The International Diabetes Closed Loop (iDCL) Trial: A Randomized Crossover Comparison of Adaptive Model Predictive Control (MPC) Artificial Pancreas Versus Sensor Augmented Pump (SAP)/Predictive Low Glucose Suspend (PLGS) in the Outpatient Setting in Type 1 Diabetes (DCLP4)
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Sansum Diabetes Research Institute

DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 1 OF 68 
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Protocol Identifier: DCLP4 
IND/IDE Sponsor: Sansum Diabetes Research Institute 
Version Number: v6.0 
14 DEC 2020 
 
JCHR Protocol Director (name/degree) 
John W. Lum, M.S. 
Signature/Date 
 
 
Clinical Lead Investigator (name/degree) 
Jordan E. Pinsker, MD 
Signature/Date 
 
 
Engineering Lead Investigator (name/degree) 
Eyal Dassau, PhD 
Signature/Date 
 
 
Medical Monitor (name/degree) 
Roy W. Beck, MD, PhD 
Signature/Date 
 
 
SIGN
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DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 2 OF 68 
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Protocol Identifying Number: DCLP4 
IND/IDE Sponsor: Sansum Diabetes Research Institute 
Funded by: National Institute of Diabetes and Digestive and Kidney Diseases 
Version Number: v6.0 
14 DEC 2020 
 
 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 3 OF 68 
TABLE OF CONTENTS 
KEY ROLES .................................................................................................................................................. 8 
LIST OF ABBREVIATIONS ............................................................................................................................ 9 
SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE ............................................................ 11 
PROTOCOL SUMMARY ............................................................................................................................... 12 
SCHEMATIC OF STUDY DESIGN ................................................................................................................ 15 
SCHEDULE OF STUDY VISITS AND PROCEDURES ..................................................................................... 16 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 17 
1.1 Introduction ....................................................................................................................................... 17 
1.1.1 Prior Clinical Evaluations of the Proposed AP System ............................................................... 17 
1.1.2 Next Generation Artificial Pancreas: Zone MPC and HMS on a Smartphone 
App ....................................................................................................................................................... 19 
1.2 Rationale ............................................................................................................................................ 20 
1.3 Automated Insulin Delivery System Description .............................................................................. 21 
1.4 Potential Risks and Benefits of the Investigational Device and Study Participation ........................ 22 
1.4.1 Known Potential Risks ................................................................................................................ 22 
1.4.1.1 Potential Risks and Benefits of the Investigational AID System ........................................ 22 
1.4.1.2 Risk of Hypoglycemia ........................................................................................................ 22 
1.4.1.3 Risk of Hyperglycemia ....................................................................................................... 23 
1.4.1.4 Insulin Infusion Risks ......................................................................................................... 23 
1.4.1.5 Venipuncture Risks ............................................................................................................. 23 
1.4.1.6 Fingerstick Risks ................................................................................................................. 23 
1.4.1.7 Subcutaneous Catheter Risks (CGM) ................................................................................. 23 
1.4.1.8 Risks Associated with Device Reuse .................................................................................. 23 
1.4.1.9 Questionnaire ...................................................................................................................... 23 
1.4.1.10 Other Risks ........................................................................................................................ 24 
1.4.2 Known Potential Benefits ............................................................................................................ 24 
1.4.3 Risk Assessment .......................................................................................................................... 24 
1.5 General Considerations...................................................................................................................... 24 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 25 
2.1 Participant Recruitment and Enrollment ........................................................................................... 25 
2.1.1 Pilot Phase ................................................................................................................................... 25 
2.2 Participant Eligibility Criteria ........................................................................................................... 25 

 
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2.2.1 Inclusion Criteria ......................................................................................................................... 25 
2.2.2 Exclusion Criteria ........................................................................................................................ 26 
2.3 Screening Procedures ........................................................................................................................ 27 
2.3.1 Data Collection and Testing ........................................................................................................ 27 
2.3.2 Screen Failures ............................................................................................................................ 28 
CHAPTER 3: PILOT PHASE ........................................................................................................................ 29 
3.1 Description ........................................................................................................................................ 29 
3.2 Enrollment and Screening Procedures ............................................................................................... 29 
3.3 Pilot Phase Visits and Procedures ..................................................................................................... 29 
3.4 Safety Review of Pilot Phase Data .................................................................................................... 29 
CHAPTER 4: CGM RUN-IN PHASE ............................................................................................................ 31 
4.1 Introduction ....................................................................................................................................... 31 
4.2 Initiation of CGM .............................................................................................................................. 31 
4.3 Assessment of Successful Completion of the CGM Run-in Phase ................................................... 31 
CHAPTER 5: RANDOMIZATION VISIT ....................................................................................................... 33 
5.1 Visit Timing ....................................................................................................................................... 33 
5.2 Data Collection and Testing .............................................................................................................. 33 
5.3 Randomization ................................................................................................................................... 33 
5.4 Device Training and Study Supplies ................................................................................................. 34 
5.4.1 CGM System Training, Initiation, and Supplies ......................................................................... 34 
5.4.2 Blood Ketone Meter Training and Supplies ................................................................................ 34 
5.4.3 Home Glucagon Emergency Kit ................................................................................................. 34 
5.4.4 Study System Training and Device Use ...................................................................................... 34 
5.4.4.1 Pump Training .................................................................................................................... 34 
5.4.4.2 Study Phone Training ......................................................................................................... 35 
5.4.4.3 General Usage Training and System Initiation ................................................................... 36 
5.4.5 SAP Training and Device Use ..................................................................................................... 37 
CHAPTER 6: CROSSOVER TRIAL HOME PROCEDURES ........................................................................... 38 
6.1 Guidance on Clinical Staff Contact ................................................................................................... 38 
6.2 Safety Measures ................................................................................................................................. 38 
6.2.1 Drug and Alcohol Use ................................................................................................................. 38 
6.2.2 CGM Calibration ......................................................................................................................... 38 
6.2.3 Study Pump Failure ..................................................................................................................... 38 
6.2.4 Insulin Dosing ............................................................................................................................. 38 
6.2.5 Optimization of Insulin Pump Settings ....................................................................................... 38 

 
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6.2.6 Hypoglycemia Safety Protocol .................................................................................................... 39 
6.2.7 Hyperglycemia Safety Protocol ................................................................................................... 39 
6.2.8 Device Data Uploads ................................................................................................................... 39 
6.2.9 Remote Monitoring ..................................................................................................................... 39 
CHAPTER 7: RCT FOLLOW-UP STUDY VISITS ......................................................................................... 41 
7.1 Timing of Visits ................................................................................................................................. 41 
7.1.1 Visit and Phone Contact Schedule during Study Periods 1 and 2 ............................................... 41 
7.2 Procedures at Phone Contacts and Follow-up Visits ......................................................................... 41 
7.2.1 Phone Contacts ............................................................................................................................ 41 
7.2.2 Procedures Performed During Each Follow-up Visit .................................................................. 41 
7.2.3 Early Termination Visit ............................................................................................................... 42 
7.2.4 Unscheduled Visits ...................................................................................................................... 42 
CHAPTER 8: STUDY DEVICES .................................................................................................................... 43 
8.1 Description of the Study Devices ...................................................................................................... 43 
8.1.1 AID Study System ....................................................................................................................... 43 
8.1.2 Insulin Pumps .............................................................................................................................. 43 
8.1.3 Continuous Glucose Monitoring ................................................................................................. 43 
8.1.4 Blood Glucose Meter and Strips .................................................................................................. 43 
8.1.5 Ketone Meter and Strips .............................................................................................................. 43 
8.2 Study Device Accountability Procedures .......................................................................................... 43 
8.3 Participant Access to Study Device at Study Closure ....................................................................... 43 
CHAPTER 9: LABORATORY TESTING AND QUESTIONNAIRES ................................................................. 44 
9.1 Laboratory Testing ............................................................................................................................ 44 
9.2 Questionnaires ................................................................................................................................... 44 
CHAPTER 10: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES ............................................ 46 
10.1 Unanticipated Problems ................................................................................................................... 46 
10.2 Adverse Events ................................................................................................................................ 46 
10.2.1 Definitions ................................................................................................................................. 46 
10.2.2 Reportable Adverse Events ....................................................................................................... 47 
10.2.3 Hypoglycemic Events ................................................................................................................ 48 
10.2.4 Hyperglycemia/Ketosis Events ................................................................................................. 48 
10.2.5 Relationship of Adverse Event to Study Device ....................................................................... 49 
10.2.6 Severity (Intensity) of Adverse Events ...................................................................................... 49 
10.2.7 Expectedness ............................................................................................................................. 49 
10.2.8 Coding of Adverse Events ......................................................................................................... 50 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
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10.2.9 Outcome of Adverse Events ...................................................................................................... 50 
10.3 Reportable Device Issues ................................................................................................................. 50 
10.4 Timing of Event Reporting .............................................................................................................. 51 
10.5 Safety Oversight .............................................................................................................................. 51 
10.6 Stopping Criteria.............................................................................................................................. 52 
10.6.1 Participant Discontinuation of Study Device ............................................................................ 52 
10.6.2 Criteria for Suspending or Stopping Overall Study ................................................................... 53 
CHAPTER 11: MISCELLANEOUS CONSIDERATIONS ................................................................................. 54 
11.1 Drugs Used as Part of the Protocol .................................................................................................. 54 
11.2 Collection of Medical Conditions and Medications ........................................................................ 54 
11.3 Prohibited Medications, Treatments, and Procedures ..................................................................... 54 
11.4 Rescue Medications ......................................................................................................................... 54 
11.5 Pregnancy Reporting ....................................................................................................................... 54 
11.6 Participant Compensation ................................................................................................................ 54 
11.7 Participant Withdrawal .................................................................................................................... 55 
11.8 Confidentiality ................................................................................................................................. 55 
CHAPTER 12: STATISTICAL CONSIDERATIONS ........................................................................................ 56 
12.1 Statistical and Analytical Plans ....................................................................................................... 56 
12.2 Statistical Hypotheses ...................................................................................................................... 56 
12.3 Sample Size ..................................................................................................................................... 56 
12.4 Outcome Measures .......................................................................................................................... 56 
12.4.1 Primary Efficacy Endpoint ........................................................................................................ 56 
12.4.2 Secondary Efficacy Endpoints .................................................................................................. 56 
12.4.2.1 Secondary Efficacy Endpoint Included in Hierarchical Analysis ..................................... 56 
12.4.2.2 Other Secondary Efficacy Endpoints ................................................................................ 57 
12.4.3 CGM Metrics Calculations ........................................................................................................ 58 
12.5 Analysis Datasets and Sensitivity Analyses .................................................................................... 58 
12.5.1 Per Protocol Analyses................................................................................................................ 58 
12.5.2 Sensitivity Analyses .................................................................................................................. 59 
12.5.2.1 Missing Data ..................................................................................................................... 59 
12.5.2.2 Carry-over Effect .............................................................................................................. 59 
12.6 Analysis of the Primary Efficacy Endpoint ..................................................................................... 59 
12.7 Analysis of the Secondary Endpoints .............................................................................................. 59 
12.7.1 Hierarchical Analyses ................................................................................................................ 59 
12.7.2 Other Endpoint Analyses ........................................................................................................... 60 
12.8 Safety Analyses ............................................................................................................................... 60 

 
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12.9 Intervention Adherence and Adaptation .......................................................................................... 61 
12.10 Adherence and Retention Analyses ............................................................................................... 61 
12.11 Baseline Descriptive Statistics ....................................................................................................... 61 
12.12 Device Issues ................................................................................................................................. 61 
12.13 Planned Interim Analyses .............................................................................................................. 62 
12.14 Subgroup Analyses ........................................................................................................................ 62 
12.15 Multiple Comparison/Multiplicity ................................................................................................. 62 
CHAPTER 13: DATA COLLECTION AND MONITORING ............................................................................ 63 
13.1 Case Report Forms and Device Data ............................................................................................... 63 
13.2 Study Records Retention ................................................................................................................. 63 
13.3 Quality Assurance and Monitoring .................................................................................................. 63 
13.4 Protocol Deviations ......................................................................................................................... 64 
CHAPTER 14: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 65 
14.1 Ethical Standard ............................................................................................................................... 65 
14.2 Institutional Review Board (IRB) (or Ethics Committee (EC)) ...................................................... 65 
14.3 Informed Consent Process ............................................................................................................... 65 
14.3.1 Consent Procedures and Documentation ................................................................................... 65 
14.3.2 Participant and Data Confidentiality ......................................................................................... 65 
CHAPTER 15: REFERENCES ....................................................................................................................... 67 
 
 
 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
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Key Roles 
 
Protocol Chairs/Co-Directors 
Name, degree 
Eyal Dassau, PhD 
Title 
Director, Biomedical Systems Engineering Research Group 
Institution Name 
Harvard John A. Paulson School of Engineering and Applied Sciences 
Name, degree 
Jordan E. Pinsker, MD 
Title 
Research Physician 
Institution Name 
Sansum Diabetes Research Institute 
 
JCHR Coordinating Center Director 
Name, degree 
John Lum, M.S. 
Title 
Director, Artificial Pancreas Coordinating Center 
Institution Name 
Jaeb Center for Health Research 
 
Medical Monitor 
Name, degree 
Roy Beck, M.D., Ph.D. 
Title 
Executive Director 
Institution Name 
Jaeb Center for Health Research 
 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 9 OF 68 
List of Abbreviations 
ABBREVIATION 
DEFINITION 
ADE 
Adverse Device Effect 
AID 
Automated Insulin Delivery 
AE 
Adverse Event 
AHCL 
Advanced Hybrid Closed-Loop 
AP 
Artificial Pancreas 
ATTD 
Advanced Technologies & Treatments for Diabetes 
AUC 
Area Under the Curve 
BG 
Blood Glucose 
BGM 
Blood Glucose Meter 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
CLC 
Closed-Loop Control 
CSII 
Continuous Subcutaneous Insulin Infusion 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
FDR 
False Discovery Rate 
FWER 
Familywise Error Rate 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCL 
Hybrid Closed Loop 
HMS 
Health Monitoring System 
iAPS 
Interoperable Artificial Pancreas System 
ID 
Identification 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IQR 
Interquartile Range 
JCHR 
Jaeb Center for Health Research 
IRB 
Institutional Review Board 
MPC 
Model Predictive Control 
NIH 
National Institutes of Health 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
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ABBREVIATION 
DEFINITION 
PID 
Proportional, Integral, and Derivative 
PLGS 
Predictive Low Glucose Suspend 
POC 
Point-of-Care 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
RCT 
Randomized Controlled/Clinical Trial 
RBM 
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 
SUS 
System Usability Scale Survey 
T1D 
Type 1 Diabetes 
TDI 
Total Daily Insulin 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 
 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
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Site Principal Investigator Statement of Compliance 
Protocol Title: The International Diabetes Closed Loop (iDCL) trial: A Randomized 
Crossover Comparison of Adaptive Model Predictive Control (MPC) Artificial Pancreas 
vs. Sensor Augmented Pump (SAP)/Predictive Low Glucose Suspend (PLGS) in the 
Outpatient Setting in Type 1 Diabetes (DCLP4) 
Protocol Version/Date: v6.0/14 DEC 2020 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
providing the Jaeb Center for Health Research, which serves as the Coordinating Center for the 
protocol, with complete and timely information, as outlined in the protocol. It is understood that 
all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
required by the following (use applicable regulations depending on study location and sponsor 
requirements; examples follow): United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 
312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training. Further, 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
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DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 12 OF 68 
Protocol Summary 
 
Title 
The International Diabetes Closed Loop (iDCL) trial: A Randomized Crossover Comparison of Adaptive 
Model Predictive Control (MPC) Artificial Pancreas Versus Sensor Augmented Pump (SAP)/Predictive 
Low Glucose Suspend (PLGS) in the Outpatient Setting in Type 1 Diabetes (DCLP4) 
Précis 
A randomized crossover trial will compare the efficacy and safety of an automated insulin delivery (AID) 
study system using an adaptive Model Predictive Control (MPC) algorithm versus SAP (which may or 
may not include PLGS; to be referred to as SAP) therapy in people with type 1 diabetes.  A Pilot Phase 
involving at least 5 participants using the study system for 10-14 days will be conducted prior to the 
crossover trial. 
Investigational 
Device 
The AID study system is composed of a Tandem t:AP pump, a Dexcom G6 continuous glucose 
monitoring sensor, and a smart phone that contains the adaptive algorithm and communicates with the 
other devices. 
Objectives 
To compare the efficacy and safety of an AID system using an adaptive MPC algorithm versus SAP or 
PLGS therapy in people with type 1 diabetes. 
Study Design 
Randomized Crossover Trial with two 13-week periods, preceded by a CGM run-in phase. 
Number of 
Sites 
5-7 U.S. sites 
Major 
Endpoints  
Superiority for time in range 70-180 mg/dL and non-inferiority for time <54 mg/dL measured with CGM 
will be considered primary endpoints, analyzed using a hierarchical gatekeeping testing procedure 
Secondary outcomes will include HbA1c and the following CGM metrics 
x 
Mean glucose 
x 
Time >180 mg/dL 
x 
Time >250 mg/dL 
x 
Time <70 mg/dL 
x 
Time <54 mg/dL (superiority) 
x 
Coefficient of variation 
Population 
Inclusion 
x 
Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year and 
using insulin for at least 1 year  
x 
Using an insulin pump for at least 3 months (which may include use of automated features)  
x 
Familiarity and use of a carbohydrate ratio for meal boluses 
x 
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x 
For females, not currently known to be pregnant 
If female and sexually active, must agree to use a form of contraception to prevent pregnancy 
while a participant in the study. A negative serum or urine pregnancy test will be required for 
all females of child-bearing potential. Participants who become pregnant will be discontinued 
from the study. Also, participants who during the study develop and express the intention to 
become pregnant within the timespan of the study will be discontinued. 
x 
If using a personal CGM, willingness to use a Dexcom G6 CGM and discontinue personal 
CGM use during the study 
x 
Willing not to begin use of, or not to continue use of if currently using, a personal AID 
(closed loop control) system during the study; note if the system offers an open-loop mode or 
can be switched to a PLGS mode that is compatible with the Dexcom G6, the system may be 
used during the study in these modes only 
x 
Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, and to use 
no other insulin besides lispro (Humalog) or aspart (Novolog) during the study 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 13 OF 68 
 
x 
Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
trial, and not to use Afrezza during the trial 
x 
Investigator believes that the participant can successfully and safely operate all study devices 
and is capable of adhering to the protocol 
Exclusion Criteria 
1) 
Use of Afrezza or any non-insulin glucose-lowering agent other than metformin (including 
GLP-1 agonists, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas) unless participant is 
willing to discontinue during the trial. 
2) 
Two or more episodes of DKA requiring an emergency room visit or hospitalization in the past 
6 months  
3) 
Two or more episodes of severe hypoglycemia with seizure or loss of consciousness in the last 6 
months 
4) 
Hemophilia or any other bleeding disorder 
5) 
A medical or other condition that in the opinion of the investigator could create a safety concern 
for the participant or put the study at risk 
a. 
History of frequent severe hypoglycemia or history of frequent severe hyperglycemia 
and/or ketosis, without emergency room visit or hospitalization, due to poor diabetes 
self-management may be disqualifying per investigator judgment 
6) 
Participation in another pharmaceutical or device trial at the time of enrollment or during the 
study 
Sample Size 
Up to 35 individuals randomized in the crossover trial with the goal of at least 32 completing the trial 
Treatment 
Groups 
Random assignment (1:1) to begin period 1 either with the AID study system or with SAP using home 
pump and then cross over to the other respective treatment in period 2 
Participant 
Duration 
6-7 months 
Protocol 
Overview/ 
Synopsis 
Screening and Enrollment 
x 
Informed consent will be signed, and eligibility will be assessed 
x 
Medical history and physical examination 
x 
HbA1c measurement using point-of-care device (if not available from prior 3 months) 
x 
Urine pregnancy test (if applicable) 
x 
Baseline questionnaires completed 
Pilot Phase 
The Pilot Phase will include 1-2 participants at each site, using a personal Dexcom G5/6 with use on at 
least 11 of the prior 14 days and the investigator believes that a CGM run-in is unnecessary.  The Pilot 
Phase is intended to (1) test the functionality of all aspects of the study System and (2) train the clinical 
staff on the execution of the clinical protocol, including hands-on training with the device prior to 
initiating the RCT Period.  Screening and study system start up procedures will be the same as for the 
Crossover Trial. Participants will use the study system for 10-14 days.  After at least 5 total participants 
from at least 3 different sites have completed the Pilot Phase, the data will be reviewed for preset safety 
criteria before proceeding to the RCT.  Assuming there are no significant safety or device issues that 
occur, the Crossover Trial will begin. 
CGM Run-In (2-4 weeks) 
Eligible participants using a personal Dexcom G5/G6 sensor, with use on at least 11 of the prior 14 days 
may skip the CGM run-in unless the investigator believes that there is a need to optimize insulin pump 
settings prior to randomization.  Participants skipping the run-in can go directly to the randomization visit. 
Eligible participants not currently using a personal Dexcom G5/G6 sensor or using a Dexcom G5/G6 
sensor with readings captured on less than 11 out of the prior 14 days will initiate a CGM run-in phase 
with a study Dexcom G6 sensor.   
x 
Users of a sensor other than Dexcom G5/G6 (eg, Medtronic, Abbott) must be willing to 
discontinue use of that sensor for the duration of the study and users of an AID (closed loop 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 14 OF 68 
 
control) system must be willing to discontinue its use during the study (PLGS mode can be used 
during the study if feasible). 
Duration of the run-in will be 2-4 weeks at investigator discretion. During this time, Study Staff will 
review uploaded CGM data and may optimize insulin pump settings as needed by phone contact with 
subjects. Prior to each phone contact, the participant will be asked to upload the CGM and if possible 
pump data for study staff review.  Successful completion of the run-in will require use of the sensor for at 
least 11 days during a final assessment period of 14 days. 
The run-in may be extended at investigator discretion if the investigator believes that additional training is 
needed or the participant should have another opportunity to achieve the 11 day use criterion. 
Randomized Cross-Over Trial 
Eligible participants will be randomly assigned to one of two treatment groups for 13 weeks each: 
1. 
Group A: study system for period 1 for 13 weeks, then SAP for period 2 for 13 weeks 
2. 
Group B: SAP for period 1 for 13 weeks, then study system for Period 2 for 13 weeks 
Study System Period: The participant will be trained regarding AID study system use including meal 
announcement, meal bolusing, correction doses, and exercise. Participants will be expected to use the 
study system at all times at home with the exception of times of illness.   
SAP Period:  During the SAP period, participants will use their own insulin pump and a study-provided 
Dexcom G6 sensor.   
x 
PLGS mode on the pump can be used if feasible but an AID system cannot be used. 
Study Flow 
Period 1 will commence on the day of randomization with initiation of the study system or continued use 
of personal pump SAP. 
Both groups will have the same contact and visit schedule in both period 1 and period 2 
x 
Visits at 2 weeks, 6 weeks, and 13 weeks 
x 
Phone contacts at 3 days, 4 weeks, and 9 weeks 
At randomization, and at each end of period visit, central lab HbA1c measurement will be made, a 
pregnancy test will be performed in applicable subjects, and quality of life and treatment satisfaction 
questionnaires will be completed. 
At the end of period 1 visit, the intervention will be switched to the study system or SAP for period 2.  
There will not be a washout period. 
Throughout the study, the occurrence of adverse events and device issues will be solicited and recorded. 
 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 15 OF 68 
Schematic of Study Design 
 
Figure 1. Schematic of Study Design; note clinic visits at 2, 6, and 13 weeks may be replaced by 
videoconferences at investigator discretion, as detailed in Chapter 7:. 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 16 OF 68 
Schedule of Study Visits and Procedures 
Table 1. Schedule of Visits and Procedures During the Crossover Trial 
1. Two 13-Week treatment periods with no intervening washout 
2. Will coincide with Randomization Visit for study period 1 
3. For study period 2 only 
4. For Group B participants (those assigned to use SAP during period 1) only 
 
 
Screening 
Visit 
CGM 
Run-in Visit 
Randomization 
Visit 
Days (d) or Weeks (w) from the Start of 
Each of Two 13-Week Study Periods1 
 
0d2 
3d 
2w 
4w 
6w 
9w 
13w 
Visit (V) or Contact (C) 
 
 
V 
V 
C 
V 
C 
V 
C 
V 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
Medical history/ 
physical exam 
X 
 
 
 
 
 
 
 
 
 
Height, weight, 
blood pressure and pulse 
X 
 
 
 
 
 
 
 
 
X 
HbAlc (POC or local lab, if 
needed) 
X 
 
 
 
 
 
 
 
 
 
HbA1c (Central lab)  
 
 
X 
 
 
 
 
 
 
X 
C-peptide and 
blood glucose (Central Lab) 
 
 
X 
 
 
 
 
 
 
 
Pregnancy test (females 
of child-bearing potential) 
X 
 
X 
X3 
 
 
 
 
 
 
Questionnaires  
X 
 
 
 
 
 
 
 
 
X 
Assessment of CGM use 
X 
X 
 
 
 
 
 
 
 
 
Study system training 
 
 
X 
X4 
 
 
 
 
 
 
AE Assessment 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Upload device data 
from home 
 
 
 
 
X 
 
X 
 
X 
 
Download device data 
at clinic visit 
 
X 
 
 
 
X 
 
X 
 
X 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
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Chapter 1: Background Information 
1 
1.1 Introduction 
2 
Type 1 diabetes (T1D) causes autoimmune pancreatic beta cell destruction and lifelong 
3 
dependency on exogenous insulin. Subsequently, patients with T1D are at risk for long-term life-
4 
threatening microvascular and macrovascular complications that can be abated by aiming to 
5 
achieve near-normal blood glucose. However, this tight control is associated with a threefold 
6 
increase in the risk of severe hypoglycemic events, one of the most feared and dangerous events 
7 
for patients and their parents or caregivers (1). Therefore, the ultimate goal in diabetes care is to 
8 
keep blood glucose in a narrow desired range with minimal hypoglycemic events. Over the past 
9 
decade, the use of insulin pumps and sensors and their combination (sensor-augmented pumps) 
10 
have shown advances towards improving glucose control (2-4). However, recent data from 
11 
diabetes centers in Europe and the United States (US) indicate that the glycemic control achieved 
12 
is still not satisfactory and is complicated by the risk of hypoglycemia (5,6), despite the use of 
13 
the advanced technological tools now available (7). Some progress is being made with the 
14 
introduction of the threshold suspend or predictive low-glucose suspend (PLGS) sensor and 
15 
pump systems in the United States. We now need to combine predictive features with PLGS 
16 
features to minimize hyperglycemia as well (8), without causing anxiety and burden for patients 
17 
and caregivers due to the demand for continual attention to how well the systems cover meals, 
18 
snacks and periods of illness. This is especially true in adolescents and some young adults whose 
19 
compliance with treatment can be low, with 50% omitting or delaying insulin boluses needed for 
20 
meals (9). Automated decision support systems, and ultimately, full automated management 
21 
solutions, are strongly desired by patients with T1D and their caregivers to improve metabolic 
22 
control and relieve them of the stress and burden of daily treatment of this chronic disease. 
23 
1.1.1 Prior Clinical Evaluations of the Proposed AP System 
24 
Several clinical studies using the novel zone MPC control framework which is the basis for the 
25 
proposed research shows consistently that the Artificial Pancreas (AP) is able to improve glucose 
26 
regulation in T1D. Dassau et al. (FDA IDE G090129) published in 2013 results of a pilot clinical 
27 
trial conducted at Sansum Diabetes Research Institute (SDRI), evaluating individualized, fully 
28 
automated (no premeal bolus) AP using commercial devices (1). Two trials (n= 22, n=17) were 
29 
conducted using a multi parametric formulation of MPC and an insulin-on-board algorithm. 
30 
Continuous glucose monitor (CGM) glucose was maintained in the near-normal range 70-180 
31 
mg/dL for an average of 70% of the trial time. These results showed the ability of a control 
32 
algorithm tailored to an individual's physiology to successfully regulate glycemia, even when 
33 
faced with unannounced meals or initial hyperglycemia. We (FDA IDE G110093) studied the 
34 
safety and efficacy of a fully automated AP using zone MPC with the health monitoring system 
35 
(HMS) during unannounced meals and overnight and exercise periods. A fully automated closed-
36 
loop AP was evaluated in 12 subjects with T1D and demonstrated 80% and 92% time in the 70±
37 
180 mg/dL range for the entire session and overnight, respectively. These results showed that the 
38 
combination of the zone MPC controller and the HMS hypoglycemia prevention algorithm was 
39 
able to safely regulate glucose in a tight range with no adverse events despite the challenges of 
40 
unannounced meals and moderate exercise. The zone MPC algorithm was successfully used in 
41 
2015 (FDA IDE G130147), when Drs. Dassau and Doyle AP team, Mayo Clinic and SDRI, 
42 
among other sites, showed in a randomized clinical trial of 32 subjects in a transitional 
43 
environment (such as hotel) that algorithmic adjustment of individualized insulin dosing 
44 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 18 OF 68 
parameters was safe and effective for AP use (2). As part of the DP3DK094331 research project, 
45 
the fruitful collaboration among Drs. Dassau and Doyle AP team, UVA, Mayo Clinic, SDRI and 
46 
other collaborators yielded a large outpatient clinical trial of the zone MPC and HMS system 
47 
(FDA IDE G150063), where 30 adult subjects each used AP at home for three months (3). This 
48 
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49 
SDQGK\SRJO\FHPLDGXULQJWKHGD\IURPWRí&,íWRí
50 
p<0.001) over the three months of AP use (Figure 2). 
51 
 
52 
Figure 2. Change in HbA1c compared to percent time hypoglycemia in a three-month outpatient study 
53 
comparing our zone MPC algorithm to SAP use in patients with T1D (3). Mean HbA1c change and 
54 
reduction in percent time CGM glucose <70 mg/dL are shown by the black line and filled in black circles. 
55 
Individual subjects are shown by the colored lines and colored circles. 
56 
The zone MPC controller has also been used for outpatient studies in adolescents (FDA IDE 
57 
G150122), with unannounced exercise multiple times per day and large meals. Mean CGM 
58 
glucose was significantly lower during AP vs. SAP use (150±19 vs 173±32, P = 0.042) (4). We 
59 
also recently concluded a randomized-crossover study comparing glycemic control of the zone 
60 
MPC AP system versus SAP therapy use at home in which insulin infusion set (IIS) and CGM 
61 
failures were precipitated in 7 and 21 days of use, respectively, in which results were 
62 
significantly better for zone MPC compared to SAP use (5). Our second generation target MPC 
63 
AP system (enhanced MPC, or eMPC) (6) with the addition of a trust index that weights future 
64 
insulin delivery based on past glucose predictions (7) was evaluated in 15 adult subjects studied 
65 
for 48 hours in SDRI, and achieved 88% time in the target glucose range 70-180 mg/dL (8). 
66 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 19 OF 68 
1.1.2 Next Generation Artificial Pancreas: Zone MPC and HMS on a Smartphone App 
67 
The zone MPC algorithm has been implemented on the interoperable Artificial Pancreas System 
68 
(iAPS), a novel, user friendly smartphone application and the system was clinically evaluated in 
69 
a feasibility study (FDA IDE G180011), where it achieved 83% time in glucose range 70-180 
70 
mg/dL and mean CGM of 136 mg/dL (9). 
71 
iAPS is a smartphone-based artificial pancreas platform which provides seamless integration 
72 
with Dexcom G5 and G6 CGM, and two different insulin pumps: Tandem t:slim and Insulet 
73 
Omnipod. The app is designed to be cross-platform (Android and iOS), can be used concurrently 
74 
with typical apps in a smartphone, and is designed to be interoperable and compatible with 
75 
leading devices for diabetes management. As the app resides in a smartphone and connects 
76 
wirelessly to the CGM and the insulin pump, the complete system is very portable and user 
77 
friendly. 
78 
In addition to the hardware integration, the iAPS app provides an interface to the algorithms for 
79 
AP glucose regulation, namely the zone MPC and the HMS, which provides an audio-visual 
80 
advisory alarm for hypoglycemia. The app has an intuitive user interface (UI) allowing the user 
81 
to request an insulin bolus for meal/correction and providing ability to log various activities such 
82 
as exercise (Figure 3). It also provides alarms for system malfunction, e.g. loss of connectivity 
83 
with devices, including text-PHVVDJHVWRWKHVXEMHFW¶VFDUHSDUWQHUVIRUDODUPHYHQWVVXFKDV
84 
impending hypoglycemia. A web-based remote monitoring facility complements the app running 
85 
on the smartphone allowing the clinician to verify salient features of subjects¶ glycemic health. 
86 
 
87 
Figure 3. iAPS Interface 
88 
Our AP algorithms have been clinically evaluated in previous clinical studies (17 IDEs) with 
89 
over 76,000 hours of human use as shown in Table 2. 
90 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 20 OF 68 
Table 2. Summary of use of prior studies with the Artificial Pancreas System (APS) in different hardware 
91 
configurations, as well as different variants of the Model Predictive Control (MPC) and Health 
92 
Monitoring System (HMS) algorithms. 
93 
Study 
Year 
IDE # 
Components 
Platform 
Hours of 
Human Use 
Location 
PubMed Link 
2019 
G180011/S002 
t:slim-Dexcom 
(ZMPC and HMS) 
iAPS 
>4,000 Hours 
12 Subjects 
Outpatient at 
Home 
In Progress 
2019 
G180011/S001 
t:slim-Dexcom 
(ZMPC and HMS) 
iAPS 
>3,500 Hours 
10 Subjects 
Outpatient at 
Home 
In Progress 
2018 
G160279/S002 
t:slim-Dexcom 
(ZMPC and HMS) 
iAPS 
800 Hours 
18 Subjects 
Supervised 
Outpatient 
In Progress 
2018 
G180011 
t:slim/OmniPod-Dexcom 
(ZMPC and HMS) 
iAPS 
300 Hours 
6 Subjects 
Supervised 
Outpatient 
30547670 
2017 
G150063 
Roche-Dexcom 
(ZMPC and HMS) 
DiAs 
>60,000 Hours 
30 Subjects 
Outpatient at 
Home 
29030383 
2017 
G150122/S003 
Roche-Dexcom 
(ZMPC and HMS) 
DiAs 
>6,000 Hours 
19 Subjects 
Outpatient at 
Home 
28584075 
2017 
G160281 
OmniPod-Dexcom 
(PBH algorithm) 
pAPS 
>50 Hours 
10 Subjects 
Supervised 
CRC 
29355439 
2017 
G160281 
OmniPod-Dexcom 
(Target eMPC and HMS) 
pAPS 
>700 Hours 
15 Subjects 
Supervised 
CRC 
29958023 
2016 
G150122 
Roche-Dexcom 
(ZMPC and HMS) 
DiAs 
>700 Hours 
10 Subjects 
Supervised 
Hotel 
28459617 
2016 
G160169 
OmniPod-Dexcom 
(Target eMPC and HMS) 
pAPS 
>1,950 Hours 
54 Subjects 
Supervised 
CRC 
29431513 
2015 
G130147 
Animas-Dexcom 
(ZMPC and HMS) 
pAPS 
>1,500 Hours 
32 Subjects 
Supervised 
CRC 
26204135 
2015 
G130236 
Animas-Dexcom 
(Target MPC/PID - 
HMS) 
pAPS 
>1,500 Hours 
30 Subjects 
Supervised 
CRC 
27289127 
2013 
G110093/S006 
Animas-Dexcom 
(ZMPC and HMS) 
APS 
36 Hours 
4 Subjects 
Supervised 
CRC 
24351171 
2013 
G110093/S003 
OmniPod-Dexcom 
(ZMPC/HMS, Inhaled 
Insulin) 
APS 
>200 Hours 
9 Subjects 
Supervised 
CRC 
25901023 
2012 
G110093 
Animas-Dexcom 
(Zone MPC and HMS) 
APS 
>275 Hours 
12 Subjects 
Supervised 
CRC 
24471561 
2012 
G110069 
Animas-Dexcom 
(ZMPC and HMS) 
APS 
>250 Hours 
13 Subjects 
Supervised 
CRC 
24876535 
1.2 Rationale 
94 
We aim to compare the efficacy and safety of an AID system using an adaptive MPC algorithm 
95 
versus SAP (which may or may not include PLGS; to be referred to as SAP) in people with type 
96 
1 diabetes. 
97 
This study builds on the ideas presented in G150063 (3), where adaptation of insulin delivery 
98 
settings occurred weekly to improve closed-loop function. In this study, adaptations of insulin 
99 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 21 OF 68 
delivery settings occur weekly inside the study phone. These adaptations are posted on the study 
100 
web monitoring website for complete visibility to study staff.  
101 
Current studies of Artificial Pancreas are initialized using fixed clinical inputs such as basal rate, 
102 
insulin to carbohydrate ration and correction factors that are updated and managed by the clinical 
103 
team, as well as fixed controller parameters. However, these settings frequently need adjustment 
104 
over time. A major goal of this initiative is to reduce the burden of adapting these settings over 
105 
time from the clinical team and the patient to move toward an automated system that gradually 
106 
and continually optimizes these settings for the patient, as we believe this will aid controller 
107 
function to improve time-in-range beyond what can be done today. 
108 
1.3 Automated Insulin Delivery System Description 
109 
The interoperable Artificial Pancreas System (iAPS) is an artificial pancreas system (as 
110 
described in MAF-1625, Amendment #10), composed primarily of an insulin pump, a CGM, and 
111 
a cellular phone device to connect the components. The portable AP device is intended to adjust 
112 
insulin doses when glucose concentration is, or is predicted to be, outside the specified target 
113 
range of 90-120 mg/dL. It includes a redundant safety control that will send warnings of 
114 
impending hypoglycemia and recommend ingesting carbohydrates immediately to prevent 
115 
hypoglycemia. 
116 
iAPS is described in MAF-1625, Amendment #10, and for this study will include: 
117 
x A cellular phone device to connect to the insulin pump and CGM transmitter. 
118 
¡ Google Pixel 1, 2, 3 or 4 Cellular Phone. For subjects who agree, they may move their 
119 
personal phone SIM card to the study phone and use the study phone as their personal 
120 
phone during closed-loop. 
121 
x Dexcom G6® Sensor & Transmitter 
122 
x An insulin pump consisting of the Tandem t:AP insulin pump (San Diego, CA) 
123 
(MAF 2032-A003) 
124 
x The same core control algorithm successfully used in IDE G180011/S002, G180011/S001 
125 
and G160279/S002 (Zone MPC with HMS). 
126 
x The same Health Monitoring System (HMS) algorithm used in G180011/S002, 
127 
G180011/S001 and G160279/S002 which issues safety notifications to the subject and 
128 
support personnel to prevent impending hypoglycemia. 
129 
A schematic of the iAPS system is shown in Figure 4. 
130 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 22 OF 68 
 
131 
Figure 4. Schematic of the supported principal system hardware components of iAPS. For this study, 
132 
only the Tandem t:AP pump and Dexcom G6 sensor will be used. 
133 
1.4 Potential Risks and Benefits of the Investigational Device and Study Participation 
134 
Risks and benefits are detailed below. Loss of confidentiality is a potential risk; however, data 
135 
are handled to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are 
136 
always a risk in participants with type 1 diabetes and participants will be monitored for this. 
137 
1.4.1 Known Potential Risks 
138 
1.4.1.1 Potential Risks and Benefits of the Investigational AID System 
139 
Even though the study system has been tested prior to this study, there is still a risk that parts of 
140 
the system may not function properly. The following are possible reasons the system may deliver 
141 
too much insulin or incorrectly stop insulin delivery: 
142 
x CGM sensor reads higher or lower than the actual glucose level which increases risk for 
143 
hypoglycemia and hyperglycemia with automated insulin delivery system; 
144 
x Device malfunctions that could produce a suspension of insulin delivery or over delivery 
145 
of insulin. 
146 
1.4.1.2 Risk of Hypoglycemia 
147 
As with any person having type 1 diabetes and using insulin, there is always a risk of 
148 
hypoglycemia.  The frequency of hypoglycemia should be no more and possibly less than it 
149 
would be as part of daily living.  Symptoms of hypoglycemia can include sweating, jitteriness, 
150 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 23 OF 68 
and not feeling well.  Severe hypoglycemia is possible with loss of consciousness or seizures. 
151 
Recurrent hypoglycemia may reduce hypoglycemia awareness. A CGM functioning poorly and 
152 
significantly over-reading glucose values could lead to inappropriate insulin delivery. 
153 
1.4.1.3 Risk of Hyperglycemia 
154 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
155 
extended period or if the pump or infusion set is not working properly.  A CGM functioning 
156 
poorly and significantly under-reading glucose values could lead to inappropriate suspension of 
157 
insulin delivery. 
158 
1.4.1.4 Insulin Infusion Risks 
159 
The pump infusion set is inserted under the skin.  An infection can occur very infrequently, but, 
160 
if an infection was to occur, oral and/or topical antibiotics can be used. Infusion set failure 
161 
(clogs, kinks, accidental removal) may occur, leading to hyperglycemia or ketosis. 
162 
1.4.1.5 Venipuncture Risks 
163 
Blood draws can cause some common reactions like pain, bruising, or redness at the sampling 
164 
site.  Less common reactions include bleeding from the sampling site, formation of a small blood 
165 
clot or swelling of the vein and surrounding tissues, and fainting. 
166 
1.4.1.6 Fingerstick Risks 
167 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
168 
HbA1c or other tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small 
169 
amount of bleeding under the skin will produce a bruise.  A small scar may persist for several 
170 
weeks.  The risk of local infection is less than 1 in 1000.  This should not be a significant 
171 
contributor to risks in this study as fingersticks are part of the usual care for people with diabetes. 
172 
1.4.1.7 Subcutaneous Catheter Risks (CGM) 
173 
Use of CGM has a low risk for developing a local skin infection at the site of the sensor needle 
174 
placement.  There may be bleeding where the catheter is put in and bleeding under the skin 
175 
causes a bruise (1 in 10 risk). 
176 
On rare occasions, the sensor may break and leave a small portion of the sensor under the skin 
177 
that may cause redness, swelling or pain at the insertion site. 
178 
1.4.1.8 Risks Associated with Device Reuse 
179 
In the study, we may reuse CGM receivers after careful cleaning.  The CGM transmitters and 
180 
sensors will not be reused. 
181 
In the study, the insulin pump may be reused after careful cleaning. 
182 
1.4.1.9 Questionnaire 
183 
As part of the study, participants will complete questionnaires which include questions about 
184 
their private attitudes, feelings and behavior related to the investigational equipment as well as 
185 
managing diabetes.  It is possible that some people may find these questionnaires to be mildly 
186 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 24 OF 68 
upsetting. Similar questionnaires have been used in previous research and these types of 
187 
reactions have been uncommon. 
188 
1.4.1.10 Other Risks 
189 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
190 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
191 
,IWKHVHUHDFWLRQVRFFXUGLIIHUHQWDGKHVLYHVRU³XQGHU-WDSLQJ´VXFKDVZLWK,97HJDGHUP
192 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
193 
medication may be required. 
194 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be 
195 
collected for the study as measures of diabetes self-management behaviors.  Some people may be 
196 
uncomfortable with the researchers' having such detailed information about their daily diabetes 
197 
habits. 
198 
1.4.2 Known Potential Benefits 
199 
It is expected that this protocol will yield increased knowledge about using an automated closed-
200 
loop to control the glucose level. In addition, it is the belief of the investigators that this study 
201 
also presents prospect of direct benefit to the participants who may learn how to better control 
202 
their diabetes after the study ends and general benefit to others with diabetes. 
203 
1.4.3 Risk Assessment 
204 
The investigators believe that the risk of study participation is small over and above the daily 
205 
risks of type 1 diabetes outside of a study, based on the facts that (1) people with diabetes 
206 
experience mild hypoglycemia and hyperglycemia frequently as a consequence of the disease 
207 
and its management, (2) although the study intervention involves periodic automated insulin 
208 
dosing that may could increase the likelihood of hypoglycemia, and periodic automated 
209 
attenuation of insulin delivery that may could increase the likelihood of hyperglycemia, it is 
210 
more likely that the study intervention will decrease both hypoglycemia and hyperglycemia, and 
211 
(3) mitigations are in place that limit the likelihood of excessive insulin dosing or prolonged 
212 
withdrawal of insulin. 
213 
1.5 General Considerations 
214 
The study is being conducted in compliance with the policies described in the study policies 
215 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
216 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
217 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
218 
considered the source data. 
219 
The protocol is considered a significant risk device study, due to the fact that the AID study 
220 
system is experimental. Therefore, an investigational device exemption (IDE) from the U.S. 
221 
Food and Drug Administration (FDA) is required to conduct the study in the US. 
222 
 
223 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 25 OF 68 
Chapter 2: Study Enrollment and Screening 
224 
2.1 Participant Recruitment and Enrollment 
225 
Enrollment will proceed with the goal of at least 35 starting and 32 participants completing the 
226 
crossover trial. A maximum of 60 individuals may be enrolled into screening (i.e., sign the 
227 
informed consent form and initiate screening).  Participants who have signed consent and started 
228 
the screening process will be permitted to continue into the crossover trial, if eligible, even if the 
229 
crossover trial randomization goal has been reached. All eligible participants will be included 
230 
without regard to sex, gender, race, or ethnicity. 
231 
Study participants will be enrolled at approximately 5-7 clinical centers. All sites are experienced 
232 
in type 1 diabetes and use of AID systems. 
233 
The recruitment goal for each site for the RCT is the same (approximately 5-7 participants per 
234 
site); however, certain sites may recruit additional participants if necessary for the study to meet 
235 
the overall recruitment goal.  The maximum number to be enrolled into screening at a single site 
236 
will be 15. 
237 
Potential eligibility may be assessed as part of a routine-care examination. Prior to completing 
238 
any procedures or collecting any data that are not part of usual care, written informed consent 
239 
will be obtained. The study protocol will be discussed with the potential study participant by 
240 
study staff. The potential study participant will be given the Informed Consent Form to read and 
241 
will be given the opportunity to ask questions. Potential study participants will be encouraged to 
242 
discuss the study with family members and their personal physicians(s) before deciding whether 
243 
to participate in the study. 
244 
As part of the informed consent process, each participant will be asked to sign an authorization 
245 
for release of personal information. The investigator, or their designee, will review the study-
246 
specific information that will be collected and to whom that information will be disclosed. After 
247 
speaking with the participant, questions will be answered about the details regarding 
248 
authorization. 
249 
A participant is considered enrolled when the informed consent form, and assent form if 
250 
applicable, has been signed. 
251 
2.1.1 Pilot Phase 
252 
The Pilot Phase (details in Chapter 3) will include 1-2 participants at each site.  All participants 
253 
in the Pilot Phase must use CSII and a Dexcom G5/G6 sensor for their usual care.  Participants in 
254 
the Pilot Phase may subsequently participate in the Crossover Trial. 
255 
2.2 Participant Eligibility Criteria 
256 
2.2.1 Inclusion Criteria 
257 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
258 
in the study: 
259 
1) Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one 
260 
year and using insulin for at least 1 year 
261 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 26 OF 68 
2) Using an insulin pump for at least 3 months (which may include use of automated 
262 
features) 
263 
3) Familiarity and use of a carbohydrate ratio for meal boluses 
264 
4) $JH\HDUVROG 
265 
5) For females, not currently known to be pregnant 
266 
a. If female and sexually active, must agree to use a form of contraception to prevent 
267 
pregnancy while a participant in the study. A negative serum or urine pregnancy test 
268 
will be required for all females of child-bearing potential. Participants who become 
269 
pregnant will be discontinued from the study. Also, participants who during the study 
270 
develop and express the intention to become pregnant within the timespan of the 
271 
study will be discontinued. 
272 
6) If using a personal CGM, willingness to use a Dexcom G6 CGM and discontinue 
273 
personal CGM use during the study 
274 
7) Willing not to begin use of, or not to continue use of if currently using, a personal AID 
275 
(closed loop control) system during the study; note if the system offers an open-loop 
276 
mode or can be switched to a PLGS mode that is compatible with the Dexcom G6, the 
277 
system may be used during the study in these modes only 
278 
8) Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, and to 
279 
use no other insulin besides lispro (Humalog) or aspart (Novolog) during the study 
280 
9) Willingness not to start any new non-insulin glucose-lowering agent during the course of 
281 
the trial, and not to use Afrezza during the trial 
282 
10) Investigator believes that the participant can successfully and safely operate all study 
283 
devices and is capable of adhering to the protocol 
284 
2.2.2 Exclusion Criteria 
285 
1) Use of Afrezza or any non-insulin glucose-lowering agent other than metformin 
286 
(including GLP-1 agonists, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas) unless 
287 
participant is willing to discontinue during the trial. 
288 
2) Two or more episodes of DKA requiring an emergency room visit or hospitalization in 
289 
the past 6 months  
290 
3) Two or more episodes of severe hypoglycemia with seizure or loss of consciousness in 
291 
the last 6 months 
292 
4) Hemophilia or any other bleeding disorder 
293 
5) A medical or other condition that in the opinion of the investigator could create a safety 
294 
concern for the participant or put the study at risk 
295 
a. History of frequent severe hypoglycemia or history of frequent severe 
296 
hyperglycemia and/or ketosis, without emergency room visit or hospitalization, 
297 
due to poor diabetes self-management may be disqualifying per investigator 
298 
judgment 
299 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 27 OF 68 
6) Participation in another pharmaceutical or device trial at the time of enrollment or during 
300 
the study 
301 
2.3 Screening Procedures 
302 
After informed consent has been signed, a potential participant will be evaluated for study 
303 
eligibility through the elicitation of a medical history, performance of a physical examination 
304 
by study personnel, and local laboratory testing if needed to screen for exclusionary medical 
305 
conditions. 
306 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
307 
date per investigator discretion. Individuals who do meet eligibility criteria will proceed to the 
308 
Pilot Phase, CGM Run-In period, or Crossover Trial (as applicable, see below), which will be 
309 
expected to start on the same day as screening, or up to 14 days thereafter. 
310 
2.3.1 Data Collection and Testing 
311 
A standard physical exam (including vital signs and height and weight measurements) will be 
312 
performed by the study investigator or qualified designee (e.g. a physician, fellow, nurse 
313 
practitioner, or a physician assistant). 
314 
The following procedures will be performed/data collected/eligibility criteria checked and 
315 
documented: 
316 
x Inclusion and exclusion criteria assessed 
317 
x Demographics (socioeconomic status, date of birth, sex, race, and ethnicity) 
318 
x Contact information (retained at the site and not entered into study database) 
319 
x Medical history 
320 
x Diabetes history 
321 
x Concomitant medications 
322 
x Physical examination to include: 
323 
¡ Weight, height 
324 
¡ Vital signs including measurement of blood pressure and pulse 
325 
x Blood draw or fingerstick for HbA1c level measured using the DCA Vantage or similar 
326 
point-of-care device or local lab, if measurement not available from past 3 months   
327 
x Urine pregnancy test for all females of child-bearing potential  
328 
x The following questionnaires will be administered: 
329 
¡ Diabetes Distress Scale 
330 
¡ Glucose Monitoring Satisfaction Survey 
331 
¡ Hypoglycemia Confidence 
332 
¡ Diabetes Technology Attitudes 
333 
¡ INSPIRE Survey 
334 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 28 OF 68 
Screening procedures may last approximately 1-2 hours. 
335 
2.3.2 Screen Failures 
336 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
337 
date per investigator discretion. 
338 
 
339 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 29 OF 68 
Chapter 3: Pilot Phase 
340 
3.1 Description 
341 
The Pilot Phase will include 1-2 participants at each site, using a personal Dexcom G5/6, with 
342 
use on at least 11 of the prior 14 days and for whom the investigator believes that a CGM run-in 
343 
is unnecessary. 
344 
The Pilot Phase is intended to (1) test the functionality of all aspects of the study system and (2) 
345 
train the clinical staff on the execution of the clinical protocol, including hands-on training with 
346 
the device prior to initiating the RCT Period. 
347 
3.2 Enrollment and Screening Procedures 
348 
Participants in the Pilot Phase must meet all of the inclusion and none of the exclusion criteria 
349 
listed in section 2.2.  Additionally, they must be using a Dexcom G5/6 sensor and meet the 
350 
criteria for skipping the CGM Run-In Phase.  These participants will undergo the same screening 
351 
procedures planned for the Crossover Trial as described in section 2.3. 
352 
Study system start up procedures will be the same as for the Crossover Trial. 
353 
3.3 Pilot Phase Visits and Procedures 
354 
The Pilot Phase will have one study start up visit that will follow the same procedures described 
355 
in section 2.3 for the Screening Visit.  
356 
Participants will use the study system at home for 10-14 days and will follow all outpatient 
357 
procedures described in Chapter 5 for use of the study system. Participants will have a phone call 
358 
3 days (+/- 1 days) after initiation of home use of the study system. Procedures will match those 
359 
described in section 7.2.1. 
360 
Participants will have a follow up visit at the end of the home use period. Visit procedures will 
361 
include the following: 
362 
x Assessment of adverse events, adverse device effects, and device issues 
363 
x Download of study system and CGM data  
364 
x Download of blood glucose meter and ketone meter 
365 
x Return of AID study system components (phone and insulin pump) and switch back to 
366 
personal insulin pump 
367 
¡ Participants interested in participating in the RCT may at the discretion of the 
368 
investigator retain study CGM and meters for continued use until the Crossover Trial 
369 
begins, at which time a Randomization Visit will occur as described in Chapter 5. 
370 
3.4 Safety Review of Pilot Phase Data 
371 
After at least 5 total participants from at least 3 different sites have completed the Pilot Phase, 
372 
the data will be reviewed.  If there are no significant safety, usability, or system functionality 
373 
issues that occur as defined in the list of criteria below, the Crossover Trial may begin for sites 
374 
who have completed at least 1 Pilot Phase participant. If any issues are identified, then the Pilot 
375 
Phase may be repeated after the issues have been resolved and any associated approvals (IRB, 
376 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 30 OF 68 
FDA, DSMB) have been obtained.  If repeated, participants could have participated in the earlier 
377 
pilot phase or could be new participants. 
378 
Specific criteria for proceeding to the main RCT include: 
379 
a) No serious adverse events related to use of the iAPS during the pilot phase. 
380 
b) All subjects have demonstrated an independent ability to initiate the iAPS system 
381 
and operate it safely, as judged by the site investigators. 
382 
c) Investigators and engineering team are able to confirm that adaptation of clinical 
383 
parameters is running successfully within the predefined bounds. 
384 
 
385 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 31 OF 68 
Chapter 4: CGM Run-in Phase 
386 
4.1 Introduction 
387 
Eligible participants using a personal Dexcom G5/G6 sensor, with use on at least 11 of the prior 
388 
14 days may skip the CGM run-in unless the investigator believes that a run-in is necessary prior 
389 
to randomization.  Participants skipping the run-in can go directly to the randomization visit. 
390 
Eligible participants not currently using a personal Dexcom G5/G6 sensor or using a Dexcom 
391 
G5/G6 sensor with readings captured on less than 11 out of the previous 14 days will initiate a 
392 
CGM run-in phase with a Dexcom G6 sensor. 
393 
x Users of a sensor other than Dexcom G5/G6 (eg, Medtronic, Abbott) must be willing to 
394 
discontinue use of that sensor for the duration of the study and users of an AID (closed 
395 
loop control) system must be willing to discontinue its use during the study (PLGS mode 
396 
can be used during the study if feasible). 
397 
4.2 Initiation of CGM 
398 
The participant will be provided with sensors and a transmitter and a blood glucose meter, and 
399 
instructed to use the study CGM on a daily basis.  Training will be provided to participants not 
400 
experienced with CGM use as to how to use the CGM in real-time to make management 
401 
decisions and how to review the data after an upload for retrospective review. Participants using 
402 
a personal CGM prior to the study will discontinue the personal CGM beginning in this period. 
403 
x The participant will be given a CGM receiver (if desired) and trained on its use, or will be 
404 
trained on the installation and use of the Dexcom phone-based mobile app 
405 
¡ Participants may use available Dexcom software and features of the study CGM related 
406 
to mobile data access or remote monitoring, but will be instructed not to use any third-
407 
party components for this purpose 
408 
x A study CGM training checklist will be used to document and facilitate the training 
409 
process. 
410 
$SK\VLFDORUHOHFWURQLFFRS\RIWKHVWXG\&*0XVHU¶VJXLGHZLOOEHSURYLGHGIRUWKHSDUWLFLSDQW
411 
to take home. 
412 
4.3 Assessment of Successful Completion of the CGM Run-in Phase 
413 
Enrolled participants will return approximately 14 days after the initiation of the run-in phase to 
414 
assess progress or successful completion of the phase.  If needed, one or more interim visits or 
415 
phone contacts may occur to assist the participant with any system use issues and for pump 
416 
settings optimization.  
417 
Visit procedures will include the following: 
418 
x Uploading of CGM data and assessment of amount of use of the CGM 
419 
x Assessment of skin reaction in areas where a CGM sensor was worn 
420 
x Assessment of eligibility to continue to the RCT phase of the study 
421 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 32 OF 68 
To enter the randomized trial, participants must have obtained CGM readings on at least 11 out 
422 
of the previous 14 days.  If a participant fails to meet this criterion, or if it is determined that the 
423 
participant will benefit from additional time with CGM use, the run-in period may be extended at 
424 
the discretion of the investigator. One additional period may occur, with another clinic visit to 
425 
assess results after the second period using the same criteria as above. The run-in duration will 
426 
therefore vary from approximately 2 to 4 weeks, depending on the participant. Additional visits 
427 
and phone contacts for further training are at investigator discretion. 
428 
Participants who are unable to meet the CGM compliance requirements will be withdrawn from 
429 
the study, as will participants who no longer meet all of the inclusion and exclusion criteria. 
430 
 
431 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 33 OF 68 
Chapter 5: Randomization Visit 
432 
Once a study participant is randomized, that participant will be counted regardless of whether the 
433 
assigned treatment is received. Thus, the investigator must not proceed to randomize an 
434 
individual until they are convinced that the participant is eligible and will accept assignment to 
435 
either of the two treatment orders. 
436 
5.1 Visit Timing 
437 
The randomization visit is expected to begin on the same day the CGM Run-In period is 
438 
completed (or it can be on the same day of screening if the run-in phase is skipped).  If not on the 
439 
same day, the randomization visit should occur within 14 days of the end of the run-in phase (or 
440 
screening visit if run-in skipped). 
441 
Participants in the Pilot Phase will be on hold until the safety assessment of the Pilot Phase has 
442 
been completed and the RCT begins.  Once the RCT is initiated, Pilot Phase participants who 
443 
will participate in the RCT will complete the consent process for the RCT and will then be able 
444 
to complete the randomization visit. 
445 
If it has been more than 30 days since the Screening visit, changes in medications and medical 
446 
conditions since screening will be solicited, and if necessary the standard physical exam 
447 
described in section 2.3 will be repeated. 
448 
Eligibility criteria from screening will be reviewed again (if not the same day) to verify 
449 
eligibility, and the study staff will evaluate whether the participant can safely use the study 
450 
system.  If the participant is no longer eligible based on these criteria, the participant will be 
451 
dropped from the study. 
452 
5.2 Data Collection and Testing 
453 
The following procedures will be done at the randomization visit: 
454 
x Blood sample to send to the central laboratory for HbA1c; random, non-fasting C-peptide; 
455 
and glucose 
456 
x Urine pregnancy test for all females of child-bearing potential (if not performed within the 
457 
prior 6 days) 
458 
5.3 Randomization 
459 
Eligible participants will be randomly assigned, stratified by site, to one of two groups to 
460 
determine treatment order during the 26-week study: 
461 
1. Group A: study system for period 1 for 13 weeks, then SAP for period 2 for 13 weeks 
462 
2. Group B: SAP for period 1 for 13 weeks, then study system for Period 2 for 13 weeks 
463 
Participant randomization assignment is determined after the Randomization Visit data are 
464 
entered on the study website. The data from this visit and where applicable, prior visits, are 
465 
assessed to verify eligibility prior to the randomization process being completed. 
466 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 34 OF 68 
5.4 Device Training and Study Supplies 
467 
5.4.1 CGM System Training, Initiation, and Supplies 
468 
Participants who were eligible to skip the CGM Run-In phase will have the study CGM initiated 
469 
at this time as described in section 4.2. At investigator discretion, applicable elements of the 
470 
CGM system training may be completed as refresher training. 
471 
The participant will be provided with a supply of CGM sensors, a backup CGM transmitter, and 
472 
blood glucose strips to last until the next study visit. 
473 
5.4.2 Blood Ketone Meter Training and Supplies 
474 
The participant will be provided with a study blood ketone meter and strips and instructed on the 
475 
use of this device. 
476 
5.4.3 Home Glucagon Emergency Kit 
477 
Participants will be required to have a home glucagon emergency kit. Participants who currently 
478 
do not have one will be given a prescription for the glucagon emergency kit. 
479 
5.4.4 Study System Training and Device Use 
480 
Participants assigned to Group A will receive study system training prior to initiating period 1 of 
481 
the crossover trial. These training sessions can occur on the same day as the randomization visit 
482 
or extend to up to one additional session within the next 7 days if needed; participants will not 
483 
take the study system home and initiate period 1 until training has been completed. 
484 
Participants assigned to Group B will receive study system training upon completion of period 1 
485 
(the SAP period). These participants will have the same option as above of completing training 
486 
the same day as the period 1 13-Week Visit, or else within a 7-day period following that visit, 
487 
prior to initiating home use of the study system. 
488 
Participants will receive study system training by the clinical center study team. The study 
489 
system includes the Tandem t:AP insulin pump and Dexcom G6 CGM. The system also includes 
490 
the study phone. 
491 
5.4.4.1 Pump Training 
492 
Pump training will include the following: 
493 
x The participant will be fully instructed on the study insulin pump. A member of the study 
494 
research team will conduct the training and in particular discuss differences from their 
495 
home pump in important aspects such as calculation of insulin on board and correction 
496 
boluses. Additional topics not limited to but may include: infusion site initiation, 
497 
cartridge/priming procedures, setting up the pump, charging the pump, navigation through 
498 
menus, bolus procedures including stopping a bolus, etc. 
499 
x The study team will assist the participant in study pump infusion site initiation and will 
500 
start the participant on the study pump. The study pump will be programmed with the 
501 
SDUWLFLSDQW¶VXVXDOEDVDOUDWHVDQGSXPSSDUDPHWHUV7KHSDUWLFLSDQW¶VSHUVRQDOSXPSZLOO
502 
be removed. 
503 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 35 OF 68 
x The participant will be supervised with the study pump during at least one meal or snack 
504 
bolus to ensure participant understanding of the pump features. 
505 
x The participant will be encouraged to review the literature provided with the pump and 
506 
infusion sets after the training is completed. 
507 
x The appropriate study pump training checklist will be used to document and facilitate the 
508 
training process; a physical or electronic copy of the pump user guide will be provided for 
509 
the participant to take home. 
510 
x Participants will be provided with sufficient insulin infusion supplies to last until the 
511 
subsequent visit. 
512 
5.4.4.2 Study Phone Training 
513 
Study phone training will include: 
514 
x 7KHVWXG\WHDPZLOOFRQILUPWKHVXEMHFW¶VSDUDPHWHUVDUHHQWHUHGLQWKHV\VWHP$3650
515 
with the study physician. 
516 
x How to switch the system between Pump mode (open-loop, preprogrammed basal insulin 
517 
delivery) and Closed Loop mode depending on circumstances.  
518 
x +RZWRFDOLEUDWHWKH&*0XQLWGXULQJWKHVWXG\DVSHUPDQXIDFWXUHU¶VLQVWUXFWLRQVDQGSHU
519 
clinical need. 
520 
x How to access the CGM trace from the sensor on the phone screen. Study staff will also 
521 
H[SODLQWKHFRQFHSWRI³VDIHEDVDO´WRWKHVXEMHFWVZKLFKFDQEHDFWLYDWHGDIWHU&*0
522 
connectivity is interrupted to the study phone. 
523 
x How to activate the meal bolus screen of the phone system any time insulin will be given 
524 
with a meal or any time additional correction insulin is desired. 
525 
¡ Specifically, study staff will follow inform the subject that: 
526 
x The bolus screen correction calculation is based on the last CGM value. 
527 
x They can add a fingerstick value into the bolus screen, and this will adjust the 
528 
correction slider calculated correction dose. If there is any concern about the 
529 
accuracy of the current CGM value, a fingerstick is generally more accurate and 
530 
should be performed instead of relying on the current CGM value. 
531 
x They can adjust the correction slider calculated correction dose. 
532 
x They can use the total dose box to adjust the final dose to be delivered, regardless of 
533 
what settings are entered into the other boxes (glucose value, carbohydrates, 
534 
correction). The amount shown in this box will be delivered. 
535 
x CGM trend information is not used in the meal bolus or correction bolus calculation. 
536 
x Study staff will observe them using all buttons and boxes on the meal bolus screen to 
537 
show us they understand how to use the meal bolus screen. 
538 
x How to inform the system of hypoglycemia treatment via a hypoglycemia treatment 
539 
button on the phone UI after each hypoglycemic treatment is consumed. 
540 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 36 OF 68 
x What to do when exercising while using the system. 
541 
x The participant will be assessed for understanding of the system interface and how to react 
542 
to safety/alert messages. 
543 
x How to perform blood ketone testing. 
544 
x Review of the iAPS App User Guide; a physical or electronic copy will be provided for 
545 
the participant to take home. 
546 
x The study iAPS training checklist will be used to document and facilitate the training 
547 
process. 
548 
x Review of the adaptation procedure, to inform subjects that the adapted closed-loop 
549 
settings are internal to the system, and to ask study staff at any time if they have questions 
550 
about ongoing adaptation. 
551 
For subjects who agree, they may move their personal phone SIM card to the study phone and 
552 
use the study phone as their personal phone during closed-loop. Subjects will be assisted by 
553 
study staff in this setup process. At the end of study system use, the study phone will be factory 
554 
reset to remove any personal data from the study device. 
555 
5.4.4.3 General Usage Training and System Initiation 
556 
The participant will be instructed to use the system in closed-loop mode except 1) when no CGM 
557 
sensor is available or 2) if insulin is delivered by any means other than the study pump (e.g. 
558 
injection of subcutaneous insulin via syringe in the event of infusion site failure). If insulin is 
559 
delivered by any means other than the study pump, participant will be instructed to turn off 
560 
closed-loop mode for approximately four hours. 
561 
The participant will also be instructed to contact study staff during periods of illness with an 
562 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
563 
illness, or during periods of use of medications such as epinephrine for the emergency treatment 
564 
of a severe allergic reaction or asthma attack in addition to use of oral or injectable 
565 
glucocorticoids to determine if closed-loop use should be temporarily discontinued. 
566 
Participants will be specifically instructed: 
567 
1) Not to upgrade the phone operating system or the iAPS app will no longer allow closed-
568 
loop operation. 
569 
2) Not to plug headphones into the study phone or alerts will be silenced. 
570 
3) Not to put the phone on vibrate mode or alerts will be silenced. 
571 
4) Not to use any manufacturer provided (e.g. Dexcom G6 Mobile App) or third-party 
572 
components for CGM connectivity and monitoring, as this will interfere with 
573 
connectivity to the study phone. 
574 
After study system training has been completed, participants in Group A will proceed with home 
575 
use of the study system. Participants may use the study pump and study phone without closed-
576 
loop and study CGM during periods of component disconnections or technical difficulties. 
577 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 37 OF 68 
5.4.5 SAP Training and Device Use 
578 
During the SAP period, participants will use their own insulin pump and the study Dexcom G6 
579 
sensor. If a participant is using a home pump with PLGS capability compatible with the study 
580 
sensor, he/she may keep the pump in PLGS mode; however, an AID system cannot be used. 
581 
All participants will have used a pump and sensor either prior to enrolling in the study or during 
582 
the CGM run-in phase. Study staff will review use of pump and sensor therapy in diabetes self-
583 
management, uploading of device data as needed, and reviewing of data visualizations. 
584 
Participants may use available Dexcom software and features of the study CGM related to 
585 
mobile data access or remote monitoring, but will be instructed not to use any third-party 
586 
components for this purpose. 
587 
 
588 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 38 OF 68 
Chapter 6: Crossover Trial Home Procedures 
589 
6.1 Guidance on Clinical Staff Contact 
590 
Participants will be provided with contact information and will be asked to call the study clinical 
591 
staff for any health-related issues and for technical issues with any study-provided device. 
592 
Questions relating to the study protocol will be dealt with by a study staff member on call.  
593 
Participants will be referred to their own medical providers for issues not directly related to the 
594 
study and to local Emergency Medical Services for medical emergencies 
595 
Study staff will discuss with the participant that routine contact is required and will make 
596 
arrangements with the participant for the contacts. Participants who are not compliant with the 
597 
arranged contacts may be discontinued at the discretion of the investigator. 
598 
6.2 Safety Measures 
599 
6.2.1 Drug and Alcohol Use 
600 
Participants will be advised not to use alcohol or other drugs in sufficient quantity to reduce 
601 
sensitivity to symptoms of hypoglycemia or hinder appropriate decision-making. There are no 
602 
other restrictions on diet, exercise, or other activities. 
603 
6.2.2 CGM Calibration 
604 
Throughout the study, participants will be instructed to calibrate the study CGM in accordance 
605 
with manufacturer labeling. 
606 
6.2.3 Study Pump Failure 
607 
In the event of a study pump failure, the participant will be instructed to use their personal 
608 
insulin regimen until the problem can be resolved. 
609 
6.2.4 Insulin Dosing 
610 
During the Study System period of the Crossover Trial, all insulin dosing is supervised by the 
611 
study system. Insulin injection for meal boluses must be performed using the pump bolus 
612 
calculator. 
613 
During the SAP period, participants will dose insulin in accordance with manufacturer labeling 
614 
of their insulin pumps and the study CGM system. 
615 
6.2.5 Optimization of Insulin Pump Settings 
616 
Data-driven optimization of pump settings is not allowed during the study. Insulin pump settings 
617 
may be adjusted for safety concerns only if the study participant contacts the study physician due 
618 
to concerns about pump settings due to recurring hypo- or hyperglycemia, or if the study 
619 
physician has overriding concerns for safety. 
620 
During the AID period, if there is a safety concern necessitating a pump settings change, this will 
621 
force a reset of the stored adaptation of pump parameters. In this case, the investigator will 
622 
contact the protocol chairs to review the need for safety adjustments, who will then help the 
623 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 39 OF 68 
study site reset the APS RM pump parameters, assure those settings match the settings on the 
624 
study pump, and then reset the adaption on the APS RM website. 
625 
In the SAP arm, if there is a safety concern necessitating a pump settings change, the site 
626 
investigator may make the adjustments and document this on the appropriate study CRF. 
627 
However, the goal of the study is not to have physicians perform data-driven optimizations of 
628 
pump settings, but instead to try to limit changes to safety concerns only. 
629 
6.2.6 Hypoglycemia Safety Protocol 
630 
During the course of the study, participants will be permitted to change the CGM low glucose 
631 
threshold alert setting on their device or mobile app (as applicable), but will be instructed to 
632 
choose a value no less than 60 mg/dL. 
633 
If a participant receives a CGM hypoglycemia threshold or predictive alarm or notes that the 
634 
CGM glucose is below the hypoglycemia threshold alarm value, confirmatory fingerstick testing 
635 
will be performed if required by CGM labeling and the participant will be instructed to treat 
636 
hypoglycemia with ~15 grams of fast-acting oral glucose. 
637 
6.2.7 Hyperglycemia Safety Protocol 
638 
During the course of the study, participants will be permitted to change the CGM high glucose 
639 
threshold alert setting on their device or mobile app (as applicable), but will be instructed to 
640 
choose a value no greater than 300 mg/dL. 
641 
If a participant receives a CGM hyperglycemia threshold alarm or notes that the CGM glucose 
642 
is above the hyperglycemia threshold alarm value, confirmatory fingerstick testing will be 
643 
performed if required by CGM labeling. 
644 
,IDSDUWLFLSDQW¶V&*0UHDGLQJLV!PJG/IRURYHUKRXUVRUPJG/DWDQ\point, the 
645 
participant will be instructed to take the following steps: 
646 
x Perform a blood glucose meter check. 
647 
x If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
648 
x If the ketone level is >0.6 mmol/L, take correction insulin, change insulin (pump) infusion 
649 
site and contact study staff. 
650 
x If a participant administers correction insulin via insulin syringe, participants will be 
651 
instructed to disable closed-loop control for approximately four hours. 
652 
6.2.8 Device Data Uploads 
653 
The study system phones will include a study-supplied SIM card (if personal SIM card is not 
654 
being used) to ensure near continuous automatic upload of data to the remote monitoring system. 
655 
During the SAP study period, participants will be asked to upload CGM data (and pump data, if 
656 
possible) prior to each scheduled phone call or clinic visit. 
657 
6.2.9 Remote Monitoring 
658 
During the 2-week Pilot Phase, subjects will have real-time event-based remote monitoring alerts 
659 
present from the study phone to notify study staff of prolonged periods of hypoglycemia (>30 
660 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 40 OF 68 
minutes <70 mg/dL) or hyperglycemia (>2 hours above 300 mg/dL, or greater than 400 mg/dL at 
661 
any time). On-call clinic staff will contact the participant following these alerts to evaluate the 
662 
situation and provide guidance with respect to device use and management of the hypo- or 
663 
hyperglycemia. 
664 
During the 2-week pilot phase, study clinicians at each site will review the weekly adaptation 
665 
changes no later than 6 hours from time of adaptation and log that the review occurred. If there is 
666 
a safety concern about the adaptation, site clinicians will follow the procedures in Section 6.2.5 - 
667 
Optimization of Insulin Pump Settings to contact the protocol chairs and discuss if reset of 
668 
adaptation parameters is needed. 
669 
During the RCT, remote real time alerts for participants using the study system will not be 
670 
enabled unless requested or deemed to be useful by study staff and participants for 
671 
troubleshooting connectivity issues. Instead, study staff will review the data from all subjects 
672 
using the study system on the web interface for iAPS at least once a week so they can evaluate 
673 
ongoing data and adaptations, and will contact participants if there are ongoing issues related to 
674 
connectivity or other areas. Study staff may contact the subjects at any time for concerns arising 
675 
from remote monitoring data. 
676 
 
677 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 41 OF 68 
Chapter 7: RCT Follow-up Study Visits 
678 
7.1 Timing of Visits 
679 
7.1.1 Visit and Phone Contact Schedule during Study Periods 1 and 2 
680 
During each of the two 13-Week study periods, visits and contacts will be scheduled as outlined 
681 
in Table 3 below: 
682 
Table 3. Visit and Phone Contact Schedule 
683 
Target Day/Week 
Type 
Target/Allowable Window 
(around Target Day/Week) 
3 days* 
Phone 
+/- 2 days 
2 weeks 
Visit** 
+/- 4 days 
4 weeks 
Phone 
+/- 7 days 
6 weeks 
Visit** 
+/- 7 days 
9 weeks 
Phone 
+/- 7 days 
13 weeks 
Visit** 
+/- 7 days 
* During the study system use period, this 3 days will be with respect to the start of home use of the study system, 
684 
rather than with respect to the start of the period 
685 
** Videoconferences may be performed instead of in-person visits at investigator discretion, for example in case of 
686 
local restrictions on in-clinic visits or participant-specific quarantine/isolation requirements; 13-Week visits 
687 
involving iAPS system training/initiation must be in-clinic unless formal permission is obtained from clinical 
688 
Protocol Chair to perform the visit remotely  
689 
Additional contacts or visits may occur as needed. 
690 
7.2 Procedures at Phone Contacts and Follow-up Visits 
691 
7.2.1 Phone Contacts 
692 
Prior to each phone contact, the participant will be asked to upload device data as described in 
693 
section 6.2.8 for study staff review.  During the phone call, study staff will: 
694 
x Assess compliance with study device use 
695 
x Answer questions about using the study system 
696 
x Assess adverse events, adverse device effects, and device issues 
697 
x Review glycemic control 
698 
Phone contacts may be performed via videoconference at investigator discretion. 
699 
7.2.2 Procedures Performed During Each Follow-up Visit 
700 
The following procedures will be done at all visits in both periods, unless otherwise stated 
701 
x Assessment of compliance with study device use 
702 
x Retraining on system use as needed 
703 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 42 OF 68 
x Assessment of adverse events, adverse device effects, and device issues 
704 
x Download of CGM data (when available), blood glucose meter data, and blood ketone 
705 
meter data (for videoconferences, participant upload of any devices that supports cloud 
706 
upload, and subsequent download by clinic staff) 
707 
x During clinic visits, QC test blood glucose meter with the available concentration(s) of 
708 
control solution if the meter is brought to the visit (except for 13-week visit of period 2) 
709 
In addition, the following will be done at the 13-week visit in each period, unless otherwise 
710 
stated: 
711 
x Urine pregnancy test for females of child-bearing potential (period 1 only); for 
712 
videoconferences, test can be performed at home with a study-provided kit and verbal 
713 
report of test result 
714 
x Participant weight, height, and blood pressure and pulse; for videoconferences, a verbal 
715 
UHSRUWRIWKHSDUWLFLSDQW¶VZHLJKWDQGKHLJKWZLOOEHDFFHSWDEOH 
716 
x Collection of a blood sample to send to the central laboratory for HbA1c determination; 
717 
for videoconferences, a capillary sample may be obtained at home with a study-provided 
718 
kit and mailed to the central laboratory 
719 
x Completion of the following questionnaires: 
720 
¡ Diabetes Distress Scale 
721 
¡ Glucose Monitoring Satisfaction Survey 
722 
¡ Hypoglycemia Confidence 
723 
¡ Diabetes Technology Attitudes 
724 
¡ INSPIRE Survey (following study system period only) 
725 
¡ System Usability Scale Survey (SUS) (following study system period only) 
726 
x Return study devices as appropriate 
727 
x Initiate period 2 devices (end of period 1 only) 
728 
x Place back on pre-study insulin delivery method and glucose monitoring method at 
729 
13-week visit (end of period 2 only). 
730 
7.2.3 Early Termination Visit 
731 
If a participant discontinues the study early, an attempt will be made to have a clinic visit or 
732 
videoconference to return study devices and supplies, to record any adverse events or device 
733 
issues that have occurred, complete final questionnaires, and collect a final HbA1c. 
734 
7.2.4 Unscheduled Visits 
735 
An Unscheduled Visit form will be completed for any contact the participant has with the site for 
736 
significant protocol-related issues/questions outside the visit schedule. 
737 
 
738 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 43 OF 68 
Chapter 8: Study Devices 
739 
8.1 Description of the Study Devices 
740 
8.1.1 AID Study System 
741 
The study system is composed of a Tandem t:AP pump, a Dexcom G6 continuous glucose 
742 
monitoring sensor, and a smart phone that contains the adaptive algorithm and communicates 
743 
with the other devices. 
744 
8.1.2 Insulin Pumps 
745 
During the study system period, participants will use a Tandem t:AP pump.  During the SAP 
746 
period, participants will use their personal pump. 
747 
8.1.3 Continuous Glucose Monitoring 
748 
Participants in both arms will use a Dexcom G6 sensor, identical to the commercially available 
749 
G6 sensor. A transcutaneous glucose sensor for the Dexcom G6 CGM will be inserted in the 
750 
subcutaneous tissue and will provide input to the controller.  The CGM sensor will be replaced at 
751 
least once every 10 days. Only approved insertion sites will be used (abdomen). 
752 
8.1.4 Blood Glucose Meter and Strips 
753 
Blood glucose levels will be measured using the study-assigned blood glucose meter 
754 
(glucometer) and the CGM device will be calibrated if needed using the study glucometer and 
755 
VWULSVLQDFFRUGDQFHZLWKWKHPDQXIDFWXUHU¶VODEHOLQJ 
756 
8.1.5 Ketone Meter and Strips 
757 
Blood ketone levels will be measured using the Abbott Precision Xtra (or equivalent meter, such 
758 
as the Optium Neo) meter and strips in accordance with manufacturer labeling. Any blood 
759 
glucose meter component of ketone meters will not be used. 
760 
8.2 Study Device Accountability Procedures 
761 
Device accountability procedures will be detailed in the site procedures manual. 
762 
8.3 Participant Access to Study Device at Study Closure 
763 
Participants will be permitted to keep the blood glucometer and blood ketone meter at the end of 
764 
the study, but will need to return all other devices, including study phone, insulin pump, and 
765 
CGM components and related supplies. 
766 
 
767 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 44 OF 68 
Chapter 9: Laboratory Testing and Questionnaires 
768 
9.1 Laboratory Testing 
769 
HbA1c: 
770 
x HbA1c level measured using the DCA2000 or comparable point of care device or local lab 
771 
at the Screening visit, if no measurement is available from the past 3 months 
772 
x A blood sample will be obtained for central lab analysis at Randomization and at the 
773 
conclusion of each 13-Week Crossover Trial period. Final HbA1c also may be collected 
774 
from participants who withdraw from the study. 
775 
Random C-Peptide and Glucose: 
776 
x Collected at Randomization for central lab analysis  
777 
Urine Pregnancy: 
778 
x Performed locally for females of child-bearing potential at Screening, randomization (if 
779 
not performed within the prior 6 days) and at the beginning of the second study period 
780 
during the crossover trial. This test may also be performed at any time pregnancy is 
781 
suspected. 
782 
9.2 Questionnaires 
783 
The following questionnaires will be completed at Screening and at the end of each 13-week 
784 
periods during the crossover trial (except for the SUS survey, which will only be administered 
785 
after the AID period, and the INSPIRE survey, which will only be administered at Screening and 
786 
after the AID period). Final questionnaires also may be collected for participants who withdraw 
787 
from the study. 
788 
Each questionnaire is described briefly in Table 4 below. The procedures for administration are 
789 
described in the study procedures manual. 
790 
Table 4. Questionnaires 
791 
Measure 
Construct Measured/Relevant Points 
Diabetes Distress Scale 
Gold standard measure for understanding distress symptoms related to diabetes. 
A recently validated version for adults with T1D, but will also be administered 
to adolescents (17 items; 6 min) 
Glucose Monitoring Satisfaction Survey 
This recently validated survey is an outgrowth of DirecNet and JDRF CGM 
surveys; evaluates treatment satisfaction and burden. Administered to all 
participants (15 items; 4 min) 
Hypoglycemia Confidence 
Includes 8 different common situations where hypoglycemia occurs (e.g., 
physical activity, driving) and evaluates level of confidence in those situations 
(8 items; 3 min) 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 45 OF 68 
Measure 
Construct Measured/Relevant Points 
Diabetes Technology Attitudes 
Subjective questions about attitudes related to diabetes technologies and 
devices (5 items; 3 min) 
INSPIRE Survey 
Measures the psychological side of automated insulin delivery. Adult 
survey has 22 items; adolescent version 17 items. (6-8 mins) 
System Usability Scale (SUS) 
A 10-item questionnaire that measures the overall usability of a system. 
It is a valid and reliable measure of the perceived usability of a system 
and is technology-agnostic. 
 
792 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 46 OF 68 
Chapter 10: Adverse Events, Device Issues, and Stopping Rules 
793 
10.1 Unanticipated Problems 
794 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
795 
problems meeting the criteria below. Additionally, unanticipated problems must be reported to 
796 
the JCHR IRB within 7 calendar days of recognition.   
797 
For this protocol, an unanticipated problem is an incident, experience, or outcome that meets all 
798 
of the following criteria: 
799 
x Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
800 
that are described in the protocol related documents, such as the IRB-approved research 
801 
protocol and informed consent document; and (b) the characteristics of the subject 
802 
population being studied 
803 
x Related or possibly related to participation in the research (possibly related means there is 
804 
a reasonable possibility that the incident, experience, or outcome may have been caused 
805 
by the procedures involved in the research) 
806 
x Suggests that the research places participants or others at a greater risk of harm than was 
807 
previously known or recognized (including physical, psychological, economic, or social 
808 
harm) 
809 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
810 
involving a specific site such as unanticipated problems that occur at the Coordinating Center or 
811 
at another participating entity such as the central laboratory. 
812 
10.2 Adverse Events 
813 
10.2.1 Definitions 
814 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
815 
relationship between the adverse event and the device(s) under investigation. 
816 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
817 
x Results in death. 
818 
x Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
819 
have become life-threatening, is not necessarily considered a serious adverse event). 
820 
x Requires inpatient hospitalization or prolongation of existing hospitalization. 
821 
x Results in persistent or significant disability/incapacity or substantial disruption of the 
822 
ability to conduct normal life functions (sight threatening). 
823 
x Is a congenital anomaly or birth defect. 
824 
x Is considered a significant medical event by the investigator based on medical judgment 
825 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
826 
prevent one of the outcomes listed above). 
827 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 47 OF 68 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
828 
any life-threatening problem or death caused by, or associated with, a study device, if that effect, 
829 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
830 
investigational plan or application (including a supplementary plan or application), or any other 
831 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
832 
welfare of participants (21 CFR 812.3(s)). 
833 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which a 
834 
study device may have caused or to which the device may have contributed (note that an Adverse 
835 
Event Form is to be completed in addition to a Device Deficiency or Issue Form, unless excluded 
836 
from reporting as defined in ). An event that occurs solely due to participant (i.e., user) error in 
837 
which the device functions properly generally will not be considered an ADE unless it is 
838 
determined that the instructions on the screen of the device or user manual (or similar training 
839 
materials) may have contributed to the event (note: the event may still meet criteria for reporting 
840 
as an adverse event). 
841 
Device Complaints and Malfunctions: A device complication or complaint is something that 
842 
happens to a device or related to device performance, whereas an adverse event happens to a 
843 
participant.  A device complaint may occur independently from an AE, or along with an AE.  An 
844 
AE may occur without a device complaint or there may be an AE related to a device complaint.  
845 
A device malfunction is any failure of a device to meet its performance specifications or 
846 
otherwise perform as intended.  Performance specifications include all claims made in the 
847 
labeling for the device.  The intended performance of a device refers to the intended use for 
848 
which the device is labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, sites will 
849 
not be asked to distinguish between device complaints and malfunctions. 
850 
10.2.2 Reportable Adverse Events 
851 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
852 
meets one of the following criteria: 
853 
x An SAE 
854 
x An ADE as defined in section 10.2.1, unless excluded from reporting in section 10.3 
855 
x An AE as defined in 10.2.1 occurring in association with a study procedure 
856 
x An AE as defined in 10.2.1 not related to a device issue which leads to temporary or 
857 
permanent discontinuation of  a study device 
858 
x An AE as defined in 10.2.1 WKDWDIIHFWVWKHSDUWLFLSDQW¶VDELOLW\WRFRPSOHWHDQ\VWXdy 
859 
procedures 
860 
x An AE as defined in 10.2.1 for which a visit is made to a hospital emergency department 
861 
x Hypoglycemia meeting the definition of severe hypoglycemia as defined below 
862 
x Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, hyperglycemia 
863 
or ketosis event meeting the criteria defined below 
864 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
865 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor placement 
866 
are only reportable if severe and/or required treatment. 
867 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 48 OF 68 
All reportable AEs²whether volunteered by the participant, discovered by study personnel 
868 
during questioning, or detected through physical examination, laboratory test, or other means²
869 
will be reported on an AE form online.  Each AE form is reviewed by the Medical Monitor to 
870 
assess safety and to verify the coding and the reporting that is required. 
871 
10.2.3 Hypoglycemic Events 
872 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
873 
event when the following definition for severe hypoglycemia is met: the event required 
874 
assistance of another person due to altered consciousness, and required another person to actively 
875 
administer carbohydrate, glucagon, or other resuscitative actions.  This means that the participant 
876 
was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable 
877 
to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure 
878 
or loss of consciousness.  These episodes may be associated with sufficient neuroglycopenia to 
879 
induce seizure or loss of consciousness.  If plasma glucose measurements are not available 
880 
during such an event, neurological recovery attributable to the restoration of plasma glucose to 
881 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
882 
concentration. 
883 
When a hypoglycemic event meets the above reporting requirements, a Hypoglycemia Form 
884 
should be completed in addition to the Adverse Event Form. Severe hypoglycemia events should 
885 
be considered to be serious adverse events with respect to reporting requirements. 
886 
10.2.4 Hyperglycemia/Ketosis Events 
887 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
888 
event when one of the following 3 criteria is met: 
889 
x The event involved DKA, as defined by the Diabetes Control and Complications Trial 
890 
(DCCT) and described below 
891 
x Evaluation or treatment was obtained at a health care provider facility for an acute event 
892 
involving hyperglycemia or ketosis, or the participant contacted the site and received 
893 
guidance on how to manage the hyperglycemia/ketosis 
894 
x %ORRGNHWRQHOHYHOPPRO/HYHQ if there was no communication with a health care 
895 
provider at the time of the event 
896 
Hyperglycemic events are classified as DKA if the following are present: 
897 
x Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
898 
x Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
899 
x Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate (or CO2) <15; 
900 
and 
901 
x Treatment provided in a health care facility. 
902 
When a hyperglycemia/ketotic event meets the above reporting requirements, a Hyperglycemia/ 
903 
DKA Form should be completed in addition to the Adverse Event Form. Events meeting DKA 
904 
criteria are considered to be serious adverse events with respect to reporting requirements. 
905 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 49 OF 68 
Hyperglycemia events not meeting criteria for DKA generally will not be considered as serious 
906 
adverse events unless one of the SAE criteria in section 10.2.1 is met. 
907 
10.2.5 Relationship of Adverse Event to Study Device 
908 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
909 
by determining if there is a reasonable possibility that the adverse event may have been caused 
910 
by the study device. 
911 
To ensure consistency of adverse event causality assessments, investigators should apply the 
912 
following general guideline when determining whether an adverse event is related: 
913 
Yes 
914 
There is a plausible temporal relationship between the onset of the adverse event and the study 
915 
intervention, and the adverse event cannot be readily explDLQHGE\WKHSDUWLFLSDQW¶VFOLQLFDOVWDWH
916 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
917 
of response to the study intervention; and/or the adverse event abates or resolves upon 
918 
discontinuation of the study intervention or dose reduction and, if applicable, reappears upon re 
919 
challenge. 
920 
No 
921 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
922 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
923 
medication); and/or the adverse event has no plausible temporal relationship to study 
924 
intervention. 
925 
10.2.6 Severity (Intensity) of Adverse Events 
926 
The severity (intensity) of an adverse event will be rated on a three point scale: (1) mild, 
927 
(2) moderate, or (3) severe.  A severity assessment is a clinical determination of the intensity 
928 
of an event.  Thus, a severe adverse event is not necessarily serious.  For example, itching for 
929 
several days may be rated as severe, but may not be clinically serious. 
930 
x MILD: Usually transient, requires no special treatment, and does not interfere with the 
931 
SDUWLFLSDQW¶VGDLO\DFWLYLWLHV 
932 
x MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
933 
participant and may interfere with daily activities, but is usually ameliorated by simple 
934 
therapeutic measures and participant is able to continue in study. 
935 
x 6(9(5(,QWHUUXSWVDSDUWLFLSDQW¶VXVXDOGDLO\DFWLYLWLHVFDXVHVVHYHUHGLVFRPIRUWPD\
936 
cause discontinuation of study device, and generally requires systemic drug therapy or 
937 
other treatment. 
938 
10.2.7 Expectedness 
939 
For a serious adverse event that is considered possibly related to study device, the Medical 
940 
Monitor will classify the event as unexpected if the nature, severity, or frequency of the event 
941 
is not consistent with known risk information. 
942 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 50 OF 68 
10.2.8 Coding of Adverse Events 
943 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will 
944 
enter a preliminary MedDRA code which the Medical Monitor may accept or change (the 
945 
Medical MonitRU¶V0HG'5$FRGLQJZLOOEHXVHGIRUDOOUHSRUWLQJ7KH0HGLFDO0RQLWRUZLOO
946 
UHYLHZWKHLQYHVWLJDWRU¶VDVVHVVPHQWRIFDXVDOLW\DQGPD\DJUHHRUGLVDJUHH%RWKWKH
947 
LQYHVWLJDWRU¶VDQG0HGLFDO0RQLWRU¶VDVVHVVPHQWVZLOOEHUHFRUGHG7KH0HGLFDO0RQLWRUZLOO 
948 
have the final say in determining the causality as well as whether an event is classified as a 
949 
serious adverse event and/or an unanticipated adverse device effect. 
950 
10.2.9 Outcome of Adverse Events 
951 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
952 
x RECOVERED/RESOLVED: The participant recovered from the AE/SAE without 
953 
sequelae.  Record the AE/SAE stop date. 
954 
x RECOVERED/RESOLVED WITH SEQUELAE: The event persisted and had stabilized 
955 
without change in the event anticipated.  Record the AE/SAE stop date. 
956 
x FATAL: A fatal outcome is defined as the SAE that resulted in death.  Only the event that 
957 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the 
958 
time of death; however, were not the cause of deatKZLOOEHUHFRUGHGDV³UHVROYHG´DWWKH
959 
time of death. 
960 
x NOT RECOVERED/NOT RESOLVED (ONGOING): An ongoing AE/SAE is defined as 
961 
the event was ongoing with an undetermined outcome. 
962 
An ongoing outcome will require follow-up by the site in order to determine the final outcome of 
963 
the AE/SAE. 
964 
The outcome of an ongoing event at the time of death that was not the cause of death, will be 
965 
XSGDWHGDQGUHFRUGHGDV³UHVROYHG´ZLWKWKHGDWHRIGHDWKUHFRUGHGDVWKHVWRSGDWH 
966 
UNKNOWN: An unknown outcome is defined as an inability to access the participant or the 
967 
SDUWLFLSDQW¶VUHFRUGVWRGHWHUPLQHWKHRXWFRPHIRUH[DPSOHDSDUWLFLSDQWWKDWZDVORVWWR
968 
follow-up). 
969 
If any reported adverse events are ongoing when a participant completes the study (or 
970 
withdraws), adverse events classified UADEs will be followed until they are either resolved, or 
971 
have no prospect of improvement or change, even after the participant has completed all 
972 
applicable study visits/contacts.  For all other adverse events, data collection will end at the time 
973 
the participant completes the study. Note: participants should continue to receive appropriate 
974 
medical care for an adverse event after their participation in the study ends. 
975 
10.3 Reportable Device Issues 
976 
All UADEs and ADEs as defined in section 10.2.1 will be reported on both a device issue form 
977 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
978 
placement that do not require pharmacologic treatment. As noted in section 10.2.1, events that 
979 
occur due to participant (user) error generally will not require completion of a device issue form. 
980 
6XFKµHUURUV¶FRXOGLQFOXGHLPSURSHUXVHRIDQLQVXOLQSXPSRUXVLQJDSXPSLQIXVLRQVHWRU
981 
CGM sensor for a period of time longer than its labeling. 
982 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 51 OF 68 
Device complaints and device malfunctions will be reported except in the following 
983 
circumstances. These occurrences are expected and will not be reported on a Device Issue Form 
984 
assuming criteria for a UADE or ADE have not been met: 
985 
x CGM sensor lasting fewer days than expected per manufacturer 
986 
x CGM tape adherence issues 
987 
x Battery lifespan deficiency due to inadequate charging or extensive wireless 
988 
communication 
989 
x Intermittent device component disconnections/communication failures not requiring 
990 
system replacement or workaround/resolution not specified in user guide/manual 
991 
x Device issues clearly addressed in the user guide manual that do not require additional 
992 
troubleshooting 
993 
10.4 Timing of Event Reporting 
994 
SAEs possibly related to a study device or study participation and UADEs must be reported to 
995 
the Coordinating Center within 24 hours of the site becoming aware of the event.  This can occur 
996 
via phone or email, or by completion of the online serious adverse event form and device issue 
997 
form if applicable.  If the form is not initially completed, it should be competed as soon as 
998 
possible after there is sufficient information to evaluate the event. All other reportable ADEs and 
999 
other reportable AEs should be submitted by completion on the on line form within 7 days of the 
1000 
site becoming aware of the event. 
1001 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1002 
serious, related, and unexpected.  Notification will be made within 10 days after the 
1003 
Coordinating Center becomes aware of the event. 
1004 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1005 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1006 
Ethics Committee. The JCHR IRB must be informed of all UADEs within seven calendar days. 
1007 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report 
1008 
the results of the investigation to all overseeing IRBs, and the FDA within 10 working days of 
1009 
the Sponsor becoming aware of the UADE per 21CFR 812.46(b) (2).  The Medical Monitor must 
1010 
determine if the UADE presents an unreasonable risk to participants.  If so, the Medical Monitor 
1011 
must ensure that all investigations, or parts of investigations presenting that risk, are terminated 
1012 
as soon as possible but no later than 5 working days after the Medical Monitor makes this 
1013 
determination and no later than 15 working days after first receipt notice of the UADE. 
1014 
Device malfunctions will be handled by the Sponsor or designee as described below.  In the case 
1015 
of a CGM transmitter or sensor device malfunction, information will be forwarded to Dexcom by 
1016 
the site personnel, to be handled by their complaint management system. 
1017 
10.5 Safety Oversight 
1018 
The study Medical Monitor will review all adverse events and adverse device events that are 
1019 
reported during the study.  SAEs typically will be reviewed within 24 hours of reporting.  Other 
1020 
AEs typically will be reviewed on a weekly basis. Additionally, the Medical Monitor will review 
1021 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 52 OF 68 
compiled safety data at periodic intervals (generally timed to the review of compiled safety data 
1022 
by the DSMB). 
1023 
The Clinical Study Director will be informed of all cases of severe hypoglycemia and DKA and 
1024 
the Medical MonLWRU¶VDVVHVVPHQWRIUHODWLRQVKLSWRWKHVWXG\GHYLFHDQGLQIRUPHGRIDOO
1025 
reported device issues. 
1026 
A Data and Safety Monitoring Board (DSMB) will provide safety oversight.  The DSMB will be 
1027 
informed of all cases of severe hypoglycemia and diabetic ketoacidosis irrespective of device 
1028 
relationship, all device-related SAEs, and all UADEs at the time that they occur during the study 
1029 
and will review compiled safety data at periodic intervals.  The DSMB also will be informed of 
1030 
any ADEs not meeting criteria for a UADE if the Medical Monitor requests the DSMB review.  
1031 
The DSMB can request modifications to the study protocol or suspension or outright stoppage of 
1032 
the study if deemed necessary based on the totality of safety data available.  Details regarding the 
1033 
'60%¶VUROHZLOOEHGRFXPHQWHGLQDVHSDUDWH'60%GRFXPHQW 
1034 
10.6 Stopping Criteria 
1035 
10.6.1 Participant Discontinuation of Study Device 
1036 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA 
1037 
event (or a malfunction that could have led to severe hypoglycemia or DKA), use of the study 
1038 
system will be suspended while the problem is diagnosed. The UADE will be reported to the 
1039 
IRB, DSMB, and FDA. After assessment of the problem and any correction, use of the system 
1040 
will not be restarted until approval is received from the IRB, DSMB, and FDA. 
1041 
In the absence of a device malfunction, use of the study system by a participant will be 
1042 
discontinued if any of the following occur: 
1043 
x The investigator believes it is unsafe for the participant to continue on the intervention.  
1044 
This could be due to the development of a new medical condition or worsening of an 
1045 
existing condition; or participant behavior contrary to the indications for use of the device 
1046 
WKDWLPSRVHVRQWKHSDUWLFLSDQW¶VVDIHW\ 
1047 
x The participant requests that the treatment be stopped 
1048 
x Participant pregnancy 
1049 
x Two distinct episodes of DKA as defined in 10.2.4 
1050 
x Two distinct severe hypoglycemia events as defined in section 10.2.3 
1051 
x One episode of DKA as defined in section 10.2.4 and one severe hypoglycemia event as 
1052 
defined in section 10.2.3 
1053 
Each DKA or severe hypoglycemia event will be reviewed by the Medical Monitor and by the 
1054 
DSMB with respect to determination of cause and whether the occurrence of the event can be 
1055 
attributed to use of the study system. 
1056 
An additional requirement for continued [study device] use following a single DKA or severe 
1057 
hypoglycemia event will be that (1) the site investigator believes that the event is explainable, 
1058 
unlikely to recur, and that it is safe for the participant to continue to use the system and (2) the 
1059 
Medical Monitor and DSMB concur. If either the Medical Monitor or DSMB determines that the 
1060 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 53 OF 68 
occurrence of the event indicates that it is not safe for the participant to continue to use the BP 
1061 
system, use will be discontinued. 
1062 
10.6.2 Criteria for Suspending or Stopping Overall Study 
1063 
In addition to the suspension of device use due to a UADE as described in 10.6.1, study activities 
1064 
could be similarly suspended if the manufacturer of any constituent study device requires 
1065 
stoppage of device use for safety reasons (e.g. product recall).  In addition to suspension of 
1066 
device use due to a UADE, the study will be suspended for 2 severe hypoglycemia and/or DKA 
1067 
related events related to device function. The affected study activities may resume if the 
1068 
underlying problem can be corrected by a protocol or system modification that will not invalidate 
1069 
the results obtained prior to suspension. 
1070 
The Medical Monitor or the DSMB may request suspension of study activities or stoppage of the 
1071 
study at any time if deemed necessary based on the totality of safety data available. 
1072 
 
1073 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 54 OF 68 
Chapter 11: Miscellaneous Considerations 
1074 
11.1 Drugs Used as Part of the Protocol 
1075 
U-100 rapid acting insulin analogues, Aspart or Lispro, will be used during the study since these 
1076 
are the only insulins approved for the study pump. 
1077 
11.2 Collection of Medical Conditions and Medications 
1078 
Pre-Existing Condition: Any medical condition that is either present at screening, a chronic 
1079 
disease, RUDSULRUFRQGLWLRQWKDWFRXOGLPSDFWWKHSDUWLFLSDQW¶VKHDOWKGXULQJWKHFRXUVHRIWKH
1080 
study (e.g., prior myocardial infarction or stroke). 
1081 
Medical Conditions during the study: The following medical conditions that do not qualify for 
1082 
reporting on an Adverse Event Form should be reported on the Medical Conditions Form: (1) 
1083 
new diagnosis of a chronic disease (i.e., not present at the time of enrollment) and (2) any 
1084 
PHGLFDOFRQGLWLRQWKDWFRXOGDIIHFWWKHSDUWLFLSDQW¶VDELOLW\WRFDUU\RXWDQ\DVSHFWRIWKHprotocol 
1085 
RUFRXOGDIIHFWDQRXWFRPHDVVHVVPHQW7UDQVLHQWFRQGLWLRQVWKDWGRQRWDIIHFWWKHSDUWLFLSDQW¶V
1086 
ability to carry out the protocol or study data related to any study outcome do not need to be 
1087 
reported. 
1088 
Medications: All medications that the participant is currently taking at screening and during the 
1089 
course of the study should be recorded.  Nutraceuticals and preventative treatment also should be 
1090 
recorded.  This will include the treatment of chronic pre-existing conditions, medical conditions 
1091 
that occur during the study (both reportable and not-reportable medical conditions), and/or 
1092 
adverse events. Medications only taken as needed either can be recorded when prescribed or only 
1093 
recorded if used during the study.  Glucagon for treatment of severe hypoglycemia will only be 
1094 
recorded if used during the study. 
1095 
11.3 Prohibited Medications, Treatments, and Procedures 
1096 
Participants are not permitted to use Afrezza or any non-insulin glucose-lowering agent other 
1097 
than metformin (including GLP-1 agonists, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas). 
1098 
Participants are not permitted to use diabetes management devices that are not FDA approved 
1099 
(such as do-it-yourself closed-loop systems). 
1100 
11.4 Rescue Medications 
1101 
All participants will be required to have a commercially available glucagon (or glucagon analog) 
1102 
preparation for treatment as needed of severe hypoglycemia. 
1103 
11.5 Pregnancy Reporting 
1104 
If pregnancy occurs, the study intervention will be discontinued while continuing safety follow 
1105 
up.  The occurrence of pregnancy will be reported to the Coordinating Center and to the JCHR 
1106 
IRB as an Unanticipated Problem within 7 calendar days of becoming aware of the pregnancy. 
1107 
11.6 Participant Compensation 
1108 
Participant compensation will be specified in the informed consent form. 
1109 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 55 OF 68 
11.7 Participant Withdrawal 
1110 
Participation in the study is voluntary, and a participant may withdraw at any time. For 
1111 
participants who withdraw, their data will be used up until the time of withdrawal. An early 
1112 
termination visit may be completed to collect final study data. 
1113 
If participants wish to discontinue using the study device without withdrawing, participants will 
1114 
be encouraged to remain in the study through the final study visit. 
1115 
11.8 Confidentiality 
1116 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1117 
used instead of their name. Protected health information gathered for this study will be shared 
1118 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
1119 
participant information may also be provided to research sites involved in the study. 
1120 
 
1121 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 56 OF 68 
Chapter 12: Statistical Considerations 
1122 
12.1 Statistical and Analytical Plans 
1123 
The outcome metrics and the statistical analyses are summarized below. A detailed Statistical 
1124 
Analysis Plan will be written and finalized prior to the first tabulation of data by treatment group 
1125 
(i.e., for DSMB review).   
1126 
12.2 Statistical Hypotheses 
1127 
The primary outcome for this study is CGM-measured % in range 70-180 mg/dL over 12 weeks 
1128 
in each one of the two crossover periods. The intervention will be considered effective if time in 
1129 
range during the CLC period is superior to the SAP period using a statistical significance of 
1130 
Į and the model specified below (section 12.6). 
1131 
The null/alternative hypotheses are: 
1132 
a. Null Hypothesis: There is no difference in mean CGM-measured % in range 70-180 
1133 
mg/dL over 12 weeks between SAP and CLC periods 
1134 
b. Alternative Hypothesis: The mean CGM-measured % in range 70-180 mg/dL over 12 
1135 
weeks is different for SAP and CLC periods. 
1136 
12.3 Sample Size 
1137 
Sample size has been computed for the primary outcome (CGM-measured % in range 70-180 
1138 
mg/dL). Data from the SAP group in DCLP3 (The International Diabetes Closed Loop Protocol 3 
1139 
Pivotal Trial of t:slim X2 with Control-IQ Technology) were used to calculate sample size specific 
1140 
to 18 years age group. For the SAP group, the standard deviation for time in range 70-180 mg/dL 
1141 
over the course of the first 3 months was 12% (95% CI 10% to 16%) and the correlation between 
1142 
the first 3 months and last 3 months was 0.92. 
1143 
A total sample size was computed to be N=31 for the following assumptions: (1) two 3-month 
1144 
periods [CLC:SAP] crossover randomization, (2) 90% power, (3) a 8% absolute increase in % 
1145 
time in range 70-180 mg/dL, (4) a SD of 17%, (5) a correlation between the two periods of 0.70, 
1146 
and (6) 2-sided type 1 error of 0.05. 
1147 
The total sample size has been increased to N=35 to account for potential dropouts.  
1148 
12.4 Outcome Measures 
1149 
12.4.1 Primary Efficacy Endpoint 
1150 
CGM-measured % in range 70-180 mg/dL 
1151 
12.4.2 Secondary Efficacy Endpoints 
1152 
12.4.2.1 Secondary Efficacy Endpoint Included in Hierarchical Analysis 
1153 
CGM-measured % below 54 mg/dL (non-inferiority outcome with a non-inferiority limit of 
1154 
1.0%) will be tested in a hierarchical fashion as described in section 12.7.1. This is the only non-
1155 
inferiority outcome in the study; all others are superiority. 
1156 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 57 OF 68 
12.4.2.2 Other Secondary Efficacy Endpoints 
1157 
The following endpoints are considered exploratory. 
1158 
CGM-Measured: 
1159 
x % in range 70-140 mg/dL 
1160 
x mean glucose 
1161 
x glucose variability measured with the coefficient of variation (CV) 
1162 
x glucose variability measured with the standard deviation (SD) 
1163 
x % <70 mg/dL 
1164 
x % <60 mg/dL 
1165 
x % <54 mg/dL  
1166 
x low blood glucose index 
1167 
x hypoglycemia events (defined as at least 15 consecutive minutes <70 mg/dL) 
1168 
x % >180 mg/dL 
1169 
x % >250 mg/dL 
1170 
x % >300 mg/dL  
1171 
x high blood glucose index 
1172 
x CGM metrics by time of day. Calculate all CGM metrics listed above (including the 
1173 
primary outcome) for: 
1174 
¡ All 24 hours of the day  
1175 
¡ Daytime only (06:00AM to 00:00AM) 
1176 
¡ Nighttime only (00:00AM to 06:00AM) 
1177 
HbA1c: 
1178 
x HbA1c at 13 weeks 
1179 
x HbA1c <7.0% at 13 weeks 
1180 
x HbA1c <7.5% at 13 weeks 
1181 
x HbA1c improvement from baseline to 13 weeks >0.5% 
1182 
x HbA1c improvement from baseline to 13 weeks >1.0% 
1183 
x HbA1c relative improvement from baseline to 13 weeks >10% 
1184 
Questionnaires: 
1185 
x Diabetes Distress Scale at 13 weeks ± total score and 4 subscales: 
1186 
¡ Emotional burden 
1187 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 58 OF 68 
¡ Physician-related distress 
1188 
¡ Regimen-related distress 
1189 
¡ Interpersonal distress 
1190 
x Glucose Monitoring Satisfaction Survey ± satisfaction, burden, and total scores 
1191 
x Hypoglycemia Confidence Scale 
1192 
x Diabetes Technology Attitudes survey 
1193 
x INSPIRE survey scores - following study system period only 
1194 
x SUS survey scores - following study system period and at 13 weeks only 
1195 
Other: 
1196 
x Insulin at 13 weeks 
1197 
¡ Total daily insulin (units/kg) 
1198 
¡ Basal: bolus insulin ratio 
1199 
x Weight and Body Mass Index (BMI) at 13 weeks 
1200 
12.4.3 CGM Metrics Calculations 
1201 
The last 2 weeks of personal CGM data or last 2 weeks of CGM run-in data will serve as 
1202 
baseline. Since participants will receive up to 7 days of training before taking the CLC system 
1203 
home, the first 7 days in the SAP and CLC periods will not be included in the CGM analyses. 
1204 
CGM data starting from day 8 following randomization visit through the 13-week visit for first 
1205 
period and from day 8 following treatment reassignment through the second 13-week visit for the 
1206 
second crossover period will be included in the calculation of CGM metrics. At least 72hr of 
1207 
CGM data at baseline and in each one of the two periods are needed in order for the metrics to be 
1208 
calculated. 
1209 
12.5 Analysis Datasets and Sensitivity Analyses 
1210 
All analyses comparing the CLC period with SAP period will follow the intention-to-treat (ITT) 
1211 
principle with each period and participant analyzed according to the randomization. All 
1212 
randomized periods with at least 72hr of CGM data will be included in the primary and 
1213 
secondary hierarchical analyses. 
1214 
Safety outcomes will be reported for all enrolled participants, irrespective of whether the 
1215 
participant was randomized or the study was completed. 
1216 
12.5.1 Per Protocol Analyses 
1217 
x If more than 10% of participants in a treatment period have fewer than 168 hours of CGM 
1218 
data, the primary analysis will be replicated excluding such subjects. 
1219 
x The primary analysis will be replicated only with participants who used the system in CL 
1220 
mode for >80% during the CLC period and used the sensor for >80% during the SAP 
1221 
period. 
1222 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 59 OF 68 
12.5.2 Sensitivity Analyses  
1223 
12.5.2.1 Missing Data 
1224 
It is worth emphasizing that any statistical method for handling missing data makes a number of 
1225 
untestable assumptions.  The goal will be to minimize the amount of missing data in this study so 
1226 
that results and conclusions will not be sensitive to which statistical method is used. To that end, 
1227 
sensitivity analyses will be performed to explore whether results are similar for primary analysis 
1228 
when using different methods.  The following methods will be applied: 
1229 
x $YDLODEOHFDVHVRQO\KULQDWOHDVWRQHRIWKHWZRFURVV-over periods, primary analysis 
1230 
described below) 
1231 
x 5XELQ¶VPXOWLSOHLPSXWDWLRQ 
1232 
12.5.2.2 Carry-over Effect 
1233 
A model will be run for the primary outcome to test for any carry-over effects, by adding a 
1234 
treatment by period interaction term. 
1235 
12.6 Analysis of the Primary Efficacy Endpoint 
1236 
Summary statistics [mean ± SD or median (IQR)] will be reported for the CGM-measured % in 
1237 
range 70-180 mg/dL and for baseline and two randomized cross-over periods. 
1238 
A repeated measures linear regression model will be fit for CGM-measured % in range 70-180 
1239 
mg/dL. The model will include pre-randomization baseline, the two cross-over periods, and will 
1240 
adjust for period and site (as random effect). Residual values will be examined for an 
1241 
approximate normal distribution.  If residuals are highly skewed, then a transformation or robust 
1242 
statistical method (e.g., non-parametric or MM estimation) will be used instead. It is expected 
1243 
that the residual values for CGM-measured % in range 70-180 mg/dL will follow an approximate 
1244 
normal distribution. 
1245 
12.7 Analysis of the Secondary Endpoints 
1246 
Point estimates and confidence intervals for the treatment period differences will be presented 
1247 
for all secondary metrics. Models similar with the one described above will be implemented. 
1248 
12.7.1 Hierarchical Analyses 
1249 
To preserve the overall type 1 error for CGM-measured % below 54 mg/dL, a hierarchical 
1250 
testing procedure will be used. A formal statistical assessment of non-inferiority (limit 1%) for 
1251 
time below 54 mg/dl will only be performed if the primary analysis for time in range described 
1252 
above results in a statistically significant result (p < 0.05). 
1253 
Regardless of the results for the primary outcome, summary statistics appropriate to the 
1254 
distribution will be tabulated by treatment period for CGM-measured non-inferiority % below 54 
1255 
mg/dL.  However, the reported one-sided 95% confidence interval for CGM-measured % below 
1256 
54 mg/dL that excludes the non-inferiority limit of 1.0% will not be considered a statistically 
1257 
significant result if the primary outcome failed to reach statistical significance. 
1258 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 60 OF 68 
12.7.2 Other Endpoint Analyses 
1259 
CGM-Measured Outcomes 
1260 
The analyses for the secondary CGM-measured outcomes will parallel those mentioned above 
1261 
for the primary outcome. 
1262 
HbA1c 
1263 
Summary statistics [mean ± SD or median (IQR)] will be reported for the central lab HbA1c at 
1264 
randomization and 13 weeks in each treatment period. 
1265 
Lab HbA1c values at 13 weeks will be compared between the two treatment periods using a 
1266 
linear model while adjusting for period, site (random effect), and baseline value.  
1267 
For the binary HbA1c outcomes listed above, risk-adjusted percentages by treatment period will 
1268 
be computed from a logistic regression model.  The logistic regression will adjust for the same 
1269 
factors mentioned above for the analysis with HbA1c as a continuous factor (i.e., period, site, 
1270 
and baseline value). 
1271 
Questionnaires and Other Outcomes 
1272 
For questionnaires administered during both randomization periods, comparisons will be made 
1273 
using similar linear models as described above for the primary outcomes. Separate models will 
1274 
be run for the total score and each of the subscales listed above. 
1275 
Similarly, for insulin, weight and BMI metrics comparisons will be made using similar linear 
1276 
models as described above for the primary HbA1c analysis. 
1277 
12.8 Safety Analyses 
1278 
All enrolled participants will be included in these analyses and all their safety events will be 
1279 
reported. 
1280 
The circumstances of all reportable cases of the following will be summarized and tabulated by 
1281 
treatment period: 
1282 
x Severe hypoglycemia  
1283 
x Diabetic ketoacidosis  
1284 
x .HWRQHHYHQWVGHILQHGDVGD\ZLWKNHWRQHOHYHOPPRO/ 
1285 
x CGM-PHDVXUHGK\SRJO\FHPLFHYHQWVPLQXWHVZLWKJOXFRVHFRQFHQWUDWLRQ
1286 
mg/dL) 
1287 
x CGM-PHDVXUHGK\SHUJO\FHPLFHYHQWVPLQXWHVZLWKJOXFRVHFRQFHQWUDWLRQ!
1288 
mg/dL) 
1289 
x Worsening of HbA1c from start of the period to 13 weeks by >0.5% 
1290 
x Other serious adverse events (SAE) and serious adverse device events (SADE) 
1291 
x Adverse device effects (ADE) 
1292 
x Unanticipated adverse device effects (UADE) 
1293 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 61 OF 68 
Statistical analyses to compare rates of severe hypoglycemia and rates of diabetic ketoacidosis 
1294 
between treatment arms will only be performed if there are at least 10 events after 
1295 
randomization.  If yes, the numbers will be compared between the two treatment periods using a 
1296 
robust Poisson regression. The amount of follow up will be included as an offset covariate to 
1297 
compare the rates. 
1298 
Comparison of safety outcomes between the two treatment periods only include those events 
1299 
occurring on or after randomization until the final 13 week visit.  
1300 
Any pre-randomization adverse events will be tabulated separately and will include participants 
1301 
who were never randomized. 
1302 
12.9 Intervention Adherence and Adaptation 
1303 
The following tabulations and analyses will be performed by treatment period to assess 
1304 
intervention adherence for the study: 
1305 
x Sensor use ±percent time of use, overall and by 4-weekly 
1306 
x The overall daily frequency of downloaded BGM use  
1307 
x For CLC period only, the following will be tabulated: 
1308 
¡ Percent time in different operational modes - overall and by month 
1309 
¡ Percent change of clinical and controller adaptation parameters throughout closed-loop 
1310 
use 
1311 
12.10 Adherence and Retention Analyses 
1312 
The following tabulations and analyses will be performed by treatment period to assess protocol 
1313 
adherence for the study: 
1314 
x Number of protocol and procedural deviations per participant along with the number and 
1315 
percentage of participants with each number of deviations 
1316 
x Number of protocol and procedural deviations by severity with brief descriptions listed 
1317 
x Flow chart accounting for all participants at all scheduled visits and phone contacts post 
1318 
treatment initiation to assess visit and phone completion rates 
1319 
x Number of and reasons for unscheduled visits and phone calls 
1320 
x Number of participants who stopped treatment and reasons 
1321 
12.11 Baseline Descriptive Statistics 
1322 
Baseline demographic and clinical characteristics of the cohort of all randomized participants 
1323 
will be summarized using summary statistics appropriate to the distribution of each variable. 
1324 
12.12 Device Issues 
1325 
Reported Device malfunctions and other reported device issues will be tabulated. 
1326 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 62 OF 68 
12.13 Planned Interim Analyses 
1327 
The DSMB will review all cases of severe hypoglycemia and diabetic ketoacidosis irrespective 
1328 
of device relationship, all device-related SAEs, and all UADEs at the time that they occur during 
1329 
the study and will review compiled safety data at periodic intervals. The DSMB can request 
1330 
modifications to the study protocol or suspension or outright stoppage of the study if deemed 
1331 
necessary. 
1332 
12.14 Subgroup Analyses 
1333 
In exploratory analyses, the primary outcome will be assessed separately with tests of interaction 
1334 
in various subgroups and for continuous variables according to the baseline value, which will be 
1335 
described in the Statistical Analysis Plan. 
1336 
12.15 Multiple Comparison/Multiplicity 
1337 
Hierarchical testing will be done to control the type 1 error for the time in range and time below 
1338 
54 mg/dl outcomes as described above in Section 12.7.1. 
1339 
No multiplicity adjustment will be done for safety analyses.  For all other secondary analyses, 
1340 
the false discovery rate will be controlled using the adaptive Benjamini-Hochberg procedure. 
1341 
 
1342 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 63 OF 68 
Chapter 13: Data Collection and Monitoring 
1343 
13.1 Case Report Forms and Device Data 
1344 
The main study data are collected on electronic case report forms (CRFs). When data are directly 
1345 
collected in electronic case report forms, this will be considered the source data. For any data 
1346 
points for which the eCRF is not considered source (e.g. lab results that are transcribed from a 
1347 
printed report into the eCRF), the original source documentation must be maintained in the 
1348 
SDUWLFLSDQW¶VVWXG\FKDUWRUPHGLFDOUHFRUG7KLVVRXUFHPXVWEHUHDGLO\YHULILDEOHDJDLQVWWKH
1349 
values entered into eCRF. Even where all study data are directly entered into the eCRFs at office 
1350 
visits, evidence of interaction with a live subject must be recorded (e.g., office note, visit record, 
1351 
etc.). 
1352 
Electronic device data files are obtained from the study software and individual hardware 
1353 
components.  These electronic device files are considered the primary source documentation. 
1354 
13.2 Study Records Retention 
1355 
Each participating site will maintain appropriate medical and research records for this trial, in 
1356 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1357 
confidentiality of participants. 
1358 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1359 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1360 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1361 
discontinuation of clinical development of the investigational product. These documents should 
1362 
be retained for a longer period, however, if required by local regulations. No records will be 
1363 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
1364 
sponsor to inform the investigator when these documents no longer need to be retained. 
1365 
13.3 Quality Assurance and Monitoring 
1366 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1367 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1368 
conducted and data are generated, documented and reported in compliance with the protocol, 
1369 
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1370 
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1371 
accurate, complete, and verifiable. Adverse events will be prioritized for monitoring. 
1372 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1373 
RIWKHVWXG\FRQVLVWHQWZLWKWKH)'$³*XLGDQFHIRU,QGXVWU\2YHUVLJKWRI&OLQLFDO
1374 
Investigations ± A Risk-%DVHG$SSURDFKWR0RQLWRULQJ´$XJXVW6WXG\FRQGXFWDQG
1375 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. This plan describes in 
1376 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
1377 
of detail monitoring will be performed, and the distribution of monitoring reports. 
1378 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1379 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1380 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1381 
verity and completeness of the key site data. Elements of the RBM may include: 
1382 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 64 OF 68 
x Qualification assessment, training, and certification for sites and site personnel 
1383 
x Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1384 
x Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1385 
review of entered data and edits, statistical monitoring, study closeout 
1386 
x On-site monitoring (site visits): source data verification, site visit report 
1387 
x Device accountability 
1388 
x Communications with site staff 
1389 
x Participant retention and visit completion 
1390 
x Quality control reports 
1391 
x Management of noncompliance 
1392 
x Documenting monitoring activities 
1393 
x Adverse event reporting and monitoring 
1394 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1395 
order to maintain current and personal knowledge of the study through review of the records, 
1396 
comparison with source documents, observation and discussion of the conduct and progress of 
1397 
the study. The investigational site will provide direct access to all trial related sites, source 
1398 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1399 
inspection by local and regulatory authorities. 
1400 
13.4 Protocol Deviations 
1401 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1402 
requirements.  The noncompliance may be either on the part of the participant, the investigator, 
1403 
or the study site staff.  As a result of deviations, corrective actions are to be developed by the site 
1404 
and implemented promptly. 
1405 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
1406 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1407 
 
1408 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 65 OF 68 
Chapter 14: Ethics/Protection of Human Participants 
1409 
14.1 Ethical Standard 
1410 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1411 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1412 
21 CFR Part 56, and/or the ICH E6. 
1413 
14.2 Institutional Review Board (IRB) (or Ethics Committee (EC)) 
1414 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1415 
be submitted to the IRB/EC for review and approval. Approval of both the protocol and the 
1416 
consent form must be obtained before any participant is enrolled. Any amendment to the 
1417 
protocol will require review and approval by the IRB/EC before the changes are implemented to 
1418 
the study. All changes to the consent form will be IRB/EC approved; a determination will be 
1419 
made regarding whether previously consented participants need to be re-consented. 
1420 
14.3 Informed Consent Process 
1421 
14.3.1 Consent Procedures and Documentation 
1422 
Informed consent is a process that is initiated priRUWRWKHLQGLYLGXDO¶VDJUHHLQJWRSDUWLFLSDWHLQ
1423 
WKHVWXG\DQGFRQWLQXHVWKURXJKRXWWKHLQGLYLGXDO¶VVWXG\SDUWLFLSDWLRQ([WHQVLYHGLVFXVVLRQRI
1424 
risks and possible benefits of participation will be provided to the participants and their families. 
1425 
Consent forms will be IRB/EC-approved and the participant will be asked to read and review the 
1426 
document. The investigator will explain the research study to the participant and answer any 
1427 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
1428 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1429 
research participants. Participants will have the opportunity to carefully review the written 
1430 
consent form and ask questions prior to signing. 
1431 
The participants should have the opportunity to discuss the study with their surrogates or think 
1432 
about it prior to agreeing to participate. The participant will sign the informed consent document 
1433 
prior to any procedures being done specifically for the study. The participants may withdraw 
1434 
consent at any time throughout the course of the trial. A copy of the informed consent document 
1435 
will be given to the participants for their records. The rights and welfare of the participants will 
1436 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1437 
affected if they decline to participate in this study. 
1438 
14.3.2 Participant and Data Confidentiality 
1439 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1440 
and the Coordinating Center(s) and their agents. This confidentiality is extended to cover testing 
1441 
of biological samples in addition to the clinical information relating to participants. Therefore, 
1442 
the study protocol, documentation, data, and all other information generated will be held in strict 
1443 
confidence. No information concerning the study or the data will be released to any unauthorized 
1444 
third party without prior written approval of the Steering Committee. 
1445 
The study monitor, other authorized representatives of the Coordinating Center, representatives 
1446 
of the IRB/EC or device company supplying study product may inspect all documents and 
1447 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 66 OF 68 
records required to be maintained by the investigator, including but not limited to, medical 
1448 
records (office, clinic, or hospital) for the participants in this study. The clinical study site will 
1449 
permit access to such records. 
1450 
7KHVWXG\SDUWLFLSDQW¶VFRQWDFWLQIRUPDWLRQZLOOEHVHFXUHO\VWRUHGDWHDFKFOLQLFDOVLWHIRU
1451 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1452 
secure location for as long a period as dictated by local IRB and Institutional/national 
1453 
regulations. 
1454 
Study participant research data, which is for purposes of statistical analysis and scientific 
1455 
reporting, will be transmitted to and stored either at the Jaeb Center for Health Research (JCHR) 
1456 
in Tampa, FL, USA or at Harvard University in Cambridge, MA, USA. Harvard uses a cloud-
1457 
based provider for storage of the closed-loop system data. These data will not include the 
1458 
SDUWLFLSDQW¶VFRQWDFWRULGHQWLI\LQJLQIRUPDWLRQXQOHVVRWKHUZLVHVSHFLILHGLQWKHLQIRUPHG
1459 
consent form. Rather, individual participants and their research data will be identified by a 
1460 
unique study identification number. The study data entry and study management systems used by 
1461 
clinical sites and by the JCHR research staff will be secured and password protected. At the end 
1462 
of the study, all study databases will be de-identified and archived at the JCHR in Tampa, FL. 
1463 
Permission to transmit data will be included in the informed consent. 
1464 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1465 
obtained from the NIH. This certificate protects identifiable research information from forced 
1466 
disclosure. It allows the investigator and others who have access to research records to refuse to 
1467 
disclose identifying information on research participation in any civil, criminal, administrative, 
1468 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
1469 
researchers and institutions from being compelled to disclose information that would identify 
1470 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1471 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1472 
 
1473 

 
DCLP4 PROTOCOL V6.0 14DEC2020 
PAGE 67 OF 68 
Chapter 15: References 
1. Dassau E, Zisser H, Harvey RA, Percival MW, Grosman B, Bevier W, Atlas E, Miller S, 
1LPUL5-RYDQRYLþ L, Doyle III FJ. Clinical Evaluation of a Personalized Artificial Pancreas. 
Diabetes Care. 2013;36:801-9. doi: 10.2337/dc12-0948. 
2. Dassau E, Brown SA, Basu A, Pinsker JE, Kudva YC, Gondhalekar R, Patek S, Lv D, 
Schiavon M, Lee JB, Dalla Man C, Hinshaw L, Castorino K, Mallad A, Dadlani V, 
McCrady-Spitzer SK, McElwee-Malloy M, Wakeman CA, Bevier WC, Bradley PK, 
Kovatchev B, Cobelli C, Zisser HC, Doyle III FJ. Adjustment of Open-Loop Settings to 
Improve Closed-Loop Results in Type 1 Diabetes: A Multicenter Randomized Trial. J Clin 
Endocrinol Metab. 2015;100(10):3878-86. Epub 2015/07/24. doi: 10.1210/jc.2015-2081. 
PubMed PMID: 26204135; PMCID: PMC4596045. 
3. Dassau E, Pinsker JE, Kudva YC, Brown SA, Gondhalekar R, Dalla Man C, Patek S, 
Schiavon M, Dadlani V, Dasanayake I, Church MM, Carter RE, Bevier WC, Huyett LM, 
Hughes J, Anderson S, Lv D, Schertz E, Emory E, McCrady-Spitzer SK, Jean T, Bradley PK, 
Hinshaw L, Laguna Sanz AJ, Basu A, Kovatchev B, Cobelli C, Doyle III FJ. 12 Week 24/7 
Ambulatory Artificial Pancreas with Weekly Adaptation of Insulin Delivery Settings: Effect 
on Hemoglobin A1c and Hypoglycemia. Diabetes Care. 2017;40(12):1719-26. 
4. Huyett LM, Ly TT, Forlenza GP, Reuschel-DiVirgilio S, Messer LH, Wadwa RP, 
Gondhalekar R, Doyle III FJ, Pinsker JE, Maahs DM, Buckingham BA, Dassau E. Outpatient 
Closed-Loop Control with Unannounced Moderate Exercise in Adolescents Using Zone 
Model Predictive Control. Diabetes Technol Ther. 2017;19(6):331-9. Epub 2017/05/02. doi: 
10.1089/dia.2016.0399. PubMed PMID: 28459617; PMCID: PMC5510043. 
5. Forlenza GP, Deshpande S, Ly TT, Howsmon DP, Cameron F, Baysal N, Mauritzen E, 
Marcal T, Towers L, Bequette BW, Huyett LM, Pinsker JE, Gondhalekar R, Doyle III FJ, 
Maahs DM, Buckingham BA, Dassau E. Application of Zone Model Predictive Control 
Artificial Pancreas During Extended Use of Infusion Set and Sensor: A Randomized 
Crossover-Controlled Home-Use Trial. Diabetes Care. 2017. 
6. Lee JB, Dassau E, Gondhalekar R, Seborg DE, Pinsker JE, Doyle III FJ. Enhanced Model 
Predictive Control (eMPC) Strategy for Automated Glucose Control. Ind Eng Chem Res. 
2016;55(46):11857-68. doi: 10.1021/acs.iecr.6b02718. 
7. Laguna Sanz AJ, Doyle III FJ, Dassau E. An Enhanced Model Predictive Control for the 
Artificial Pancreas Using a Confidence Index Based on Residual Analysis of Past 
Predictions. J Diabetes Sci Technol. 2017;11(3):537-44. doi: 
doi:10.1177/1932296816680632. 
8. Pinsker JE, Laguna Sanz AJ, Lee JB, Church M, Andre C, Lindsey L, E,, Doyle III FJ, 
Dassau E. Evaluation of an Artificial Pancreas with Enhanced Model Predictive Control 
(eMPC) and a Glucose Prediction Trust Index with Unannounced Exercise. Diabetes Technol 
Ther. 2018;20(7):455-64. doi: 10.1089/dia.2018.0031. 

 
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9. Deshpande S, Pinsker JE, Zavitsanou S, Shi D, Tompot R, Church MM, Andre C, Doyle III 
FJ, Dassau E. Design and Clinical Evaluation of the Interoperable Artificial Pancreas System 
(iAPS) Smartphone App: Interoperable Components with Modular Design for Progressive 
Artificial Pancreas Research and Development. Diabetes Technol Ther. 2019;21(1):35-43. 
Epub 2018/12/15. doi: 10.1089/dia.2018.0278. PubMed PMID: 30547670; PMCID: 
PMC6350072.