTICIPANT AREA 
DESCRIPTION 
o
Participants will continue use of their personal insulin delivery
method (pump or MDI)
•
Clinic visit after 21-28 days
•
Participant must have used CGM for at least 85% of the time during the
most recent 14 days.  If this requirement is not met, the run-in phase can
be extended for an additional 14-21 days at the investigator’s discretion.
•
The most recent 14 days of CGM data will be used as the baseline for
analyses
Randomization Visit 
•
For participants completing the CGM Run-in, Randomization Visit
typically occurs on same day as End of Run-in Visit; if participant is not
ready to start the AID system if randomly assigned to the intervention
group, it must occur within 14 days after completion of the run-in phase.
For participants skipping the CGM Run-in, Randomization Visit may
occur on same day as Screening Visit (so long as all eligibility criteria
have been verified) or within 14 days following the Screening Visit.
•
If not on same day as Screening Visit,
o
Solicit any changes in medical conditions since screening that
could affect eligibility for the RCT
o
Vital signs
o
Urine pregnancy test for participants capable of becoming
pregnant
•
Blood draw for central lab measurement of HbA1c, lipids, creatinine, C-
peptide, glucose, and GAD antibodies
•
Randomization to the AID group or Control group
o
AID group: Initiation of AID system and training on its use
(initial training typically will be completed and AID system use
initiated on day of randomization but if investigator does not
believe that participant is ready to start the study pump, initiation
of the study pump can be deferred for further training, but
initiation of the AID system must occur within 7 days of
randomization). Insulin aspart will be provided for participants
who prefer to use the study insulin.
o
Control group: Training on use of study CGM and continuing
pre-study basal-bolus insulin therapy
13-week RCT protocol
•
Participants in AID group will have a contact 3 ±1 days after initiation of
closed loop (may coincide with 7-day visit) for further review of training
materials and to answer questions.  Participants will be specifically
instructed to contact the site for any issues that arise during the first
infusion set change.
•
Participants in AID group will be expected to use the system continuously
until the 13-week visit (unless a condition occurs, such as illness, in which
the participant is instructed by the site to temporarily switch to open-loop)
•
Addition of glucose-lowering or weight reduction medications or dose
changes in such medications in use at the time of randomization are
prohibited during the 13 weeks of the RCT, unless determined by the
investigator to be necessary for safety.

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PARTICIPANT AREA 
DESCRIPTION 
o
If a participant in the AID group has a change in dose or addition
of a new glucose-lowering or weight-reduction medication, an
unscheduled visit will occur after 1-2 days and ~7 days to assess
safety.
•
Instructions will be provided for when to test for ketones and management
when ketosis is present (see section 4.6.4).
•
Participants will not be restricted on diet or exercise.
•
Participants in the Control group will be expected to use CGM on daily
basis.
RCT Visits and Contacts 
•
As noted earlier, the AID group will have a contact 3 ±1 days after
initiating the AID system to address any questions after initial use of the
AID system and further training as needed.
•
For both groups, in-clinic visits will occur 4 weeks ± 4 days and 13 weeks
± 4 days; and a remote (phone or video) visit will occur after 7±2 days for
a safety check. An additional clinic visit or contact will occur after 8
weeks ± 4 days (depending on whether participant is able to upload device
data at home and whether investigator believes clinic visit is needed).
At each scheduled visit/contact: 
o
Review medications and doses
o
AID system and CGM data will be reviewed (participants without
the ability to upload the device data from home will be provided
with a laptop to use during the study)
o
Site investigators may adjust insulin delivery profile settings
ONLY for safety concerns and will document reasons for change
in the CRF
o
Occurrence of adverse events will be solicited
o
Assessment of TDD over last week
At 13-week visit, the following also will be done:
o
Height, weight, blood pressure/pulse
o
Blood draw for central lab measurement of HbA1c, lipids,
creatinine
o
PRO surveys completed, including frequency of non-severe
hypoglycemia during the prior 3 months
•
At the completion of the RCT, participants will be transitioned back to
their pre-study insulin regimen and have a safety contact after 3 ± 1 days.
•
Additional visits and contacts may occur at investigator discretion
Exercise and Meal Challenges
•
All participants in the AID group will perform the meal challenges and all
participants in the AID group will perform the exercise challenges unless
ineligible due to cardiac or other safety concerns.
•
Each participant will perform 3 meal and 3 exercise challenges during the
RCT. This will include a full bolus, half bolus, and no bolus meal, as well
as three one-hour exercise periods (with at least 30 minutes moderate
exercise). All challenges will be performed unsupervised at home, with
required study team contacts before and after each challenge. For each

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PARTICIPANT AREA 
DESCRIPTION 
exercise challenge, an individual (care partner) capable of providing 
treatment for severe hypoglycemia will need to be present. 
•
Approximately 25% of each type of challenge (meal or exercise) will be
performed on 3 consecutive days within each of the following 4 periods
time from randomization: 1-2 weeks, 3-4 weeks, 5-6 weeks, 7-8 weeks.
Challenges that cannot be scheduled during these time periods or
challenges that need to be rescheduled may be performed, if necessary
between weeks 9 and 13.
•
Participants will be instructed to communicate with study staff within one
day prior to each challenge to review procedures and to have a contact
with study staff after the completion of each challenge within one day.
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 study safety plan and per CGM 
manufacturer instructions. Ketone readings will be performed per the study 
safety plan, based largely on the development of symptoms suggestive of 
ketosis. 
Site investigators may adjust insulin delivery profile settings ONLY for safety 
concerns as needed throughout the study in accordance with their clinical 
practice. Reasons for the change will be documented in the CRF. 
A Data and Safety Monitoring Board will provide study oversight. All severe 
hypoglycemia, DKA, and HHS events will be reported expeditiously to the 
DSMB as described in section 9.5. 
Analysis Plan 
At the end of the RCT, it is planned that the database will be locked and 
analyses performed in preparation for 510K submission.  

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Figure 1: Schematic of Study Design 
Week 0 - 13
Week -2 to-6
Screening &
CGM Run-In
AID Group
t:slim X2 pump with Control-IQ
SC Group
MDI or Personal Pump + Study
CGM
1:2 RandomizaƟon
RCT data analysis

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Table 1: Schedule of Study Visits and Procedures 
Visit Designation 
Screening 
End of Run-in 
Randomization 
(Day 0) 
3d 
1w 
4w 
8w 
13w 
Visit Window 
* 
** 
± 1da 
±2da 
±4d 
±4d 
±4d 
Visit (V) or Contact (C) 
V 
V 
V 
C 
C 
V 
V or Cb 
V 
Informed Consent/Assent 
X 
Eligibility Assessment 
X 
Medical history/ 
focused physicalc 
X 
Review medications and 
doses 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure, pulse, 
height & weightd
X 
Xe 
X 
Xb
X 
HbAlc (POC or local lab) 
Xf
Pregnancy test (for 
participants capable of 
becoming pregnant) 
X 
Xe 
HbA1c (central lab) 
X 
X 
Lipids, creatinine (central 
lab)
X 
X 
C-peptide, glucose, GAD
antibodies (central lab)
X 
Subjective Numeracy Scale 
X 
Questionnaires/Surveys 
(PRO Assessments)g
X 
X 
Initiation of Study CGMh
X 
Assessment of CGM Use 
X 
Study system training; 
dispense study insulin 
Xi
X 
Upload device data 
from home or at clinic visit 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
EKG and assessment of 
eligibility for exercise 
challengesj
X 
Exercise and Meal 
challengesk
See below 
*Clinic visit after 21-28 days for participants required to complete CGM run-in.
•
To proceed to randomization, participant must have used CGM for at least 85% of the time during the most
recent 14 days.  If this requirement is not met, the run-in phase can be extended for an additional 14-21
days at investigator discretion.

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•
The most recent 14 days of CGM data will be used as the baseline for analyses
** Randomization Visit should be on the same day as the End of Run-in visit, following which closed-loop 
participants have up to 14 days to begin study pump use. Pump training can occur over more than 1 session if 
necessary.  
a Target and windows for 3-day visit, and 7-day visit are calculated from study pump initiation date for AID group. 
b At 8 weeks, clinic visit or contact depending on whether participant is able to upload device data at home and 
whether investigator believes clinic visit is needed. 
c A focused physical exam will be performed by the study investigator or designee (a physician, fellow, nurse 
practitioner, physician assistant, or equivalent licensed provider). This will include parts of the exam relevant to 
device use, such as skin changes from device or insulin use. At screening, it may include physical exam techniques 
related to assessment of cardiovascular disease if participation in the exercise and meal challenges is being 
considered.  
d Vital signs (including blood pressure and pulse) and height and weight measurements may be obtained by non-
study support staff according to the clinic’s usual processes. 
e Not performed if Randomization Visit is same day as Screening Visit. May be performed at other visits at the 
discretion of the investigator. 
f Can be skipped if result is available from within prior 30 days 
g See section 8.3 for list of questionnaires to be completed; includes frequency of non-severe hypoglycemia during 
the prior 3 months 
h Study CGM training provided and CGM use initiated for all participants except those who are experienced current 
users of the study CGM with at least 85% of readings available from the prior 14 days 
I Only for participants assigned to AID group; initial training typically will be completed and AID system use 
initiated on day of randomization but if investigator does not believe that participant is ready to start the study pump, 
initiation of the study pump can be deferred for further training but initiation of the AID system must occur within 7 
days of randomization. Insulin aspart will be provided for participants who prefer to use the study insulin. 
j EKG not required if performed within prior 12 months 
k Exercise and meal challenges:  
•
All participants in the AID group will perform the meal challenges and all without a safety contraindication
will perform the exercise challenges.
•
Each participant will perform 3 meal and 3 exercise challenges during the RCT. This will include a full
bolus, half bolus, and no bolus meal, as well as three one-hour exercise periods (with at least 30 minutes
moderate exercise). All challenges will be performed unsupervised at home, with required study team
contacts before and after each challenge.
•
Approximately 25% of each type of challenge (meal or exercise) will be performed on 3 consecutive days
within each of the following 4 periods time from randomization: 1-2 weeks, 3-4 weeks, 5-6 weeks, 7-8
weeks.  Challenges that cannot be scheduled during these time periods or challenges that need to be
rescheduled may be performed, if necessary between weeks 9 and 13.

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Chapter 1: Background Information 
1 
1.1 Disease Background 
2 
More than 34 million people in the United States have diabetes, with type 2 diabetes accounting 
3 
for approximately 90% to 95% of cases. In the last 20 years, the number of adults diagnosed with 
4 
diabetes has more than doubled as the American population has aged and become more 
5 
overweight or obese. Diabetes is the 7th leading cause of death in the United States (and may be 
6 
underreported) (1). 
7 
1.2 Device Background 
8 
The t:slim X2 insulin pump with Control-IQ technology (Control-IQ) is an advanced hybrid 
9 
closed-loop (HCL) system, developed and manufactured by Tandem Diabetes Care, Inc. and 
10 
cleared in the U.S. by the FDA for individuals with type 1 diabetes. Control-IQ is integrated with 
11 
the Dexcom G6 continuous glucose monitor (CGM) and uses CGM values to predict glucose 
12 
values 30 minutes in the future. Based on the predicted glucose, Control-IQ modulates basal 
13 
insulin delivery, and delivers automated correction boluses to mitigate impending 
14 
hyperglycemia. The current Control-IQ system is FDA approved down to age 6 years old for 
15 
individuals with type 1 diabetes, and has been found to improve time in range (70-180 mg/dL) 
16 
and decrease both time <70 mg/dL and time >180 mg/dL (2,3). There are over 150,000 users of 
17 
the system since it became commercially available in 2020.  A recent evaluation of real-world 
18 
use of the system in 9,451 users age ≥6 years with at least 12 months of system use found results 
19 
comparable to those found in the randomized trials (4). 
20 
21 
22 
Figure 2. t:slim X2 with Control-IQ and Dexcom G6 system 
23 
Since the initial approval of the system, modifications have been made in the software, which is 
24 
referred to as version 1.5. These modifications include modest usability improvements and other 
25 
enhancements intended to further reduce risk. The Control-IQ 1.5 algorithm also removes the 3 
26 
units/hr basal clipping, allowing the pump to deliver programmed user profile basal rates above 3 
27 
units/hr. This has the potential to further improve outcomes in individuals with type 2 diabetes 
28 
who are often using basal rates at or above this threshold. 
29 
1.3 Control-IQ Use in Type 2 Diabetes 
30 
31 

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Insulin pump use in individuals with type 2 diabetes is relatively low. However, there is an 
32 
increasing uptake of pump use in this population. The benefits of insulin pump use with 
33 
Automated Insulin Dosing (AID) technology in individuals with type 2 diabetes has not been 
34 
well established in clinical trials, although real-world data have shown that use of Control-IQ can 
35 
produce significant glycemic benefits in this population, whether transitioning from multiple 
36 
daily injections (MDI) or prior pump use. Retrospective analysis of 134 prior pump users with 
37 
type 2 diabetes who purchased a new Tandem insulin pump with Control-IQ technology showed 
38 
time in range was 76% (IQR 69-82%) and time below range was 0.5% (IQR 0.2-1.0%) after 180 
39 
days of use. For 173 participants transitioning from MDI, use of Control-IQ technology resulted 
40 
in time of range 70-180 mg/dL of 74% (IQR 63-83%) and time below  70 mg/dL 0.3% (IQR 0.1-
41 
0.6%) at 180 days of use (5). Additionally, retrospective analysis of real-world use out to one 
42 
year in 378 individuals with type 2 diabetes who software updated from Basal-IQ technology to 
43 
Control-IQ technology showed significant improvements in time in range 70-180 mg/dL (69% at 
44 
baseline versus 78% at one year) (4). In an analysis of Medicare and Medicaid Control-IQ users, 
45 
500 individuals with type 2 diabetes improved from 64% TIR at baseline to 72% after using 
46 
Control-IQ for at least 30 days (6). 
47 
A prospective single-arm 6-week trial, conducted to provide preliminary data on the safety and 
48 
glycemic outcomes with use of Control-IQ in adults with T2D, showed that use of Control-IQ 
49 
was safe, with no increase in CGM-measured hypoglycemia and a substantial improvement in 
50 
time in range and mean glucose related to a reduction in hyperglycemia (7). Thirty adults with 
51 
T2D (mean age 54±12 years, mean HbA1c 8.6±1.2, median BMI 31) using either MDI (N=15), 
52 
pump (N=2) or basal without bolus insulin (N=13) collected unblinded CGM data (baseline) 
53 
followed by an open-loop period prior to initiating use of CIQ for 6 weeks. Primary outcomes 
54 
were superiority for CGM time >180 mg/dL and non-inferiority for time <54 mg/dL. Mean time 
55 
>180 mg/dL decreased from 44% at baseline to 29% with CIQ, a reduction of 3.6 hours per day
56 
(P=0.004), mean time 70-180 mg/dL increased from 56% to 71% (P= 0.004), and mean glucose 
57 
decreased from 184 to 163 mg/dL (P=0.01). Median time >250 mg/dL decreased by more than 
58 
one hour per day. Median time <54 mg/dL was 0.00% at baseline and during CIQ use (IQR -
59 
0.02% - +0.02%). Median time in closed loop was 96% (interquartile range 93% to 96%). There 
60 
were no severe hypoglycemia or DKA events. On the Diabetes Impact and Device Satisfaction 
61 
Scale, participants indicated a high level of satisfaction with CIQ (mean item score 8.8±1.9 on 
62 
scale of 1-10). Both prior MDI or pump and prior basal insulin only participants showed similar 
63 
levels of improvement in all outcomes. 
64 
1.4 Rationale and Objectives 
65 
There are many patients with T2D who are unable to achieve optimal glucose control despite the 
66 
use of intensive insulin therapy often with the concomitant use of other glucose-lowering drugs.  
67 
An AID system such as Control-IQ offers the potential for lower HbA1c levels and increased 
68 
time in range without increasing hypoglycemia and for improved quality of life.  In view of the 
69 
promising results from the preliminary study evaluating Control-IQ in T2D, a larger trial with a 
70 
randomized trial design is needed to more broadly and rigorously evaluate the efficacy and safety 
71 
of Control-IQ in adults with T2D using basal-bolus insulin therapy with or without additional 
72 
glucose-lowering medications.  Thus, the main objectives of this trial are: 
73 

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•
To assess the safety of use of Control-IQ in adults with type 2 diabetes using basal-bolus 
74 
insulin therapy 
75 
• To assess the efficacy of use of Control-IQ in adults with type 2 diabetes using basal-bolus
76 
insulin therapy 
77 
• To assess user satisfaction and quality of life with use of Control-IQ in adults with type 2
78 
diabetes using basal-bolus insulin therapy 
79 
1.5 Potential Risks and Benefits of the Investigational Device 
80 
Risks and benefits are detailed below. Loss of confidentiality is a potential risk; however, data 
81 
are handled securely to minimize this risk. Hypoglycemia and hyperglycemia and ketone 
82 
formation are always a risk in participants with type 2 diabetes and insulin treatment, and 
83 
participants will be monitored for this. 
84 
1.5.1 Known Potential Risks 
85 
1.5.1.1 Potential Risks of the AID System 
86 
Even though the study system has been tested prior to this study, there is still a risk that parts of 
87 
the system may not function properly. The following are possible reasons the system may deliver 
88 
too much insulin or incorrectly stop insulin delivery: 
89 
CGM sensor reads higher or lower than the actual glucose level which increases risk for 
90 
hypoglycemia and hyperglycemia with automated insulin delivery system; 
91 
Device malfunctions that could produce a suspension of insulin delivery or over delivery of 
92 
insulin. 
93 
1.5.1.1 Potential Risks of Using Insulin Aspart 
94 
Potential adverse reactions with study-provided insulin aspart are similar to other insulins: 
95 
hypoglycemia, hypokalemia, allergic reactions, injection-site reactions, lipodystrophy, localized 
96 
cutaneous amyloidosis, pruritus, rash, weight gain, and peripheral edema. 
97 
1.5.1.2 Potential Risks of CGM 
98 
CGM will be used by the control group without automation of insulin delivery.  There is risk of 
99 
CGM inaccuracy that could lead to an under dosing of insulin producing hyperglycemia or 
100 
overdosing of insulin producing hypoglycemia. 
101 
1.5.1.3 Risk of Hypoglycemia 
102 
As with any person having diabetes and using insulin, there is always a risk of hypoglycemia. 
103 
The frequency of hypoglycemia should be no more and possibly less than it would be as part of 
104 
daily living. Symptoms of hypoglycemia can include sweating, jitteriness, and not feeling well. 
105 
Just as at home, there is the possibility of fainting or seizures (convulsions) and that for a few 
106 
days the participant may not be as aware of symptoms of hypoglycemia. A CGM functioning 
107 
poorly and significantly over-reading glucose values could lead to inappropriate insulin delivery. 
108 

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1.5.1.4 Risk of Hyperglycemia 
109 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
110 
extended period or if the pump or infusion set is not working properly. Although less common in 
111 
individuals with type 2 diabetes than in those with type 1 diabetes, DKA can still occur. Extreme 
112 
levels of hyperglycemia and dehydration can lead to hyperosmolar hyperglycemic syndrome 
113 
(HHS). A CGM functioning poorly and significantly under-reading glucose values could lead to 
114 
inappropriate suspension of insulin delivery. All subjects will be issued a glucose meter and 
115 
glucose test strips, as well as a ketone meter and ketone test strips, to use to carefully monitor for 
116 
hyperglycemia and ketones and be given instructions on how to mitigate hyperglycemia and 
117 
ketosis should it occur. 
118 
1.5.1.5 Fingerstick Risks 
119 
About 1 drop of blood will be removed by fingerstick for measuring blood glucose, ketones, and 
120 
sometimes Hemoglobin A1c (HbA1c). This is a standard method used to obtain blood for routine 
121 
hospital laboratory tests. Pain is common at the time of lancing. In about 1 in 10 cases, a small 
122 
amount of bleeding under the skin will produce a bruise. A small scar may persist for several 
123 
weeks. The risk of local infection is less than 1 in 1000. This should not be a significant 
124 
contributor to risks in this study as fingersticks are part of the usual care for people with diabetes. 
125 
1.5.1.6 Venipuncture Risks 
126 
A hollow needle/plastic tube may be placed in the arm for taking blood samples. Blood draws 
127 
can cause some common reactions like pain, bruising, or redness at the sampling site. Less 
128 
common reactions include bleeding from the sampling site, formation of a small blood clot or 
129 
swelling of the vein and surrounding tissues, and fainting. 
130 
1.5.1.7 Subcutaneous Catheter Risks 
131 
Whenever the skin is broken there is the possibility of bleeding and bruising. The CGM sensor 
132 
and pump infusion sets are inserted under the skin. It is possible that any part that is inserted 
133 
under the skin may cause an infection, which could produce swelling, redness, and pain. These 
134 
occur very infrequently, but if an infection were to occur, oral and/or topical antibiotics may be 
135 
prescribed. The risk of skin problems could be greater if a sensor or infusion set is used for 
136 
longer than it is intended to be used. Therefore, participants will be carefully instructed about 
137 
proper use of these components. 
138 
On rare occasions, the CGM sensor may break and leave a small portion of the sensor probe 
139 
under the skin that may cause redness, swelling or pain at the insertion site. The participant will 
140 
be instructed to notify the site immediately if this occurs. 
141 
1.5.1.8 Risk of Exercise 
142 
Exercise may lead to injury, hypoglycemia or hyperglycemia, or significant events, such as 
143 
myocardial infarction or other significant cardiac events.  Participants completing the exercise 
144 
challenges will be evaluated for their suitability to participate in the exercise challenges, which 
145 
will minimize the risk. Participants will be instructed on how to prepare for exercise by study staff 
146 
and intended use of the exercise activity feature. 
147 

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1.5.1.9 Risk of Device Reuse 
148 
All devices will be used by a single study participant only. There will be no device reuse. 
149 
1.5.1.10 Questionnaires 
150 
As part of the study, participants will complete questionnaires which include questions about 
151 
their private attitudes, feelings and behavior related to the investigational equipment as well as 
152 
managing diabetes. It is possible that some people may find these questionnaires and interviews 
153 
to be mildly upsetting. Similar questionnaires and interviews have been used in previous research 
154 
and these types of reactions have been uncommon. 
155 
1.5.1.11 Other Risks 
156 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
157 
the CGM, or from tape to secure the insulin infusion sets for the continuous subcutaneous insulin 
158 
infusion. If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, 
159 
Tegaderm, etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or 
160 
other medication may be required. 
161 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be 
162 
collected for the study as measures of diabetes self-management behaviors. Downloaded data 
163 
from the participant’s personal CGM or pump (if any) will include data from prior to the date of 
164 
the screening visit. Some people may be uncomfortable with the researchers’ having such 
165 
detailed information about their daily diabetes habits. 
166 
1.5.2 Known Potential Benefits 
167 
Participants may experience a significant improvement in glucose control. Hypoglycemia is the 
168 
number one fear of many individuals taking insulin, and this fear often prevents optimal 
169 
glycemic control. Hyperglycemia will likely be reduced as well. 
170 
In addition, users of insulin pumps often take less insulin than users of basal/bolus injection 
171 
therapy. This may lead to weight loss, which will be tracked over the course of the study. 
172 
It is expected that this protocol will yield increased knowledge about using an AID system to 
173 
control glucose levels in people with type 2 diabetes. The individual participant may or may not 
174 
benefit from study participation. 
175 
1.5.3 Risk Assessment 
176 
It is the assessment of the investigators that this protocol is a clinical investigation involving 
177 
greater than minimal risk but that it does present the prospect of direct benefit to individual 
178 
subjects based on the following: (1) individuals with diabetes experience hypoglycemia and 
179 
hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
180 
intervention involves periodic automated insulin dosing that may reduce the likelihood of 
181 
hypoglycemia, and periodic automated attenuation of insulin delivery that may reduce the 
182 
likelihood of hyperglycemia, (3) if any, hypo and/or hyperglycemia occur, mitigations are in 
183 
place, and have been tested in prior studies using the investigational device system in the home 
184 
setting, that limit the likelihood of excessive insulin dosing or prolonged withdrawal of insulin, 
185 
and (4) rapid reversal of hypoglycemia and hyperglycemia can be achieved, In addition, it is the 
186 

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belief of the investigators that this study also presents prospect of general benefit to others with 
187 
diabetes. 
188 
1.6 General Considerations 
189 
The study is being conducted in compliance with the policies described in the study policies 
190 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
191 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
192 
In accordance with 21 CFR 812.66, the protocol is considered a significant risk device study, due 
193 
to the fact that the closed loop system is investigational in the population under study.  
194 
Therefore, an investigational device exemption (IDE) from the U.S. Food and Drug 
195 
Administration (FDA) is required to conduct the study. 
196 

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Chapter 2: Study Enrollment and Screening 
197 
2.1 Participant Recruitment and Enrollment 
198 
Enrollment will proceed with the goal of 330 participants being randomized in the trial and at 
199 
least 300 participants completing the trial. A maximum of 450 individuals may be consented for 
200 
screening in order to achieve this goal.  Participants who have signed consent and started the 
201 
screening process may be permitted to continue into the trial, if eligible, even if the completion 
202 
goal has been reached. 
203 
Study participants will be recruited from ~20-25 clinical sites in the United States and Canada. 
204 
The maximum number that can be randomized by any site is 66.  Up to 30 participants will be 
205 
randomized from Canada. All eligible participants will be included without regard to gender, 
206 
race, or ethnicity. There is no restriction on the number of participants to be enrolled by each 
207 
clinical center toward the overall recruitment goal. 
208 
There will be approximate recruitment goals for the following: 
209 
-
Minimum 25% MDI users
210 
-
Minimum 30% of a minority race or ethnicity
211 
-
Minimum 10% older than 50 years old
212 
-
Minimum 20% using an SGLT2 inhibitor, 20% using a GLP-1 receptor agonist and a
213 
minimum of 10% using both
214 
-
Minimum of 15% with TDI>100 units/day and attempt to enrich cohort with participants
215 
with TDI >200 units
216 
-
Minimum of 25% using a form of fixed dosing to calculate meal boluses (e.g., fixed dose
217 
at meal or fixed dose for small/medium/large meal [i.e., dose not determined by
218 
carbohydrate counting])
219 
-
Maximum of 60% with HbA1c <8% (based on screening HbA1c or HbA1c available
220 
within the last 30 days) and maximum of 10% with screening HbA1c <7%
221 
Individuals generally will be recruited from each site’s existing patient population or from a list 
222 
of individuals who contact the site. Study recruitment methods may consist of one or more of the 
223 
following: 
224 
o
Culling of pre-existing databases at the clinical sites to identify patients who may be
225 
eligible. Those identified will be contacted via IRB-approved mailing sent through post,
226 
email, or via phone and will be provided information about the study and how to proceed
227 
if potentially interested;
228 
o
IRB-approved press release announcing study and study fact sheet;
229 
o
IRB-approved information about the study distributed through support groups, other
230 
internet groups, patient education classes, not-for-profit organizations;
231 
o
IRB-approved paper and digital advertisements;
232 
o
IRB-approved digital advertisements posted on social media sites like LinkedIn, Twitter,
233 
YouTube, Instagram, Facebook, and other public forums;
234 
o
In-person recruitment of patients seen in the clinic; and
235 

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o
An IRB-approved website dedicated to clinical trial recruitment. 
236 
All recruitment methods and specific advertising materials will be approved by the Central 
237 
and/or local IRB prior to their implementation. The JCHR IRB is the Central IRB for this study, 
238 
and where permissible, sites shall rely on the JCHR IRB. 
239 
2.1.1 Informed Consent and Authorization Procedures 
240 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing 
241 
any procedures or collecting any data that are not part of usual care, documented informed 
242 
consent will be obtained. Additionally, as part of the informed consent process, each participant 
243 
will be asked to sign an authorization for release of personal information. The informed consent 
244 
process is described in section 13.3. 
245 
A participant is considered enrolled when the informed consent form has been signed. 
246 
2.2 Participant Eligibility Criteria 
247 
2.2.1 Participant Inclusion Criteria 
248 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
249 
in the study. 
250 
1. Age ≥18 years old at time of screening
251 
2. Currently resides in the U.S. or Canada with the ability to complete in-person study visits at
252 
one of the participating clinical sites 
253 
3. Clinical diagnosis, based on investigator assessment, of type 2 diabetes of at least 6 months
254 
duration at time of screening. 
255 
4. Using basal-bolus insulin therapy with at least one injection containing rapid-acting insulin
256 
per day or an insulin pump for at least 3 months prior to enrollment, with no major 
257 
modification to insulin regime in the last 3 months 
258 
•
Mixed insulin with a rapid component is acceptable
259 
5. If using noninsulin glucose-lowering medications (such as GLP-1 receptor agonist, SGLT2
260 
inhibitor, or other) or weight-reduction medications, dose has been stable for the 3 months 
261 
prior to screening; and participant is willing to not change the dose unless required for safety 
262 
purposes 
263 
6. Participant willing to not initiate use of any new glucose-lowering medications during the
264 
trial 
265 
7. Willing to use an approved insulin while using the study pump if assigned to the AID group
266 
8. Willing to not use concentrated insulin above U-100 or inhaled insulin while using the study
267 
pump 
268 
9. Willing to participate in the study meal and exercise challenges, and have a care partner,
269 
trained in hypoglycemia treatment guidelines, to include glucagon use, present during and 
270 
immediately after the exercise challenges. 
271 
10. Has the ability to read and understand written English
272 

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11. Investigator believes that the participant has the cognitive capacity to provide informed 
273 
consent
274 
12. Investigator believes that the participant can successfully and safely operate all study devices
275 
and is capable of adhering to the protocol and completing the study 
276 
13. No medical, psychiatric, or other conditions, or medications being taken that in the
277 
investigator’s judgement would be a safety concern for participation in the study 
278 
•
This includes considering the potential impact of medical conditions known to be present
279 
including cardiovascular, liver, kidney disease, thyroid disease, adrenal disease,
280 
malignancies, vision difficulties, active proliferative retinopathy, and other medical
281 
conditions; psychiatric conditions including eating disorders; drug or alcohol abuse.
282 
14. Participants capable of becoming pregnant must meet one of the following criteria:
283 
a.
has a negative urine pregnancy test and agrees to use one of the accepted
284 
contraceptive regimens throughout the entire duration of the trial from screening
285 
until last follow-up visit. The following contraceptive measures are considered
286 
adequate:
287 
i.
Combined estrogen and progestogen containing hormonal contraception
288 
associated with inhibition of ovulation (oral, intravaginal, transdermal)
289 
ii.
Progestogen-only hormonal contraception associated with inhibition of
290 
ovulation (oral, injectable, implantable)
291 
iii.
Placement of an intrauterine device or intrauterine hormone-releasing system
292 
iv.
Bilateral tubal occlusion
293 
v.
Barrier methods of contraception (condom or occlusive cap with spermicidal
294 
foam/gel/film/cream/suppository).
295 
vi.
Has a vasectomized or sterile partner (where partner is sole partner of subject)
296 
and where vasectomy has been confirmed by medical assessment
297 
vii.
Exercises true sexual abstinence. Sexual abstinence is defined as refraining
298 
from heterosexual intercourse during the entire period of risk associated with
299 
the study treatments. The reliability of sexual abstinence needs to be evaluated
300 
in relation to the duration of the clinical trial and the preferred and usual
301 
lifestyle of the subject.
302 
Or 
303 
b. Participant is of non-childbearing potential due to menopause with at least one
304 
year since last menses or a medical condition confirmed by the investigator
305 
2.2.2 Participant Exclusion Criteria
306 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from 
307 
study participation. 
308 
1. Current use of hybrid closed-loop system
309 
2. Current use of systemic glucocorticoids or anticipated use of glucocorticoids during the RCT
310 
(topical or inhaled -ie, non-systemic is acceptable). 
311 
3. Current use of sulfonylurea or meglitinide medications
312 

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4. Current use of hydroxyurea
313 
5. Tape allergy or skin condition that will preclude use of the study pump or CGM
314 
6. Presence of a hemoglobinopathy or other condition that is expected to affect the
315 
measurement of HbA1c 
316 
7. Pregnant (positive urine hCG), breast feeding, plan to become pregnant during the study
317 
period, or sexually active without use of accepted contraceptive measures 
318 
8. Current participation in another diabetes-related interventional clinical trial
319 
9. Anticipated change of residency or travel for more than 7 days at a time during the study that
320 
may, per investigator judgment, interfere with the completion of study visits, contacts, or 
321 
procedures 
322 
10. Immediate family member (spouse, biological or legal guardian, child, sibling, parent) who is
323 
an investigative site personnel directly affiliated with this study or who is an employee of 
324 
Tandem Diabetes Care, Inc. 
325 
326 
2.2.3 Eligibility for Exercise Challenges 
327 
328 
All participants will have a screening EKG or review of an EKG completed in the 12 months 
329 
prior to screening. 
330 
To participate in the exercise challenges, a participant must not have a history of a cardiovascular 
331 
event in the year prior to screening and/or EKG abnormalities associated with increased risk 
332 
during exercise.  
333 
2.3 Screening Procedures 
334 
After informed consent has been signed, a potential participant will be evaluated for study 
335 
eligibility through the elicitation of a medical history, performance of a focused physical 
336 
examination by study personnel and local laboratory testing if needed to screen for exclusionary 
337 
medical conditions. 
338 
The screening visit may be completed on one or over multiple days but must be completed 
339 
within 28 days of participant enrollment. 
340 
2.3.1 Data Collection and Testing 
341 
The following procedures will be performed/data collected/eligibility criteria checked and 
342 
documented: 
343 
•
Inclusion and exclusion criteria assessed
344 
•
Demographics (date of birth, sex, race, and ethnicity)
345 
•
Contact information (retained at the site and not entered into study database)
346 
•
Medical history, including existing comorbidities deemed clinically relevant (e.g.
347 
retinopathy, nephropathy, neuropathy, history of cardiovascular events); in addition,
348 

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details specific to type 2 diabetes, including age at diagnosis, duration of disease, 
349 
previous therapy, and frequency of severe hypoglycemia and diabetic ketoacidosis 
350 
(DKA) and hyperosmolar hyperglycemic syndrome (HHS), and hospitalization for these 
351 
glycemic events will be collected 
352 
•
Concomitant medications
353 
•
Focused physical examination
354 
o
Performed by study investigator or designee (physician, fellow, nurse practitioner,
355 
physician assistant, or equivalent licensed provider)
356 
o
Weight, height, and vital signs (blood pressure and pulse) may be obtained by non-
357 
study support staff according to the clinic’s usual processes.
358 
•
If applicable, assessment will be made with respect to eligibility for the exercise
359 
challenges (see section 2.2.3)
360 
•
Fingerstick or blood draw for point-of-care or local laboratory determination of HbA1c
361 
level (not required if HbA1c result available from prior 30 days)
362 
•
Urine pregnancy test for participants capable of becoming pregnant
363 
•
EKG unless performed within the 12 months prior to screening
364 
•
Completion of Subjective Numeracy Scale
365 
•
Completion of PRO questionnaires by participant, described in section 8.3, including
366 
recording of frequency of non-severe hypoglycemia in the prior 3 months using a
367 
validated survey (Davis et al. Current Medical Research and Opinion, 21:9, 1477-1483,
368 
DOI: 10.1185/030079905X61929)
369 
Screening procedures will last approximately 1-2 hours. 
370 
2.4 Screen Failures 
371 
Individuals who do not initially meet study eligibility requirements may be rescreened once at a 
372 
later date per investigator discretion.
373 

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Chapter 3: CGM Run-in 
374 
3.1 CGM Run-in Overview 
375 
This phase will generally begin on the day when screening is complete but must begin within 7 
376 
days of completion of screening. The purpose of this CGM run-in phase is 1) to initiate use of 
377 
the study CGM (unblinded) in participants without current use of a Dexcom CGM and 2) to 
378 
assess compliance with use of the CGM and study procedures over a period of at least 21 days.  
379 
Participants who currently use a Dexcom G6 CGM with at least 85% of possible CGM readings 
380 
captured during the 14 days prior to enrollment can skip the CGM Run-in phase. Participants 
381 
who do not currently use a Dexcom G6 CGM, or who do use that CGM but have <85% of 
382 
possible CGM readings in the 14 days prior to the time of enrollment, will be required to 
383 
participate in the CGM Run-in. 
384 
Participants will continue to use their personal insulin delivery method (pump or MDI) during 
385 
the Run-in. 
386 
Participants will be provided with CGM supplies, the study blood glucose meter, study ketone 
387 
meter, and test strips; and will be trained on their use. 
388 
3.2 Initiation of CGM 
389 
During an in-clinic visit, participants required to complete the CGM Run-in will be trained and a 
390 
sensor will be inserted. Study CGM supplies will be provided and the participant will be 
391 
instructed to use the study CGM on a daily basis. Participants using a personal CGM prior to the 
392 
study will discontinue their personal CGM while using a study CGM. 
393 
3.2.1 CGM Training 
394 
CGM training will be provided by a qualified trainer to participants not currently using a 
395 
personal CGM identical to the study CGM with respect to how to use it in real-time to make 
396 
management decisions and how to review the data after an upload for retrospective review. CGM 
397 
training will include: 
398 
•
Instruction on how to insert the sensor and transmitter, including observation/supervision
399 
of placement of a sensor
400 
•
Instruction on how to calibrate the CGM, if needed, in accordance with manufacturer
401 
labelling
402 
•
Guidance on accessing the CGM trace, either through a manufacturer-provided software
403 
app or via a study-provided CGM receiver unit, or via a personal insulin pump if
404 
participants use a pump that integrates with the study CGM
405 
•
Participants will be asked to perform fingerstick blood glucose measurements in
406 
accordance with the labeling of the study CGM device
407 
A copy of the study CGM user’s guide will be provided to the participant. 
408 

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Participants may use available manufacturer-provided CGM software and features of the study 
409 
CGM related to mobile data access or remote monitoring, but will be instructed not to use any 
410 
third-party components for this purpose. 
411 
Upon completion of the CGM training components, study staff will document, using a checklist, 
412 
that the participant is familiar with the functions/features/tasks addressed during the training. 
413 
At investigator discretion or participant request, contacts may occur with participant during run-
414 
in phase for further training on use of CGM. 
415 
Adjustments can be made in the participant’s insulin dosing at investigator discretion during the 
416 
CGM Run-in. 
417 
3.3 Assessment of Successful Completion of the CGM Run-in Phase 
418 
Participants will have a follow-up visit 21-28 days (target 21 days) after initiation of the run-in 
419 
phase to assess CGM usage.  Procedures will include downloading of the study CGM data and 
420 
the following: 
421 
•
Assessment of compliance with the use of CGM to obtain at least 85% of possible CGM
422 
values during the most recent 14 days of CGM data collection
423 
•
Assessment of skin reaction in areas where a CGM sensor was worn or other safety
424 
issues associated with CGM use
425 
Participants who fail to meet the minimum CGM use requirement, or whom the investigator 
426 
believes may benefit from an extension of the CGM run-in period, may at the investigator’s 
427 
discretion be allowed to continue CGM run-in for up to an additional 14 days. These participants 
428 
will have another follow-up visit approximately 14 days after the prior visit for a reassessment 
429 
using the same procedures as described above. 
430 
Participants who do not meet CGM use requirements after the second CGM wear period or 
431 
otherwise fail to meet study eligibility requirements will be withdrawn from the study. 
432 
For participants entering the RCT, the most recent 14 days of CGM data will be used as the 
433 
baseline for analyses. 
434 
435 

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Chapter 4: Randomization Visit 
436 
4.1 Overview 
437 
For participants completing the CGM Run-in, the randomization visit generally will occur on the 
438 
same day immediately following the CGM Run-in Visit.  If the participant is not ready to start 
439 
the AID system if assigned to the intervention group, the Randomization Visit must occur within 
440 
14 days after completion of the run-in phase. For participants skipping the CGM Run-in, the 
441 
Randomization Visit could occur on same day as Screening Visit (once all eligibility has been 
442 
verified) or within 14 days following the Screening Visit. 
443 
At this visit, eligibility will be reaffirmed and participants will be randomly assigned to the AID 
444 
group or Control group. 
445 
4.2 Testing and Procedures 
446 
The following will be done at the Randomization Visit: 
447 
•
Review medical history since Screening Visit to verify that there have been no changes or
448 
events that affect participant eligibility, any adverse events that may have occurred since
449 
their last study visit, and any changes in medications or doses (if not on the same day as
450 
the Screening Visit)
451 
•
Verify that participant understands the protocol and is willing to accept assignment to
452 
either treatment group
453 
•
Measure height, weight, blood pressure and pulse (if Randomization Visit is not on same
454 
day as Screening Visit)
455 
•
Urine pregnancy test for participants capable of becoming pregnant (if Randomization
456 
Visit is not on the same day as the Screening Visit)
457 
•
Blood draw for central lab measurements of HbA1c, lipids, creatinine, C-peptide,
458 
glucose, GAD antibodies
459 
•
Randomization
460 
•
Training and instructions for each treatment group
461 
•
Distribution of study devices and supplies to participants according to the assigned
462 
treatment group
463 
o
Both groups will be provided with Dexcom G6 sensors and transmitters, the study
464 
blood glucose meter, study ketone meter, and test strips; and will be trained on their
465 
use
466 
4.3 Randomization 
467 
Participants will be randomly assigned in a 2:1 ratio to the AID group or the Control group. 
468 
The participant’s randomization group assignment is determined by entering the Randomization 
469 
Visit data on the study website.  JCHR will construct a Master Randomization List using a block 
470 
design separately for each center. 
471 

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Note: To minimize an imbalance in the number of participants assigned to each group, 
472 
randomization will not be stratified by age, HbA1c or other factors because of the small number 
473 
per site that is possible and considering the 2:1 randomization. 
474 
4.4 Instructions for Both Groups 
475 
Study staff will review the use of the study CGM, blood glucose meter, and ketone meter. The 
476 
following instructions will be given to both groups: 
477 
•
Participants will be advised not to use alcohol or other drugs in sufficient quantity to
478 
reduce sensitivity to symptoms of hypoglycemia or hinder appropriate decision-making.
479 
•
Any medical advice needed by the participants during their participation that is not
480 
directly related to the study protocol should be obtained in the usual manner with their
481 
own physician.
482 
•
There are no restrictions of any kind on diet, exercise, or other activities
483 
•
Hypoglycemia low threshold alerts will be set to no lower than 70 mg/dL. If a low alarm
484 
occurs, the participant will be trained to verify the glucose level with a fingerstick
485 
glucose using the study blood glucose meter. If the blood glucose meter confirms
486 
hypoglycemia, participants will be instructed to treat with ~15 grams of carbohydrate and
487 
to continue to monitor their glucose levels until hypoglycemia has resolved.
488 
•
Additional material that is IRB approved, to include Tandem infusion set insertion
489 
videos, may be used to supplement training. The IRB approved handouts related to fixed
490 
dosing, small/medium/large meals, carb counting, and pump therapy basics may be used
491 
by the training staff as judged necessary for a given participant’s needs, whether in the
492 
Control or AID group.
493 
4.5 Instructions for the Control Group 
494 
Participants in the Control group will be instructed to follow their usual diabetes management 
495 
with respect to insulin delivery. They will be asked to use CGM daily throughout the RCT in 
496 
accordance with manufacturer labelling. Participants will receive training on hyperglycemia and 
497 
ketosis management, similar to that described for the AID Group in section 4.6.4, that is 
498 
customized for the participant based on the type of insulin delivery being used. 
499 
4.6 Instructions for the AID Group 
500 
The approach to training will depend on whether the participant is already a pump user.  The 
501 
training on use of the AID system may occur completely at this visit or may be spread out over a 
502 
few days in multiple visits or contacts.  Initiation of the study pump and closed-loop control 
503 
generally will occur on the day of the Randomization Visit but can be deferred if the investigator 
504 
believes additional training is needed prior to initiating the study pump.  In such cases, initiation 
505 
of the study pump and Control IQ should occur no more than 7 days following randomization. 
506 
Participants will be informed of the need to have a care partner trained and capable of treating 
507 
severe hypoglycemia, including use of glucagon as indicated in section 6.3. 
508 

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4.6.1 Study Pump Training 
509 
Participants will receive study pump training on use of the pump in open-loop mode by a 
510 
qualified trainer: 
511 
•
Participants will be fully instructed on the study insulin pump. The trainer will discuss
512 
differences from the participant’s personal pump, if applicable, in important aspects such
513 
as calculation of insulin on board and correction boluses and optional additional topics
514 
such as: infusion site initiation, cartridge/priming procedures, setting up the pump,
515 
charging the pump, navigation through menus, bolus procedures including stopping a
516 
bolus, etc.
517 
•
Participants will be instructed to change the study insulin pump infusion set at least once
518 
every 3 days or per manufacturer guidelines, whichever is shorter.
519 
•
Participants will be trained to use the pump’s bolus calculator.
520 
•
The study team will assist the participant in study pump infusion site initiation and will
521 
start the participant on the study pump. The study pump will be programmed with the
522 
participant’s usual basal rates and pump parameters, if applicable. The participant’s
523 
personal pump, if used, will be removed.
524 
•
The participant will be supervised with the study pump during at least one meal or snack
525 
bolus to ensure participant understanding of the pump features.
526 
•
The participant will be encouraged to review the written information provided with the
527 
pump and infusion sets after the training is completed.
528 
•
The participant will be trained on severe hypoglycemia emergency procedures including
529 
removal of the study pump and administration of glucagon.
530 
•
The participant will be assessed for understanding of the system interface and how to react
531 
to safety/alert messages.
532 
•
To prevent insulin stacking from long-acting basal insulin that is on board, participants
533 
using long-acting insulin injections at baseline will be instructed, and supervised by study
534 
staff, to set a temp basal rate to 0% that will end 24 hours after last injection of long-acting
535 
insulin, at which time the pre-programmed basal rate will be turned on. Study investigators
536 
may adjust this procedure per their usual clinical practice, and may customize this plan
537 
based on the type of basal insulin used (for example, insulin degludec with a longer half-
538 
life may require a basal rate of 50% for a second day).
539 
A copy of the study pump user’s guide will be provided to the participant. 
540 
Study-provided insulin aspart will be offered to the participant, who will be instructed on the 
541 
proper storage and use of the insulin during the course of the study. 
542 
4.6.1.1 Initiation of Pump by MDI Participants 
543 
For MDI participants being started on the study pump, an initial basal insulin profile will be 
544 
customized on a per-participant basis. Total daily insulin dose will be reduced by approximately 
545 
20% as a general rule, with a recommended method outlined in a separate procedures’ manual. 
546 
547 

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Site investigators may make further adjustment to insulin delivery profile settings ONLY for safety 
548 
concerns and will document reasons for change in the CRF. 
549 
4.6.2 Training on Using the Pump with Control-IQ Technology 
550 
Participants will receive instruction from a qualified trainer on use of the study pump in closed-
551 
loop mode, to include the following: 
552 
•
How to turn on and off Control-IQ technology
553 
•
How to understand when Control-IQ is increasing or decreasing basal rates
554 
•
How to administer a meal or correction boluses during closed-loop system use
555 
•
What to do when exercising while using the system in closed-loop mode
556 
•
How to enable the sleep function and set the sleep schedule
557 
o
Sleep activity will be enabled during normal sleep time for all users unless a
558 
safety concern arises as judged by the investigator.
559 
•
The participant will be assessed for understanding of the system interface and how to react
560 
to safety/alert messages.
561 
Upon completion of the study pump training components, study staff will document, using a 
562 
checklist, that the participant is familiar with the functions/features/tasks addressed during the 
563 
training. 
564 
4.6.3 System Use Guidelines 
565 
The participant will be instructed to use the system in closed-loop mode except if insulin is 
566 
delivered by any means other than the study pump (e.g. injection of subcutaneous insulin via 
567 
syringe in the event of infusion site failure). 
568 
•
If insulin is delivered by any means other than the study pump, the participant will be
569 
instructed to turn off Control-IQ for four hours.
570 
Participants will be provided with contact information and will be asked to call the study 
571 
clinical staff for any health-related issues and for technical issues with the system. They will be 
572 
instructed to contact study staff in case of illness with an elevated temperature >101.5 degrees 
573 
Fahrenheit (38.6 degrees Celsius), other periods of significant illness, or during periods of use of 
574 
medications such as epinephrine for the emergency treatment of a severe allergic reaction or 
575 
asthma attack in addition to use of oral or injectable glucocorticoids to determine if closed-loop 
576 
use should be temporarily discontinued. 
577 
Participants may use the study pump without Control-IQ activated and study CGM during periods 
578 
of component disconnections or technical difficulties. 
579 
4.6.4 Hyperglycemia and Ketosis Detection and Management 
580 
Unlike in type 1 diabetes, for participants with type 2 diabetes, hyperglycemia by itself, without 
581 
any other symptoms, is not a medical emergency indicating the need for ketone checking. 
582 
Participants may have had significant amount of hyperglycemia prior to the study and may 
583 
periodically have hyperglycemia for missed boluses. Participants who are on SGLT inhibitors, 
584 

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GLP-1 receptor agonists, or DPP-IV inhibitors could also develop ketones at lower glucose 
585 
values (<250 mg/dl), where euglycemic DKA could occur. Therefore, participants will be 
586 
instructed to check ketones based on signs or symptoms of ketonemia or general illness, to 
587 
include abdominal pain/nausea/emesis/increased polyuria or feeling unwell, as well as during 
588 
times of intercurrent illness (i.e., fever). Participants will be instructed to contact the study site 
589 
for any ketone values ≥ 0.6 mmol/L or for additional guidance on sick day management. If the 
590 
ketone value is <0.6 mmol/L but symptoms persist, the participant will be instructed to recheck 
591 
ketones after one hour. 
592 
If ketone level is ≥ 0.6 mmol/L and study staff cannot be immediately contacted, the participant 
593 
will be instructed to: 
594 
•
Perform a blood glucose meter check.
595 
•
Take correction insulin calculated to achieve a target glucose of 150 mg/dL with an
596 
insulin syringe and change insulin pump infusion site.
597 
•
Continue to monitor their glucose and blood ketone levels until ketones are < 0.6
598 
mmol/L.
599 
•
If correction insulin is administered via insulin syringe, turn Control-IQ off for four
600 
hours.
601 
•
If vomiting, go to the Emergency Room.
602 
Participants will be permitted to change the hyperglycemia alarm setting, but will be instructed 
603 
to choose a value no greater than 300 mg/dL. 
604 
605 

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Chapter 5: RCT 
606 
5.1 Overview 
607 
The RCT will last for 13 weeks.  Procedures to be followed by the Control Group are described in 
608 
section 4.5 and procedures to be followed by the AID group in section 4.6. 
609 
5.2 Follow-up Visits and Contacts 
610 
The AID group will have a training/check-in contact 3 ±1 days after initiating the AID system 
611 
for further review of training materials and to answer questions. Participants will be specifically 
612 
instructed to contact the site for any issues that arise during the first infusion set change.  
613 
Otherwise the visit and contact schedule will be the same for both groups. 
614 
•
Contact (phone or video) will occur after 7±2 days for a safety check.
615 
•
Clinic visits will occur at 4 weeks ± 4 days and 13 weeks ± 4 days.
616 
•
Visit or contact at 8 weeks ± 4 days (depending on whether participant is able to upload
617 
device data at home and whether investigator believes clinic visit is needed).
618 
Additional office visits may occur as needed at investigator discretion. 
619 
If necessary, visits should be completed out-of-window rather than missed. A visit is not 
620 
considered missed until the next visit/phone window opens. In the event that in-person visits 
621 
cannot be conducted due to institutional restrictions or the participant’s unwillingness to attend 
622 
an in-person clinic visit, visits may be conducted virtually via a HIPAA-compliant Zoom or 
623 
similar video conference mechanism to collect whatever data is possible to collect remotely.  
624 
Participants will be instructed to download the study CGM and pump prior to each scheduled 
625 
contact. 
626 
5.2.1 Contact and Visit Procedures 
627 
At each scheduled contact and visit for both groups, the following will be done: 
628 
•
AID system and CGM data will be reviewed (participants without the ability to upload
629 
the device data from home will be provided with a laptop to use during the study)
630 
•
Site investigators may adjust insulin delivery profile settings ONLY for safety concerns
631 
and will document reasons for changes in the CRF.
632 
•
Occurrence of adverse events will be solicited
633 
•
Assessment of TDD over last week
634 
At the 4-week clinic visit and 8-week clinic visit (if it occurs in clinic), the following also will be 
635 
done: 
636 
•
Height, weight, blood pressure/pulse measured
637 
638 
At 13-week visit, the following also will be done: 
639 
•
Height, weight, blood pressure/pulse measured
640 

TANDEM 2IQP PROTOCOL V8.0 2023-10-31.DOCX 
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•
Blood draw for central lab measurement of HbA1c, lipids, creatinine 
641 
•
PRO surveys completed
642 
5.3 Transition to Pre-study Insulin Therapy 
643 
At the end of the RCT, study staff will supervise the participant’s transition back to their prior 
644 
therapy. 
645 
•
Study staff will re-evaluate the subject’s baseline therapy doses, noting changes in basal
646 
rates, carbohydrate ratios, and correction factors in use at the end of the trial.
647 
•
Participants must have two CGM or fingerstick blood glucose values, separated by at
648 
least 15 minutes, that are above 80 mg/dL prior to discharge from the clinic.
649 
•
Study staff will confirm subjects have carbohydrates on hand for their drive back home,
650 
and instruct subjects to check their glucose levels when they arrive at home, prior to
651 
bedtime, and at least one time overnight on the first night to monitor for hypoglycemia,
652 
reminding subjects that insulin on board can be active for the next few hours even after
653 
stopping the study pump.
654 
5.3.1 3-Day Post-Study or Discontinuation of AID System Contact 
655 
Participants will have a post-study contact 3 (±1) days after permanently discontinuing the study 
656 
AID system and transitioning back to their prior insulin therapy (which for most participants will 
657 
be at the end of the RCT), during which the following will occur: 
658 
•
Check on transition back to usual home diabetes care
659 
•
Assessment of adverse events
660 
5.4 Safety Visits Following Changes in Glucose-Lowering or Weight-
661 
Reduction Medications 
662 
The only changes of glucose-lowering or weight-reduction medications permitted will be a 
663 
reduction in dose for safety reasons, or an adjustment to an equivalent dose of a different 
664 
formulation if participant’s insurance coverage changes. No increased doses or initiation of a 
665 
new glucose-lowering or weight-reduction medication will be permitted. 
666 
If a participant in the AID group has a reduction in dose or requires a change of glucose-
667 
lowering or weight-reduction medication due to insurance coverage, an unscheduled visit will 
668 
occur after 1-2 days and 7 days to assess safety. 
669 
5.5 Early Termination Visit 
670 
Participants in the AID group who discontinue use of the AID system will be asked to continue 
671 
using the study CGM and remain in the study through the 13-week visit. 
672 
In the event of participant withdrawal or early termination in both groups, participants will be 
673 
asked to come to clinic for an end of study visit.  If the visit occurs 4 or more weeks after 
674 
randomization, the procedures listed for the 13-week visit will be completed (may be combined 
675 
with the 4-week visit if in window for the 4-week visit). 
676 

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Participants in the AID group who discontinue use of the AID system prior to the end of the RCT 
677 
and have not already resumed their pre-study insulin regimen will be transitioned back to their pre-
678 
study insulin regimen as described in section 5.3 and will have a 3-day post-study call.  
679 
680 

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Chapter 6: Exercise and Meal Challenges 
681 
6.1 Overview 
682 
All participants in the AID group will be asked to perform 3 meal challenges and 3 exercise 
683 
challenges unless ineligible due to cardiac or other safety concerns, with the expectation that the 
684 
majority of participants in the AID group will complete all challenges. 
685 
Participants will be advised that for the exercise challenges, they must have a care partner 
686 
capable of providing treatment for severe hypoglycemia, including glucagon use, who will be 
687 
present during and for one hour following each study exercise challenge. Training will be 
688 
provided by study staff to the care partner as needed. 
689 
Approximately 25% of each type of challenge (meal or exercise) will be performed on 3 
690 
consecutive days within each of the following 4 periods time from randomization: 1-2 weeks, 3-
691 
4 weeks, 5-6 weeks, 7-8 weeks.  Challenges that cannot be scheduled during these time periods 
692 
or challenges that need to be rescheduled may be performed, if necessary, between weeks 9 and 
693 
13.
694 
Participants will be instructed to communicate with study staff within one day prior to each 
695 
challenge to review procedures and to have a contact with study staff after the completion of 
696 
each challenge within one day. 
697 
6.2 Meal Challenges 
698 
The 3 meal challenges will be performed on 3 consecutive days while the study AID system is 
699 
being used. The same meal should be used for each of the 3 meal challenges—either lunch or 
700 
dinner (participant choice). 
701 
The three meal challenges will consist of: 
702 
•
No bolus for the meal
703 
•
50% bolus – calculate the bolus dose using the bolus calculator and deliver half the
704 
recommended dose of insulin.
705 
•
Full bolus for the meal based on calculated bolus dose using the bolus calculator.
706 
For each meal challenge, participants will: 
707 
1. Be in a fasting state for two hours prior to consuming the meal and the last manual
708 
insulin bolus more than two hours prior to the meal.
709 
2. Only begin the meal challenge if CGM glucose is between 70 mg/dL and 200 mg/dL and
710 
CGM trend arrow is not rapidly rising (straight up arrow).  Subjects with hyperglycemia
711 
> 200mg/dL will reschedule their challenge for another time. If < 70 mg/dL,
712 
carbohydrate treatment can be given, after which the meal challenge can continue.
713 
3. Consume at least 50 grams carbohydrate for the meal. Each participant will use the same
714 
meal for all of their meal challenges in the study. Participants will be encouraged to use
715 
the same frozen entrée of their choice for consistency.
716 

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4. Write down the start and end time of eating the meal, as well as the meal content (to 
717 
include amount of carbohydrate, protein and fat) on the study provided logbook. 
718 
5. Not give an additional bolus for up to 3 hours after the meal challenge, unless BG is
719 
above 300 mg/dL for more than 1 hour, or symptoms of hyperglycemia develop.
720 
6. Not take additional carbohydrates for up to 3 hours after the meal challenge, unless BG is
721 
< 70 mg/dL, or symptoms of hypoglycemia develop.
722 
7. Not exercise for 3 hours after the meal challenge.
723 
8. Notify the site within 24 hours after completion of each meal challenge.
724 
9. The meal challenge will end 3 hours after the meal is completed.
725 
If a meal challenge needs to be rescheduled due to out-of-range glucose value or an unforeseen 
726 
circumstance, it should be completed on a separate day (same meal, lunch or dinner) as soon as 
727 
possible. 
728 
6.3 Exercise Challenges 
729 
The 3 exercise challenges will be performed on 3 consecutive days while the study AID system 
730 
is being used. 
731 
The 3 exercise challenges will include one-hour exercise periods, which include at least 30 
732 
minutes of moderate exercise. All challenges will be performed unsupervised at home, with 
733 
required study team contacts before and after each challenge. As indicated below, a care partner 
734 
will need to be present during and for one hour after the exercise session. 
735 
For each exercise challenge, participants will: 
736 
1. Have a care partner, capable of providing treatment for severe hypoglycemia, to include
737 
glucagon use, who is present during and for 1 hour after the exercise challenges. The care
738 
partner will receive training as needed.
739 
2. Have carbohydrate containing snacks and glucagon on hand during and after exercise.
740 
3.
Activate “exercise activity” (required) on the pump up to 45 to 60 minutes ahead of
741 
actual exercise, to allow for less insulin on board when starting exercise. The timing of
742 
exercise activity activation may be adjusted per their usual routine and investigator
743 
guidance. Consider reducing the last meal bolus prior to exercise as a way to reduce
744 
insulin on board and limit hypoglycemia.
745 
4. Perform one hour of exercise, including at least half an hour of moderate activity.
746 
Exercise does not need to be the same activity each time.
747 
5. Only begin exercise if CGM glucose is ≥ 120 mg/dL and CGM glucose is not trending
748 
downward. If glucose is <120 mg/dL, carbohydrate can be taken and exercise may begin
749 
once the glucose level is ≥120 mg/dL.
750 
6. Write down the start time of last meal and amount and time of last insulin dose, whether
751 
the prior meal insulin bolus was intentionally reduced in preparation for exercise, type of
752 
exercise performed, as well as the start and stop time of each exercise session in the study
753 
logbook (as this may not correlate exactly with exercise activity use on the pump).
754 
Participants may take breaks if needed, as long as the full hour of activity is completed.
755 

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7. Stop the exercise challenges at any point for injury or development of new symptoms;
756 
development of chest pain/pressure, feeling unwell, development of hypoglycemic
757 
symptoms, undue shortness of breath, signs of poor perfusion (leg pain/claudication), or
758 
for any other reason.
759 
8. Immediately contact the study team for acute symptoms (such as chest pain, leg pain,
760 
persistent shortness of breath), or seek immediate medical assistance for acute symptoms
761 
if the study team is not reachable.
762 
9. Notify the site within 24 hours after completion of each exercise challenge. Participants
763 
will be asked if they developed new symptoms and review guidance on the need to stop
764 
future exercise challenges if any adverse events or new symptoms occurred per clinician
765 
judgement based on the severity of symptoms.
766 
10. The exercise challenge will end after 1 hour of the required activity is completed.
767 
If an exercise challenge needs to be rescheduled due to out-of-range glucose value or an 
768 
unforeseen circumstance, it should be completed on a separate day as soon as possible. 
769 
6.4 Meal and Exercise Challenge Follow-Up 
770 
Participants will be instructed to contact study staff within 24 hours of completing each exercise 
771 
challenge. The follow up call will review: 
772 
•
The start and stop time, as well as the type of exercise performed.
773 
•
Assessment of adverse events
774 
•
Documentation of any safety concerns if future exercise challenges are cancelled.
775 
776 

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Chapter 7: Study Devices and Study Insulin 
777 
7.1 Description of the Investigational Device 
778 
7.1.1 Insulin Pump 
779 
The study system will include the Tandem t:slim X2 insulin pump (K201214, Tandem Diabetes 
780 
Care, San Diego, CA) using the Control-IQ version 1.5 algorithm. The study insulin pump is 
781 
designed to revert to open-loop delivery of preprogrammed basal insulin levels in the event that 
782 
CGM data are not available. The pump also includes various alarms and alerts to notify the user 
783 
when there is a problem with insulin delivery. 
784 
7.1.2 Continuous Glucose Monitoring 
785 
The study CGM will include Dexcom G6 transmitter and sensors. The CGM sensor will be 
786 
replaced at least once every 10 days or as per manufacturer instructions. 
787 
7.1.3 Blood Glucose Meter and Strips 
788 
Blood glucose levels will be measured using the study-assigned blood glucose meter (Contour 
789 
NEXT or Contour NEXT ONE, Ascensia Diabetes Care US, Inc., 5 Wood Hollow Rd, 
790 
Parsippany, NJ 07054 USA) and the CGM device will be calibrated if needed using the study 
791 
glucometer and strips in accordance with the manufacturer’s labeling. 
792 
7.1.4 Ketone Meter 
793 
The study blood ketone meter is the Precision Xtra Blood Glucose and Ketone Monitoring 
794 
System for U.S. sites and the FreeStyle Precision Neo for Canadian sites (Abbott Diabetes Care). 
795 
Blood ketone levels will be measured when indicated as described in section 4.6.4. The blood 
796 
glucose meter component of the device will not be used. 
797 
7.2 Description of Study-Provided Insulin 
798 
The study drug offered to AID group participants only is NovoLog (insulin aspart injection) 100 
799 
U/mL, branded as NovoRapid for Canadian sites. The insulin is provided by Novo Nordisk. This 
800 
is a non-investigational insulin that is functionally identical to commercially-available NovoLog. 
801 
•
Acquisition
802 
The study insulin will be shipped by the manufacturer, in coordination with the study
803 
Coordinating Center, directly to each clinical site for storage and dispensation to study
804 
participants.
805 
•
Formulation, Appearance, Packaging, and Labeling
806 
The study insulin is a sterile, aqueous, clear, and colorless solution for subcutaneous or
807 
intravenous administration. Each mL contains 100 units of insulin aspart. Package
808 
labelling will be functionally identical to commercial drug.
809 
•
Product Storage and Stability
810 
Dispense in the original sealed carton with the enclosed Instructions for Use.
811 

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Refrigerate unopened study insulin vials between 36°F to 46°F (2°C to 8°C) until time of 
812 
use and keep in the original carton to protect from light. Do not freeze or use study 
813 
insulin if it has been frozen. Do not expose to direct heat. Discard opened or unopened 
814 
study insulin vials stored at room temperature below 86°F (30°C) after 28 days. 
815 
•
Post-Study Disposal
816 
At the conclusion of study activities, remaining unopened vials of study insulin will be
817 
disposed/destroyed by each clinical site in accordance with local disposal policies.
818 
7.3 Study Device Accountability Procedures 
819 
Device and drug accountability procedures will be detailed in the site procedures manual. 
820 
7.4 Participant Access to Study Device at Study Closure 
821 
Participants will be returned to their pre-study insulin therapy at the conclusion of the study and 
822 
must return study-assigned devices and unopened insulin to the clinical site as instructed by 
823 
study staff.  
824 

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Chapter 8: Testing Procedures and Questionnaires 
825 
8.1 Laboratory Testing 
826 
1. HbA1c:
827 
•
HbA1c level measured using the DCA2000 or comparable point of care device or
828 
local lab at the Screening visit, if no comparable measurement is available within 30
829 
days prior to enrollment (since this measurement is not used for analysis, there will
830 
be no centralized quality control measures implemented)
831 
•
HbA1c level measured at a Central Lab from blood draw performed at
832 
Randomization Visit and 13-week Visit.
833 
2. C-peptide/Glucose:
834 
•
C-peptide with concurrent glucose level measured at a Central Lab from blood draw
835 
performed at Randomization Visit
836 
3. Urine Pregnancy:
837 
•
Performed locally for participants capable of becoming pregnant at Screening Visit
838 
and Randomization Visit.  Pregnancy testing will also be done anytime pregnancy is
839 
suspected.
840 
4. GAD Antibodies:
841 
•
GAD antibodies measured by Central Lab at Randomization Visit
842 
5. Lipid Levels and Creatinine
843 
•
Measured by Central Lab at Randomization Visit and 13-week Visit.
844 
Local laboratory testing will be performed if needed to screen for medical conditions that might 
845 
preclude study participation. 
846 
8.2 Physical Examination 
847 
A focused physical exam will be performed by the study investigator or designee (a physician, 
848 
fellow, nurse practitioner, physician assistant, or equivalent licensed provider). This will include 
849 
parts of the exam relevant to device use, such as skin changes from device or insulin use. At 
850 
screening, it may include physical exam techniques related to assessment of cardiovascular 
851 
disease if participation in the exercise and meal challenges is being considered. 
852 
Vital signs and height and weight measurements may be obtained by non-study support staff 
853 
according to the clinic’s usual processes. 
854 
8.3 Questionnaires 
855 
8.3.1 Baseline Surveys 
856 
The following surveys will be completed at the Screening Visit to characterize the cohort: 
857 
858 

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MEASURE 
DESCRIPTION 
Subjective Numeracy Survey 
A validated tool that subjectively measures (i.e., self-assessment) a 
person’s quantitative ability that distinguishes low- and high-numerate 
individuals. Four items measure people's beliefs about their skill in 
performing various mathematical operations, and 4 items measure 
people's preferences regarding the presentation of numerical 
information. (2 min) 
8.3.2 Patient-reported Outcome Surveys 
859 
The PRO questionnaires are completed by all participants at the study visits indicated in the table 
860 
below. Each questionnaire is described briefly below.  The procedures for administration are 
861 
described in the study procedures manual. 
862 
Table 2. Study Patient-reported Outcome Questionnaires 
863 
MEASURE 
CONSTRUCT MEASURED/RELEVANT POINTS 
ADMINISTRATION 
POINTS 
Type 2 Diabetes 
Distress Assessment 
System (T2-DDAS 
Combined - Core 
and Source)  
A 29-item questionnaire includes a Core Tool (8 items) and a 
Sources Tool (assessing 7 separate Sources of diabetes distress, 
each with 3 items). The new T2-DDAS allows for an enhanced 
level of assessment precision: it makes it possible to differentiate 
between the level or intensity of diabetes distress experienced 
and the primary sources of diabetes distress. (3 min). 
Baseline, 13 weeks 
DAWN Impact of 
Diabetes Profile 
(DIDP) 
A 7-item questionnaire providing a valid and reliable measure of 
the perceived impact of diabetes on quality of life, suitable for 
adults with Type 1 or Type 2 diabetes mellitus. (2 min) 
Baseline, 13 weeks 
Diabetes Impact and 
Satisfaction (DIDS) 
Scale 
An 11-item questionnaire focused on satisfaction related to 
insulin delivery devices (e.g., trust and ease of use) and diabetes-
related impact on daily life, such as worry around hypoglycemia 
and sleep interruptions. (3 min) 
Baseline, 13 weeks 
PROMIS Sleep-
Related Impairment 
Questionnaire 
An 8-item questionnaire that measures sleep disturbance and 
sleep-related impairment. (2 min) 
Baseline, 13 weeks 
System Usability 
Scale (SUS) 
A 10-item questionnaire that measures the overall usability of a 
system. It is a valid and reliable measure of the perceived 
usability of a system and is technology-agnostic. (2 min) 
Baseline, 13 weeks 
Hypoglycemia Fear 
Survey II 
A 33-item survey that measures several dimensions of fear of 
hypoglycemia among individuals with diabetes. It measures 
worry (18 items) and behavior (15 items) (5-10 min) 
Baseline, 13 weeks 
EQ5D-5L 
A 5-item NICE approved Quality of Life (QOL) measure that 
translates into economics (2 min) 
Baseline, 13 weeks 
Study-specific survey 
A 2-item questionnaire that explores time spent on insulin 
management and insulin dosing with meals (2 min) 
Baseline, 13 weeks 
Hypoglycemia 
Frequency Last 3 
Months Survey 
A 4-item questionnaire that captures occurrence and frequency 
of mild, moderate, severe, and nocturnal hypoglycemia over the 
past 3 months (3 min) 
Baseline, 13 weeks 
864 

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Chapter 9: Unanticipated Problem, Adverse Event, and Device Issue 
865 
Reporting 
866 
9.1 Unanticipated Problems 
867 
Site investigators will promptly report all unanticipated problems meeting the criteria below on 
868 
an eCRF. Sites relying on the Central IRB must report potential Unanticipated Problems to the 
869 
IRB within seven (7) calendar days of recognition. For this protocol, an unanticipated problem is 
870 
an incident, experience, or outcome that meets all of the following criteria: 
871 
•
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures
872 
that are described in the protocol related documents, such as the IRB-approved research
873 
protocol and informed consent document; and (b) the characteristics of the subject
874 
population being studied
875 
•
Related or possibly related to participation in the research (possibly related means there is
876 
a reasonable possibility that the incident, experience, or outcome may have been caused
877 
by the procedures involved in the research)
878 
•
Suggests that the research places participants or others at a greater risk of harm than was
879 
previously known or recognized (including physical, psychological, economic, or social
880 
harm)
881 
The Sponsor (or CRO on behalf of the Sponsor) also will report to the Central IRB all potential 
882 
unanticipated problems not directly involving a specific site such as unanticipated problems that 
883 
occur study-wide or at another participating entity such as a pharmacy or laboratory. These 
884 
instances must be reported to the Central IRB within seven (7) calendar days of recognition. The 
885 
Director of the Human Research Protection Program (HRPP) will report to the appropriate 
886 
regulatory authorities if the IRB determines that the event indeed meets the criteria of an 
887 
Unanticipated Problem requiring additional reporting to fulfill the reporting obligations of the 
888 
HRPP. 
889 
9.2 Adverse Events 
890 
9.2.1 Definitions 
891 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) 
892 
associated with study procedures or occurring during the course of a study in which a device, 
893 
biologic, or drug is used in humans, including any comparator used, whether or not the event is 
894 
considered related (i.e., irrespective of the relationship between the adverse event and the 
895 
device(s) under investigation). 
896 
For this protocol an adverse event is considered any untoward medical occurrence, unintended 
897 
disease or injury, or untoward clinically significant clinical sign (including abnormal laboratory 
898 
findings) in a research participant that manifests while in the study if it was not present before 
899 
enrolling in the study, or if it was present before enrolling, it has increased in severity, frequency 
900 
or type since enrolling in the study. As used here, a participant is considered enrolled once 
901 
consent has been executed. 
902 

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Serious Adverse Event (SAE): Any untoward medical occurrence that results in any of the 
903 
following outcomes: 
904 
•
Death.
905 
•
A life-threatening adverse event; (a non-life-threatening event which, had it been more
906 
severe, might have become life-threatening, is not necessarily considered a serious
907 
adverse event).
908 
•
Inpatient hospitalization or prolongation of existing hospitalization.
909 
•
A persistent or significant disability/incapacity or substantial disruption of the ability to
910 
conduct normal life functions (sight threatening).
911 
•
A congenital anomaly or birth defect.
912 
An important medical event that may not result in death, be life-threatening, or require 
913 
hospitalization may be considered serious when, based upon appropriate medical judgment, it 
914 
may jeopardize the patient or subject and may require medical and surgical intervention to 
915 
prevent one of the outcomes listed in this definition. Note: If either the Sponsor or investigator 
916 
believes that the event is serious, the event must be considered serious and evaluated by the 
917 
Sponsor for expedited reporting. Suspicion of transmission of infectious agents must always be 
918 
considered an SAE. 
919 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
920 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
921 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
922 
investigational plan or application (including a supplementary plan or application), or any other 
923 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
924 
welfare of participants (21 CFR 812.3(s)). 
925 
Adverse Device Effect (ADE): An adverse event related to the use of an investigational medical 
926 
device. This definition includes adverse events resulting from insufficient or inadequate 
927 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
928 
the investigational medical device. This definition includes any event resulting from use error or 
929 
from intentional misuse of the investigational medical device. This includes comparator if the 
930 
comparator is a medical device. (Note that an Adverse Event Form is to be completed in addition 
931 
to a Device Deficiency or Issue Form, unless excluded from reporting as defined in section 9.3). 
932 
Adverse Reaction (AR): An AR is an AE for which the causal relationship between a drug and 
933 
the AE is suspected. 
934 
Serious Adverse Reaction (SAR): An Adverse event which fulfill both the criteria for a Serious 
935 
Adverse Event and the criteria for an Adverse Reaction. 
936 
Suspected Unexpected Serious Adverse Reaction (SUSAR): An SAR which is unexpected and 
937 
regarded as possibly or probably related to the trial/study drug product. This event requires a 
938 
submission of an IND Safety Report. See 21 CFR 312 for more information. 
939 
Comparator: Medical device, therapy (e.g. active treatment, normal clinical practice), placebo or 
940 
no treatment, used in the control group in a clinical investigation. (ISO 14155:2020) 
941 

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Device Complaints and Malfunctions: A device complication or complaint is something that 
942 
happens to a device or related to device performance, whereas an adverse event happens to a 
943 
participant.  A device complaint may occur independently from an AE, or along with an AE.  An 
944 
AE may occur without a device complaint or there may be an AE related to a device complaint.  
945 
A device malfunction is any failure of a device to meet its performance specifications or 
946 
otherwise perform as intended.  Performance specifications include all claims made in the 
947 
labeling for the device.  The intended performance of a device refers to the intended use for 
948 
which the device is labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, sites will 
949 
not be asked to distinguish between device complaints and malfunctions. 
950 
Use Error: User action or lack of user action while using the medical device (3.34) that leads to a 
951 
different result than that intended by the manufacturer or expected by the user. Includes the 
952 
inability of the user to complete a task. Use errors can result from a mismatch between the 
953 
characteristics of the user, user interface, task or use environment. Users might be aware or 
954 
unaware that a use error has occurred. An unexpected physiological response of the patient is not 
955 
by itself considered a use error. A malfunction of a medical device that causes an unexpected 
956 
result is not considered a use error. (ISO 14155:2020) 
957 
958 
9.2.2 Reportable Adverse Events 
959 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
960 
meets one of the following criteria: 
961 
1. An SAE as defined in section 9.2.1
962 
2. An ADE as defined in section 9.2.1, unless excluded from reporting in section 9.3
963 
3. An AE as defined in 9.2.1 occurring in association with a study procedure
964 
4. An AE as defined in 9.2.1not related to a device issue which leads to temporary or permanent
965 
discontinuation of a study device 
966 
5. An AE as defined in 9.2.1that affects the participant’s ability to complete any study
967 
procedures 
968 
6. An AE as defined in 9.2.1for which a visit is made to a hospital emergency department
969 
7. Hypoglycemia meeting the definition of reportable hypoglycemia in section 9.2.3
970 
8. Hyperglycemia or ketosis event meeting the criteria defined in section 9.2.4.
971 
9. An AE as defined in section 9.2.1 considered to be related to either ineffective insulin (e.g.,
972 
insulin exposed to high temperature that loses potency), signs or symptoms related to insulin 
973 
infusion, or changing of type of insulin related to an AE. 
974 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
975 
events unless associated with an Adverse Device Effect or discontinuation of the study device.  
976 
Skin reactions from sensor placement are only reportable if severe and/or required treatment. 
977 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
978 
during questioning, or detected through physical examination, laboratory test, or other means—
979 

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will be reported on an AE form online.  Each AE form is reviewed by the Medical Monitor to 
980 
assess safety and to verify the coding and the reporting that is required. 
981 
9.2.3 Hypoglycemic Events 
982 
Hypoglycemia is only reportable as an adverse event when one of the following criteria is met: 
983 
•
A hypoglycemic event occurred meeting the following definition of severe
984 
hypoglycemia:  the event required assistance of another person due to altered
985 
consciousness, and required another person to actively administer carbohydrate,
986 
glucagon, or other resuscitative actions.  This means that the participant was impaired
987 
cognitively to the point that he/she was unable to treat himself/herself independently, was
988 
unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or
989 
experienced seizure or loss of consciousness.  These episodes may be associated with
990 
sufficient neuroglycopenia to induce seizure or loss of consciousness.  If glucose
991 
measurements are not available during such an event, neurological recovery attributable
992 
to the restoration of glucose to normal is considered sufficient evidence that the event
993 
was induced by a low glucose concentration.
994 
•
Evaluation or treatment was obtained at a health care provider facility for an acute event
995 
involving hypoglycemia, or the participant contacted the site and received guidance
996 
following the occurrence of an acute event involving hypoglycemia
997 
•
Participant contacted the site because of the occurrence of hypoglycemia
998 
•
Hypoglycemia occurred that was associated with an ADE as defined in section 9.2.1
999 
•
Study device discontinued due to hypoglycemia
1000 
When a severe hypoglycemia event occurs (as defined above), a Hypoglycemia Form should be 
1001 
completed in addition to the Adverse Event Form. Severe hypoglycemia events should be 
1002 
considered to be serious adverse events with respect to reporting requirements. When a severe 
1003 
hypoglycemia event occurs during use of a study device, it generally will be considered to be 
1004 
unrelated to the device (per section 9.2.5) if the device functioned as intended and there does not 
1005 
appear to be a flaw in how the device is intended to function. 
1006 
9.2.4 Hyperglycemic/Ketotic Events 
1007 
Hyperglycemia is only reportable as an adverse event when one of the following criteria is met:  
1008 
•
Evaluation or treatment was obtained at a health care provider facility for an acute event
1009 
involving hyperglycemia or ketosis, or the participant contacted the site and received
1010 
guidance on how to manage the hyperglycemia/ketosis
1011 
•
The event involved DKA, as defined by the Diabetes Control and Complications Trial
1012 
(DCCT) and described below
1013 
o
Symptoms such as polyuria, polydipsia, nausea, or vomiting;
1014 
o
Serum ketones >1.5 mmol/L or large/moderate urine ketones;
1015 
o
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate (or CO2)
1016 
<15; and
1017 

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o
Treatment provided in a health care facility 
1018 
•
The event involved hyperosmolar hyperglycemic syndrome (HHS), as defined by the
1019 
American Diabetes Association and described below
1020 
o
Symptoms such as polyuria, polydipsia, nausea, or vomiting;
1021 
o
Plasma glucose levels are very elevated (typically > 600 mg/dL);
1022 
o
Plasma effective osmolarity is >320 mOsm/L;
1023 
o
Absence of significant ketones; and
1024 
o
Treatment provided in a health care facility
1025 
•
Hyperglycemia occurred that was associated with an ADE as defined in section 9.2.1
1026 
•
Study device discontinued due to hyperglycemia
1027 
When a hyperglycemia/ketotic event qualifies as an AE, or as an SAE as defined in section 9.2.1, 
1028 
a Hyperglycemia/DKA Form should be completed in addition to the Adverse Event Form. 
1029 
Events meeting DKA or HHS criteria should be considered to be serious adverse events with 
1030 
respect to reporting requirements. Hyperglycemia events not meeting criteria for DKA or HHS 
1031 
generally will not be considered as serious adverse events unless one of the SAE criteria in 
1032 
section 9.2.1 is met. 
1033 
When a hyperglycemia/DKA event occurs during use of a study device, it generally will be 
1034 
considered to be unrelated to the device (per section 9.2.5) if the device functioned as intended 
1035 
and there does not appear to be a flaw in how the device is intended to function. 
1036 
9.2.5 Relationship of Adverse Event to Study Investigational Device or Study 
1037 
Procedure 
1038 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1039 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1040 
by the study device or study procedure. The Medical Monitor also will make this assessment, 
1041 
which may or may not agree with that of the site investigator. The Medical Monitor will have the 
1042 
final say in determining the causality as well as whether an event is classified as a serious 
1043 
adverse event and/or an unanticipated adverse device effect. Reporting requirements will be 
1044 
based on the Medical Monitor’s assessment as the Sponsor’s representative, with both the site 
1045 
investigator’s and the Medical Monitor’s assessment reported. 
1046 
Reporting requirements will be based on the Medical Monitor’s assessment as the Sponsor’s 
1047 
representative. 
1048 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1049 
following general guideline when determining whether an adverse event is related: 
1050 
Unrelated: The AE is clearly not related to a study device/procedure and a likely alternative 
1051 
etiology exists such as an underlying disease, environmental or toxic factors or other 
1052 
therapy. 
1053 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after 
1054 
use of study device or a study procedure and a more likely alternative etiology exists such 
1055 
as an underlying disease, environmental or toxic factors, or other therapy.  
1056 

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Possibly Related: The AE occurred in a reasonable time during or after use of study device 
1057 
or a study procedure; but could be related to another factor such as an underlying disease, 
1058 
environmental or toxic factors, or other therapy; and there is a possible, though weak, 
1059 
scientific basis for establishing a causal association between the AE and the study 
1060 
drug/device. 
1061 
Probably Related: The AE occurred in a reasonable time during or after use of study device 
1062 
or a study procedure; is unlikely to be related to another factor such as an underlying 
1063 
disease, environmental or toxic factors, or other therapy; and there is a plausible, though 
1064 
not strong, scientific basis for establishing a causal association between the AE and the 
1065 
study drug/device.  
1066 
Definitely Related: The AE occurred in a reasonable time during or after use of study device 
1067 
or a study procedure; cannot be explained by another factor such as an underlying disease, 
1068 
environmental or toxic factors, or therapy; and there is a strong scientific basis for 
1069 
establishing a causal association between the AE and the study drug/device.  
1070 
Where these relatedness categories are used, events determined to be Possibly Related, Probably 
1071 
Related, or Definitely Related will be considered to meet the reasonable possibility causality 
1072 
standard for relatedness and necessitate reporting as required (see 21 CFR 312.32 for more 
1073 
information about this standard). 
1074 
9.2.6 Severity (Intensity) of Adverse Events 
1075 
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) 
1076 
moderate, or (3) severe.  A severity assessment is a clinical determination of the intensity of an 
1077 
event. Thus, a severe adverse event is not necessarily serious.  For example, itching for several 
1078 
days may be rated as severe, but may not be clinically serious. 
1079 
MILD: Usually transient, requires no special treatment, and does not interfere with the 
1080 
participant’s daily activities. 
1081 
MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
1082 
participant and may interfere with daily activities, but is usually ameliorated by simple 
1083 
therapeutic measures and participant is able to continue in study. 
1084 
SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may cause 
1085 
discontinuation of study device, and generally requires systemic drug therapy or other treatment. 
1086 
9.2.7 Expectedness 
1087 
For a serious adverse event that is considered possibly related to the study, a study procedure, or 
1088 
the study device, the Medical Monitor will classify the event as unexpected if the nature, 
1089 
severity, or frequency of the event is not consistent with the risk information previously 
1090 
described in the approved labelling of the study system (most recent summary of product 
1091 
characteristics in the labelling). 
1092 
9.2.8 Coding of Adverse Events 
1093 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will 
1094 
enter a preliminary MedDRA code which the Medical Monitor may accept or change (the 
1095 
Medical Monitor’s MedDRA coding will be used for all reporting). 
1096 

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9.2.9 Outcome of Adverse Events 
1097 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1098 
o
RECOVERED/RESOLVED (COMPLETE RECOVERY) – The participant recovered
1099 
from the AE/SAE without sequelae. Record the AE/SAE stop date.
1100 
o
RECOVERED/RESOLVED WITH SEQUELAE – AE/SAE where the subject
1101 
recuperated but retained pathological conditions resulting from the prior disease or injury.
1102 
Record the AE/SAE stop date.
1103 
o
FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event
1104 
that was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at
1105 
the time of death; however, were not the cause of death, will be recorded as “resolved” at
1106 
the time of death.
1107 
o
ONGOING (NOT RECOVERED/NOT RESOLVED) – An ongoing AE/SAE is defined
1108 
as an ongoing event with an undetermined outcome.
1109 
An ongoing outcome will require follow-up by the site in order to determine the final 
1110 
outcome of the AE/SAE. 
1111 
The outcome of an ongoing event at the time of death that was not the cause of death, 
1112 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1113 
date. 
1114 
o
ONGOING (MEDICALLY STABLE) – AE/SAE is ongoing, but medically stable. For
1115 
example, a chronic condition where no further change is expected.
1116 
If any reported adverse events are ongoing when a participant completes the study (or 
1117 
withdraws), adverse events classified as UADEs or related SAEs will be followed until they are 
1118 
either resolved, or have no prospect of improvement or change, even after the participant has 
1119 
completed all applicable study visits/contacts. For all other adverse events, data collection will 
1120 
end at the time the participant completes the study, unless further follow up is requested by the 
1121 
Medical Monitor. Note: participants should continue to receive appropriate medical care for an 
1122 
adverse event after their participation in the study ends. 
1123 
If a participant is lost to follow up and participant outcome cannot be determined, outcome 
1124 
classification will be the last known outcome. 
1125 
9.3 Reportable Device Issues 
1126 
All UADEs and ADEs as defined in section 9.2.1will be reported on both a device issue form 
1127 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1128 
placement that do not require pharmacologic treatment.  
1129 
Device complaints and device malfunctions will be reported except in the following 
1130 
circumstances. These occurrences are expected and will not be reported on a Device Issue Form 
1131 
assuming criteria for a UADE or ADE have not been met: 
1132 
•
CGM sensor needing replacement prior to labelled maximum use duration
1133 
•
Infusion set needing replacement prior to labelled maximum use duration
1134 
•
CGM tape adherence issues
1135 

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•
Battery lifespan deficiency due to inadequate charging or extensive wireless 
1136 
communication
1137 
•
Intermittent device component disconnections/communication failures not requiring
1138 
system replacement or workaround/resolution not specified in user guide/manual.
1139 
•
Device issues clearly addressed in the user guide manual that do not require additional
1140 
troubleshooting
1141 
User error (as defined in section 9.2.1) will only be reported on a Device Issue form if an AE as 
1142 
defined in section 9.2.1 results from the error. In these cases, both a Device Issue form and an 
1143 
Adverse Event form will be completed. 
1144 
9.4 Timing of Event Reporting 
1145 
SAEs possibly related to a study device or study participation and UADEs must be reported by 
1146 
the investigator to the Coordinating Center within twenty-four (24) hours of the site becoming 
1147 
aware of the event.  This can occur via phone or email, or by completion of the online serious 
1148 
adverse event form and device issue form if applicable. If the form is not initially completed, it 
1149 
should be competed as soon as possible after there is sufficient information to evaluate the event. 
1150 
All other reportable ADEs and other reportable AEs should be submitted by completion on the 
1151 
online form within seven (7) days of the site becoming aware of the event. 
1152 
The Sponsor (or CRO) will notify all participating investigators of any adverse event that is 
1153 
serious, related, and unexpected. Notification will be made within ten (10) working days after the 
1154 
Sponsor becomes aware of the event. 
1155 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1156 
abiding by any other reporting requirements of his/her local Institutional Review Board or Ethics 
1157 
Committee and the Central IRB (as applicable). Sites relying on the Central IRB must report all 
1158 
serious, related adverse events within seven (7) calendar days (in addition to meeting any local 
1159 
IRB reporting requirements). 
1160 
Upon receipt of a qualifying event, the Sponsor will investigate the event to determine if a 
1161 
UADE is confirmed, and if indicated, report the results of the investigation to all overseeing 
1162 
IRBs, and the FDA within ten (10) working days of the Sponsor becoming aware of the UADE 
1163 
per 21CFR 812.46(b)(2).  The Sponsor in conjunction with the Medical Monitor must determine 
1164 
if the UADE presents an unreasonable risk to participants.  If so, the Sponsor must ensure that all 
1165 
investigations, or parts of investigations presenting that risk, are terminated as soon as possible 
1166 
but no later than five (5 )working days after the Sponsor makes this determination and no later 
1167 
than fifteen (15) working days after first receipt notice of the UADE. The investigator(s) may 
1168 
then be required to provide approval or acknowledgment of receipt of that notification and must 
1169 
submit to their local IRB as required. 
1170 
The investigators are also required to report, without unjustified delay, all reportable device 
1171 
deficiencies, irrespective of whether an adverse event occurred. 
1172 
Device malfunctions will be handled by the Sponsor or designee as described below.  In the case 
1173 
of a CGM transmitter or sensor device malfunction, information will be forwarded to Dexcom by 
1174 
the site personnel, to be handled by their complaint management system. 
1175 
1176 

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Where an adverse event is suspected to be related only to the study provided insulin from Novo 
1177 
Nordisk, and does not result from a possible interaction with the investigational medical device, 
1178 
the investigator or the sponsor are encouraged to report the case to the FDA or competent 
1179 
authority. Where made aware of such case, the competent authority should apply the guidance 
1180 
provided in the Good Pharmacovigilance Practices Module VI with regard to the management of 
1181 
this type of safety report. While reporting the suspected adverse reaction, the relevant 
1182 
information regarding the CT (i.e. clinical trial number) or Study ID number must be included in 
1183 
the report. 
1184 
9.5 Safety Oversight 
1185 
The study Medical Monitor will review all adverse events and adverse device events that are 
1186 
reported during the study.  SAEs typically will be reviewed within twenty-four (24) hours of 
1187 
reporting.  Other AEs typically will be reviewed on a weekly basis. 
1188 
The Sponsor and Clinical Study Director will be informed of all cases of severe hypoglycemia 
1189 
and DKA or HSS and the Medical Monitor’s assessment of relationship to the study device; and 
1190 
informed of all reported device issues. A Data and Safety Monitoring Board (DSMB) will 
1191 
provide safety oversight. The DSMB will be informed of all cases of severe hypoglycemia, 
1192 
DKA, and HHS irrespective of device relationship, all device-related SAEs, and all UADEs at 
1193 
the time that they occur during the study and will review compiled safety data at periodic 
1194 
intervals. The DSMB also will be informed of any ADEs not meeting criteria for a UADE if the 
1195 
Medical Monitor requests the DSMB review. The DSMB can request modifications to the study 
1196 
protocol or suspension or outright stoppage of the study if deemed necessary based on the 
1197 
totality of safety data available. Details regarding the DSMB’s role will be documented in a 
1198 
separate DSMB charter. 
1199 
9.6 Stopping Criteria 
1200 
9.6.1 Participant Discontinuation of Study Device 
1201 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA 
1202 
event (or a malfunction that could have led to severe hypoglycemia or DKA), use of closed-loop 
1203 
mode will be suspended while the problem is diagnosed. The UADE will be reported to the IRB, 
1204 
DSMB, and FDA. After assessment of the problem and any correction, use of closed-loop mode 
1205 
will not be restarted until approval is received from the IRB, DSMB, and FDA. 
1206 
In the absence of a device malfunction, a participant will be discontinued from the study if any of 
1207 
the following occur: 
1208 
•
The investigator believes it is unsafe for the participant to continue on the intervention.
1209 
This could be due to the development of a new medical condition or worsening of an
1210 
existing condition; or participant behavior contrary to the indications for use of the
1211 
device that imposes on the participant’s safety.
1212 
•
The participant requests that the treatment be stopped
1213 
•
Participant pregnancy
1214 
•
Two distinct episodes of DKA, HHS, or severe hypoglycemia as defined in sections 9.2.3
1215 
and 9.2.4, respectively.
1216 

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Each DKA or severe hypoglycemia event will be reviewed by the Medical Monitor with respect 
1217 
to determination of cause and whether the occurrence of the event can be attributed to use of the 
1218 
study device. 
1219 
An additional requirement for continued study participation following a single DKA or severe 
1220 
hypoglycemia event will be that (1) the site investigator believes that the event is explainable, 
1221 
unlikely to recur, and that it is safe for the participant to continue to use the system and (2) the 
1222 
Medical Monitor concurs. If the Medical Monitor determines that the occurrence of the event 
1223 
indicates that it is not safe for the participant to continue to use the study system, the participant 
1224 
will be discontinued from the study. 
1225 
Even if the study device system is discontinued, the participant will be encouraged to remain in 
1226 
the study (using CGM only) through the final study visit. 
1227 
9.6.2 Criteria for Suspending or Stopping Overall Study 
1228 
The DSMB will be immediately notified of all adverse events related to SH, DKA, or HHS, as 
1229 
well as any recurrence of these events across participants or study sites. In addition to the 
1230 
suspension of closed-loop mode use due to a UADE as described above, closed-loop system use 
1231 
could be similarly suspended if the manufacturer of any constituent study device requires 
1232 
stoppage of device use for safety reasons (e.g. product recall).  The affected study activities may 
1233 
resume if the underlying problem can be corrected by a protocol or system modification that will 
1234 
not invalidate the results obtained prior to suspension. 
1235 
Additionally, the Medical Monitor or the DSMB may request suspension of study activities or 
1236 
stoppage of the study if deemed necessary based on the totality of safety data available. The 
1237 
Central IRB also has the authority to suspend or terminate study activities, and local IRBs have 
1238 
the authority to suspend or terminate activities at the sites that they oversee. 
1239 
1240 

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Chapter 10: Miscellaneous Considerations 
1241 
10.1 Drugs Used as Part of the Protocol 
1242 
Participants using the study pump will use only insulin approved by the FDA for use in the study 
1243 
pump. 
1244 
10.2 Collection of Medical Conditions and Medications 
1245 
Pre-Existing Condition: Any medical condition that is either present at screening, a chronic 
1246 
disease, or a prior condition that could impact the participant’s health during the course of the 
1247 
study (e.g., prior myocardial infarction or stroke). 
1248 
Medical Conditions during the study: In addition to conditions meeting the reporting 
1249 
requirements for an adverse event as described in section 9.2.2, the following medical conditions 
1250 
should also be reported: (1) new diagnosis of a chronic disease (i.e., not present at the time of 
1251 
enrollment), and (2) any medical condition that could affect the participant’s ability to carry out 
1252 
any aspect of the protocol or could affect an outcome assessment. 
1253 
Medications: All medication for the treatment of chronic pre-existing conditions, medical 
1254 
conditions (including medical conditions that do not require recording), and/or adverse events 
1255 
that the participant is currently taking at screening and during the course of the study should be 
1256 
recorded.  Nutraceuticals and preventative treatment also should be recorded.  Medications only 
1257 
taken as needed either be captured with a frequency of “PRN”, or can be recorded when used 
1258 
during the study.  Glucagon for treatment of severe hypoglycemia will only be recorded if used 
1259 
during the study. 
1260 
10.3 Prohibited Medications, Devices, Treatments, and Procedures 
1261 
Only insulins approved for the study pump can be used in the study pump. Afrezza (inhaled 
1262 
insulin) or concurrent use of basal insulin will not be permitted during use of Control-IQ in the 
1263 
trial. 
1264 
Sulfonylurea use and meglitinide use will not be allowed during the trial. 
1265 
Addition of glucose-lowering or weight-reduction medications not in use at the time of 
1266 
randomization are prohibited during the 13 weeks of the RCT. 
1267 
Dose increases in glucose-lowering or weight-reduction medications in use at the time of 
1268 
randomization are not permitted. 
1269 
Hydroxyurea use is not allowed during the trial, as it may interfere with the study CGM sensor. 
1270 
Additional medications may be excluded per judgement of the investigator. 
1271 
The body-worn study devices (study insulin pump, study CGM system) must be removed before 
1272 
Magnetic Resonance Imaging (MRI), Computed Tomography (CT) or diathermy treatment. 
1273 
Participants may continue in the trial after temporarily discontinuing use if requiring one of the 
1274 
treatments above. 
1275 
10.4 Precautionary Medications, Treatments, and Procedures 
1276 
Not applicable. 
1277 

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10.5 Prophylactic Medications, Treatments, and Procedures 
1278 
Not applicable. 
1279 
10.6 Rescue Medications, Treatments, and Procedures 
1280 
Participants in the AID group who perform exercise challenges will be expected to have a 
1281 
commercially available glucagon (or glucagon analog) preparation for treatment as needed for 
1282 
severe hypoglycemia.  Glucagon will be offered to these participants by the study team. 
1283 
10.7 Pregnancy Reporting 
1284 
If pregnancy occurs, the participant will be discontinued from the study.  The occurrence of 
1285 
pregnancy will be reported to the Sponsor/CRO within seven (7) calendar days and to the Central 
1286 
IRB on the Unanticipated Problem form within seven (7) calendar days. 
1287 
10.8 Participant Compensation 
1288 
Participant compensation will be specified in the informed consent form. 
1289 
10.9 Participant Withdrawal 
1290 
Participation in the study is voluntary, and a participant may withdraw at any time.  For 
1291 
participants who withdraw, their data will be used up until the time of withdrawal. 
1292 
10.10 Confidentiality 
1293 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1294 
used instead of their name.  Protected health information gathered for this study will be shared 
1295 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL.  De-identified 
1296 
participant information may also be provided to research sites involved in the study.
1297 

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Chapter 11: Statistical Considerations 
1298 
11.1 Statistical and Analytical Plans 
1299 
The approach to sample size and statistical analyses are summarized below.  A detailed 
1300 
Statistical Analysis Plan will be written and finalized prior to the completion of the study. 
1301 
The primary statistical analyses will involve comparisons of the randomized treatment groups.  
1302 
Additionally, certain single-arm analyses will be conducted on the data collected for the AID 
1303 
group as described in section 11.15. 
1304 
11.2 Statistical Hypotheses 
1305 
The primary endpoint for this study is HbA1c at 13-weeks adjusted for baseline HbA1c. The 
1306 
intervention will be considered effective if the AID group is superior to the Control group using 
1307 
a statistical significance of α=0.05. 
1308 
The null/alternative hypotheses for the primary endpoint are: 
1309 
•
Null Hypothesis: There is no difference in mean HbA1c at 13 weeks between AID and
1310 
Control
1311 
•
Alternative Hypothesis: Mean HbA1c at 13 weeks is different for AID and Control.
1312 
Similarly, the null and alternative hypotheses for all of the secondary efficacy endpoints in the 
1313 
hierarchy are: 
1314 
•
Null Hypothesis: There is no difference in the endpoint at 13 weeks between AID and
1315 
Control
1316 
•
Alternative Hypothesis: Endpoint at 13 weeks is different for AID and Control.
1317 
11.3 Sample Size 
1318 
The sample size of 330 randomized participants was selected to provide sufficient exposure to 
1319 
the AID system for regulatory purposes.  This equates with a maximum of 220 using the AID 
1320 
system for 13 weeks. Assuming 10% drop out rate in each group, there will be 200 using the 
1321 
system for 13 weeks. 
1322 
HbA1c data from N=30 participants in the 2IQ pilot study were used to estimate the SD for the 
1323 
power calculation. The SD for baseline values was 1.0%. Assuming a similar SD at follow-up, 
1324 
correlation of 0.3 with baseline, and a two-sided test with type 1 error at 5%, a sample size of 
1325 
N=300 completers will be able to detect an HbA1c difference as small as 0.38% with 90% 
1326 
power. There will be 85% power to detect a difference of 0.35% and 80% power for a difference 
1327 
of 0.33%. 
1328 
11.4 Efficacy Outcome Measures 
1329 
11.4.1 Primary Efficacy Endpoint 
1330 
•
HbA1c at 13 weeks (superiority)
1331 

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11.4.2 Secondary Efficacy Endpoints Included in Hierarchical Analysis 
1332 
The following secondary endpoints will be tested for superiority, with a hierarchical testing 
1333 
approach to protect the type 1 error rate as described in section 11.13. 
1334 
•
Time in range 70-180 mg/dL
1335 
•
Mean glucose
1336 
•
Time >180 mg/dL
1337 
•
Time >250 mg/dL
1338 
•
CGM-measured prolonged hyperglycemia events (defined in section 11.7.1)
1339 
•
Time <70 mg/dL
1340 
•
Time <54 mg/dL
1341 
•
CGM-measured hypoglycemia events (defined in section 11.7.1)
1342 
•
Coefficient of variation
1343 
1344 
11.4.3 Other Secondary Efficacy Endpoints 
1345 
The following efficacy endpoints are considered exploratory as they are not included in the 
1346 
overall type 1 error rate. All statistical tests are for superiority. 
1347 
Binary HbA1c Endpoints: 
1348 
HbA1c <7.0% at 13 weeks 
1349 
HbA1c <7.0% at 13 weeks in participants with baseline HbA1c >7.5% 
1350 
HbA1c <7.5% at 13 weeks 
1351 
HbA1c improvement from baseline to 13 weeks >0.5% 
1352 
HbA1c improvement from baseline to 13 weeks >1.0% 
1353 
HbA1c relative improvement from baseline to 13 weeks >10% 
1354 
HbA1c improvement from baseline to 13 weeks >1.0% or HbA1c <7.0% at 13 weeks 
1355 
Continuous CGM-Measured Endpoints: 
1356 
Time in range 70-140 mg/dL 
1357 
Area over the curve (70 mg/dL) 
1358 
Low blood glucose index 
1359 
Time >300 mg/dL  
1360 
Area under the curve (180 mg/dL) 
1361 
High blood glucose index 
1362 
Binary CGM-Measure Endpoints 
1363 
Time in range 70-180 mg/dL >70% 
1364 
Time in range 70-180 mg/dL improvement from baseline to 13 weeks ≥5% 
1365 

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Time in range 70-180 mg/dL improvement from baseline to 13 weeks ≥10% 
1366 
Time <70 mg/dL <4% 
1367 
Time <54 mg/dL <1% 
1368 
Time in range 70-180 mg/dL >70% and time <54 mg/dL <1% 
1369 
Other Endpoints (analyzed for superiority as continuous variables): 
1370 
•
Insulin
1371 
o
Total daily insulin delivery
1372 
o
Percentage of insulin delivered as basal
1373 
•
Weight change
1374 
•
Change in lipid levels
1375 
•
Cardiovascular events
1376 
•
Patient-reported outcome (PRO) measures (see section 8.3)
1377 
11.4.4 Safety Endpoints 
1378 
•
Severe hypoglycemia
1379 
•
Diabetic ketoacidosis
1380 
•
Hyperosmolar hyperglycemic syndrome
1381 
•
Other serious adverse events
1382 
•
Unanticipated adverse device effects
1383 
•
Hypoglycemia and prolonged hyperglycemia endpoints listed as effectiveness endpoints
1384 
•
Infusion set failures
1385 
•
Other device malfunctions/device issues
1386 
11.5 Analysis Datasets and Sensitivity Analyses 
1387 
All analyses comparing the AID arm with Control arm will follow intention-to-treatment 
1388 
approach, which means participants will be analyzed in the treatment arm assigned by 
1389 
randomization regardless of actual system use. All randomized participants will be included in 
1390 
the primary analysis and secondary analyses of CGM metrics. 
1391 
Safety outcomes will be reported for all enrolled participants, irrespective of whether the 
1392 
participant was randomized, or the study was completed. 
1393 
11.5.1 Per Protocol Analyses 
1394 
Per-protocol analyses will be performed for primary outcome and secondary hierarchical 
1395 
outcomes only if >5% of participants will be excluded. All of the following criteria must be met 
1396 
for a participant to be included in the per-protocol analyses. The criteria are as follows: 
1397 
•
13-week visit completed
1398 
•
No major protocol deviations
1399 

TANDEM 2IQP PROTOCOL V8.0 2023-10-31.DOCX 
PAGE 70 OF 79 
•
Device use: AID group - closed loop mode active for at least 80% of the time over the 
1400 
13-week period; control group - CGM use for at least 80% of the time over the13-week
1401 
visit period
1402 
11.5.2 Other Sensitivity Analyses 
1403 
Confounding 
1404 
A sensitivity analysis will also be conducted if potential confounding factors collected at 
1405 
baseline are detected. 
1406 
The imbalance will be assessed based on clinical judgment reviewing the distributions in the two 
1407 
treatment arms, not on a p-value. The person making this judgement will be unaware of whether 
1408 
there is an association between baseline variables and study outcome. All variables obtained on a 
1409 
continuous scale will be entered into the models as continuous variables, unless it is determined 
1410 
that a variable does not have a linear relationship with the outcome. In such a case, 
1411 
categorization and/or transformation will be explored. 
1412 
Missing Data 
1413 
Missing data will be handled using direct likelihood method for the primary analysis. It is worth 
1414 
noting that all statistical methods for handling missing data rely on untestable assumptions and 
1415 
there is no one correct way to handle missing data. Our goal is to minimize the amount of 
1416 
missing data so that the results will not be sensitive to which statistical method is used. 
1417 
To that end, sensitivity analyses will be performed to explore whether results are similar for 
1418 
primary analysis when using different methods. The following methods will be applied: 
1419 
•
Rubin’s multiple imputation with treatment group in the imputation model
1420 
•
Available cases only
1421 
•
Multiple imputation with pattern mixture model assuming the dropout trajectory of the
1422 
AID group was that of the Control group (Mallinckrodt and Clark, 2003)
1423 
•
Tipping point analysis to determine the magnitude of selective dropout bias necessary to
1424 
alter conclusions of the study.
1425 
11.6 Analysis of the Primary Efficacy Endpoint: HbA1c 
1426 
HbA1c at 13 weeks will be compared between the AID and Control Groups using a linear mixed 
1427 
effects regression model adjusting for baseline HbA1c and clinical center (random factor).  A 
1428 
separate variance will be modelled for each treatment group. HbA1c is expected to be normally 
1429 
distributed, but regression diagnostics will be performed to check the residuals and an 
1430 
appropriate alternative transformation or robust statistical method (e.g., non-parametric or MM 
1431 
estimation) will be performed if the residuals have a skewed distribution.  In the event that some 
1432 
HbA1c values are not available at 13 weeks, then the linear mixed effect regression model will 
1433 
use the method of direct likelihood to incorporate information from baseline measurements to 
1434 
calculate the maximum likelihood at 13 weeks. Only central lab HbA1c measurements will be 
1435 
used in the analyses. Imbalances between groups in important covariates are not expected to be 
1436 
of sufficient magnitude to produce confounding. However, the presence of confounding will be 
1437 
evaluated in the sensitivity analyses by including factors potentially associated with the outcome 
1438 
for which there is an imbalance between groups (11.5.2). 
1439 

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11.7 Analysis of Secondary Endpoints 
1440 
11.7.1 CGM Metrics 
1441 
Baseline values for each CGM metric will be computed from 14 days of CGM data prior to 
1442 
randomization. A minimum of 72 hours of CGM data will be required to calculate baseline 
1443 
metrics. 
1444 
CGM data starting from randomization visit through the 13-week visit will be included in the 
1445 
calculation of each CGM metric for each participant, giving equal weight to each CGM point. 
1446 
Calculation of CGM metrics for the treatment group comparisons will exclude the challenges 
1447 
and the period through 6 AM on the day following the end of the challenge. CGM metrics during 
1448 
and following the challenges will be reported separately as described in section 11.15.3 and an 
1449 
overall analysis within the AID group will be performed for all CGM data including the 
1450 
challenge data as described in section 11.15.2. 
1451 
CGM-measured prolonged hyperglycemia events are defined as ≥90 cumulative minutes with 
1452 
CGM glucose >300 mg/dL within a 120-minute period (the participant becomes eligible for 
1453 
another prolonged hyperglycemia event after the CGM glucose is <180 mg/dL for ≥15 
1454 
consecutive minutes). CGM-measured hypoglycemia events are defined as ≥15 consecutive 
1455 
minutes with CGM glucose <54 mg/dL (the participant becomes eligible for another 
1456 
hypoglycemia event after the CGM glucose is ≥70 mg/dL for ≥15 consecutive minutes).  For 
1457 
each of these metrics, the number of events per week is calculated for each participant and each 
1458 
metric is then analyzed as a continuous variable as described below. 
1459 
Summary statistics (mean ± SD or median (quartiles)) will be reported for the CGM-measured 
1460 
metrics at baseline and during follow up as well as for differences from baseline by treatment 
1461 
group. CGM metric differences between AID and Control Groups will be compared using a 
1462 
linear mixed effects regression model adjusting for the baseline value of the metric and clinical 
1463 
center (random effect).  A separate variance will be modelled for each group. Residual values 
1464 
will be examined for an approximate normal distribution.  If residuals are highly skewed, then a 
1465 
transformation or robust statistical method (e.g., non-parametric or MM estimation) will be used 
1466 
instead. Missing data will be handled using direct likelihood. 
1467 
11.7.2 Binary Outcomes 
1468 
For the binary HbA1c outcomes, risk-adjusted percentages by treatment group will be computed 
1469 
at 13 weeks from a logistic regression model. The logistic regression will adjust for baseline 
1470 
HbA1c (as a continuous factor) and clinical site using generalized estimating equations (GEE). 
1471 
Similar analyses will be done for the binary CGM outcomes. 
1472 
11.8 Questionnaires and Other Outcomes Analyses 
1473 
For questionnaires administered to both randomization groups, comparisons will be made using 
1474 
similar linear models as described above for the primary and key secondary outcomes. If 
1475 
questionnaires include a total score, separate models will be run for the total score and selected 
1476 
subscales. 
1477 
Similarly, for insulin, weight and BMI metrics comparisons will be made using similar linear 
1478 
models as described above for the primary HbA1c analysis. 
1479 

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11.9 Safety Analyses 
1480 
All randomized participants will be included in the safety analyses and all of their post-
1481 
randomization safety events will be reported.  Separately, any adverse events occurring between 
1482 
screening and randomization will be reported. 
1483 
All reportable adverse events will be tabulated by treatment group.  Details will be provided in a 
1484 
listing of each event, including Medical Dictionary for Regulatory Activities (MedDRA) term 
1485 
and MedDRA System Organ Class.  Safety analyses for the RCT will include events occurring 
1486 
on or after randomization until and including the 13-week visit or Day 98 from randomization, 
1487 
whichever occurs first. 
1488 
Formal statistical testing only will be performed for selected safety endpoints. For the following 
1489 
outcomes, mean ± SD or summary statistics appropriate to the distribution will be tabulated by 
1490 
treatment group and formal statistical comparisons will be performed if there are enough events 
1491 
(at least 5 events combined between the two treatment groups): 
1492 
•
Number of SH events and SH event rate per 100 person-years
1493 
•
Number of DKA events and DKA event rate per 100 person-years
1494 
•
Number of hyperosmolar hyperglycemic syndrome events and rate per 100 person-years
1495 
•
Other serious adverse events
1496 
If enough events occur for the severe hypoglycemia and DKA outcomes and other serious 
1497 
adverse events, the numbers of events will be compared between the two treatment groups 
1498 
during the RCT using a robust Poisson regression as detailed in the SAP.  
1499 
11.9.1 Safety Tabulations Specific to the AID Group 
1500 
For the AID Group, all of the following will be tabulated: 
1501 
•
Adverse device effects (ADE)
1502 
•
Serious adverse device events (SADE)
1503 
•
Unanticipated adverse device effects (UADE)
1504 
11.10 Additional Tabulations and Analyses 
1505 
The following tabulations will be performed according to treatment group: 
1506 
•
Baseline demographics and clinical characteristics
1507 
•
A flow chart accounting for all participants for all visits
1508 
•
Visit completion rates for each follow-up visit
1509 
•
Protocol deviations
1510 
•
Modifications in non-insulin diabetes drugs during the study
1511 
•
Number and reasons for unscheduled visits and phone calls
1512 
•
Amount of CGM data during the 13 weeks of the study
1513 
11.11 Planned Interim Analyses 
1514 
No formal interim efficacy analyses are planned. The DSMB will review safety data at intervals, 
1515 
with no formal stopping rules other than the guidelines provided in the participant-level and 
1516 
study-level stopping criteria (as defined in Section 9.6.2). 
1517 

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11.12 Subgroup Analyses 
1518 
In exploratory analyses, the primary outcome (HbA1c) and time in range 70-180 mg/dL will be 
1519 
compared in baseline subgroups. Treatment group by subgroup factor interaction terms will be 
1520 
added to the linear models described above. 
1521 
Formal tests will be done only if the overall result is statistically significant. Results will be 
1522 
tabulated by subgroups regardless of statistical significance.  For continuous variables, results 
1523 
will be displayed in subgroups based on cutpoints although the analysis will utilize the variable 
1524 
as continuous. If there is insufficient sample size in a given subgroup, the cutpoints for 
1525 
continuous measures may be adjusted per the observed distribution of values. Cutpoint selection 
1526 
for display purposes will be made masked to the outcome data. 
1527 
Subgroups will be analyzed according to the following baseline factors: 
1528 
•
Baseline HbA1c
1529 
•
Baseline time in range 70-180 mg/dL
1530 
•
Diabetic medication use
1531 
•
Body mass index
1532 
•
Total daily insulin (<100 units versus ≥100 units)
1533 
•
Sex
1534 
•
Age (>50 years old versus ≤50 years old—assuming sufficient numbers in each category)
1535 
•
Race/Ethnicity
1536 
•
Scores on the Subjective Numeracy Survey
1537 
•
C-peptide level
1538 
•
Additional subgroups to be defined in the SAP
1539 
1540 
11.13 Multiple Comparison/Multiplicity 
1541 
Hierarchical Analyses 
1542 
To preserve the overall type 1 error for the primary endpoint and key secondary endpoints as 
1543 
listed in section 11.4.2, a hierarchical testing procedure will be used.  If the primary analysis for 
1544 
HbA1c results in a statistically significant result (p < 0.05), then testing at the 0.05 level will 
1545 
proceed to the next outcome metric.  This process continues iteratively moving to the next 
1546 
variable down on the list until a non-significant result is observed, or all 10 variables have been 
1547 
tested.  If a non-significant result is encountered, then formal statistical hypothesis testing is 
1548 
terminated and any variables lower on the list will not be formally tested. 
1549 
Regardless of the results of the hierarchical testing, summary statistics appropriate to the 
1550 
distribution will be tabulated by treatment group for each hierarchical outcome.  A 95% 
1551 
confidence interval for the treatment group difference also will be calculated for all hierarchical 
1552 
outcomes listed above.  However, a confidence interval that excludes zero will not be considered 
1553 
a statistically significant result if an outcome variable higher on the hierarchical list failed to 
1554 
reach statistical significance. 
1555 
All Other Secondary Analyses 
1556 
For the other secondary analyses, the false discovery rate will be controlled using the adaptive 
1557 
Benjamini-Hochberg procedure. 
1558 

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P-values from safety analyses, sensitivity analyses, and per-protocol analyses will not be adjusted 
1559 
for multiple comparisons. 
1560 
11.14 Exploratory Treatment Group Comparisons 
1561 
The following additional treatment group comparisons will be performed: 
1562 
•
Separate CGM analyses for daytime and nighttime
1563 
•
Separate sub-analyses for participants negative for GAD antibodies (if GAD antibodies
1564 
are present in ≥5% of participants) Efficacy and safety outcomes in participants using an
1565 
SGLT2 inhibitor
1566 
•
Efficacy and safety outcomes in participants using a GLP-1 receptor agonist
1567 
•
Efficacy and safety outcomes in participants with TDI ≥100 units, ≥ 150 units, ≥ 200
1568 
units. These may include subgroup analyses.
1569 
11.15 Additional Analyses and Tabulations for the Single-Arm AID Group 
1570 
11.15.1 Tabulations Specific to the AID Group 
1571 
The following tabulations will be made for the AID group 
1572 
•
Number of participants who stopped AID use and reasons
1573 
•
% time in closed loop
1574 
•
Occlusion events that occur while using the AID system
1575 
•
Reportable device malfunctions and other reported device issues
1576 
•
Frequency of use of sleep mode and exploratory outcomes for times with versus without
1577 
sleep mode
1578 
•
Frequency of use of exercise mode
1579 
11.15.2 Analyses of Complete CGM Data Set 
1580 
CGM metrics will computed over the entire 13 weeks of the trial (including the challenge 
1581 
periods) and compared with the baseline CGM metrics using paired t-tests or nonparametric 
1582 
approaches depending on the distribution of the data. Binary outcomes will be assessed using 
1583 
McNemar’s test. 
1584 
11.15.3 Analysis of Data from Meal and Exercise Challenges 
1585 
The number of each challenge per participant will be tabulated.  Any adverse events occurring 
1586 
during these challenges will be reported by type of challenge in addition to their being included in 
1587 
the overall safety analyses. Selected CGM metrics for hypoglycemia and hyperglycemia will be 
1588 
computed for each challenge and reported as summary statistics for the time period during and 
1589 
until 6 AM on the day following each challenge. 
1590 

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Chapter 12: Data Collection and Monitoring 
1591 
12.1 Case Report Forms and Other Data Collection 
1592 
The main study data are collected on electronic case report forms (CRFs). When data are directly 
1593 
collected in electronic case report forms, this will be considered the source data. For any data 
1594 
points for which the eCRF is not considered source (e.g. lab results that are transcribed from a 
1595 
printed report into the eCRF), the original source documentation must be maintained in the 
1596 
participant’s study chart or medical record. This source must be readily verifiable against the 
1597 
values entered into eCRF. Even where all study data are directly entered into the eCRFs at office 
1598 
visits, evidence of interaction with a live subject must be recorded (e.g., office note, visit record, 
1599 
etc.) 
1600 
Electronic device data files are obtained from the study software and individual hardware 
1601 
components.  These electronic device files are considered the primary source documentation. 
1602 
12.2 Study Records Retention 
1603 
Each participating site will maintain appropriate medical and research records for this trial, in 
1604 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1605 
confidentiality of participants. 
1606 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1607 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1608 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1609 
discontinuation of clinical development of the investigational product.  These documents should 
1610 
be retained for a longer period, however, if required by local regulations.  No records will be 
1611 
destroyed without the written consent of the sponsor, if applicable.  It is the responsibility of the 
1612 
sponsor to inform the investigator when these documents no longer need to be retained. 
1613 
12.3 Quality Assurance and Monitoring 
1614 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1615 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1616 
conducted and data are generated, documented and reported in compliance with the protocol, 
1617 
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1618 
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1619 
accurate, complete, and verifiable.  Adverse events will be prioritized for monitoring. 
1620 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1621 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1622 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1623 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. This plan describes in 
1624 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
1625 
of detail monitoring will be performed, and the distribution of monitoring reports. 
1626 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1627 
events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1628 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1629 
verity and completeness of the key site data.  Elements of the RBM may include: 
1630 

TANDEM 2IQP PROTOCOL V8.0 2023-10-31.DOCX 
PAGE 76 OF 79 
•
Qualification assessment, training, and certification for sites and site personnel 
1631 
•
Oversight of Institutional Review Board (IRB) coverage and informed consent
1632 
procedures
1633 
•
Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol
1634 
review of entered data and edits, statistical monitoring, study closeout
1635 
•
On-site monitoring (site visits): source data verification, site visit report
1636 
•
Agent/Device accountability
1637 
•
Communications with site staff
1638 
•
Patient retention and visit completion
1639 
•
Quality control reports
1640 
•
Management of noncompliance
1641 
•
Documenting monitoring activities
1642 
•
Adverse event reporting and monitoring
1643 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1644 
order to maintain current and personal knowledge of the study through review of the records, 
1645 
comparison with source documents, observation and discussion of the conduct and progress of 
1646 
the study. The investigational site will provide direct access to all trial related sites, source 
1647 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1648 
inspection by local and regulatory authorities. 
1649 
12.4 Protocol Deviations 
1650 
A protocol deviation is any noncompliance with federal regulation, the clinical trial protocol, 
1651 
GCP, IRB requirements, or procedure requirements.  The noncompliance may be either on the 
1652 
part of the participant, the investigator, or the study site staff.  A significant (or major) deviation 
1653 
is any deviation that departs from the established materials in such a way that it poses an increase 
1654 
in the risk to subjects, adversely affects the welfare, rights, or safety of the research subjects, or 
1655 
negatively influences the scientific study integrity. As a result of a significant deviation, a 
1656 
corrective and preventive action plan shall be developed by the site and implemented promptly. 
1657 
The site PI/study staff is responsible for knowing and adhering to all applicable IRB 
1658 
requirements.  Further details about the handling of protocol deviations will be included in the 
1659 
monitoring plan. 
1660 

TANDEM 2IQP PROTOCOL V8.0 2023-10-31.DOCX 
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Chapter 13: Ethics/Protection of Human Participants 
1661 
13.1 Ethical Standard 
1662 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1663 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1664 
21 CFR Part 56, and/or the ICH E6. 
1665 
13.2 Institutional Review Boards 
1666 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1667 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1668 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1669 
require review and approval by the IRB before the changes are implemented to the study.  All 
1670 
changes to the consent form will be IRB approved; a determination will be made regarding 
1671 
whether previously consented participants need to be re-consented. 
1672 
13.3 Informed Consent Process 
1673 
13.3.1 Consent Procedures and Documentation 
1674 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1675 
the study and continues throughout the individual’s study participation. The consent process may 
1676 
be done electronically and virtually, if approved by the IRB.  Extensive discussion of risks and 
1677 
possible benefits of participation will be provided to the participants.  Consent forms will be 
1678 
IRB-approved and the participant will be asked to read and review the document.  The 
1679 
investigator will explain the research study to the participant and answer any questions that may 
1680 
arise.  All participants will receive a verbal explanation in terms suited to their comprehension of 
1681 
the purposes, procedures, and potential risks of the study and of their rights as research 
1682 
participants.  Participants will have the opportunity to carefully review the consent form and ask 
1683 
questions prior to signing. 
1684 
The participants should have the opportunity to discuss the study with their surrogates or think 
1685 
about it prior to agreeing to participate.  The participant will sign the informed consent document 
1686 
prior to any procedures being done specifically for the study.  
1687 
The participants may withdraw consent at any time throughout the course of the trial.  A copy of 
1688 
the informed consent document will be given to the participants for their records.  The rights and 
1689 
welfare of the participants will be protected by emphasizing to them that the quality of their 
1690 
medical care will not be adversely affected if they decline to participate in this study. 
1691 
This process shall be document in the study records at each site (e.g., consent process note). 
1692 
13.3.2 Participant and Data Confidentiality 
1693 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1694 
and the sponsor(s) and their agents.  This confidentiality is extended to cover testing of 
1695 
biological samples and genetic tests in addition to the clinical information relating to 
1696 
participants.  Therefore, the study protocol, documentation, data, and all other information 
1697 
generated will be held in strict confidence.  No information concerning the study or the data will 
1698 
be released to any unauthorized third party without prior written approval of the sponsor. 
1699 

TANDEM 2IQP PROTOCOL V8.0 2023-10-31.DOCX 
PAGE 78 OF 79 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1700 
regulatory agencies or company supplying study product may inspect all documents and records 
1701 
required to be maintained by the investigator, including but not limited to, medical records 
1702 
(office, clinic, or hospital) and pharmacy records for the participants in this study.  The clinical 
1703 
study site will permit access to such records. 
1704 
The study participant’s contact information will be securely stored at each clinical site for 
1705 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1706 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1707 
sponsor requirements. 
1708 
Study participant research data, which is for purposes of statistical analysis and scientific 
1709 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research (JCHR).  This 
1710 
will not include the participant’s contact or identifying information, unless otherwise specified in 
1711 
the informed consent form.  Rather, individual participants and their research data will be 
1712 
identified by a unique study identification number.  The study data entry and study management 
1713 
systems used by clinical sites and by JCHR research staff will be secured and password 
1714 
protected.  At the end of the study, all study databases will be archived at the JCHR. 
1715 

TANDEM 2IQP PROTOCOL V8.0 2023-10-31.DOCX 
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Chapter 14: References 
1716 
1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020.
1717 
Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and
1718 
Human Services; 2020
1719 
2. Brown SA, Kovatchev BP, Raghinaru D, Lum JW et al. Six-month randomized,
1720 
multicenter trial of closed-loop control in type 1 diabetes. N Engl J Med. 2019;
1721 
381(18):1707-1717.
1722 
3. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L et al. A randomized trial of closed-
1723 
loop control in children with type 1 diabetes. N Engl J Med. 2020; 383(9):836-845.
1724 
4. Breton MD, Kovatchev BP. One Year Real-World Use of the Control-IQ Advanced
1725 
Hybrid Closed-Loop Technology. Diabetes Technol Ther. 2021;
1726 
5. Morberg JN, Singh H, McElwee-Malloy M, Habif S, Constantin A. Real-World
1727 
Evaluation of Glycemic Outcomes by Prior Therapy for People with Type 1 and Type 2
1728 
Diabetes Onboarding to Control-IQ Technology. Diabetes. 2021; 70(Supplement 1):710-
1729 
P.
1730 
6. Forlenza GP, Carlson AL, et al. Real-World Evidence Supporting Tandem Control-IQ
1731 
Hybrid Closed-Loop Success in the Medicare and Medicaid Type 1 and Type 2 Diabetes
1732 
Populations. Diabetes Technol Ther. 2022 Nov; 24(11):814-823.
1733 
7. Levy CJ, Raghinaru D, Lum J, Beck RW, et al. Significant Reduction in Hyperglycemia
1734 
and High Satisfaction with Use of Control-IQ Technology in Prior MDI and Basal Only
1735 
Insulin Users with Type 2 Diabetes (T2D). Presented at the 22nd Annual Diabetes
1736 
Technology Meeting, November 2022.
1737 
1738