A Randomized Cross-over Trial Evaluating Automated Insulin Delivery Technologies on Hypoglycemia and Quality of Life in Elderly Adults With Type 1 Diabetes
Phase: PHASE4
Conditions: Type 1 Diabetes Mellitus
Sponsor: Jaeb Center for Health Research

AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Signature Page 
Automated Insulin Delivery in Elderly with Type 1 Diabetes 
(AIDE T1D): 
A Randomized Cross-over Trial Evaluating Automated 
Insulin Delivery Technologies on Hypoglycemia and Quality 
of Life in Elderly Adults with Type 1 Diabetes 
 
Sponsor: Jaeb Center for Health Research 
Version Number: 5.0 
05 May 2021 
 
JCHR Protocol Director, Name, degree 
Kellee Miller, PhD 
Signature/Date 
 
 
Clinical Lead Investigator, Name, 
degree 
Richard Pratley, MD 
Signature/Date 
 
 
Clinical Lead Investigator, Name, 
degree 
Yogish Kudva, MD 
Signature/Date 
 
 
Clinical Lead Investigator, Name, 
degree 
Michael Rickels, MD 

AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
 
Signature/Date 
 
Neuropsychologist Lead Investigator, 
Name, degree 
Naomi Chaytor, PhD 
Signature/Date 
 
 
Medical Monitor, Name, degree 
Roy W. Beck, MD, PhD 
Signature/Date 
 
 

JAEB CENTER FOR HEALTH RESEARCH 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Automated Insulin Delivery in Elderly with Type 1 Diabetes 
(AIDE T1D): 
A Randomized Cross-over Trial Evaluating Automated 
Insulin Delivery Technologies on Hypoglycemia and Quality 
of Life in Elderly Adults with Type 1 Diabetes 
 
Sponsor: Jaeb Center for Health Research 
 
Funded by: NIH 
 
Version Number: 5.0 
 

JAEB CENTER FOR HEALTH RESEARCH 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
KEY ROLES 
 
Name, degree 
Richard Pratley, MD 
Title 
Clinical Principal Investigator 
Institution Name 
AdventHealth Translational Research Institute 
Name, degree 
Yogish Kudva, MD 
Title 
Clinical Principal Investigator 
Institution Name 
Mayo Clinic 
Name, degree 
Michael Rickels, MD 
Title 
Clinical Principal Investigator 
Institution Name 
University of Pennsylvania 
Name, degree 
Naomi Chaytor, PhD 
Title 
Neuropsychology Principal Investigator 
Institution Name 
Washington State University 
 
Name, degree 
Kellee Miller, PhD 
Title 
Principal Investigator  & Coordinator Center Director 
Institution Name 
Jaeb Center for Health Research (JCHR) 
 
Name, degree 
Roy Beck, MD 
Title 
Medical Monitor 
Institution Name 
Jaeb Center for Health Research (JCHR) 
 
Sponsor 
Jaeb Center for Health Research (JCHR) 
 

JAEB CENTER FOR HEALTH RESEARCH 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 18 
1.1 Introduction ....................................................................................................................................... 18 
1.1.1 Background and Importance ........................................................................................................ 18 
1.1.2 Predictive Low-Glucose Suspend Systems ................................................................................. 19 
1.1.3 Hybrid Closed Loop Systems ...................................................................................................... 19 
1.1.4 Quality of Life Outcomes in Automated Insulin Delivery Trials ................................................ 20 
1.2 Rationale ............................................................................................................................................ 21 
1.3 Potential Risks and Benefits .............................................................................................................. 21 
1.3.1 Known Potential Risks ................................................................................................................ 21 
1.3.2 Risk Assessment .......................................................................................................................... 22 
1.3.3 Known Potential Benefits ............................................................................................................ 23 
1.4 General Considerations...................................................................................................................... 23 
1.5 Virtual Visits ..................................................................................................................................... 23 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 24 
2.1 Participant Recruitment and Enrollment ........................................................................................... 24 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 24 
2.2 Participant Inclusion Criteria ............................................................................................................. 25 
2.3 Participant Exclusion Criteria ............................................................................................................ 25 
2.4 Screening Procedures ........................................................................................................................ 26 
2.4.1 Data Collection and Testing ........................................................................................................ 26 
2.5 Screen Failures .................................................................................................................................. 27 
CHAPTER 3: RUN-IN TRAINING PHASE .................................................................................................... 28 
3.1 Introduction ....................................................................................................................................... 28 
3.2 Start of Run-In Visit (Same day as screening or within 14 days) (virtual or in-clinic) ..................... 29 
3.2.1 Participants using CGM at Screening .......................................................................................... 29 
3.2.2 Participants not using CGM at screening/start of run-in ............................................................. 29 
3.3 CGM Training Visit (virtual or in-clinic) .......................................................................................... 29 
3.4 SAP Initiation Visit (Required In-clinic Visit) .................................................................................. 29 
3.5 SAP Evaluation Visit (virtual or in-clinic) ........................................................................................ 30 
3.6 Device Data Uploads ......................................................................................................................... 31 
CHAPTER 4: RANDOMIZATION & START OF PERIOD 1 VISIT ................................................................. 32 
4.1 Randomization ................................................................................................................................... 32 
4.2 Start of Period 1 ................................................................................................................................. 32 

JAEB CENTER FOR HEALTH RESEARCH 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
CHAPTER 5: CROSSOVER TRIAL ............................................................................................................... 33 
5.1 Start of Period Visit ........................................................................................................................... 33 
5.1.1 HCL or PLGS System Training .................................................................................................. 33 
5.1.2 Study Visits and Contacts for Periods 1, 2 and 3 ........................................................................ 33 
5.1.3 Procedures during Study Periods ................................................................................................. 34 
5.1.3.1 Procedures Performed during Each Contact and 4-week period visits ............................... 34 
5.1.3.2 Procedures Performed during Each End of Study Period Follow-up Visit ......................... 34 
5.1.3.3 Device Data Uploads During the Crossover Trial .............................................................. 35 
5.1.4 Early Termination Visit ............................................................................................................... 35 
5.1.5 Unscheduled Visits ...................................................................................................................... 35 
CHAPTER 6: EXTENSION STUDY ............................................................................................................... 36 
6.1 Study Procedures During the Extension Study .................................................................................. 36 
6.1.1 End of Study Visit (Required In-clinic Visit) .............................................................................. 36 
CHAPTER 7: STUDY DEVICES AND SAFETY .............................................................................................. 37 
7.1 Description of the Study Devices ...................................................................................................... 37 
7.1.1 Insulin Pump ................................................................................................................................ 37 
7.1.1.1 Tandem t:slim X2 pump with Basal-IQ Technology .......................................................... 37 
7.1.1.2 Tandem t:slim X2 pump with Control-IQ Technology ....................................................... 37 
7.1.2 Continuous Glucose Monitoring ................................................................................................. 38 
7.1.3 Ketone Meters and Strips ............................................................................................................ 38 
7.1.4 Study Device Accountability Procedures .................................................................................... 38 
7.2 Safety Measures ................................................................................................................................. 38 
7.2.1 CGM Calibration ......................................................................................................................... 38 
7.2.2 Pump System Failure ................................................................................................................... 38 
7.2.3 Hypoglycemia Threshold Alarm and Safety Protocol ................................................................. 39 
7.2.4 Hyperglycemia Threshold Alarm and Safety Protocol ................................................................ 39 
7.3 Participant Access to Study Device at Study Closure ....................................................................... 40 
7.4 Cognitive Assessment after SAE Occurence ..................................................................................... 40 
CHAPTER 8: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 41 
8.1 Testing Procedures ............................................................................................................................ 41 
8.2 Questionnaires ................................................................................................................................... 42 
CHAPTER 9: ADVERSE EVENTS, DEVICE ISSUES AND STOPPING RULES ............................................... 44 
9.1 Adverse Events .................................................................................................................................. 44 
9.1.1 Definitions ................................................................................................................................... 44 
9.1.2 Reportable Adverse Events ......................................................................................................... 44 

JAEB CENTER FOR HEALTH RESEARCH 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
9.1.2.1 Hypoglycemic Events ......................................................................................................... 45 
9.1.2.2 Hyperglycemic/Ketosis Events ........................................................................................... 45 
9.1.3 Relationship of Adverse Event to Study Investigational Device ................................................. 46 
9.1.4 Severity (Intensity) of Adverse Events ........................................................................................ 47 
9.1.5 Expectedness ............................................................................................................................... 47 
9.1.6 Coding of Adverse Events ........................................................................................................... 47 
9.1.7 Outcome of Adverse Events ........................................................................................................ 47 
9.2 Reportable Device Issues ................................................................................................................... 48 
9.3 Timing of Event Reporting ................................................................................................................ 49 
9.4 Stopping Criteria ............................................................................................................................... 49 
9.4.1 Participant Discontinuation of Study Phase ................................................................................ 49 
9.4.2 Criteria for Suspending or Stopping Overall Study ..................................................................... 50 
9.5 Independent Safety Oversight ........................................................................................................... 50 
CHAPTER 10: MISCELLANEOUS CONSIDERATIONS ................................................................................. 51 
10.1 Drugs Used as Part of the Protocol .................................................................................................. 51 
10.2 Collection of Medical Conditions and Medications ........................................................................ 51 
10.3 Participant Compensation ................................................................................................................ 51 
10.4 Participant Withdrawal .................................................................................................................... 51 
10.5 Confidentiality ................................................................................................................................. 51 
CHAPTER 11: STATISTICAL CONSIDERATIONS ........................................................................................ 52 
11.1 Statistical and Analytical Plans ....................................................................................................... 52 
11.2 Statistical Hypotheses ...................................................................................................................... 52 
11.3 Sample Size ..................................................................................................................................... 52 
11.4 Outcome Measures .......................................................................................................................... 53 
11.5 Analysis Datasets and Sensitivity Analysis ..................................................................................... 54 
11.5.1 Per-protocol Analysis ................................................................................................................ 54 
11.5.2 Other Sensitivity Analysis ......................................................................................................... 54 
11.6 Analysis of the Primary Efficacy Endpoint ..................................................................................... 55 
11.7 Analysis of the Secondary Endpoints .............................................................................................. 55 
11.7.1 Secondary Hypoglycemia CGM Endpoints .............................................................................. 55 
11.7.2 Additional CGM Endpoints ....................................................................................................... 55 
11.7.3 HbA1c ....................................................................................................................................... 55 
11.7.4 Questionnaires ........................................................................................................................... 56 
11.8 Safety Analyses ............................................................................................................................... 56 
11.9 Protocol Adherence and Retention .................................................................................................. 56 
11.10 Baseline Descriptive Statistics ....................................................................................................... 57 

JAEB CENTER FOR HEALTH RESEARCH 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
11.11 Planned Interim Analyses .............................................................................................................. 57 
11.12 Sub-Group Analyses ...................................................................................................................... 57 
11.13 Exploratory Analyses .................................................................................................................... 57 
11.14 Additional Tabulations and Analysis ............................................................................................ 58 
11.15 Multiple Comparison/Multiplicity ................................................................................................. 58 
11.16 Extension Phase ............................................................................................................................. 59 
CHAPTER 12: DATA COLLECTION AND MONITORING ............................................................................ 60 
12.1 Case Report Forms and Other Data Collection ............................................................................... 60 
12.2 Study Records Retention ................................................................................................................. 60 
12.3 Quality Assurance and Monitoring .................................................................................................. 60 
12.4 Protocol Deviations ......................................................................................................................... 61 
CHAPTER 13: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 62 
13.1 Ethical Standard ............................................................................................................................... 62 
13.2 Institutional Review Boards ............................................................................................................ 62 
13.3 Informed Consent Process ............................................................................................................... 62 
13.3.1 Consent Procedures and Documentation ................................................................................... 62 
13.3.2 Participant and Data Confidentiality ......................................................................................... 62 
CHAPTER 14: REFERENCES ....................................................................................................................... 64 
 
 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AP 
Artificial Pancreas 
AUC 
Area Under the Curve 
BG 
Blood Glucose 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
CSII 
Continuous Subcutaneous Insulin Infusion 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCL 
Hybrid Closed Loop 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IQR 
Interquartile Range 
NIH 
National Institutes of Health 
PLGS 
Predictive Low Glucose Suspend 
POC 
Point-of-Care 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled/Clinical Trial 
RMB 
Risk-Based Monitoring 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SAP 
Sensor-Augmented Pump 
SD 
Standard Deviation 
SH 
Severe Hypoglycemia 
SMBG 
Self-Monitoring of Blood Glucose 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
ABBREVIATION 
DEFINITION 
TDI 
Total Daily Insulin 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 
 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
A Randomized Cross-over Trial Evaluating Automated Insulin Delivery 
(AID) Technologies on Hypoglycemia and Quality of Life (QOL) in 
Elderly Adults with Type 1 Diabetes (T1D) 
Précis 
The primary objective of this protocol is to assess the safety and 
effectiveness of both hybrid closed loop control (HCL) technology and 
predictive low-glucose insulin suspension (PLGS) on hypoglycemia and 
other glycemic outcomes, QOL and usability compared with sensor-
augmented pump (SAP) therapy in older adults with T1D. A secondary 
objective is to identify patient characteristics associated with use of SAP, 
HCL or PLGS during a 12-week patient preference extension phase. The 
study aims will be completed via a multi-center, randomized, crossover 
trial consisting of three sequential 12-week periods, with the HCL feature 
used during one period, the PLGS feature used during one period and 
SAP therapy (control) during one period. The crossover trial will be 
preceded by a run-in phase in which participants will receive training 
using the study devices (Dexcom G6 and Tandem t:slim X2 pump). After 
the last crossover period, participants will be given the opportunity to use 
study devices for an additional 12 weeks to assess preference of system 
use (PLGS, HCL or SAP) and associated characteristics, durability and 
safety in a more real-world setting with less frequent study contact. 
Investigational Device 
The HCL intervention arm will utilize the Tandem t:slim X2 with 
Control-IQ Technology and Dexcom G6 CGM. 
 
The PLGS intervention arm will utilize the Tandem t:slim X2 with Basal-
IQ Technology and Dexcom G6 CGM. 
 
The control arm will utilize the Tandem t:slim X2 pump and Dexcom G6 
CGM without HCL or PLGS features turned on. 
Objectives 
Primary RCT Objectives: 
1) 
Determine the effect of HCL on hypoglycemia in adults with 
T1D ≥65 years old. 
2) 
Determine the effect of PLGS on hypoglycemia in adults with 
T1D ≥65 years old.  
Extension Phase Objective: Determine user preferences of available CGM 
augmented pump technologies (PLGS, HCL or SAP) among elderly 
adults with T1D ≥65 years old in a more real-world setting during the 
twelve-week extension phase 
 
Study Design 
A multi-center, randomized, crossover trial consisting of three sequential 
12-week periods, with the HCL feature used during one period, the PLGS 
feature used during one period and SAP therapy (control) during one 
period. The crossover trial will be preceded by a run-in phase in which 
participants will receive training using the study devices (Dexcom G6 and 
Tandem t:slim X2 pump). After the last crossover period, participants will 
be given the opportunity to use study devices for an additional 12 weeks 
to assess preference of system use (PLGS, HCL or SAP) and associated 
characteristics, durability and safety in a more real-world setting with less 
frequent study contact. 
Number of Sites 
3 to 5 in the United States 
Endpoint 
Primary Efficacy Outcome: CGM-measured time spent <70 mg/dL  
Key Secondary Efficacy Outcomes: 
Hypoglycemia 
• 
Percentage of values <54 mg/dL  

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
PARTICIPANT AREA 
DESCRIPTION 
• 
Incidence of CGM-measured hypoglycemic events  
Glucose Control 
• 
Mean glucose 
• 
Percentage of values 70 to 180 mg/dL 
• 
HbA1c 
Hyperglycemia 
• 
Percentage of values >250 mg/dL 
• 
Percentage of values >180 mg/dL 
Glycemic Variability 
• 
Coefficient of variation 
 
Key Safety Outcomes: 
• 
Diabetic ketoacidosis (DKA), as defined by the Diabetes 
Control and Complications Trial (DCCT) 
• 
Severe clinical hypoglycemic events such that the participant 
required active assistance from another person due to altered 
consciousness to actively administer carbohydrate, glucagon, or 
engage in other resuscitative actions; note severe hypoglycemia 
could be considered both an efficacy and safety outcome 
• 
Emergency room and hospitalizations related to SH and DKA 
• 
Severe adverse events 
• 
Unanticipated adverse device effects 
 
Other Outcomes: 
• 
Hypoglycemia unawareness 
• 
Participant reported outcomes: diabetes distress, hypoglycemic 
fear, hypoglycemia confidence and general quality of life 
• 
Usability and patient perspective of each system 
 
Population 
Key Inclusion Criteria: 
• 
Clinical diagnosis of T1D  
• 
Age ≥ 65 years old 
• 
T1D Duration of at least 1 year 
• 
HbA1c < 10.0% from point of care or local lab within 6 months 
• 
Insulin regimen involves basal/bolus insulin via insulin pump or 
multiple daily injections  
• 
Ability to download study devices at home or willing to come 
into clinic for devices to be downloaded at visits and when 
needed for safety 
 
Key Exclusion Criteria: 
• 
Use of PLGS technology or HCL insulin delivery in the past 1 
month 
 
Sample Size 
At least 90 participants completing the crossover trial 
Phase 
N/A 
Treatment Groups 
Random assignment (1:1:1) to one of the following treatment orders: 
(A) HCL in period 1, PLGS in period 2, SAP in period 3 
(B) HCL in period 1, SAP in period 2, PLGS in period 3 
(C) PLGS in period 1, HCL in period 2, SAP in period 3 
(D) PLGS in period 1, SAP in period 2, HCL in period 3 
(E) SAP in period 1, HCL in period 2, PLGS in period 3  
(F) SAP in period 1, PLGS in period 2, HCL in period 3  
Participant Duration 
~ 54 weeks 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
PARTICIPANT AREA 
DESCRIPTION 
Protocol Overview/Synopsis 
1) 
Screening and Enrollment 
• 
Informed consent will be signed and eligibility will be assessed 
• 
Medical history obtained 
• 
HbA1c measurement if historical data within 6 months prior to 
enrollment not available (see eligibility criteria) 
• 
Evaluation of CGM experience and CGM use  
• 
CGM training and initiation of study CGM 
• 
Baseline patient reported outcomes  
• 
Brief cognitive assessment for eligibility (5 min MoCA) 
 
2) 
CGM and SAP Run-In 
a. 
CGM Training Period (~ 10 to 30 days): After ~10 days 
following the initial study CGM placement, participants who 
were not already CGM users at screening will have a visit for 
additional CGM training. 
b. 
SAP Training Period (~14 to 35 days): Participants will be 
provided the Tandem t:slim X2 pump which will be integrated 
with the Dexcom G6. Participants will be contacted 1 and 7 
days following initiation of SAP and a SAP evaluation visit will 
occur 14 – 21 days following initiation of SAP. Basal and bolus 
insulin delivery will be adjusted as needed.  
 
 
Prior to initiating the cross-over trial the following will be done: 
 
• 
The clinician will confirm the participant’s willingness to 
participate in the crossover trial 
• 
Study devices downloaded for baseline assessment and 
eligibility of device wear time   
• 
Baseline patient reported outcomes (at screening or prior to 
randomization) 
• 
Cognitive testing (In-person) 
• 
Frailty assessment 
• 
Physical Exam 
• 
Blood draw for central lab samples 
 
3) 
Randomized Crossover Trial 
Eligible participants will continue into randomized cross-over trial: 
• 
Random assignment to:  
(A) HCL in period 1, PLGS in period 2, SAP in period 3 
(B) HCL in period 1, SAP in period 2, PLGS in period 3 
(C) PLGS in period 1, HCL in period 2, SAP in period 3 
(D) PLGS in period 1, SAP in period 2, HCL in period 3 
(E) SAP in period 1, HCL in period 2 and PLGS in period 3  
(F) SAP in period 1, PLGS in period 2, HCL in period 3  
 
During each of the three 12-week intervention periods, a phone or virtual 
contact will occur at 2 and 8 weeks and a visit (in clinic or virtual) at 4 
and 12 weeks. HbA1c will be measured at the end of each period either in 
clinic or using an at-home sample collection kit. 
 
4) 
Extension phase 
At the start of the extension phase participants will be given the 
opportunity to choose between SAP, PLGS or HCL and will be followed 
for an additional 12 weeks.  
 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
SCHEMATIC OF STUDY DESIGN 
 
 
 
SAP Training Period 
SAP use at home; Required In-clinic visit at initiation of SAP 
Contact at 1 and 7 days after, Virtual or In-clinic visit at 14-21 days after 
**Repeat of Contact and Visit may occur 
 
CGM Training Period 
CGM wear at home; Virtual or In-clinic visit at ~ day10  
*May be skipped based on current CGM use; repeat training visits may occur 
Screening & Start of Run-In Visit 
Eligibility assessment and informed consent, baseline cognition, tech and PRO assessments 
Real-time CGM Initiated - Initial CGM training 
Crossover Trial  
 
HCL 
Group A and Group B 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
PLGS 
Group C and Group D 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
Study Period 1 
SAP 
Group E and Group F 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
End of Study Period 3 (12 weeks)  
Virtual or In-Clinic Visit  
End of Study Period 1 (12 weeks)  
Virtual or In-Clinic Visit 
  
Study Period 2 
HCL 
Group C and Group E 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
PLGS 
Group A and Group F 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
SAP 
Group B and Group D 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
Study Period 3 
End of Study Period 2 (12 weeks)  
Virtual or In-Clinic Visit 
  
HCL 
Group D and Group F 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
PLGS 
Group B and Group E 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
SAP 
Group A and Group C 
Contact 2 and 8 wks 
Virtual or In-Clinic visit at 4 wks 
Extension Phase (12 weeks)  
Required In-Clinic Visit 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
SCHEDULE OF STUDY VISITS AND PROCEDURES 
1 
Table 1. Schedule of Visits and Procedures during Screening and Run-In 
2 
 
Screening/Sta
rt of Run-In1 
CGM 
Run-In  
SAP Run-In 
CGM 
Training 
Visit3  
Initiation 
of SAP4 
 
SAP Training 
Contacts5 
SAP 
Evaluation6 
Time from Randomization2 
At least 14 
days prior 
At least 
14 days 
prior 
At least 
14 days 
prior 
 
0 to 7 days 
prior 
In-clinic Visit or Virtual Visit 
(V) or Contact (C) 
V 
V 
In-clinic 
Visit 
C 
V 
Informed Consent  
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical exam, Height, 
weight, blood pressure 
 
 
X 
 
 
HbA1c – point-of-care or 
local lab if historical value 
within 6 months not available 
X 
 
 
 
 
Blood draw - central lab8 
 
 
X 
 
 
10-foot timed walk 
 
 
X 
 
 
5-min MoCA  
X 
 
 
 
 
Cognitive Assessments  
 
 
X 
 
 
Questionnaires9 
X 
 
 
 
 
Study CGM training  
X 
X 
 
 
 
Study pump with integrated 
CGM training 
 
 
X 
X 
X 
Hypo Assessment10  
X 
 
X 
 
 
CGM Compliance 
 
 
 
 
X 
Skin Assessment11 
 
X 
X 
 
X 
Upload device data 
 
X 
X 
X 
X 
Review blood sugars and 
make insulin adjustments as 
needed 
 
X 
X 
X 
X 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
 
Screening/Sta
rt of Run-In1 
CGM 
Run-In  
SAP Run-In 
CGM 
Training 
Visit3  
Initiation 
of SAP4 
 
SAP Training 
Contacts5 
SAP 
Evaluation6 
1The Screening and start of run-in training visits may occur on the same day or separate days but no more than 14 
days apart. 
2Visit timing will depend on experience with study devices. 
3Participants using real-time CGM may skip CGM training period and proceed to SAP training period.  
4Required in-clinic visit. Pump training will occur after participant is comfortable with use of CGM and meets 
minimum hypoglycemia requirement. Participants using both a Tandem t:slim X2 pump and Dexcom CGM may 
skip both the CGM training and SAP initiation visits but will need to use study devices for 14 days prior to 
randomization visit and have one in-person visit (screening or SAP evaluation) for completion of testing and 
assessments. 
5Phone or video contacts to take place 1 day after SAP initiation and 7 days after SAP initiation and may be 
repeated as needed. Participants who are not able to upload device data from home may need to bring device to 
clinic to be downloaded and reviewed.  Ability to upload device will be assessed during training on the device. 
6Evaluate SAP use to determine eligibility and if ready to proceed with randomized trial. Participants who need 
additional training on pump may have a repeat visit.  
7HbA1c obtained at screening only if not done as usual care in the prior 6 months from enrollment  
8Blood draw for central lab HbA1c and C-peptide will take place on initiation of SAP for baseline assessment.  
9Completed at screening or prior to randomization electronically or on paper if preferred.  
10Assessment of amount of hypoglycemia for eligibility may be performed either at screening for those using 
CGM with available data or at the SAP initiation period. 
11When possible via video for virtual visit. 
 
 
 
3 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Table 2. Schedule of Visits and Procedures During the Crossover Trial and Extension 
4 
 
Randomization 
Start of 
Period1  
Crossover 
Period 1, 2 & 3 
End of 
Period1 
Extension 
Phase 
Start 
End of 
Extension 
Phase 
Time from 
Randomization 
or beginning of 
period 
0 
0 
2w 
± 
4d 
4w 
± 
7d 
8w 
± 
7d 
12w ± 7d 
End of 
Period 3 
Visit 
± 7d 
48w±14d 
In-clinic Visit or 
Virtual Visit (V) 
or Contact (C) 
V 
V 
C5 
V 
C5 
V 
V 
In-clinic Visit 
Re-review of 
eligibility 
X 
 
 
 
 
 
 
 
Randomization 
of treatment 
order  
X 
 
 
 
 
 
 
 
Height, weight, 
blood pressure2 
 
 
 
 
 
X 
 
X 
HbA1c central 
lab3 
 
 
 
 
 
X 
 
X 
Questionnaires4 
 
 
 
 
 
X 
 
X 
Cognitive 
Assessments 
 
 
 
 
 
 
 
X 
AE Assessment 
 
 
X 
X 
X 
X 
 
X 
Upload device 
data  
 
 
X 
X 
X 
X 
 
X 
Review glucose 
patterns 
 
X 
X 
X 
X 
X 
X 
X 
Training on 
PLGS or HCL 
user interface if 
starting next 
period 
 
X 
 
 
 
X 
 
 
1Start of period 1 will take place on same day as randomization. Start of period 2 and 3 will take place on same day at 
end of previous period or within 7 days. Start of extension phase should take place on same day of end of period 3.  
2Completed for in-clinic visit but allowed to skip for virtual visit. 
3Central lab HbA1c will be collected in-clinic or at home for virtual visits at the end of period 1, period 2, period 3. 
Collected in-clinic at the end of the extension phase. 
4 Completed electronically by participant or on paper if preferred. 
5 Device data review may take place during follow up contacts if participant can upload data from home. Clinic visit 
may be completed if participant cannot upload data from home.  Ability to upload device will be assessed during 
training on the device.  
 
 
5 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
 
6 
Chapter 1: Background Information 
7 
1.1 Introduction 
8 
1.1.1 Background and Importance 
9 
Older adults with type 1 diabetes (T1D) are a growing but under-evaluated population (1-4). 
10 
Older adults, particularly those with longstanding diabetes, are more prone to hypoglycemia and 
11 
hypoglycemia unawareness. Hypoglycemia, which in addition to producing altered mental status 
12 
and sometimes seizure or loss of consciousness, can be associated with falls leading to fractures, 
13 
and cardiac arrhythmias resulting in sudden death (5-7). In Medicare beneficiaries with diabetes, 
14 
hospitalizations related to hypoglycemia are now more frequent than those for hyperglycemia 
15 
and are associated with high 1-year mortality (6; 8). Emergency room visits due to hypoglycemia 
16 
also are common (5). These reports likely underestimate the risk of hypoglycemia in older adults 
17 
with T1D since they include individuals with the more prevalent type 2 diabetes in whom severe 
18 
hypoglycemic events are likely considerably less frequent than they are in individuals with T1D.   
19 
Current strategies for avoidance of hypoglycemia in older adults are insufficient. Unlike 
20 
treatment guidelines in younger individuals with T1D, guidelines for older adults with T1D are 
21 
focused on minimizing hypoglycemia rather than attempting to achieve low glycated hemoglobin 
22 
(HbA1c) levels (9; 10).  Despite these efforts, biochemical hypoglycemia occurs frequently and 
23 
severe hypoglycemia (SH) occurs more often in older than younger adults with T1D. Data from 
24 
the T1D Exchange registry has shown a remarkably high frequency of SH in older adults with 
25 
longstanding T1D: 18% of registry participants >60 years old reported seizure or loss of 
26 
consciousness due to hypoglycemia in the prior 12 months (11). In addition, T1D Exchange 
27 
registry data indicate that SH is just as common with HbA1c levels >8.0% as it is for HbA1c 
28 
levels <7.0% (11). A prior study we conducted within the T1D Exchange (12) of 201 adults ≥60 
29 
years old with T1D duration ≥20 years (101 with SH in the prior year and 100 without SH in the 
30 
prior 3 years) found that glucose concentrations measured with blinded continuous glucose 
31 
monitoring (CGM) were <70 mg/dL for a median of 91 minutes per day. Furthermore, mean 
32 
HbA1c was similar in the individuals who had experienced SH in the prior year compared with 
33 
those who had not experienced SH in the prior 3 years (7.8% versus 7.7%). These data in 
34 
addition to the T1D exchange registry data do not support the strategy of “raising the HbA1c” as 
35 
being a desirable or effective approach for hypoglycemia prevention in older adults with T1D. 
36 
Hypoglycemia impacts quality of life (QOL). Poor glycemic control, including frequent 
37 
hypoglycemia, has adverse effects on QOL of both the individuals with T1D (13; 14) and their 
38 
families (15). In fact, hypoglycemia has a stronger impact than diabetes complications on QOL 
39 
in older adults (16). Hypoglycemic episodes and hypoglycemia fear limit participation in 
40 
activities that are beneficial to emotional, cognitive and physical well-being (e.g., exercise, 
41 
socializing, and travelling). Diabetes-related distress (i.e., the emotions, stresses and worries 
42 
associated with diabetes) is also an important component of QOL for people with T1D and is 
43 
associated with poor glycemic control, longer duration of diabetes, higher rates of depression, 
44 
and SH (17). Automated insulin delivery (AID) systems hold promise for improving QOL via 
45 
reductions in hypoglycemia. However, there are also possible adverse QOL impacts of advanced 
46 
diabetes technologies that may limit uptake of these systems (18; 19).  
47 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Older adults with T1D have unique needs. The prevalence of hypoglycemia unawareness, or 
48 
the loss of physiological symptoms associated with low blood glucose, is remarkably high in 
49 
older adults with recent SH, with 58% of those with SH within the prior year having 
50 
hypoglycemic unawareness compared with 25% in those with no SH in the prior 3 years (12). 
51 
Furthermore, glycemic variability is greater for those having experienced SH within the prior 
52 
year. Aging is associated with normative decline in cognitive functioning that may impact 
53 
diabetes self-management and contribute to hypoglycemia risk. In addition, older adults with 
54 
T1D have high rates of mild cognitive impairment (48% of those >60 years old (20), and 
55 
cognitive impairment is associated with hypoglycemia unawareness and recent SH (20; 21). 
56 
Further, we previously found that psychomotor processing speed, fine motor dexterity and 
57 
executive functioning were poorer in older adults with SH in the past year (12) and was 
58 
associated with simulated diabetes self-management skill (22). Thus, older adults with T1D may 
59 
have more difficulty with the cognitive demands of diabetes self-management, coupled with high 
60 
glycemic variability and hypoglycemia unawareness, that all contribute to hypoglycemia (21; 
61 
23). AID has the potential to reduce the cognitive burden of daily diabetes management 
62 
decisions, thereby improving overall control in those with diminished cognitive resources. 
63 
Conversely, learning and adopting new technologies and trouble-shooting component failures 
64 
may be overwhelming for older adults with cognitive decline. Thus, it is imperative to assess 
65 
whether automation of insulin delivery can be successfully implemented into diabetes 
66 
management of older adults with and without cognitive impairment.  
67 
1.1.2 Predictive Low-Glucose Suspend Systems 
68 
Many episodes of SH occur during the night, specifically during sleep (24; 25).  Even with the 
69 
advent of real-time CGM, patients do not awaken to over 70% of nocturnal alarms (26). Studies 
70 
have demonstrated that using a CGM device with a hypoglycemic prediction algorithm to 
71 
suspend basal insulin delivery when hypoglycemia is predicted is both safe and effective (27-29).  
72 
The suspension of insulin delivery when glucose is declining to prevent hypoglycemia was one 
73 
of the first steps towards the development of an artificial pancreas. The first PLGS system was 
74 
the Medtronic 640G which received approval outside of the US in 2015 after results showed the 
75 
device to be safe and effective in reducing hypoglycemia (30). The first large RCT of the PLGS 
76 
algorithm that was ultimately implemented in the Tandem Basal-IQ pump, published in 2013, 
77 
showed a reduction in overnight hypoglycemia of about 50% (27). The Tandem Basal-IQ PLGS 
78 
system, planned for this proposed study, received FDA approval in 2018 following results of a 
79 
pivotal trial showing significant reduction in hypoglycemia with PLGS use (see Section 1.7 
80 
Preliminary Results). 
81 
 
82 
1.1.3 Hybrid Closed Loop Systems 
83 
Hybrid closed loop (HCL) systems are a further step towards reducing the burden of diabetes 
84 
management through the development of an artificial pancreas. These systems are classified as 
85 
“hybrid” due to the fact that users still need to bolus for carbohydrate intake; however, basal 
86 
insulin delivery is modulated without user input based on sensor glucose readings. Specifically, 
87 
the various systems decrease insulin delivery when a patient’s sensor glucose is predicted to be 
88 
low and increase insulin delivery when a patient’s sensor glucose is predicted to be high. Several 
89 
years of HCL studies conducted for short durations with intense remote monitoring and study 
90 
staff support for enrolled patients led to the first pivotal trial of the Medtronic 670 G system. 
91 
This system was the first to be approved in the US in September 2016 following the single arm 
92 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
clinical trial conducted in 2015/2016. This study enrolled 124 subjects with T1D of which 30 
93 
were age 14-21 years and the rest 22-75 years with mean 44 ± 12 years.  There were ~ 10 
94 
subjects age ≥ 65 years in this study.  Time spent < 70 mg/dL was reduced from 90 to 49 minutes 
95 
in the adult cohort (p<.001) with A1c reduction from 7.3 % to 6.8 % (p<.001) (31).  Currently, 
96 
Medtronic is conducting a study randomizing subjects to 670 G HCL that includes older adults, 
97 
but it is not focused on hypoglycemia.  Subjects being enrolled are up to 80 years old.  Another 
98 
HCL algorithm was developed at Cambridge University and has been tested in a series of studies 
99 
referred to as APCAM. Results of the at home study of APCAM HCL algorithm were published 
100 
in Lancet in October 2018 and showed significant improvement in time in range in the HCL 
101 
group compared with control as well as a reduction in hypoglycemia (% < 70 mg/dL) (32).  In 
102 
2011, the Diabetes Assistant (DiAs) was developed – a smart-phone multi-use platform designed 
103 
at the University of Virginia (UVA) to operate in several treatment modes ranging from CGM or 
104 
insulin pump support to overnight and 24/7 HCL (33). Since its introduction in 2011, DiAs has 
105 
earned regulatory approvals in the U.S., France, Italy, Netherlands, and Israel; 3 different control 
106 
algorithms have been implemented on the DiAs platform and used in approximately 20 clinical 
107 
trials, including long-term studies at home.  
108 
The Tandem X2 insulin pump with Control-IQ Technology is a third-generation HCL 
109 
system retaining the same control algorithm that was initially tested by UVA’s DiAs system and 
110 
then implemented in the inControl system (33-36).  The pivotal trial for the Tandem Control-IQ 
111 
was published in the New England Journal of Medicine in October 2019 (37). This 6-month 
112 
randomized trial included 168 patients age 14 to 71 years with 112 assigned to use HCL 
113 
(Tandem Control-IQ) and 56 sensor augmented pump (SAP) therapy. Participants in the HCL 
114 
group had significant improvements in time in target glucose range of 70 to 180 mg/dL as well 
115 
as significant reductions in time spent in hypoglycemia (< 70mg/dL and <54mg/dL) and time 
116 
spent in hyperglycemia (>180mg/dL). The Tandem X2 pump with Control-IQ technology 
117 
received FDA approval on December 13, 2019. 
118 
 
119 
1.1.4 Quality of Life Outcomes in Automated Insulin Delivery Trials 
120 
There is increasing recognition that positive glycemic outcomes with AID systems may not 
121 
necessarily be indicative of positive user experiences. Thus, it is important to assess psychosocial 
122 
and QOL impacts of AID systems (18; 19; 38; 39). Early systems were evaluated under artificial 
123 
conditions (e.g., diabetes camp, inpatient or supervised hotel), in very small samples and for 
124 
relatively short durations (typically under 1 week), making evaluation of QOL impacts difficult. 
125 
Nonetheless, AID systems do appear to be associated with a generally positive user experience 
126 
(40), including reduced diabetes management distress and improved attitudes towards diabetes 
127 
technology (41). However, significant barriers have also been identified, including variable trust 
128 
in the system, physical bulk, technical glitches and incorporation in daily life (40). As a result, it 
129 
is possible that many patients may prefer a PLGS-only AID system compared with an HCL 
130 
system. While our understanding of patient expectations of and experiences with AID systems is 
131 
increasing, there continues to be very little data, especially with prolonged outpatient use (18). 
132 
This is particularly true for the older adult population, as there is no available published data on 
133 
the user experience and QOL impacts of AID in older adults.  
134 
 
135 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
1.2 Rationale 
136 
Automated insulin delivery (AID) technologies hold the promise of optimizing glycemic control 
137 
and reducing the burden of diabetes care for patients with Type 1 Diabetes (T1D). However, 
138 
clinical trials of lower burden AID technologies have not included older adults in sufficient 
139 
numbers to allow for focused evaluation of efficacy and quality of life (QOL) impacts that may 
140 
differ from those observed in younger age groups. Most notably, primary endpoints have focused 
141 
on reducing hyperglycemia, while avoidance of hypoglycemia is of upmost concern for older 
142 
adults with T1D. T1D Exchange clinic registry data have shown severe hypoglycemia (SH) 
143 
occurs more commonly in older adults with longstanding T1D than in younger individuals with 
144 
events occurring just as often with HbA1c levels >8.0% as with HbA1c levels <7.0%. These data 
145 
do not support the strategy of “raising the HbA1c” as being an effective approach for 
146 
hypoglycemia prevention in older adults with T1D. In addition to acutely altered mental status, 
147 
hypoglycemia is associated with an increased risk for falls leading to fractures, car accidents, 
148 
emergency room (ER) visits, hospitalizations, and mortality resulting in substantial societal 
149 
costs. The occurrence of hypoglycemia, hypoglycemia unawareness and fear of hypoglycemia 
150 
have adverse effects on overall QOL of both individuals with T1D and their families. 
151 
 
152 
While continuous glucose monitoring (CGM) technology alone has been shown to be beneficial 
153 
in reducing hypoglycemia in older patients, our data from the Wireless Innovations for Seniors 
154 
with Diabetes Mellitus (WISDM) trial shows a majority of patients still have frequent 
155 
hypoglycemia even when using CGM (42). Thus, knowledge of CGM alone may not be 
156 
sufficient to avoid hypoglycemia in this population. Predictive low-glucose suspend algorithms 
157 
have particular promise when the primary goal is hypoglycemia avoidance rather than glucose 
158 
reduction. Whether the added complexity of closed loop systems provides additional glycemic 
159 
benefit is not known. There is a critical need to determine whether automated insulin delivery 
160 
can reduce hypoglycemia in the older adult population with T1D.    
161 
 
162 
1.3 Potential Risks and Benefits 
163 
1.3.1 Known Potential Risks 
164 
Fingerstick Risks 
165 
A fingerstick will be performed for measuring HbA1c. This is a standard method used to obtain 
166 
blood for routine blood glucose monitoring.  Pain may occur at the time of lancing, but is less 
167 
likely in patients with T1D who are used to frequent blood glucose monitoring.  In about 1 in 10 
168 
cases, a small amount of bleeding under the skin will produce a bruise.  A small scar may persist 
169 
for several weeks.  The risk of local infection is less than 1 in 1000.  This should not be a 
170 
significant contributor to risks in this study as fingersticks are part of the usual care for people 
171 
with diabetes. 
172 
 
173 
Venipuncture Risks 
174 
Blood draws can cause some common reactions like pain, bruising, or redness at the sampling 
175 
site. Less common reactions include bleeding from the sampling site, formation of a small blood 
176 
clot or swelling of the vein and surrounding tissues, and fainting. 
177 
 
178 
 
179 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Subcutaneous Catheter Risks (CGM and Insulin Pump) 
180 
There is a low risk for developing a local skin infection at the site of the sensor or infusion 
181 
catheter placement.  Itchiness, redness, bleeding, and bruising at the insertion site may occur as 
182 
well as local tape allergies.  Sensors may fracture in situ on rare occasions. In the rare instances 
183 
when this has occurred in the past, consulting physicians and surgeons have recommended not to 
184 
remove the wire fragment from beneath the skin as long as there are no symptoms of infection or 
185 
inflammation and allow the body to expel the foreign body on its own.  
186 
 
187 
Risk of Hypoglycemia 
188 
As with any person having type 1 diabetes and using insulin, there is always a risk for 
189 
experiencing low blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no 
190 
more and possibly less than it would be as part of daily living.  A CGM functioning poorly and 
191 
significantly over-reading glucose values could lead to inappropriate insulin delivery. 
192 
Participants will be instructed to always check sensor readings with a self-monitored blood 
193 
glucose measurement (fingerstick) if the sensor readings appear out of the expected range.   
194 
 
195 
Risk of Hyperglycemia 
196 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
197 
extended period or if the pump or infusion set is not working properly.  A CGM functioning 
198 
poorly and significantly under-reading glucose values could lead to inappropriate suspension of 
199 
insulin delivery.  Again, this risk is exceedingly low. As above, participants will be instructed to 
200 
always check sensor readings with a self-monitored blood glucose measurement (fingerstick) if 
201 
the sensor readings appear out of the expected range. 
202 
 
203 
Risks of Questionnaires 
204 
As part of the study, participants will complete psychosocial questionnaires which include 
205 
questions about their private attitudes, feelings and behavior related to diabetes.  It is possible 
206 
that some people may find these questionnaires to be mildly upsetting. Similar questionnaires 
207 
have been used in previous research and these types of reactions have been uncommon. Patients 
208 
are reminded that they can refuse to answer questions that they do not wish to answer.  Brief 
209 
cognitive performance assessment will be completed at baseline and at the end of the extension 
210 
phase.  These measures may cause transient anxiety or distress, although the selected measures 
211 
are commonly encountered in the context of routine medical care for older adults.  
212 
 
213 
Other Risks 
214 
There is a possible risk of unsecured communication during the phone or telehealth contacts.  In 
215 
our experience with AP studies, this has not happened.  
216 
 
217 
The study may include other risks that are unknown at this time. 
218 
1.3.2 Risk Assessment 
219 
Risk will be minimized by having participants be well informed about how to use the study 
220 
devices and how to avoid hypoglycemia and hyperglycemia. A procedure manual including 
221 
guidelines for risk management of hypoglycemia and hyperglycemia with each technology will 
222 
be developed prior to the start of the trial.  
223 
 
224 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
The protocol risk assessment for this study has been categorized as minor increase over minimal 
225 
risk. The Tandem t:slim X2 with Basal IQ technology and the Tandem t:slim X2 with Control IQ 
226 
technology are FDA approved.  
227 
 An investigational device exemption (IDE) from the U.S. Food and Drug Administration (FDA) 
228 
is not required to conduct this study in the US. For these reasons, this study is being considered a 
229 
non-significant risk device study. 
230 
 
231 
1.3.3 Known Potential Benefits 
232 
It is expected that CGM has an important role in the management of diabetes in older adults with 
233 
T1D. It is hoped that the HCL or PLGS technologies will reduce hypoglycemia more than just 
234 
CGM alone. Therefore, the results of this study are likely to be beneficial for older patients with 
235 
diabetes.   
236 
 
237 
It is possible that participants will not directly benefit from being a part of this study.  However, 
238 
it is also possible that the glucose information from the CGM and automated suspension of 
239 
insulin delivery will provide a direct benefit.  
240 
 
241 
1.4 General Considerations 
242 
The study is being conducted in compliance with the policies described in the study policies 
243 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
244 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
245 
When feasible, data will be directly collected in electronic case report forms, which will be 
246 
considered the source data. 
247 
1.5 Virtual Visits 
248 
Due to the highly vulnerable nature of this patient population in relation to the COVID-19 virus, 
249 
there is the option of virtual visit completion for certain visits. Virtual visits will take place using 
250 
the institution’s approved software for telehealth/telemedicine or via phone call when video is 
251 
not possible.  The procedures for virtual study visits that cannot be done virtually (such as height, 
252 
weight and blood pressure) will be missing. Height, weight and blood pressure during follow-up 
253 
is not considered to be key data but will be obtained when possible for exploratory analysis. 
254 
Weight from baseline data collection may be used for calculation of total daily insulin.  
255 
 
256 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 2: Study Enrollment and Screening 
257 
2.1 Participant Recruitment and Enrollment 
258 
Enrollment will proceed with the goal of at least 90 participants completing the crossover trial.  
259 
A maximum of 150 individuals may be enrolled in the study in order to achieve this goal. It is 
260 
expected that about 40 participants may be excluded based on eligibility criteria during the 
261 
screening/run-in period. Participants who have signed consent and started the screening process 
262 
may be permitted to continue into the trial, if eligible, even if the randomization goal has been 
263 
reached. 
264 
 
265 
Study participants will be recruited from 3 to 5 clinical centers in the United States of America.  
266 
All eligible participants will be included without regard to gender, race, or ethnicity.  
267 
 
268 
The recruitment goal for each site is the same (approximately 30 participants per site); however, 
269 
certain sites may recruit additional participants to meet the overall recruitment goal. Each site 
270 
will aim to have at least 33% of their enrolled participants not currently using CGM, at least 33% 
271 
using multiple daily injections and at least 33% using insulin pump at the time of enrollment. 
272 
Across all sites the study will aim to enroll approximately 30% of participants with mild to 
273 
moderate cognitive impairment.  
274 
 
275 
2.1.1 Informed Consent and Authorization Procedures 
276 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing 
277 
any procedures or collecting any data that are not part of usual care, written informed consent 
278 
will be obtained. 
279 
The study protocol will be discussed with the potential study participant by study staff.  The 
280 
potential study participant will be given the Informed Consent Form to read.  Potential study 
281 
participants will be encouraged to discuss the study with family members and their personal 
282 
physicians(s) before deciding whether to participate in the study. 
283 
Participants who lack capacity, such that they would require the use of a legally authorized 
284 
representative, shall not be enrolled in this study due to the level of self-management required by 
285 
the participants including device set-up and use and questionnaire completion. 
286 
A consent understanding assessment consisting of 5 true/false questions about content in the 
287 
consent will be given to the participant to confirm understanding of the informed consent and 
288 
study procedures. Patients who do not answer 4 out of 5 questions correctly will have the consent 
289 
form reviewed with them again and will repeat the understanding assessment. Patients who are 
290 
not able to successfully complete the understanding assessment after two attempts will not sign 
291 
consent and not be enrolled in the study.  
292 
As part of the informed consent process, each participant will be asked to sign an authorization 
293 
for release of personal information.  The investigator, or his or her designee, will review the 
294 
study-specific information that will be collected and to whom that information will be disclosed.  
295 
After speaking with the participant, questions will be answered about the details regarding 
296 
authorization. 
297 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
A participant is considered enrolled when the informed consent form has been signed. A copy of 
298 
the informed consent form will be provided to the participant and another copy will be added to 
299 
the participant’s study record. 
300 
As an option, study staff can orally present the consent to potential participants over the phone 
301 
rather in person due to the highly vulnerable nature of this patient population in relation to the 
302 
COVID-19 virus. The procedures for administration are described in the study procedures 
303 
manual. 
304 
2.2 Participant Inclusion Criteria 
305 
Individuals must meet all the following inclusion criteria in order to be eligible to participate in 
306 
the study. 
307 
1) Clinical diagnosis of type 1 diabetes  
308 
2) Age ≥ 65 years old 
309 
3) T1D Duration of at least 1 year 
310 
4) HbA1c < 10.0% from point of care or local lab  within the past 6 months 
311 
5) Insulin regimen involves basal/bolus insulin via insulin pump or multiple daily injections  
312 
6) Most recent GFR ≥ 30 ml/min/m2 from local lab within the past 6 months 
313 
7) Willingness to use a rapid acting insulin compatible with the Tandem t:slim X2 pump 
314 
(currently aspart and lispro; other rapid acting insulins likely to be approved for pump use 
315 
prior to study initiation such as Fiasp) 
316 
8) Familiarity with and willingness to use a carbohydrate ratio for meal boluses 
317 
9) Willing to use study devices and automated insulin delivery features  
318 
10) Ability to download study devices at home or if not able to download at home willing to 
319 
come into clinic to bring devices for download of data at visits and as needed for safety 
320 
11) Participant is independently managing his/her diabetes with respect to insulin administration 
321 
and glucose monitoring (may include assistance from spouse or other caregiver) 
322 
12) Participant understands the study protocol, agrees to comply with it and is able to 
323 
successfully pass the consent understanding assessment with no more than 2 attempts.  
324 
13) Participant comprehends written and spoken English  
325 
14) At least 240 hours of CGM readings available during the end of run-in assessment 
326 
15) At least 1.5% of time with CGM glucose levels < 70 mg/dL prior to SAP initiation 
327 
16) Activeprescription for glucagon and willing and able to have glucagon available  
328 
2.3 Participant Exclusion Criteria 
329 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from 
330 
study participation. 
331 
1) Use of PLGS technology or HCL insulin delivery in the past 1 month 
332 
2) History of 1 or more Diabetic Ketoacidosis episodes in the previous 6 months 
333 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
3) Clinical diagnosis by a primary care provider, neurologist or psychiatrist of dementia, in the 
334 
investigator’s opinion a suspected severe cognitive impairment such that it would preclude 
335 
ability to understand the study or use devices, or a score of 6 or less out of 15 on the 5 min 
336 
MoCA (5-min T MoCA Version 2.1) (mild cognitive impairment is not an exclusion)  
337 
4) A condition, which in the opinion of the investigator or designee, would put the participant or 
338 
study at risk, including severe vision or hearing impairment and any contraindication to the 
339 
use of any of the study devices per FDA labeling  
340 
5) Known adhesive allergy or skin reaction during the run-in pre-randomization phase or previous 
341 
difficulty with pump and CGM insertions that would preclude participation in the randomized 
342 
trial 
343 
6) Concurrent use of any non-insulin glucose-lowering agent other than metformin (including 
344 
GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas) 
345 
7) Stage 4 or 5 renal disease   
346 
8) The presence of a significant medical or psychiatric condition or use of a medication that in 
347 
the judgment of the investigator may affect completion of any aspect of the protocol, or is 
348 
likely to be associated with life expectancy of <1 year 
349 
2.4 Screening Procedures 
350 
After the informed consent or short form has been fully signed, a potential participant will be 
351 
evaluated for study eligibility through the elicitation of a medical history, performance of a 
352 
physical examination by study personnel (when possible) and local laboratory testing if needed 
353 
to screen for exclusionary medical conditions. The screening visit should take place within 30 
354 
days of obtaining informed consent.  A local HbA1c measurement will be obtained if not already 
355 
obtained as part of usual care within the prior 6 months of the screening visit. A serum creatinine 
356 
for estimation for GFR will be obtained if one is not available within the previous 6-months. The 
357 
5-min MoCA should be completed prior to performing any other screening procedures to 
358 
confirm eligibility.  
359 
 
360 
2.4.1 Data Collection and Testing 
361 
The following procedures will be performed/data collected/eligibility criteria checked and 
362 
documented: 
363 
• Inclusion and exclusion criteria assessed 
364 
• Demographics (socioeconomic status, date of birth, sex, race and ethnicity) 
365 
• Contact information (retained at the site and not entered into study database) 
366 
• Medical history 
367 
• Diabetes history 
368 
• Concomitant medications 
369 
• Fingerstick or blood draw for: 
370 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
o HbA1c level measured using a point-of-care device or local lab will be used to assess 
371 
eligibility unless a historical value is available within 6 months of enrollment 
372 
o GFR if not available in medical record in previous 6 months 
373 
• Testing and Assessments will include the following:  
374 
o 5-min T MoCA  – perform as first screening procedure 
375 
o Hypoglycemic Awareness 
376 
o Patient Reported Outcome Questionnaires completed online (or paper if online not 
377 
possible); May be completed at time of screening visit or any time at home prior to 
378 
randomization.  
379 
▪ Functional Activities Questionnaire 
380 
▪ Hypoglycemia Fear Survey (HFS-II) 
381 
▪ Hypoglycemia Confidence Scale 
382 
▪ T1D Diabetes Distress Scale (DDS) 
383 
▪ Prospective Retrospective Memory 
384 
▪ Barkley Deficits in Executive Function Scale (BDEFS) 
385 
Screening procedures will last approximately 1-2 hours. 
386 
 
387 
2.5 Screen Failures 
388 
Participants determined to be ineligible during screening visit, with lab values out of range 
389 
(HbA1c or GFR if done at screening visit)  or who score a 6 or less on the 5-min T MoCA will 
390 
be withdrawn from the study.  
391 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
392 
date per investigator discretion.  
393 
 
394 
2.6 Eligible Participants 
395 
Individuals who meet eligibility criteria will proceed to the Run-In Phase. 
396 
 
397 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 3: Run-in Training Phase 
398 
3.1 Introduction 
399 
There are four parts of the run-in phase: 
400 
1) Start of Run-In – takes place on same day as screening or within 14 days 
401 
2) CGM Training Period – consists of a training visit and repeat training as needed 
402 
3) SAP Training Period – consists of SAP initiation visit and contacts with additional visits for 
403 
training as needed 
404 
a. If the participant is a CGM user the screening, start of run-in and SAP initiation visits 
405 
can take place on the same day if able to be in clinic to complete all procedures 
406 
4) SAP Evaluation – use of devices will be evaluated prior to initiating cross-over trial. May be 
407 
repeated if additional training needed.  
408 
 
409 
The length of the run-in phases may vary depending on prior experience with devices. Eligible 
410 
participants may complete the CGM training period and the SAP training period or may skip one 
411 
or both based on the participants’ device use at the time of enrollment, as described below.  
412 
 
413 
Table 3. CGM and SAP Training Periods Criteria 
414 
 
CGM Use 
(Real-time 
CGM only, 
does not 
include flash 
monitoring) 
Use of Tandem 
t:slim X2 pump 
CGM Training 
Period:10-30 
days 
(Includes 10-day 
CGM training 
visit and re-
training as 
needed) 
SAP Training 
Period: 14-28 days 
(Includes SAP 
initiation visit and 
training phone 
calls with 
additional training 
as needed) 
SAP Evaluation  
(Repeated if 
additional SAP 
training 
needed) 
Device Use 
YES 
YES 
Skip per 
investigator’s 
discretion 
Required 
Required 
YES 
NO 
Skip per 
investigator’s 
discretion 
Required 
Required 
NO 
YES 
Required 
Required 
Required 
NO 
NO 
Required 
Required 
Required 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
 
415 
3.2 Start of Run-In Visit (Same day as screening or within 14 days) (virtual or in-clinic) 
416 
3.2.1 Participants using CGM at Screening 
417 
• If the CGM device is able to be downloaded study personnel will assess whether the 
418 
participant has at least 1.5% of sensor glucose values <70 mg/dL (average of ~30 minutes 
419 
per day). 
420 
o Participants with < 1.5% of time spent with glucose levels < 70 mg/dL will be 
421 
excluded in order to ensure all participants have the possibility to reduce 
422 
hypoglycemia during the intervention periods.   
423 
• The study Dexcom G6 CGM will be given to the participant and they will receive 
424 
training on the study device similar to what is described below for those not using CGM.  
425 
• Participant will proceed to SAP initiation visit (see section 3.4) which may take place on 
426 
same day if screening/start of run-in visit is in-clinic or within 14-days. 
427 
3.2.2 Participants not using CGM at screening/start of run-in  
428 
• Participants will initiate using the study CGM and will receive initial training on its use. 
429 
• Standardized CGM training will be provided using a training checklist and training 
430 
materials will be provided to study participants. The study team will assist the participant 
431 
with sensor insertion and calibration (as needed). Each participant will be asked to use a 
432 
CGM sensor on a daily basis, inserting a new sensor as needed.  Participants will be 
433 
instructed to use the sensor according to FDA labeling. In addition, participants will be 
434 
provided guidelines for when to confirm the CGM reading with a home BGM value 
435 
including when hypo/hyperglycemia symptoms are discrepant from the CGM reading or 
436 
if there are other reasons to doubt the CGM reading. 
437 
• A second CGM training visit will occur in approximately 10 days and may be repeated if 
438 
additional training needed prior to proceeding with SAP initiation.  
439 
 
440 
3.3 CGM Training Visit (virtual or in-clinic) 
441 
• Additional CGM training will take place using standardized materials. 
442 
• A skin assessment (via virtual video when possible) will be made where sensors were 
443 
worn to be sure that the participant tolerates the sensor well enough to enter the 
444 
randomized trial.   
445 
• The participant will be provided with additional sensors to wear at home for up to 20 
446 
days  
447 
• Next visit is the SAP Initiation Visit 
448 
 
449 
3.4 SAP Initiation Visit (Required In-clinic Visit) 
450 
• Participants who haven’t been evaluated for minimum hypoglycemia requirement (non-
451 
CGM users at start of run-in) will be evaluated at the beginning of this visit. Study 
452 
personnel will assess whether the participant has at least 1.5% of sensor glucose values 
453 
<70 mg/dL (average of ~30 minutes per day). 
454 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
o Participants with < 1.5% of time spent with glucose levels < 70 mg/dL will be 
455 
excluded in order to ensure all participants have the possibility to reduce 
456 
hypoglycemia during the intervention periods.   
457 
• Participants will be provided with the Tandem t:slim X2 Basal-IQ study pump integrated 
458 
with the study Dexcom G6 CGM with Basal-IQ feature turned OFF  
459 
• Participants will be provided the Abbott Precision Xtra Meter and blood ketone strips to 
460 
measure blood ketone levels as indicated.  
461 
o Participants will be instructed on how to perform blood ketone testing per 
462 
manufacturer guidelines. 
463 
o Participants will be given a handout outlining when to check ketones and 
464 
treatment action plan for elevated blood ketones. 
465 
• Standardized device training will be provided using a training checklist and training 
466 
materials will be provided to study participants.  
467 
o For participants currently on insulin pump therapy, the Tandem SAP will be 
468 
programmed so that basal insulin delivery and other settings match the 
469 
participant’s personal pump settings. If appropriate, the pump settings will be 
470 
optimized based on study investigator review of downloaded SAP data. 
471 
o For participants not currently on insulin pump therapy, an initial basal insulin 
472 
profile will be customized on a per-participant basis. Total daily insulin dose will 
473 
be reduced by approximately 20% as a general rule, with a recommended method 
474 
outlined in a separate procedure manual.  
475 
o Further adjustments to total daily dose and intraday basal rate profile may be 
476 
made during the course of the SAP Training Period. 
477 
o Participants will be provided with a study account for t:connect and trained on 
478 
how to upload the devices.   
479 
• A standard physical exam will be performed by the study investigator or designee (a 
480 
physician, fellow, nurse practitioner or a physician assistant). 
481 
o Can be performed by clinic staff: 
482 
▪ Weight, height  
483 
▪ Vital signs including measurement of blood pressure and pulse 
484 
• A blood draw for measurement of central lab HbA1c and C-peptide will be performed.   
485 
• Frailty assessment using 10-foot timed walk 
486 
• Cognitive Assessment (See Chapter 8) 
487 
• Participants will be contacted 1 (±1 day) and 7 (±3 days) days following initiation of 
488 
SAP.   
489 
• A SAP Evaluation Visit will occur 14 -21 days following initiation of SAP  
490 
o The SAP training contacts and SAP evaluation visit may be repeated if needed for 
491 
additional training on study devices prior to initiating cross-over trial 
492 
 
493 
3.5 SAP Evaluation Visit (virtual or in-clinic) 
494 
• The CGM data will be downloaded to assess whether the participant has at least 240 
495 
hours of sensor data during the run-in. 
496 
o Participants not meeting the CGM compliance requirement may be given a 
497 
second opportunity to be evaluated. 
498 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
▪ Participants who are unable to meet the CGM usage requirements after the 
499 
second opportunity will be dropped from the study and not enter the 
500 
randomized trial. 
501 
• Participants needing additional training should receive training at the SAP Evaluation 
502 
visit and then repeat the SAP run-in period with a contact 7 days later and SAP 
503 
Evaluation Repeat Visit in ~ 14 days 
504 
 
505 
3.6 Device Data Uploads 
506 
Device data will be downloaded at each visit.  Participants will be trained on how to upload 
507 
devices from home. Participants who are unable to download devices from home will need to 
508 
come to clinic to have device downloaded at study visits/contacts or as needed for safety reasons. 
509 
 
510 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 4: Randomization & Start of Period 1 Visit 
511 
Once a study participant is randomized, that participant will be counted regardless of whether the 
512 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an 
513 
individual until he/she is convinced that the individual is eligible and willing to follow the study 
514 
period order and comply with each treatment arm. 
515 
 
516 
4.1 Randomization  
517 
• Randomization on the study website will take place after the SAP Evaluation visit and 
518 
may occur on the same day or within 7 days.   
519 
• Eligibility criteria from screening will be reviewed again and if the participant is no 
520 
longer eligible based on these criteria, the participant will be dropped from the study 
521 
prior to randomization. 
522 
• Investigators will be responsible for signing off on all CRFs and edits that occurred 
523 
prior to randomization BEFORE the randomization form is submitted.  
524 
 
525 
The main phase of the study, a 36-week randomized crossover trial, will consist of three 12-week 
526 
periods. The three treatment periods consist of HCL, PLGS and SAP. 
527 
 
528 
Participant randomization assignment is determined after the Randomization Prompt is submitted 
529 
on the study website. The data from this visit and where applicable, prior visits, are assessed to 
530 
verify eligibility prior to the randomization process being completed. 
531 
 
532 
Following confirmation of eligibility and successful completion of run-in participants will be 
533 
randomly assigned with equal probability (stratified by clinical site) to one of the following 
534 
treatment period orders: 
535 
(A) HCL in period 1, PLGS in period 2, SAP in period 3 
536 
(B)  HCL in period 1, SAP in period 2, PLGS in period 3 
537 
(C)  PLGS in period 1, HCL in period 2, SAP in period 3 
538 
(D) PLGS in period 1, SAP in period 2, HCL in period 3 
539 
(E)  SAP in period 1, HCL in period 2, PLGS in period 3  
540 
(F)  SAP in period 1, PLGS in period 2, HCL in period 3  
541 
 
542 
The following devices will be used for each period: 
543 
• During the HCL period participants will use the Tandem t:slim X2 pump with Control IQ 
544 
• During the PLGS period participants will use the Tandem t:slim X2 pump with Basal IQ 
545 
• During the SAP period participants will use the Tandem t:slim X2 pump with Basal IQ 
546 
feature turned OFF 
547 
 
548 
4.2 Start of Period 1 
549 
The Start of Period 1 visit should take place on same day as randomization.  
550 
 
 
551 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
 
552 
Chapter 5: Crossover Trial 
553 
5.1 Start of Period Visit 
554 
The Start of Period 1 visit should take place on same day as randomization. The Start of Period 2 
555 
and Period 3 visits should take place on same day as End of Period visit for previous period. See 
556 
windows in 5.1.2. 
557 
5.1.1 HCL or PLGS System Training 
558 
Potential participants will be encouraged to involve a significant other in their care/training or 
559 
invite anyone who is currently involved in their diabetes care. The participant and 
560 
partner/caregiver (if warranted) will be trained by qualified staff on user interface, alarms, meal 
561 
blousing, and exercise using standardize training materials and checklists.  Training on severe 
562 
hypoglycemia emergency procedures including removal of the study pump and administration of 
563 
glucagon also will be provided following standard clinic practices. 
564 
 
565 
Participants will be provided with a handout summarizing tips and guidelines for use of the 
566 
devices and safety measures.  
567 
 
568 
Study team members will train the participant and care partner on specific tasks including the 
569 
following: 
570 
• The study team will confirm the pump and sensor parameters entered in the system 
571 
• CGM calibration instructions (as needed) 
572 
• Meal bolus procedures 
573 
• What to do when exercising while using the system 
574 
• The participant and care partner will be assessed for understanding how to react to 
575 
safety/alert notifications 
576 
• Device data upload instructions 
577 
• Participants will be reminded to perform fingerstick blood glucose measurements in 
578 
accordance with the labeling of the study CGM device  
579 
• Participants will be instructed when to contact study staff and provided with contact 
580 
information to ask any questions they may have during the study 
581 
 
582 
Study staff will discuss the visit schedule with the participant and will make arrangements with 
583 
the participant for each visit.  If the participant cannot be reached, the participant’s other contact 
584 
methods will be utilized. Participants will be trained on how to upload devices to be able to do 
585 
this from home for study contacts and virtual visits. Participants who are not able to upload 
586 
device data from home will need to come to the clinic for the device download for each visit and 
587 
as needed for safety reasons.  
588 
 
589 
5.1.2 Study Visits and Contacts for Periods 1, 2 and 3 
590 
During each period a virtual or in-clinic visit will occur at 4 weeks with an end of period/start of 
591 
new period virtual or in-clinic visits occurring at 12 weeks. Study contacts (via phone or 
592 
telehealth) will occur at 2 and 8 weeks. The study contacts and visits may be completed remotely 
593 
(phone call or virtual visit) or in person at participant, investigator and study coordinator 
594 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
discretion. Virtual visits will take place using the institution’s approved software for 
595 
telehealth/telemedicine when possible or by phone if video not feasible. Additional contacts or 
596 
visits may occur as needed: 
597 
 
598 
Visit 
Target Day/Week 
Target Window 
(around Target 
Day/Week) 
Allowable Window 
(around Target 
Day/Week) 
Start of Period (1, 
2, 3) 
Randomization or End 
of Previous Period 
N/A 
+ 7 days 
2-week contact 
Randomization Visit 
Date + 14 days or End 
of Previous Period 
Date + 14 days 
+4 days 
± 7 days 
4-week visit 
Randomization Visit 
Date + 28 days or End 
of Previous Period 
Date + 28 days 
± 7 days 
± 14 days 
8-week contact 
Randomization Visit 
Date + 56 days or End 
of Previous Period 
Date + 56 days 
± 7 days 
± 21 days 
End of Period 1, 2, 
3 
12-week visit  
Randomization Visit 
Date + 84 days or End 
of Previous Period 
Date + 84 days 
± 7 days 
± 21 days 
 
599 
The goal will be for all participants to complete all scheduled visits.  However, participants who 
600 
(because of unforeseen circumstances) are unable or unwilling to return for all follow-up visits 
601 
will be permitted to return for key visits only as an alternative to withdrawal from the study.  
602 
When a participant is placed into this status, missed visits will not be recorded as protocol 
603 
deviations (since they would not be recorded as protocol deviations if the participant was 
604 
dropped from the study). 
605 
 
606 
5.1.3 Procedures during Study Periods 
607 
5.1.3.1 Procedures Performed during Each Contact and 4-week period visits 
608 
• The participant will be asked to upload device data for study staff review (participants not 
609 
able to upload may be asked to come to the study clinic for a device download) 
610 
• Assessment of compliance with study device use 
611 
• Answer questions about using the system 
612 
• Assessment of adverse events, adverse device effects, and device issues 
613 
• Review of glycemic control 
614 
 
615 
5.1.3.2 Procedures Performed during Each End of Study Period Follow-up Visit 
616 
Procedures listed below should be completed at the end of Periods 1, 2 and 3 (prior to start of 
617 
next period): 
618 
• Assessment of compliance with study device use 
619 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
• Retraining on system use as needed 
620 
• Assessment of adverse events, adverse device effects, and device issues 
621 
• Download of system data 
622 
• Capillary or venous collection of a blood sample to send to the central laboratory for 
623 
HbA1c determination (completed in-clinic or at home for virtual visits) 
624 
o Clinical site will provide at home HbA1c kits to participants 
625 
• Assessment of hypoglycemia unawareness 
626 
• Completion of Questionnaires -electronically or on paper if needed 
627 
o Hypoglycemia Fear Survey (HFS-II) 
628 
o Hypoglycemia Confidence Scale 
629 
o T1D Diabetes Distress Scale (DDS)  
630 
o System Usability Scale 
631 
o AIDE Technology Acceptance 
632 
 
633 
Following the completion of the end of period visit procedures, participants will be trained on the 
634 
PLGS or HCL user interface if initiating during the next study period as part of the Start of 
635 
Period visit. 
636 
 
637 
5.1.3.3 Device Data Uploads During the Crossover Trial 
638 
Device data will be downloaded during each follow-up visit.  Participants will upload devices 
639 
from home for study contacts and virtual visits. Participants without access to a computer or who 
640 
in the study staff opinion would struggle with the upload of the device may need to come to the 
641 
clinic for the study contacts and virtual visits to have devices downloaded. 
642 
 
643 
5.1.4 Early Termination Visit 
644 
If a participant discontinues the study early, an attempt will be made to have the participant 
645 
complete an end of study visit to record any adverse events or device issues that have occurred, 
646 
complete final questionnaires, and collect a final HbA1c. Study devices should be returned to the 
647 
clinic. 
648 
 
649 
Every effort will be made to keep all participants in the trial through each 12-week period. 
650 
Participants who discontinue device use or initiate non-study treatment will be encouraged to 
651 
remain in the study.  
652 
 
653 
5.1.5 Unscheduled Visits 
654 
An Unscheduled Visit Form will be completed for any contact or visit the participant has with 
655 
the site for significant protocol-related issues/questions outside the visit and contact schedule. 
656 
 
657 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 6: Extension Study 
658 
6.1 Study Procedures During the Extension Study 
659 
Following the completion of the last study period, participants will enter a 3-month extension 
660 
phase where they will be given the opportunity to choose to use either HCL, PLGS or SAP. 
661 
Participants will be asked to choose their preferred technology at the start of the extension phase 
662 
and will be permitted to change the technology being used at any time during the 3-month 
663 
period. 
664 
 
665 
6.1.1 End of Study Visit (Required In-clinic Visit) 
666 
At the end of the 3-month period, an end of study visit will occur. 
667 
 
668 
Procedures listed below will be completed at the end of study visit: 
669 
• Venous or capillary collection of a blood sample to send to the central laboratory for 
670 
HbA1c determination  
671 
• Download of system data 
672 
• Assessment of hypoglycemia unawareness 
673 
• Completion of Patient Reported Outcome Questionnaires 
674 
o Hypoglycemia Fear Survey (HFS-II) 
675 
o Hypoglycemia Confidence Scale 
676 
o T1D Diabetes Distress Scale (DDS)  
677 
o System Usability Scale 
678 
o AIDE Technology Acceptance 
679 
o Functional Activities Questionnaire 
680 
o Prospective Retrospective Memory 
681 
o Barkley Deficits in Executive Function Scale (BDEFS) 
682 
 
683 
• Completion of cognitive assessments 
684 
• Assessment of adverse events, adverse device effects, and device issues 
685 
 
686 
Additional unscheduled visits and contacts can be made. 
687 
 
 
688 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 7: Study Devices and Safety 
689 
7.1 Description of the Study Devices 
690 
7.1.1 Insulin Pump 
691 
The system proposed for use in this study is comprised of a CGM sensor and transmitter along 
692 
with an insulin pump with user interface (UI) for display of system information. 
693 
 
694 
The insulin pump used in the study is the Tandem t:slim X2 pump, which is an FDA-approved 
695 
device with no changes to its hardware or firmware components. The SAP/control arm will 
696 
utilize the Tandem t:slim X2 pump without HCL or PLGS features activated.     
697 
The PLGS intervention arm will utilize the Tandem t:slim X2 pump with Basal-IQ Technology.  
698 
The HCL intervention arm will utilize the Tandem t:slim X2 with Control-IQ Technology. The 
699 
tandem t:connect software will be used to obtain device data. Each participant will have a study 
700 
specific t:connect account created.   
701 
 
702 
7.1.1.1 Tandem t:slim X2 pump with Basal-IQ Technology  
703 
The Basal IQ System (PLGS) is able to stop and resume basal insulin delivery automatically in 
704 
response to predicted or low sensor glucose values, thereby reducing the incidence and duration 
705 
of hypoglycemic episodes. The pump includes the hypoglycemia minimization strategy that will 
706 
issue insulin delivery commands. The algorithm looks ahead 30 minutes and suspends insulin 
707 
when glucose is predicted to drop below 80 mg per dL or if glucose is currently below 70 mg per 
708 
dL and falling. The system resumes basal insulin delivery once glucose values start to rise and 
709 
are above 70 mg per dL or 2.5 hours have elapsed. Basal IQ works silently in the background 
710 
and users can choose whether or not to receive alerts when insulin is suspended/resumed. Users 
711 
can also choose to resume insulin delivery at any time when insulin is suspended. 
712 
 
713 
7.1.1.2 Tandem t:slim X2 pump with Control-IQ Technology  
714 
The Control IQ uses advanced HCL algorithms that modulate insulin to keep CGM glucose 
715 
within a targeted range, with meal time insulin boluses delivered by the user. The system 
716 
components include the t:slim X2 with integrated Control-IQ Technology and the Dexcom CGM 
717 
G6. During wakeful hours, Control-IQ modulates insulin to maintain CGM glucose within 112.5 
718 
to 160 mg/dL. While asleep, the targeted CGM glucose range is 112.5 to 120 mg/dL. During 
719 
exercise, Control-IQ modulates insulin to maintain CGM glucose within 140 mg/dL to 160 
720 
mg/dL.  
721 
Control IQ uses the following algorithm:  
722 
• 
Insulin is decreased when a CGM reading of ≤ 112.5 mg/dL is predicted 30 minutes in 
723 
the future. (≤ 140 mg/dL with exercise). 
724 
• 
Insulin is set to 0 units/hour when a CGM reading ≤ 70 mg/dL (≤ 80 mg/dL during 
725 
exercise) is predicted 30 minutes in the future. 
726 
• 
Insulin is increased when a CGM reading of ≥ 160 mg/dL (awake), ≥ 120 mg/dL 
727 
(asleep), or >160 mg/dL (exercise) is predicted 30 minutes in the future. 
728 
• 
Correction boluses (60% of the total correction bolus calculated based on correction 
729 
factor and CGM reading) are delivered when a CGM reading > 180 mg/dL is predicted 
730 
30 minutes in the future. 
731 
 
732 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
7.1.2 Continuous Glucose Monitoring 
733 
The study CGM is the Dexcom G6.  This is an FDA-approved device system with no changes to 
734 
its hardware or firmware components. The sensor probe is inserted subcutaneously and transmits 
735 
data every 5 minutes to the pump via the transmitter. The CGM sensor will be replaced in 
736 
accordance with manufacturer labeling (e.g. at least once every ten days). A study specific 
737 
Dexcom Clarity account will be created for each participant.  
738 
 
739 
7.1.3 Ketone Meters and Strips 
740 
Blood ketone levels will be measured using the Abbott Precision Xtra meter and blood ketone 
741 
strips as indicated. Blood glucose meter strips for the Precision Xtra device will not be provided.  
742 
 
743 
7.1.4 Study Device Accountability Procedures 
744 
Good clinical research practice requires that investigators and research teams ensure accurate 
745 
accountability for any investigational device used in a research trial.  It is expected that all 
746 
investigational devices or approved devices used outside their approved intended use will be 
747 
used in the manner intended during the study, that they will be stored under appropriately 
748 
controlled conditions, and that they will be used by (on) participants who have consented to 
749 
participate in the research study. 
750 
 
751 
Any investigational device or approved devices used outside their approved intended use in 
752 
clinical research must be strictly accounted for and will not be shipped to any site unless all of 
753 
the necessary approvals (e.g. Regulatory, IRB/EC) have been received. This includes keeping 
754 
records of: 
755 
1. Center receipt and inventory management 
756 
2. Storage 
757 
3. Participant Disbursement 
758 
4. Return (by Participants and Center) and/or disposal 
759 
 
760 
During the conduct of the study the investigational center staff will account for and document the 
761 
device accountability procedures as detailed in the site procedures manual. 
762 
 
763 
7.2 Safety Measures 
764 
7.2.1 CGM Calibration 
765 
Throughout the study, participants will be instructed to calibrate the study CGM in accordance 
766 
with manufacturer labelling.  The Dexcom G6 does not require calibration with the exception of 
767 
certain circumstances outlined in the user manual. 
768 
7.2.2 Pump System Failure 
769 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, Control-IQ or 
770 
Basal-IQ will not operate to automatically adjust or suspend insulin. If the CGM is not 
771 
connected, the system will revert to usual function of the pump and deliver insulin with the 
772 
insulin dosing parameters programmed in the system for that individual. Resumption of each 
773 
algorithm will occur automatically once CGM signal is available again. Participants will be 
774 
instructed to keep the alarms for CGM data loss turned on whenever possible.  
775 
 
776 
If the study system is unable to activate Control-IQ for any reason, the pump will automatically 
777 
revert to preprogrammed basal insulin delivery without any need for instruction from the user. 
778 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
If the t:slim X2 detects a system error that does not allow the pump to operate, the Malfunction 
779 
Alarm will display and the participant will be instructed to contact the study team. 
780 
 
781 
7.2.3 Hypoglycemia Threshold Alarm and Safety Protocol 
782 
During the course of the study, participants will be permitted to change the CGM low glucose 
783 
threshold alert setting on their device or mobile app, but will be instructed to choose a value no 
784 
less than 70 mg/dL. The severe low alert in the Dexcom software is set to < 55 mg/dl and cannot 
785 
be turned off.   If the participant receives a predictive Low Alert or low alert, a message appears 
786 
on the user interface (UI) that is accompanied by vibration followed by vibrations and/or sound 
787 
if not acknowledged by the user in 5 minutes.  This alert remains on the screen until 
788 
acknowledged by the user.   
789 
 
790 
If a participant receives a CGM low glucose alert or notes that the CGM glucose is below the 
791 
low glucose threshold alert value, confirmatory fingerstick testing will be recommended and the 
792 
participant will be instructed to treat hypoglycemia with ~16 grams of fast-acting oral glucose. 
793 
 
794 
The t:slim X2 with Control-IQ will suspend insulin when the system predicts BG < 70mg/dL 
795 
within 30 minutes or if in exercise mode < 80mg/dL within 30 minutes. The t:slim X2 with 
796 
Basal-IQ will suspend insulin when the system predicts BG <80 mg/dL within the next 30 
797 
minutes or passes a threshold of < 70 mg/dL.   
798 
 
799 
7.2.4 Hyperglycemia Threshold Alarm and Safety Protocol 
800 
During the course of the study, participants will be permitted to change the CGM high glucose 
801 
threshold alert setting on their device or mobile app but will be instructed to choose a value no 
802 
greater than 300 mg/dL. This feature is common for the SAP and PLGS treatment arms.  
803 
The t:slim X2 with Control-IQ system will issue a predictive hyperglycemia alert (Control-IQ 
804 
High Alert) when the system has increased insulin delivery, but detects a CGM value above 200 
805 
mg/dL and does not predict the value will decrease in the next 30 minutes. 
806 
 
807 
If the participant receives a Control-IQ High Alert, a message appears on the UI that is 
808 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user 
809 
in 5 minutes. This alert remains on the screen until acknowledged by the user. The user is 
810 
prompted to check the site for occlusion and test blood glucose. 
811 
 
812 
If a participant’s CGM reading is >300 mg/dL for over 2 hours or ≥400 mg/dL at any point, the 
813 
participant will be instructed to take the following steps: 
814 
• 
Perform a blood glucose meter check. 
815 
• 
If the blood glucose is >300 mg/dL, participants will be encouraged to perform ketone 
816 
testing using their study ketone meter  
817 
• 
If the ketone level is >0.6 mmol/L, take correction insulin, change insulin (pump) 
818 
infusion site and contact study staff. 
819 
• 
During the Control-IQ period, if a participant administers correction insulin via insulin 
820 
syringe, participants will be instructed to turn Control-IQ off for approximately four 
821 
hours. 
822 
 
823 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
7.3 Participant Access to Study Device at Study Closure 
824 
Participants who complete the study will return the study pump and may be able to keep the 
825 
other supplies assuming they are functioning at the end of the study. 
826 
   
827 
7.4 Cognitive Assessment after SAE Occurrence 
828 
Following the occurrence of an SAE, participants will be administered the 5-min MoCA at the 
829 
earliest reasonable opportunity following recovering of the event to ensure the participant is not 
830 
cognitively impaired to a level that may impact the safety of using study devices. The same 
831 
criteria for baseline eligibility of major cognitive impairment will be used to determine if 
832 
continuing to use study device is a safety concern. Investigators may refer a study participant 
833 
with evidence of major cognitive impairment for services in accordance with their practice 
834 
standards.
835 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 8: Testing Procedures and Questionnaires 
836 
8.1 Testing Procedures 
837 
 
838 
• HbA1c: 
839 
o Performed locally at the Screening visit.  This may be done within 6 months prior to 
840 
enrollment. 
841 
o Collected via blood draw for central lab analysis at SAP Initiation, at the end of each 
842 
period and at the end of extension phase. Final HbA1c may also be collected for 
843 
participants who withdraw from the study. 
844 
 
845 
• C-peptide: 
846 
o Collected via blood draw at SAP Initiation and stored for central lab analysis.  
847 
 
848 
• Frailty 10-foot walk: 
849 
o Performed locally at the SAP Initiation visit. 
850 
o This test will measure the time it takes for a participant to walk 10 feet, to obtain an 
851 
estimate of frailty. Administration time is approximately 10 minutes (43). 
852 
 
853 
• Brief Cognitive Screening 
854 
o 5-min T Montreal Cognitive Assessment (MoCA)(44): Must be completed as the first 
855 
screening visit procedure either over the phone or in person in order to exclude those 
856 
with severe cognitive impairment and after an SAE occurrence to ensure the 
857 
participant is not cognitively impaired to a level that may impact safety of using study 
858 
devices. There are 15 total points: Verbal fluency (4), delayed recall (5) and 
859 
orientation (6). Participants who obtain a total score of 6 or less will be withdrawn 
860 
from the study. Investigators may refer a study participant for services in accordance 
861 
with their practice standards.  
862 
• Cognitive Measures  
863 
o Performed locally at the SAP Initiation visit and at the end of extension phase. 
864 
Measured for cohort description, sub group analysis, and prediction of system 
865 
preference during extension phase. Each measure is described briefly below.  The 
866 
procedures for administration are described in the study procedures manual. 
867 
▪ Total score = 30. The Montreal Cognitive Assessment (MoCA); (45) – 
868 
Performance-based assessment of general mental status consisting of several short 
869 
tasks (executive function, visual spatial skills, naming, attention, language, verbal 
870 
memory and orientation).   
871 
▪ WAIS-IV Digit Symbol Coding Test (46)– Performance-based assessment of 
872 
psychomotor processing speed.  Using a key, participants copy symbols that are 
873 
paired with numbers.  Total score is the number correctly completed within a 120 
874 
second time limit. 
875 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
▪ WAIS-IV Symbol Search Test (46)- Performance-based assessment of visual 
876 
processing speed.  Participants scan a search group and indicate whether one of 
877 
the symbols in the target group matches.  Total score is the number correctly 
878 
completed, minus the number of errors, within a 120 second time limit.  
879 
 
880 
Local laboratory testing will be performed if needed to screen for exclusionary medical 
881 
conditions. 
882 
 
883 
8.2 Questionnaires 
884 
 
885 
Each questionnaire is described briefly below.  The procedures for administration are described 
886 
in the study procedures manual. 
887 
1. Diabetes Distress Scale (DDS)(48) 
888 
The DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
889 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
890 
negative social perceptions by others; eating distress; physician (health care) distress; and 
891 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very 
892 
serious problem. The scale is valid and reliable, and has been shown to be sensitive to 
893 
change over time. Administration time is 5 minutes. Completed at baseline, end of each 
894 
period and end of extension phase.  
895 
2. Hypoglycemia Fear Survey (HFS)(48) 
896 
The HFS measures several dimensions of fear of hypoglycemia among adults with type 1 
897 
diabetes. It consists of 33 items and produces two sub-scale scores; a Behavior sub-scale 
898 
that measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
899 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. All versions of 
900 
the HFS are valid and reliable. Administration time is 5-10 minutes. Completed at baseline, 
901 
end of each period and end of extension phase. 
902 
3. Hypoglycemia Confidence Scale (HCS)(49) 
903 
The HCS (20) is a 9-item self-report scale that examines the degree to which people with 
904 
diabetes feel able, secure, and comfortable regarding their ability to stay safe from 
905 
hypoglycemic-related problems. It has been validated for use in adults with type 1 diabetes 
906 
and insulin-using type 2 diabetes.  Administration time is approximately 5 minutes. 
907 
Completed at baseline, end of each period and end of extension phase. 
908 
4. System Usability Scale (50)  
909 
A 10-item questionnaire that measures the overall usability of a system. It is a valid and 
910 
reliable measure of the perceived usability of a system and is technology-agnostic. 
911 
Administered at the end of each period only. 
912 
5. AIDE Technology Acceptance Questionnaire Post Device (51) 
913 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
This diabetes technology specific questionnaire based on the Technology Acceptance Model, 
914 
assesses perceived system usefulness, ease of use and trust in the system. Administered at the 
915 
end of each period only 
916 
6. Prospective and Retrospective Memory Questionnaire (52) 
917 
Self-report measure containing items asking participants how often they have difficulty 
918 
remembering to do things in the future, as well as forgetting past events in their daily lives. 
919 
Completed at baseline and end of extension phase.  
920 
7. Barkley Deficits in Executive Function Scale (53) 
921 
Self-report measure containing items asking participants how often they have difficulty with 
922 
planning, problem solving, impulsivity, and inattention in their daily lives.  Completed at 
923 
baseline and end of extension phase. 
924 
8. Functional Activities Questionnaire (54) 
925 
Self-report measure of instrumental activities of daily living.  Completed at baseline and end 
926 
of extension phase. 
927 
 
928 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 9: Adverse Events, Device Issues and Stopping Rules 
929 
9.1 Adverse Events 
930 
9.1.1 Definitions 
931 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
932 
relationship between the adverse event and the device(s) under investigation. 
933 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
934 
• Results in death. 
935 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
936 
have become life-threatening, is not necessarily considered a serious adverse event). 
937 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
938 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
939 
ability to conduct normal life functions (sight threatening). 
940 
• Is a congenital anomaly or birth defect. 
941 
• Is considered a significant medical event by the investigator based on medical judgment 
942 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
943 
prevent one of the outcomes listed above). 
944 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
945 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
946 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
947 
investigational plan or application (including a supplementary plan or application), or any other 
948 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
949 
welfare of participants (21 CFR 812.3(s)). 
950 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
951 
the device may have caused or to which the device may have contributed (Note that an Adverse 
952 
Event Form is to be completed in addition to a Device Deficiency or Issue Form, unless excluded 
953 
from reporting as defined in section 8.2).  
954 
Device Complaints and Malfunctions: A device complication or complaint is something that 
955 
happens to a device or related to device performance, whereas an adverse event happens to a 
956 
participant.  A device complaint may occur independently from an AE, or along with an AE.  An 
957 
AE may occur without a device complaint or there may be an AE related to a device complaint.  
958 
A device malfunction is any failure of a device to meet its performance specifications or 
959 
otherwise perform as intended.  Performance specifications include all claims made in the 
960 
labeling for the device.  The intended performance of a device refers to the intended use for 
961 
which the device is labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, sites will 
962 
not be asked to distinguish between device complaints and malfunctions. 
963 
9.1.2 Reportable Adverse Events 
964 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
965 
meets one of the following criteria: 
966 
1. An SAE 
967 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
2. An ADE as defined in section 9.1.1, unless excluded from reporting in section 9.2 
968 
3. An AE as defined in 9.1.1 occurring in association with a study procedure 
969 
4. An AE as defined in 9.1.1 not related to a device issue which leads to temporary or 
970 
permanent discontinuation of a study device   
971 
5. Hypoglycemia meeting the definition of severe hypoglycemia as defined below 
972 
6. Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, hyperglycemia 
973 
or ketosis event meeting the criteria defined below 
974 
7. Falls and fractures 
975 
8. Emergency room visits 
976 
 
977 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
978 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor adhesive 
979 
placement are only reportable if severe and/or required treatment. 
980 
 
981 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
982 
during questioning, or detected through physical examination, laboratory test, or other means—
983 
will be reported on an AE form online.  Each AE form is reviewed by the Medical Monitor to 
984 
assess safety and to verify the coding and the reporting that is required. 
985 
 
986 
9.1.2.1 Hypoglycemic Events 
987 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
988 
event when the following definition for severe hypoglycemia is met:  the event required 
989 
assistance of another person due to altered consciousness, and required another person to actively 
990 
administer carbohydrate, glucagon, or other resuscitative actions.  This means that the participant 
991 
was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable 
992 
to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure 
993 
or loss of consciousness.  These episodes may be associated with sufficient neuroglycopenia to 
994 
induce seizure or loss of consciousness.  If blood glucose measurements are not available during 
995 
such an event, neurological recovery attributable to the restoration of blood glucose to normal is 
996 
considered sufficient evidence that the event was induced by a low blood glucose concentration. 
997 
Severe hypoglycemia events should be considered to be serious adverse events with respect to 
998 
reporting requirements. When a hypoglycemic event meets the criteria for severe hypoglycemia , 
999 
a Hypoglycemia Form should be completed in addition to the Adverse Event Form. 
1000 
9.1.2.2 Hyperglycemic/Ketosis Events 
1001 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1002 
event when one of the following 4 criteria is met:   
1003 
• the event involved DKA, as defined by the Diabetes Control and Complications Trial 
1004 
(DCCT) and described below 
1005 
• evaluation or treatment was obtained at a health care provider facility for an acute event 
1006 
involving hyperglycemia or ketosis, or the participant contacted the site and received 
1007 
guidance on how to manage the hyperglycemia/ketosis 
1008 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
• blood ketone level ≥1.0 mmol/L and communication occurred with a health care provider 
1009 
at the time of the event 
1010 
• blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
1011 
provider 
1012 
 
1013 
Hyperglycemic events are classified as DKA if the following are present: 
1014 
• Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
1015 
• Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
1016 
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1017 
• Treatment provided in a health care facility 
1018 
Events meeting DKA criteria should be considered to be serious adverse events with respect to 
1019 
reporting requirements. Hyperglycemia events not meeting criteria for DKA generally will not 
1020 
be considered as serious adverse events unless one of the SAE criterion in section 9.2.1 is met. 
1021 
When a hyperglycemia/ketosis event meets the criteria for an SAE, a Hyperglycemia/DKA Form 
1022 
should be completed in addition to the Adverse Event Form. 
1023 
 
1024 
9.1.3 Relationship of Adverse Event to Study Investigational Device 
1025 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1026 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1027 
by the study device. Note that this assessment will be made for the Tandem t:slim X2 with 
1028 
Control-IQ Technology, the Tandem t:slim X2 pump with Basal-IQ Technology (with or without 
1029 
Basal-IQ feature), and the Dexcom CGM. 
1030 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1031 
following general guideline when determining whether an adverse event is related: 
1032 
Unrelated: The AE is clearly not related to a study drug/device and a likely alternative etiology 
1033 
exists such as an underlying disease, environmental or toxic factors or other therapy. 
1034 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after use of 
1035 
study drug/device and a more likely alternative etiology exists such as an underlying disease, 
1036 
environmental or toxic factors, or other therapy.  
1037 
Possibly Related: The AE occurred in a reasonable time during or after use of study 
1038 
drug/device; but could be related to another factor such as an underlying disease, environmental 
1039 
or toxic factors, or other therapy; and there is a possible, though weak, scientific basis for 
1040 
establishing a causal association between the AE and the study drug/device. 
1041 
Probably Related: The AE occurred in a reasonable time during or after use of study 
1042 
drug/device; is unlikely to be related to another factor such as an underlying disease, 
1043 
environmental or toxic factors, or other therapy; and there is a plausible, though not strong, 
1044 
scientific basis for establishing a causal association between the AE and the study drug/device.  
1045 
Definitely Related: The AE occurred in a reasonable time during or after use of study 
1046 
drug/device; cannot be explained by another factor such as an underlying disease, environmental 
1047 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
or toxic factors, or therapy; and there is a strong scientific basis for establishing a causal 
1048 
association between the AE and the study drug/device.  
1049 
Not Assessable: Causality of an adverse event cannot be judged because information is 
1050 
insufficient or contradictory, and which cannot be supplemented or verified. 
1051 
 
1052 
9.1.4 Severity (Intensity) of Adverse Events 
1053 
The severity (intensity) of an adverse event will be rated on a three point scale: (1) mild, (2) 
1054 
moderate, or (3) severe.  A severity assessment is a clinical determination of the intensity of an 
1055 
event. Thus, a severe adverse event is not necessarily serious.  For example, itching for several 
1056 
days may be rated as severe, but may not be clinically serious. 
1057 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
1058 
participant’s daily activities. 
1059 
• MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
1060 
participant and may interfere with daily activities, but is usually ameliorated by simple 
1061 
therapeutic measures and participant is able to continue in study. 
1062 
• SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
1063 
cause discontinuation of study device, and generally requires systemic drug therapy or 
1064 
other treatment. 
1065 
9.1.5 Expectedness 
1066 
For a serious adverse event that is considered possibly related to study device, the Medical 
1067 
Monitor will classify the event as unexpected if the nature, severity, or frequency of the event is 
1068 
not consistent with the risk information previously described in approved labeling.  
1069 
 
1070 
9.1.6 Coding of Adverse Events 
1071 
Adverse events will be coded using the MedDRA dictionary.  The Medical Monitor at the 
1072 
Coordinating Center will review all adverse events using a web-based procedure.  When a 
1073 
serious adverse event is entered by the site, an email is triggered to prompt immediate review. 
1074 
All other adverse events are reviewed by the Medical Monitor within one week.  The Medical 
1075 
Monitor will review the investigator’s assessment of causality and may agree or disagree.  Both 
1076 
the investigator’s and Medical Monitor’s assessments will be recorded.  The Medical Monitor 
1077 
will have the final say in determining the causality. 
1078 
 
1079 
9.1.7 Outcome of Adverse Events 
1080 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1081 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without 
1082 
sequelae.  Record the AE/SAE stop date. 
1083 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had 
1084 
stabilized without change in the event anticipated.  Record the AE/SAE stop date. 
1085 
• FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event 
1086 
that was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at 
1087 
the time of death; however, were not the cause of death, will be recorded as “resolved” at 
1088 
the time of death. 
1089 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined 
1090 
as the event was ongoing with an undetermined outcome. 
1091 
o An ongoing outcome will require follow-up by the site in order to determine the final 
1092 
outcome of the AE/SAE. 
1093 
o The outcome of an ongoing event at the time of death that was not the cause of death, 
1094 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1095 
date. 
1096 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant 
1097 
or the participant’s records to determine the outcome (for example, a participant that was 
1098 
lost to follow-up). 
1099 
If any reported adverse events are ongoing when a participant completes the study (or 
1100 
withdraws), adverse events classified UADEs will be followed until they are either resolved, or 
1101 
have no prospect of improvement or change, even after the participant has completed all 
1102 
applicable study visits/contacts. For all other adverse events, data collection will end at the time 
1103 
the participant completes the study. Note: participants should continue to receive appropriate 
1104 
medical care for an adverse event after their participation in the study ends.  
1105 
9.2 Reportable Device Issues 
1106 
All UADEs and ADEs as defined in section 9.1.1 will be reported on both a device issue form 
1107 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1108 
placement that do not require pharmacologic treatment. 
1109 
Device complaints and device malfunctions will be reported except in the following 
1110 
circumstances. These occurrences are expected and will not be reported on a Device Issue Form 
1111 
assuming criteria for a UADE or ADE have not been met: 
1112 
• Component disconnections 
1113 
• CGM sensor lasting fewer than the number of expected days per CGM labeling 
1114 
• CGM tape adherence issues 
1115 
• Pump infusion set occlusion (including tubing and cartridge) not leading to ketosis ≥0.6 
1116 
mmol/L or in the absence of checking for blood ketones, blood glucose >350 mg/dL 
1117 
(19.4 mmol/L); and not requiring an intervention other than replacing the tubing and/or 
1118 
cartridge 
1119 
• Battery lifespan deficiency due to inadequate charging or extensive wireless 
1120 
communication 
1121 
• Intermittent device component disconnections/communication failures not requiring 
1122 
system replacement or workaround/resolution not specified in user guide/manual. 
1123 
• Device issues clearly addressed in the user guide manual that do not require additional 
1124 
troubleshooting 
1125 
• Skin reactions from CGM sensor placement or pump infusion set placement that do not 
1126 
meet criteria for AE reporting 
1127 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
9.3 Timing of Event Reporting 
1128 
SAEs possibly related to a study device or study participation and UADEs must be reported to 
1129 
the Coordinating Center within 24 hours of the site becoming aware of the event.  This can occur 
1130 
via phone or email, or by completion of the online serious adverse event form and device issue 
1131 
form if applicable. If the form is not initially completed, it should be competed as soon as 
1132 
possible after there is sufficient information to evaluate the event. All other reportable ADEs and 
1133 
other reportable AEs should be submitted by completion of the online form within 7 days of the 
1134 
site becoming aware of the event. 
1135 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1136 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
1137 
Center becomes aware of the event. 
1138 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1139 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1140 
Ethics Committee. 
1141 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report 
1142 
the results of the investigation to the sites’ IRBs, and the FDA within 10 working days of the 
1143 
Sponsor becoming aware of the UADE per 21CFR 812.46(b) (2).  The Medical Monitor must 
1144 
determine if the UADE presents an unreasonable risk to participants.  If so, the Medical Monitor 
1145 
must ensure that all investigations, or parts of investigations presenting that risk, are terminated 
1146 
as soon as possible but no later than 5 working days after the Medical Monitor makes this 
1147 
determination and no later than 15 working days after first receipt notice of the UADE. 
1148 
Device malfunctions will be handled by the Coordinating Center. 
1149 
 
1150 
9.4 Stopping Criteria 
1151 
9.4.1 Participant Discontinuation of Study Phase 
1152 
Rules for discontinuing study device use are described below. 
1153 
• The investigator believes it is unsafe for the participant to continue on the intervention.  
1154 
This could be due to the development of a new medical condition or worsening of an 
1155 
existing condition; or participant behavior contrary to the indications for use of the device 
1156 
that imposes on the participant’s safety 
1157 
• The participant requests that the treatment be stopped 
1158 
• Two distinct episodes of DKA (as defined in section 9.1.2) unrelated to infusion set 
1159 
failure 
1160 
• Greater than two distinct severe hypoglycemia events as defined in section 9.1.2.1 
1161 
• Participants who obtain a total score of 6 or less on the 5-min MoCA administered after 
1162 
an SAE occurrence.  
1163 
Even if the study device system is discontinued, the participant will be encouraged to remain in 
1164 
the study through the final study visit. 
1165 
 
1166 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
9.4.2 Criteria for Suspending or Stopping Overall Study 
1167 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
1168 
hyperglycemia event (as defined in Section 9.1.1), use of the study device system will be 
1169 
suspended while the problem is diagnosed. 
1170 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1171 
study device requires stoppage of device use for safety reasons (e.g. product recall).  The 
1172 
affected study activities may resume if the underlying problem can be corrected by a protocol or 
1173 
system modification that will not invalidate the results obtained prior to suspension. 
1174 
 The study Medical Monitor will review all adverse events and adverse device events that are 
1175 
reported during the study typically on a weekly basis and will review compiled safety data at 
1176 
periodic intervals (generally timed to the review of compiled safety data by the DSMB). The 
1177 
Medical Monitor may request suspension of study activities or stoppage of the study if deemed 
1178 
necessary based on the totality of safety data available. 
1179 
 
1180 
9.5 Independent Safety Oversight 
1181 
A Data and Safety Monitoring Board (DSMB) will be formed according to NIDDK requirements 
1182 
to review compiled safety data at periodic intervals (typically every 6 months). The DSMB may 
1183 
request to review certain serious adverse events (including UADEs) at the time of occurrence.   
1184 
The DSMB also will be informed of any ADEs not meeting criteria for a UADE if the Medical 
1185 
Monitor requests the DSMB review.   The DSMB can request modifications to the study protocol 
1186 
or suspension or outright stoppage of the study if deemed necessary based on the totality of 
1187 
safety data available. Details regarding DSMB review will be documented in a separate DSMB 
1188 
document. 
1189 
 
1190 
 
 
1191 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 10: Miscellaneous Considerations 
1192 
10.1 Drugs Used as Part of the Protocol 
1193 
Rapid acting insulins approved for the study pump will be used during the study. Insulins will 
1194 
not be provided by the study.   
1195 
 
1196 
10.2 Collection of Medical Conditions and Medications 
1197 
Pre-Existing Condition: Any medical condition that is either present at screening, a chronic 
1198 
disease, or a prior condition that could impact the participant’s health during the course of the 
1199 
study (e.g., prior myocardial infarction or stroke). 
1200 
Medical Conditions during the study: In addition to conditions meeting the reporting 
1201 
requirements for an adverse event or device issue as described in Section 9.1 and Section 9.2, the 
1202 
following medical conditions should also be reported: (1) new diagnosis of a chronic disease 
1203 
(i.e., not present at the time of enrollment), and (2) any medical condition that could affect the 
1204 
participant’s ability to carry out any aspect of the protocol or could affect an outcome 
1205 
assessment.  
1206 
Medications: All medication for the treatment of chronic pre-existing conditions, medical 
1207 
conditions (including medical conditions that do not require recording), and/or adverse events 
1208 
that the participant is currently taking at screening and during the course of the study should be 
1209 
recorded. Nutraceuticals and preventative treatment also should be recorded. Medications only 
1210 
taken as needed either can be recorded when prescribed or only recorded if used during the 
1211 
study. Glucagon prescription will be confirmed as part of eligibility criteria but should only be 
1212 
recorded for treatment of severe hypoglycemia if used during the study. 
1213 
10.3 Participant Compensation 
1214 
Participant compensation will be specified in the informed consent form. 
1215 
 
1216 
10.4 Participant Withdrawal 
1217 
Participation in the study is voluntary, and a participant may withdraw at any time.  For 
1218 
participants who withdraw, their data will be used up until the time of withdrawal.  An early 
1219 
termination visit may be completed to collect final study data. 
1220 
 
1221 
If participants wish to discontinue using the study device without withdrawing, participants will 
1222 
be encouraged to remain in the study through the end of study visit. 
1223 
 
1224 
10.5 Confidentiality 
1225 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1226 
used instead of their name.  Protected health information gathered for this study will be shared 
1227 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL.  De-identified 
1228 
participant information may also be provided to research sites involved in the study.
1229 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 11: Statistical Considerations 
1230 
11.1 Statistical and Analytical Plans 
1231 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1232 
analysis plan will be written and finalized prior to the completion of the study.   
1233 
11.2 Statistical Hypotheses 
1234 
A. Null hypothesis: There will be no difference in percentage of CGM-measured glucose 
1235 
values <70 mg/dL between PLGS vs SAP. 
1236 
Alternate hypothesis: There is a non-zero difference in the percentage of CGM-measured 
1237 
glucose values <70 mg/dL between PLGS vs SAP. 
1238 
B. Null hypothesis: There will be no difference in percentage of CGM-measured glucose 
1239 
values <70 mg/dL between HCL vs. SAP. 
1240 
Alternate hypothesis: There is a non-zero difference in the percentage of CGM-measured 
1241 
glucose values <70 mg/dL between HCL vs. SAP. 
1242 
11.3 Sample Size 
1243 
Data from the CGM group in the WISDM randomized clinical trial of older adults ≥ 60 years of 
1244 
age were used to estimate the standard deviation and frequency of time <70 mg/dL in the SAP 
1245 
control period. Data from the two weeks prior to the 4 week visit were used to mimic the run-in 
1246 
period in this study where the minimum hypoglycemia eligibility criteria will be assessed. Only 
1247 
WISDM CGM group participants who had ≥2% of time <70 mg/dL at the 4 week time point 
1248 
were included. Data from the two weeks prior to the 26-week visit for these participants were 
1249 
then used to estimate standard deviation and frequency of time <70 mg/dL. N=50 WISDM 
1250 
participants were included of which 28 were injection users and 22 were pump users.  
1251 
The point estimate for the simple standard deviation was 2.24%. Percent time <70 mg/dL was 
1252 
skewed, so a robust estimate of the mean, 3.14%, was used to calculate the size of a 33% and 
1253 
50% relative reduction in hypoglycemia. 
1254 
Since the primary outcome of the study involves two comparisons, the sample size calculations 
1255 
assume an alpha of 0.025 in order to control the overall type 1 error rate at 0.05. In addition, a 
1256 
two-tailed test and 90% power are assumed. We assume the standard deviation is 2.24% in all 
1257 
three periods. 
1258 
Table 1: Sample Size (Alpha=0.025, Power=90%, SD=2.24%) 
1259 
Correlation 
between Periods 
Relative Reduction in Hypoglycemia 
33% 
50% 
0 
119 
54 
0.3 
84 
38 
0.5 
61 
28 
The Tandem pivotal PLGS study, which was a 3 week period crossover of PLGS and SAP, 
1260 
observed a correlation of about 0.8 between the treatment arms (unpublished data). However, 
1261 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
since the periods in this study are longer, we assume a lower correlation of 0.3 to estimate 
1262 
sample size. A sample size of 84 will give us 90% power to detect a 33% reduction in % time 
1263 
<70 mg/dL. This is increased to 90 to account for 5% loss to follow-up. Loss to follow-up and 
1264 
missing data is expected to be minimal in this population as the retention rate in the WISDM 
1265 
study was 99% at 6 months.  
1266 
11.4 Outcome Measures 
1267 
Primary Efficacy Endpoint: 
1268 
• CGM % time <70 mg/dL 
1269 
Secondary Efficacy Endpoints: 
1270 
Hypoglycemia 
1271 
• CGM % time <54 mg/dL 
1272 
• Frequency of CGM-measured hypoglycemic events (see definition below) 
1273 
Glucose Control 
1274 
• CGM mean glucose 
1275 
• CGM % time in range 70 to 180 mg/dL 
1276 
• Coefficient of variation (CV) 
1277 
Hyperglycemia 
1278 
• CGM % time >180 mg/dL 
1279 
• CGM % time >250 mg/dL 
1280 
HbA1c 
1281 
• HbA1c 
1282 
Hypoglycemia Unawareness 
1283 
• Gold survey(55) 
1284 
Patient-reported Outcomes  
1285 
• Hypoglycemia Fear Survey (HFS-II)  
1286 
o Total score 
1287 
o Worry subscale 
1288 
• Hypoglycemia confidence 
1289 
• Diabetes Distress Scale (DDS) 
1290 
• Technology acceptance 
1291 
• System usability  
1292 
Each of the CGM metrics listed will be calculated over 24 hours and separately for daytime and 
1293 
nighttime.  Daytime and nighttime versions of CGM % time <70 mg/dL will be considered 
1294 
secondary. All sensor readings excluding the first 4 weeks will be pooled to calculate CGM 
1295 
metrics for that period. 
1296 
A CGM-measured hypoglycemic event will be defined as at least 2 sensor values <54 mg/dL that 
1297 
are 15 or more minutes apart plus no intervening values >54 mg/dL; at least 2 sensor values >70 
1298 
mg/dL that are 15 or more minutes apart with no intervening values <70 mg/dL are required to 
1299 
define the end of an event, at which point the study participant becomes eligible for a new 
1300 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
event.HbA1c and patient-reported outcomes will be collected at baseline and following each 12 
1301 
week period. 
1302 
11.5 Analysis Datasets and Sensitivity Analysis 
1303 
All analysis will follow the intention-to-treat principle with each period analyzed according to 
1304 
the treatment assigned by randomization regardless of actual system utilization. The Intention-to-
1305 
Treat (ITT) Analysis Dataset will include all randomized participants for any period in which 
1306 
they meet the minimum data requirement (≥168 hours of CGM data after excluding the first 4 
1307 
weeks for CGM metrics, non-missing for all other outcomes).  
1308 
The Safety Analysis Dataset will include all enrolled participants, irrespective of whether the 
1309 
participant was randomized or the study was completed. 
1310 
11.5.1 Per-protocol Analysis 
1311 
The Per-Protocol Analysis Dataset will include participants for any period in which they meet 
1312 
the following criteria after excluding the first 4 weeks: 
1313 
• ≥168 hours of CGM data  
1314 
• CGM use ≥80% 
1315 
• Control-IQ active ≥80% for the HCL period 
1316 
• Basal-IQ active ≥80% for the PLGS period 
1317 
• SAP active (Control-IQ and Basal-IQ not active) ≥80% for the SAP period 
1318 
A per-protocol analysis will be performed for the primary outcome to provide additional 
1319 
information regarding the magnitude of treatment effect. The per-protocol analysis will only be 
1320 
performed if at least 10% of participants in any period would be excluded by these criteria.  
1321 
The intent-to-treat analysis is considered primary and if the results of the per-protocol analysis 
1322 
and intent-to-treat analysis differ, the per-protocol analysis will be interpreted with caution. 
1323 
11.5.2 Other Sensitivity Analysis 
1324 
Missing Data 
1325 
It is worth emphasizing that any statistical method for handling missing data makes a number of 
1326 
untestable assumptions.  The goal will be to minimize the amount of missing data in this study so 
1327 
that results and conclusions will not be sensitive to which statistical method is used. To that end, 
1328 
sensitivity analyses will be performed to explore whether results are similar for the primary 
1329 
analysis when using different methods.  The following methods will be applied: 
1330 
• Direct likelihood (primary analysis described below) 
1331 
• Rubin’s multiple imputation  
1332 
• Available cases only  
1333 
Carryover 
1334 
A period by treatment interaction will be added to the primary analysis model to assess for the 
1335 
presence of a carryover effect. We do not expect a carryover effect to be present because we 
1336 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
expect the effect of the treatment administered in the prior period to wear off during the first 4 
1337 
weeks which are not included in the calculation of CGM metrics. 
1338 
11.6 Analysis of the Primary Efficacy Endpoint 
1339 
The primary analysis for CGM % time <70 mg/dL will involve two comparisons: PLGS vs. SAP 
1340 
and HCL vs. SAP. Each comparison will be allocated alpha 0.025 to control the family-wise type 
1341 
1 error at 0.05. 
1342 
Participants will be included for any period in which they have at least 168 hours of CGM data in 
1343 
the last 8 weeks.  
1344 
Summary statistics appropriate to the distribution will be calculated for % time <70 mg/dL 
1345 
separately by treatment arm. A repeated measures regression model with an unstructured 
1346 
covariance will be fit including data from baseline and all three treatment periods. The model 
1347 
will adjust for period as a covariate. If residual values from the regression model have a skewed 
1348 
distribution then an appropriate transformation, truncation, or a nonparametric analysis based on 
1349 
ranks will be performed.  
1350 
There will be no imputation of missing data in the primary analysis. Missing data will be handled 
1351 
by using a direct likelihood approach which will allow participants to be included even if they 
1352 
only have baseline and no follow-up data. 
1353 
11.7 Analysis of the Secondary Endpoints 
1354 
11.7.1 Secondary Hypoglycemia CGM Endpoints 
1355 
Summary statistics appropriate to the distribution will be given by treatment group for the 
1356 
secondary hypoglycemia CGM endpoints (time <54 mg/dL and rate of hypoglycemic events). The 
1357 
primary hypoglycemia endpoint and the secondary hypoglycemia outcomes will be evaluated in a 
1358 
hierarchical approach to control the type 1 error (see the multiple comparisons section below for 
1359 
details). If the endpoint is to be formally compared between treatment groups, analysis will parallel 
1360 
that of the primary outcome. 
1361 
Separate day and night versions of all three hypoglycemia CGM endpoints will be summarized 
1362 
by treatment group but will only be formally compared between groups in a secondary analysis if 
1363 
the overall version of the endpoint was formally compared and was statistically significant.  
1364 
11.7.2 Additional CGM Endpoints 
1365 
Summary statistics appropriate to the distribution will be given by treatment group for time in 
1366 
range 70-180 mg/dL, mean glucose, time >180mg/dL, and time >250 mg/dL. These metrics will 
1367 
be evaluated overall and separately for daytime and nighttime. Analysis will parallel the analysis 
1368 
of the primary endpoint above.  
1369 
11.7.3 HbA1c 
1370 
HbA1c will be measured by central lab at baseline and following each 12-week period. Summary 
1371 
statistics appropriate to the distribution for HbA1c will be reported by treatment group. A 
1372 
repeated measures regression model with an unstructured covariance will be fit including the 
1373 
data from baseline and all three treatment periods. The model will adjust for period as a 
1374 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
covariate.  If residual values from the regression model have a skewed distribution then an 
1375 
appropriate transformation, truncation, or a nonparametric analysis based on ranks will be 
1376 
performed.   
1377 
11.7.4 Questionnaires 
1378 
Summary statistics appropriate to the distribution will be given by treatment group for each 
1379 
patient-reported outcome. Analysis outcomes will parallel the analysis of the primary endpoint 
1380 
described above.  
1381 
11.8 Safety Analyses 
1382 
Details of all reportable adverse events will be provided in a listing by treatment group. Pre-
1383 
randomization adverse events will be listed separately and will not be included in any treatment 
1384 
group comparisons. Each period will inclusively consist of all days in between the treatment 
1385 
initiation visit and the end of treatment visit. If the subject drops out of the study in the middle of 
1386 
a period and the end of treatment visit for that particular period does not occur, then the dropout 
1387 
date will be used as the last day of the period. 
1388 
For the following outcomes, summary statistics appropriate to the distribution will be tabulated by 
1389 
treatment arm.  
1390 
• Number of adverse events 
1391 
• Number of serious adverse events 
1392 
• Number of unexpected device events 
1393 
• Number of SH events and SH incidence rate per 100 person-years 
1394 
• Number of hospitalizations related to a SH event 
1395 
• Number of ER visits related to a SH event  
1396 
• Number of fractures related to a SH event 
1397 
• Number of falls related to a SH event 
1398 
• Number of DKA events and DKA incidence rate per 100 person-years 
1399 
• Number of hospitalizations related to a DKA event or severe hyperglycemia 
1400 
• Number of ER visits related to a DKA event or severe hyperglycemia  
1401 
If there are enough events for statistical analysis, the SH and DKA incidence rates will be 
1402 
compared between treatment arms using a repeated measures Poisson regression model adjusting 
1403 
for period and whether the subject had an event in the 12 months prior to the study as a covariate. 
1404 
If there are zero events in one treatment arm, Poisson regression will not converge and so the 
1405 
number of events will be compared pairwise using Barnard's test instead. 
1406 
11.9 Protocol Adherence and Retention 
1407 
The following will be performed according to treatment arm: 
1408 
• A flow chart accounting for all participants for all visits 
1409 
• Tabulation of visit completion rates for each follow-up visit  
1410 
• Tabulation of protocol deviations  
1411 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
• Tabulation of number and reasons for unscheduled visits and phone calls 
1412 
• Tabulation of device issues 
1413 
11.10 Baseline Descriptive Statistics 
1414 
Baseline demographic and clinical characteristics will be summarized in a table. For continuous 
1415 
variables, summary statistics appropriate to the distribution will be given. For discrete variables, 
1416 
number and percentage will be reported for each category.   
1417 
11.11 Planned Interim Analyses 
1418 
No formal interim efficacy analysis is planned for this study. Safety data tabulations will be 
1419 
performed at least every 6 months for review by the Data and Safety Monitoring Board (DSMB). 
1420 
11.12 Sub-Group Analyses 
1421 
Subgroup analyses/assessments of effect modification (interaction) will be conducted for the 
1422 
primary outcome.  These analyses will be considered exploratory.  Additionally, interpretation of 
1423 
the analyses will depend on whether the overall analysis demonstrates a significant treatment 
1424 
group difference; in the absence of such an overall difference, subgroup analyses will be 
1425 
interpreted with caution.  The general approach for these exploratory analyses will be to add an 
1426 
interaction term for the subgroup factor by treatment into the models used for the primary 
1427 
analyses. 
1428 
The baseline factors listed below will be assessed: 
1429 
• Race/Ethnicity 
1430 
• Gender 
1431 
• Baseline % time <70 mg/dL 
1432 
• Age 
1433 
• Education 
1434 
• Employment Status 
1435 
• Duration of Diabetes 
1436 
• Hypoglycemia Unawareness 
1437 
• Cognition 
1438 
• Functional activities questionnaire 
1439 
• Frailty 
1440 
• Prior CGM experience 
1441 
• Prior Insulin Delivery Method 
1442 
• Previous history of SH event in past 12 months 
1443 
• C-peptide 
1444 
11.13 Exploratory Analyses 
1445 
All of the primary and secondary outcomes will be compared between PLGS and HCL in an 
1446 
exploratory analysis that parallels the analysis described above. A difference, if any, in the 
1447 
hypoglycemia outcomes between PLGS and HCL is expected to be small, so the power will be 
1448 
low. 
1449 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
11.14 Additional Tabulations and Analysis 
1450 
Device Use 
1451 
The percent of time in each system control mode and the percent of time using CGM will be 
1452 
tabulated by treatment arm overall and by 4-week intervals. These tabulations will be repeated 
1453 
separately over 24-hours, daytime, and nighttime. Overall 24-hour CGM use will be compared 
1454 
pairwise between all treatment arms using the same model described for the primary outcome.  
1455 
In addition, we will tabulate the following for the HCL period overall between treatment 
1456 
initiation and the end of treatment visit and by 4-week intervals: 
1457 
• Percent of time spent in sleep mode 
1458 
• Percent of time spent in sleep mode outside of nighttime hours 
1459 
• Percent of time spent in exercise modes 
1460 
Insulin 
1461 
Average total daily insulin per kg, basal insulin per kg, and bolus insulin per kg will be tabulated 
1462 
at baseline and by treatment arm using pump download data. Insulin metrics will be compared 
1463 
pairwise between all treatment arms using the same model described above for the primary 
1464 
outcome. 
1465 
Pump Alert and Alarms 
1466 
The number and rate per 24 hours of different alerts and alarms from the Tandem pump will be 
1467 
tabulated by treatment arm. 
1468 
BMI 
1469 
Height and weight will be measured at baseline and the end of each period when possible. BMI 
1470 
will be tabulated at baseline by treatment arm.  
1471 
BG Checks 
1472 
Average BG checks per day will be tabulated at baseline and by treatment arm.  
1473 
11.15 Multiple Comparison/Multiplicity 
1474 
For the primary comparisons of interest, PLGS vs. SAP and HCL vs. SAP, the three CGM-
1475 
measured hypoglycemia metrics will be evaluated in a hierarchical approach to control the type 1 
1476 
error at 0.05. Each comparison will be allocated alpha 0.025. The outcomes will be evaluated in 
1477 
the following order: 
1478 
• % time <70 mg/dL 
1479 
• % time <54 mg/dL 
1480 
• Rate of hypoglycemic events 
1481 
The process moves to the next variable down on the list until a non-significant result (p ≥ 0.025) 
1482 
is observed, or all outcomes have been tested.  If a non-significant result is encountered, then 
1483 
formal statistical hypothesis testing is terminated and any comparisons below on the list are not 
1484 
formally tested. If for either comparison of interest, PLGS vs. SAP or HCL vs. SAP, all three 
1485 
outcomes are rejected at the level of 0.025, the alpha can be recycled and the other comparison can 
1486 
be tested down the hierarchy at an alpha level of 0.05 rather than 0.025.  
1487 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
For all other secondary and exploratory outcomes the false discovery rate will be controlled using 
1488 
the Benjamini-Hochberg procedure adapted using the two-stage test. There will be no adjustment 
1489 
for safety outcomes.  
1490 
11.16 Extension Phase 
1491 
Exploratory analysis for the extension phase will be detailed in a separate document.
1492 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 12: Data Collection and Monitoring 
1493 
12.1 Case Report Forms and Other Data Collection 
1494 
The main study data are collected on electronic case report forms (CRFs) and electronic device 
1495 
data files obtained from the study software and individual hardware components. These 
1496 
electronic device files and electronic CRFs from the study website are considered the primary 
1497 
source documentation. 
1498 
 
1499 
When data are directly collected in electronic case report forms, this will be considered the 
1500 
source data. For any data points for which the eCRF is not considered source (e.g. lab results that 
1501 
are transcribed from a printed report into the eCRF), the original source documentation must be 
1502 
maintained in the participant’s study chart or medical record. This source must be readily 
1503 
verifiable against the values entered into eCRF. Even where all study data are directly entered 
1504 
into the eCRFs at office visits, evidence of interaction with a live subject must be recorded (e.g., 
1505 
office note, visit record, etc.).    
1506 
Each participating site will maintain appropriate medical and research records for this trial, in 
1507 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1508 
confidentiality of participants. 
1509 
12.2 Study Records Retention 
1510 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1511 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1512 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1513 
discontinuation of clinical development of the investigational product.  These documents should 
1514 
be retained for a longer period, however, if required by local regulations.  No records will be 
1515 
destroyed without the written consent of the sponsor, if applicable.  It is the responsibility of the 
1516 
sponsor to inform the investigator when these documents no longer need to be retained. 
1517 
 
1518 
12.3 Quality Assurance and Monitoring 
1519 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1520 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1521 
conducted and data are generated, documented and reported in compliance with the protocol, 
1522 
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1523 
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1524 
accurate, complete, and verifiable.  Adverse events will be prioritized for monitoring. 
1525 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1526 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1527 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1528 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. This plan describes in 
1529 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
1530 
of detail monitoring will be performed, and the distribution of monitoring reports. 
1531 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1532 
events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1533 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1534 
verity and completeness of the key site data.  Elements of the RBM may include: 
1535 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
• Qualification assessment, training, and certification for sites and site personnel 
1536 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1537 
procedures 
1538 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1539 
review of entered data and edits, statistical monitoring, study closeout 
1540 
• On-site monitoring (site visits): source data verification, site visit report 
1541 
• Device accountability 
1542 
• Communications with site staff 
1543 
• Patient retention and visit completion 
1544 
• Quality control reports 
1545 
• Management of noncompliance 
1546 
• Documenting monitoring activities 
1547 
• Adverse event reporting and monitoring 
1548 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1549 
order to maintain current and personal knowledge of the study through review of the records, 
1550 
comparison with source documents, observation and discussion of the conduct and progress of 
1551 
the study. The investigational site will provide direct access to all trial related sites, source 
1552 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1553 
inspection by local and regulatory authorities. 
1554 
12.4 Protocol Deviations 
1555 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1556 
requirements.  The noncompliance may be either on the part of the participant, the investigator, 
1557 
or the study site staff.  As a result of deviations, corrective actions are to be developed by the site 
1558 
and implemented promptly. 
1559 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
1560 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1561 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 13: Ethics/Protection of Human Participants 
1562 
13.1 Ethical Standard 
1563 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1564 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1565 
21 CFR Part 56, and/or the ICH E6. 
1566 
 
1567 
13.2 Institutional Review Boards 
1568 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1569 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1570 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1571 
require review and approval by the IRB before the changes are implemented to the study.  All 
1572 
changes to the consent form will be IRB approved; a determination will be made regarding 
1573 
whether previously consented participants need to be re-consented. 
1574 
 
1575 
13.3 Informed Consent Process 
1576 
13.3.1 Consent Procedures and Documentation 
1577 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1578 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1579 
risks and possible benefits of participation will be provided to the participants and their families.  
1580 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
1581 
document.  The investigator will explain the research study to the participant and answer any 
1582 
questions that may arise.  All participants will receive a verbal explanation in terms suited to 
1583 
their comprehension of the purposes, procedures, and potential risks of the study and of their 
1584 
rights as research participants.  Participants will have the opportunity to carefully review the 
1585 
written consent form and ask questions prior to signing. 
1586 
The participants should have the opportunity to discuss the study with their surrogates or think 
1587 
about it prior to agreeing to participate.  The participant will sign the informed consent document 
1588 
prior to any procedures being done specifically for the study.  The participants may withdraw 
1589 
consent at any time throughout the course of the trial.  A copy of the informed consent document 
1590 
will be given to the participants for their records.  The rights and welfare of the participants will 
1591 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1592 
affected if they decline to participate in this study. 
1593 
13.3.2 Participant and Data Confidentiality 
1594 
 Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1595 
and the sponsor(s) and their agents.  This confidentiality is extended to cover testing of 
1596 
biological samples and genetic tests in addition to the clinical information relating to 
1597 
participants.  Therefore, the study protocol, documentation, data, and all other information 
1598 
generated will be held in strict confidence.  No information concerning the study or the data will 
1599 
be released to any unauthorized third party without prior written approval of the sponsor. 
1600 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1601 
regulatory agencies or  company supplying study product may inspect all documents and records 
1602 
required to be maintained by the investigator, including but not limited to, medical records 
1603 
(office, clinic, or hospital) and pharmacy records for the participants in this study.  The clinical 
1604 
study site will permit access to such records. 
1605 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
The study participant’s contact information will be securely stored at each clinical site for 
1606 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1607 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1608 
sponsor requirements. 
1609 
Study participant research data, which is for purposes of statistical analysis and scientific 
1610 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research (JCHR) in 
1611 
Tampa, FL.  This will not include the participant’s contact or identifying information.  Rather, 
1612 
individual participants and their research data will be identified by a unique study identification 
1613 
number.  The study data entry and study management systems used by clinical sites and by the 
1614 
JCHR research staff will be secured and password protected.  At the end of the study, all study 
1615 
databases will be de-identified and archived at the JCHR in Tampa, FL. 
1616 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1617 
obtained from the NIH.  This certificate protects identifiable research information from forced 
1618 
disclosure.  It allows the investigator and others who have access to research records to refuse to 
1619 
disclose identifying information on research participation in any civil, criminal, administrative, 
1620 
legislative, or other proceeding, whether at the federal, state, or local level.  By protecting 
1621 
researchers and institutions from being compelled to disclose information that would identify 
1622 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1623 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1624 
 
1625 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Chapter 14: References 
1626 
1. Graham C, Waldo D: Type 1 Diabetes in Medicare: Use of Services & Program Expenditures 
1627 
in 2010. Diabetes 2013;62:A332 
1628 
2. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L: Changes in 
1629 
diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014;370:1514-
1630 
1523 
1631 
3. Ioacara S, Lichiardopol R, Ionescu-Tirgoviste C, Cheta D, Sabau S, Guja C, Farcasiu E, Tiu 
1632 
C: Improvements in life expectancy in type 1 diabetes patients in the last six decades. Diabetes 
1633 
Res Clin Pract 2009;86:146-151 
1634 
4. Lawrence JM, Imperatore G, Dabelea D, Mayer-Davis EJ, Linder B, Saydah S, Klingensmith 
1635 
GJ, Dolan L, Standiford DA, Pihoker C, Pettitt DJ, Talton JW, Thomas J, Bell RA, D'Agostino 
1636 
RB, Jr.: Trends in Incidence of Type 1 Diabetes Among non-Hispanic White Youth in the United 
1637 
States, 2002-2009. Diabetes 2014; 
1638 
5. Geller AI, Shehab N, Lovegrove MC, Kegler SR, Weidenbach KN, Ryan GJ, Budnitz DS: 
1639 
National estimates of insulin-related hypoglycemia and errors leading to emergency department 
1640 
visits and hospitalizations. JAMA Intern Med 2014;174:678-686 
1641 
6. Lipska KJ, Ross JS, Wang Y, Inzucchi SE, Minges K, Karter AJ, Huang ES, Desai MM, Gill 
1642 
TM, Krumholz HM: National trends in US hospital admissions for hyperglycemia and 
1643 
hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med 2014;174:1116-
1644 
1124 
1645 
7. Stahn A, Pistrosch F, Ganz X, Teige M, Koehler C, Bornstein S, Hanefeld M: Relationship 
1646 
between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and 
1647 
cardiovascular diseases: silent hypoglycemias and silent arrhythmias. Diabetes Care 
1648 
2014;37:516-520 
1649 
8. Lu CL, Shen HN, Hu SC, Wang JD, Li CY: A Population-Based Study of All-Cause Mortality 
1650 
and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients 
1651 
With Type 1 Diabetes. Diabetes Care 2016;39:1571-1578 
1652 
9. American DA: 6. Glycemic Targets. Diabetes Care 2015;38:S33-S40 
1653 
10. Chiang JL, Kirkman MS, Laffel LM, Peters AL: Type 1 Diabetes Through the Life Span: A 
1654 
Position Statement of the American Diabetes Association. Diabetes Care 2014;37:2034-2054 
1655 
11. Weinstock RS, Xing D, Maahs DM, Michels A, Rickels MR, Peters AL, Bergenstal RM, 
1656 
Harris B, Dubose SN, Miller KM, Beck RW: Severe hypoglycemia and diabetic ketoacidosis in 
1657 
adults with type 1 diabetes: results from the T1D Exchange clinic registry. J Clin Endocrinol 
1658 
Metab 2013;98:3411-3419 
1659 
12. Weinstock RS, DuBose SN, Bergenstal RM, Chaytor NS, Peterson C, Olson BA, Munshi 
1660 
MN, Perrin AJ, Miller KM, Beck RW, Liljenquist DR, Aleppo G, Buse JB, Kruger D, Bhargava 
1661 
A, Goland RS, Edelen RC, Pratley RE, Peters AL, Rodriguez H, Ahmann AJ, Lock JP, Garg SK, 
1662 
Rickels MR, Hirsch IB, Group TDESHiOAWTDS: Risk Factors Associated With Severe 
1663 
Hypoglycemia in Older Adults With Type 1 Diabetes. Diabetes Care 2016;39:603-610 
1664 
13. Martyn-Nemeth P, Schwarz Farabi S, Mihailescu D, Nemeth J, Quinn L: Fear of 
1665 
hypoglycemia in adults with type 1 diabetes: impact of therapeutic advances and strategies for 
1666 
prevention - a review. J Diabetes Complications 2016;30:167-177 
1667 
14. Strandberg RB, Graue M, Wentzel-Larsen T, Peyrot M, Wahl AK, Rokne B: The 
1668 
relationships among fear of hypoglycaemia, diabetes-related quality of life and psychological 
1669 
well-being in Norwegian adults with Type 1 diabetes. Diabetes Res Clin Pract 2017;124:11-19 
1670 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
15. Jorgensen HV, Pedersen-Bjergaard U, Rasmussen AK, Borch-Johnsen K: The impact of 
1671 
severe hypoglycemia and impaired awareness of hypoglycemia on relatives of patients with type 
1672 
1 diabetes. Diabetes Care 2003;26:1106-1109 
1673 
16. Laiteerapong N, Karter AJ, Liu JY, Moffet HH, Sudore R, Schillinger D, John PM, Huang 
1674 
ES: Correlates of quality of life in older adults with diabetes: the diabetes & aging study. 
1675 
Diabetes Care 2011;34:1749-1753 
1676 
17. Sturt J, Dennick K, Due-Christensen M, McCarthy K: The detection and management of 
1677 
diabetes distress in people with type 1 diabetes. Curr Diab Rep 2015;15:101 
1678 
18. Forlenza GP, Messer LH, Berget C, Wadwa RP, Driscoll KA: Biopsychosocial Factors 
1679 
Associated With Satisfaction and Sustained Use of Artificial Pancreas Technology and Its 
1680 
Components: a Call to the Technology Field. Curr Diab Rep 2018;18:114 
1681 
19. Naranjo D, Suttiratana SC, Iturralde E, Barnard KD, Weissberg-Benchell J, Laffel L, Hood 
1682 
KK: What End Users and Stakeholders Want From Automated Insulin Delivery Systems. 
1683 
Diabetes Care 2017;40:1453-1461 
1684 
20. Chaytor NS, Barbosa-Leiker C, Ryan CM, Germine LT, Hirsch IB, Weinstock RS: Clinically 
1685 
significant cognitive impairment in older adults with type 1 diabetes. J Diabetes Complications 
1686 
2018; 
1687 
21. Biessels GJ, Despa F: Cognitive decline and dementia in diabetes mellitus: mechanisms and 
1688 
clinical implications. Nat Rev Endocrinol 2018;14:591-604 
1689 
22. Chaytor NS, Riddlesworth TD, Bzdick S, Odegard PS, Gray SL, Lock JP, DuBose SN, Beck 
1690 
RW, Group TDESHiOAwTDS: The relationship between neuropsychological assessment, 
1691 
numeracy, and functional status in older adults with type 1 diabetes. Neuropsychol Rehabil 
1692 
2017;27:507-521 
1693 
23. Santos T, Lovell J, Shiell K, Johnson M, Ibrahim JE: The impact of cognitive impairment in 
1694 
dementia on self-care domains in diabetes: A systematic search and narrative review. Diabetes 
1695 
Metab Res Rev 2018;34:e3013 
1696 
24. Davis EA, Keating B, Byrne GC, Russell M, Jones TW: Hypoglycemia: incidence and 
1697 
clinical predictors in a large population-based sample of children and adolescents with IDDM. 
1698 
Diabetes Care 1997;20:22-25 
1699 
25. The Diabetes Control and Complications Trial Research Group: Hypoglycemia in the 
1700 
Diabetes Control and Complications Trial. Diabetes 1997;46:271-286 
1701 
26. Buckingham B, Block J, Burdick J, Kalajian A, Kollman C, Choy M, Wilson DM, Chase P, 
1702 
Diabetes Research in Children N: Response to nocturnal alarms using a real-time glucose sensor. 
1703 
Diabetes Technol Ther 2005;7:440-447 
1704 
27. Buckingham BA, Cameron F, Calhoun P, Maahs DM, Wilson DM, Chase HP, Bequette BW, 
1705 
Lum J, Sibayan J, Beck RW, Kollman C: Outpatient safety assessment of an in-home predictive 
1706 
low-glucose suspend system with type 1 diabetes subjects at elevated risk of nocturnal 
1707 
hypoglycemia. Diabetes Technol Ther 2013;15:622-627 
1708 
28. Buckingham BA, Raghinaru D, Cameron F, Bequette BW, Chase HP, Maahs DM, Slover R, 
1709 
Wadwa RP, Wilson DM, Ly T, Aye T, Hramiak I, Clarson C, Stein R, Gallego PH, Lum J, 
1710 
Sibayan J, Kollman C, Beck RW, In Home Closed Loop Study G: Predictive Low-Glucose 
1711 
Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without 
1712 
Increasing Ketosis. Diabetes Care 2015;38:1197-1204 
1713 
29. Maahs DM, Calhoun P, Buckingham BA, Chase HP, Hramiak I, Lum J, Cameron F, 
1714 
Bequette BW, Aye T, Paul T, Slover R, Wadwa RP, Wilson DM, Kollman C, Beck RW, In 
1715 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
Home Closed Loop Study G: A randomized trial of a home system to reduce nocturnal 
1716 
hypoglycemia in type 1 diabetes. Diabetes Care 2014;37:1885-1891 
1717 
30. Choudhary P, Olsen BS, Conget I, Welsh JB, Vorrink L, Shin JJ: Hypoglycemia Prevention 
1718 
and User Acceptance of an Insulin Pump System with Predictive Low Glucose Management. 
1719 
Diabetes Technol Ther 2016;18:288-291 
1720 
31. Garg SK, Weinzimer SA, Tamborlane WV, Buckingham BA, Bode BW, Bailey TS, Brazg 
1721 
RL, Ilany J, Slover RH, Anderson SM, Bergenstal RM, Grosman B, Roy A, Cordero TL, Shin J, 
1722 
Lee SW, Kaufman FR: Glucose Outcomes with the In-Home Use of a Hybrid Closed-Loop 
1723 
Insulin Delivery System in Adolescents and Adults with Type 1 Diabetes. Diabetes Technol Ther 
1724 
2017;19:155-163 
1725 
32. Tauschmann M, Thabit H, Bally L, Allen JM, Hartnell S, Wilinska ME, Ruan Y, Sibayan J, 
1726 
Kollman C, Cheng P, Beck RW, Acerini CL, Evans ML, Dunger DB, Elleri D, Campbell F, 
1727 
Bergenstal RM, Criego A, Shah VN, Leelarathna L, Hovorka R, Consortium AP: Closed-loop 
1728 
insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised 
1729 
trial. Lancet 2018;392:1321-1329 
1730 
33. Breton M, Farret A, Bruttomesso D, Anderson S, Magni L, Patek S, Dalla Man C, Place J, 
1731 
Demartini S, Del Favero S, Toffanin C, Hughes-Karvetski C, Dassau E, Zisser H, Doyle FJ, 3rd, 
1732 
De Nicolao G, Avogaro A, Cobelli C, Renard E, Kovatchev B, International Artificial Pancreas 
1733 
Study G: Fully integrated artificial pancreas in type 1 diabetes: modular closed-loop glucose 
1734 
control maintains near normoglycemia. Diabetes 2012;61:2230-2237 
1735 
34. Anderson SM, Raghinaru D, Pinsker JE, Boscari F, Renard E, Buckingham BA, Nimri R, 
1736 
Doyle FJ, 3rd, Brown SA, Keith-Hynes P, Breton MD, Chernavvsky D, Bevier WC, Bradley PK, 
1737 
Bruttomesso D, Del Favero S, Calore R, Cobelli C, Avogaro A, Farret A, Place J, Ly TT, 
1738 
Shanmugham S, Phillip M, Dassau E, Dasanayake IS, Kollman C, Lum JW, Beck RW, 
1739 
Kovatchev B, Control to Range Study G: Multinational Home Use of Closed-Loop Control Is 
1740 
Safe and Effective. Diabetes Care 2016;39:1143-1150 
1741 
35. Kovatchev B, Patek S, Dassau E, Doyle FJ, 3rd, Magni L, De Nicolao G, Cobelli C, Juvenile 
1742 
Diabetes Research Foundation Artificial Pancreas C: Control to range for diabetes: functionality 
1743 
and modular architecture. J Diabetes Sci Technol 2009;3:1058-1065 
1744 
36. Zisser H, Renard E, Kovatchev B, Cobelli C, Avogaro A, Nimri R, Magni L, Buckingham 
1745 
BA, Chase HP, Doyle FJ, 3rd, Lum J, Calhoun P, Kollman C, Dassau E, Farret A, Place J, 
1746 
Breton M, Anderson SM, Dalla Man C, Del Favero S, Bruttomesso D, Filippi A, Scotton R, 
1747 
Phillip M, Atlas E, Muller I, Miller S, Toffanin C, Raimondo DM, De Nicolao G, Beck RW, 
1748 
Control to Range Study G: Multicenter closed-loop insulin delivery study points to challenges 
1749 
for keeping blood glucose in a safe range by a control algorithm in adults and adolescents with 
1750 
type 1 diabetes from various sites. Diabetes Technol Ther 2014;16:613-622 
1751 
37. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM, 
1752 
Levy CJ, Pinsker JE, Wadwa RP, Dassau E, Doyle FJ, 3rd, Anderson SM, Church MM, Dadlani 
1753 
V, Ekhlaspour L, Forlenza GP, Isganaitis E, Lam DW, Kollman C, Beck RW, i DCLTRG: Six-
1754 
Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J 
1755 
Med 2019;381:1707-1717 
1756 
38. Messer LH: Why Expectations Will Determine the Future of Artificial Pancreas. Diabetes 
1757 
Technol Ther 2018;20:S265-S268 
1758 
39. Weissberg-Benchell J, Hood K, Laffel L, Heinemann L, Ball D, Kowalski A, Peters A, 
1759 
Damiano E, Schiller M, Davis A, Beck S, Barnard K: Toward Development of Psychosocial 
1760 
Measures for Automated Insulin Delivery. J Diabetes Sci Technol 2016;10:799-801 
1761 

 
AIDE T1D PROTOCOL V5.01 05-05-21 CLEAN 
40. Farrington C: Psychosocial impacts of hybrid closed-loop systems in the management of 
1762 
diabetes: a review. Diabet Med 2018;35:436-449 
1763 
41. Adams RN, Tanenbaum ML, Hanes SJ, Ambrosino JM, Ly TT, Maahs DM, Naranjo D, 
1764 
Walders-Abramson N, Weinzimer SA, Buckingham BA, Hood KK: Psychosocial and Human 
1765 
Factors During a Trial of a Hybrid Closed Loop System for Type 1 Diabetes Management. 
1766 
Diabetes Technol Ther 2018;20:648-653 
1767 
42. Miller KM, Kanapka LG, Pratley RE. Continous glucose monitoring reduces hypoglycemia 
1768 
and improves glycemic control among older adults with type 1 diabetes. In European Society for 
1769 
the Study of Diabetes (EASD). Barcelona, Spain,  
1770 
43. Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, Mitnitski A: A 
1771 
global clinical measure of fitness and frailty in elderly people. CMAJ 2005;173:489-495 
1772 
44. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings 
1773 
JL, Chertkow H: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild 
1774 
cognitive impairment. J Am Geriatr Soc 2005;53:695-699 
1775 
45. Wechsler D: Wechsler Adult Intelligence Scale-Revised. New York, Psychological 
1776 
Corporation, 1981 
1777 
46. Barkley R: Barkley Deficits in Executive Functioning Scale (BDEFS for Adults). New York, 
1778 
Guilford Press, 2011 
1779 
47. Smith G, Della Sala S, Logie RH, Maylor EA: Prospective and retrospective memory in 
1780 
normal ageing and dementia: a questionnaire study. Memory 2000;8:311-321 
1781 
48. Fisher L, Polonsky WH, Hessler DM, Masharani U, Blumer I, Peters AL, Strycker LA, 
1782 
Bowyer V: Understanding the sources of diabetes distress in adults with type 1 diabetes. J 
1783 
Diabetes Complications 2015;29:572-577 
1784 
49. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J: Fear of hypoglycemia: 
1785 
quantification, validation, and utilization. Diabetes Care 1987;10:617-621 
1786 
50. Polonsky WH, Fisher L, Hessler D, Edelman SV: Investigating Hypoglycemic Confidence in 
1787 
Type 1 and Type 2 Diabetes. Diabetes Technol Ther 2017;19:131-136 
1788 
51. Brooke J: SUS-A quick and dirty usability scale. Usability evaluation in industry 
1789 
1996;189:4-7 
1790 
52. van Bon AC, Kohinor MJ, Hoekstra JB, von Basum G, deVries JH: Patients' perception and 
1791 
future acceptance of an artificial pancreas. J Diabetes Sci Technol 2010;4:596-602 
1792 
53. Gold AE, MacLeod KM, Frier BM: Frequency of severe hypoglycemia in patients with type 
1793 
I diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994;17:697-703 
1794 
 
1795