Home Use of MD-Logic Automated Insulin Delivery System: Safety and Efficacy
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: HealthPartners Institute

 
 
 
Official Title 
 Home Use of MD-Logic Automated Insulin Delivery System:  
Safety and Efficacy 
 
Brief Title: Fuzzy Logic Automated Insulin Regulation (FLAIR) 
NCT 03040414 
Date: March 17, 2020 
 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 1 OF 74 
 
Signature Page 
1 
 
2 
FLAIR- Fuzzy Logic Automated Insulin Regulation: 
3 
A Crossover Study Comparing Two Automated Insulin Delivery System 
4 
Algorithms (PID vs. PID + Fuzzy Logic) in Individuals with Type 1 Diabetes 
5 
 
6 
IDE Sponsor: Jaeb Center for Health Research 
7 
 
8 
Version Number: v7.1 
9 
 
10 
17 Mar 2020 
11 
 
12 
 
JCHR Protocol Director, Name/degree 
Judy Sibayan, MPH, CCRP 
Signature/Date 
 
 
Clinical Lead Investigator and Protocol 
Chair, Name/degree 
Richard M. Bergenstal, MD 
Signature/Date 
 
 
Protocol Chair, Name/degree 
Moshe Phillip, MD 
Signature/Date 
 
 
Medical Monitor, Name/degree 
Roy W. Beck, MD, PhD 
Signature/Date 
 
 
13 
 
14 
 
 
15 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 2 OF 74 
 
FLAIR- Fuzzy Logic Automated Insulin Regulation: 
16 
A Crossover Study Comparing Two Automated Insulin Delivery System 
17 
Algorithms (PID vs. PID + Fuzzy Logic) in Individuals with Type 1 Diabetes 
18 
 
19 
IDE Sponsor: Jaeb Center for Health Research 
20 
 
21 
Version Number: v7.1 
22 
 
23 
17 Mar 2020 
24 
 
 
25 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 3 OF 74 
 
Key Roles 
26 
 
27 
Protocol Chairs 
Name, degree 
Richard M. Bergenstal, MD 
Institution Name 
International Diabetes Center, Health Partners Institute 
Name, Degree 
Moshe Phillip, MD 
Institution Name 
Institute for Endocrinology and Diabetes. National Center for Childhood Diabetes. 
Schneider Children's Medical Center of Israel 
Central Administration 
International Diabetes Center, Health Partners Institute 
JCHR Coordinating Center Director 
Name, degree 
Judy Sibayan, MPH, CCRP 
Institution Name 
Jaeb Center for Health Research 
Medical Monitor 
Name, degree 
Roy W. Beck, MD, PhD 
Institution Name 
Jaeb Center for Health Research 
 
 
28 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 4 OF 74 
 
Table of Contents 
29 
KEY ROLES .................................................................................................................................................. 3 
30 
TABLE OF CONTENTS .................................................................................................................................. 4 
31 
LIST OF ABBREVIATIONS ............................................................................................................................ 8 
32 
SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE .............................................................. 9 
33 
PROTOCOL SUMMARY ............................................................................................................................... 10 
34 
SCHEMATIC OF STUDY DESIGN ................................................................................................................ 15 
35 
SCHEDULE OF STUDY VISITS AND PROCEDURES ..................................................................................... 16 
36 
 BACKGROUND INFORMATION ............................................................................................. 18 
37 
 Introduction ....................................................................................................................................... 18 
38 
 Background: Studies descriptions below include data from PID, MD-Logic, 
39 
and the combined algorithms: .............................................................................................................. 18 
40 
 Pre-Clinical Testing of MD-Logic Algorithms ........................................................................... 19 
41 
 Clinical Studies using MD-Logic Systems .................................................................................. 19 
42 
 Medtronic HCL Studies ............................................................................................................... 21 
43 
 Integrated Advanced HCL System In-Silico Testing .................................................................. 24 
44 
 Further Studies and Updates to the Advanced HCL System: ...................................................... 25 
45 
 Rationale ............................................................................................................................................ 27 
46 
 Automated Insulin Delivery System Description .............................................................................. 28 
47 
 Potential Risks and Benefits of the Investigational Device ............................................................... 29 
48 
 Risk Assessment ................................................................................................................................ 35 
49 
 Known Potential Benefits .................................................................................................................. 35 
50 
 General Considerations...................................................................................................................... 35 
51 
 STUDY ENROLLMENT AND SCREENING .............................................................................. 36 
52 
 Participant Recruitment and Enrollment ........................................................................................... 36 
53 
 Participant Inclusion Criteria ............................................................................................................. 37 
54 
 Participant Exclusion Criteria ............................................................................................................ 38 
55 
 Screening Procedures ........................................................................................................................ 38 
56 
 Data Collection and Testing ........................................................................................................ 39 
57 
 Questionnaires ............................................................................................................................. 39 
58 
 RUN-IN PHASE ...................................................................................................................... 40 
59 
 Introduction ....................................................................................................................................... 40 
60 
 Pump Run-In – 670G 3.0 HCL .......................................................................................................... 40 
61 
 Pump+CGM Run-In – 670G 3.0 HCL + Guardian Sensor (3) .......................................................... 41 
62 
 Visit and Contact Schedule ................................................................................................................ 41 
63 
 Run-In Assessments .......................................................................................................................... 41 
64 
 Device Data Uploads ......................................................................................................................... 41 
65 
 RANDOMIZATION VISIT ....................................................................................................... 42 
66 
 Randomization Visit .......................................................................................................................... 42 
67 
 Randomization ............................................................................................................................. 42 
68 
 HbA1c, C-peptide, and Glucose .................................................................................................. 42 
69 
 CROSSOVER TRIAL ............................................................................................................... 43 
70 
 Study Procedures and Schedule during the Crossover Trial.............................................................. 43 
71 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 5 OF 74 
 
 AID System Training .................................................................................................................. 43 
72 
 Home Use of AID System during Study Period 1 ....................................................................... 43 
73 
 Home Use of AID System during Study Period 2 ....................................................................... 44 
74 
 Visit and Phone Contact Schedule during Study Periods 1 and 2 ............................................... 44 
75 
 Procedures During Study Periods ................................................................................................ 44 
76 
5.1.5.1 Procedures performed during each contact ......................................................................... 44 
77 
5.1.5.2 Procedures performed during each follow-up visit ............................................................. 45 
78 
5.1.5.3 Setpoint adjustments during 670G 4.0 AHCL use .............................................................. 45 
79 
 Device Data Uploads During the Crossover Trial ....................................................................... 46 
80 
 Early Termination Visit ............................................................................................................... 46 
81 
 Unscheduled Visits ...................................................................................................................... 46 
82 
 STUDY DEVICES AND SAFETY .............................................................................................. 47 
83 
 Description of the Study Devices ...................................................................................................... 47 
84 
 Insulin Pumps .............................................................................................................................. 47 
85 
 Continuous Glucose Monitoring ................................................................................................. 47 
86 
 Blood Glucose Meter and Strips .................................................................................................. 47 
87 
 Ketone Meter and Strips .............................................................................................................. 47 
88 
 Study Device Accountability Procedures .......................................................................................... 47 
89 
 Blood Glucose Meter Testing ...................................................................................................... 48 
90 
 Blood Ketone Testing .................................................................................................................. 48 
91 
 Safety Measures ................................................................................................................................. 48 
92 
 CGM Calibration ......................................................................................................................... 48 
93 
 Pump Failure ............................................................................................................................... 48 
94 
 Hypoglycemia Threshold Alarm and Safety Protocol ................................................................. 48 
95 
 Hyperglycemia Threshold Alarm and Safety Protocol ................................................................ 49 
96 
 Safety Measures Specific to AID system use .............................................................................. 49 
97 
6.3.5.1 Insulin Dosing ..................................................................................................................... 49 
98 
 Safety Measures for Open-Loop (Manual Mode) CGM Use ...................................................... 49 
99 
6.3.6.1 Hypoglycemia Safety Protocol ........................................................................................... 49 
100 
6.3.6.2 Hyperglycemia Safety Protocol .......................................................................................... 49 
101 
 LABORATORY TESTING AND QUESTIONNAIRES ................................................................. 50 
102 
 Laboratory Testing ............................................................................................................................ 50 
103 
 Questionnaires ................................................................................................................................... 50 
104 
 ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES .............................................. 51 
105 
 Adverse Events .................................................................................................................................. 51 
106 
 Definitions ................................................................................................................................... 51 
107 
 Reportable Adverse Events ......................................................................................................... 52 
108 
8.1.2.1 Hypoglycemic Events ......................................................................................................... 52 
109 
8.1.2.2 Hyperglycemic/Ketotic Events ........................................................................................... 52 
110 
 Relationship of Adverse Event to Study Device ......................................................................... 53 
111 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 6 OF 74 
 
 Intensity of Adverse Event .......................................................................................................... 53 
112 
 Coding of Adverse Events ........................................................................................................... 54 
113 
 Outcome of Adverse Event ......................................................................................................... 54 
114 
 Reportable Device Issues ................................................................................................................... 55 
115 
 Pregnancy Reporting ......................................................................................................................... 55 
116 
 Timing of Event Reporting ................................................................................................................ 55 
117 
 Stopping Criteria ............................................................................................................................... 56 
118 
 Participant Discontinuation of Investigational Device ................................................................ 56 
119 
 Criteria for Suspending or Stopping Overall Study ..................................................................... 56 
120 
 Independent Safety Oversight ........................................................................................................... 57 
121 
 MISCELLANEOUS CONSIDERATIONS ................................................................................... 58 
122 
 Drugs Used as Part of the Protocol .................................................................................................... 58 
123 
 Collection of Medical Conditions and Medications .......................................................................... 58 
124 
 Prohibited Medications, Treatments, and Procedures ....................................................................... 58 
125 
 Participant Compensation .................................................................................................................. 58 
126 
 Participant Withdrawal ...................................................................................................................... 58 
127 
 Confidentiality ................................................................................................................................... 59 
128 
 STATISTICAL CONSIDERATIONS ........................................................................................ 60 
129 
 Statistical and Analytical Plans ....................................................................................................... 60 
130 
 Statistical Hypotheses ...................................................................................................................... 60 
131 
 Sample Size ..................................................................................................................................... 60 
132 
 Outcome Measures .......................................................................................................................... 61 
133 
 Analysis Cohorts.............................................................................................................................. 62 
134 
 Analysis of the Primary Efficacy Endpoints ................................................................................... 62 
135 
 Analysis of the Secondary Endpoints .............................................................................................. 64 
136 
 Safety Analyses ............................................................................................................................... 65 
137 
 Adherence and Retention Analyses ................................................................................................. 65 
138 
 Baseline Descriptive Statistics ....................................................................................................... 65 
139 
 Planned Interim Analyses .............................................................................................................. 65 
140 
 Sub-Group Analyses ...................................................................................................................... 66 
141 
 Multiple Comparison/Multiplicity ................................................................................................. 66 
142 
 Additional Tabulations and Analyses ............................................................................................ 66 
143 
 Device Issues and Tabulations ................................................................................................ 66 
144 
 Analysis of Quality of Life Data ............................................................................................. 67 
145 
 DATA COLLECTION AND MONITORING ............................................................................ 68 
146 
 Case Report Forms and Device Data ............................................................................................... 68 
147 
 Study Records Retention ................................................................................................................. 68 
148 
 Quality Assurance and Monitoring .................................................................................................. 68 
149 
 Protocol Deviations ......................................................................................................................... 69 
150 
 ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 70 
151 
 Ethical Standard ............................................................................................................................... 70 
152 
 Institutional Review Board (IRB) (or Ethics Committee (EC)) ...................................................... 70 
153 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 7 OF 74 
 
 Informed Consent Process ............................................................................................................... 70 
154 
 Consent Procedures and Documentation ................................................................................... 70 
155 
 Participant and Data Confidentiality ......................................................................................... 70 
156 
 CareLink Clinical System ................................................................................................................ 71 
157 
 REFERENCES ....................................................................................................................... 72 
158 
 
 
159 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 8 OF 74 
 
List of Abbreviations 
160 
 
161 
 
162 
 
163 
ABBREVIATION 
DEFINITION 
AID 
Automated Insulin Delivery 
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 
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 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCL 
Hybrid Closed Loop 
ID 
Identification 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IQR 
Interquartile Range 
NIH 
National Institutes of Health 
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 
RMB 
Risk-Based Monitoring 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SAP 
Sensor-Augmented Pump 
SD 
Standard Deviation 
SH 
Severe Hypoglycemia 
SMBG 
Self-Monitoring of Blood Glucose 
TDI 
Total Daily Insulin 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 9 OF 74 
 
Site Principal Investigator Statement of Compliance 
164 
Protocol Title: FLAIR- Fuzzy Logic Automated Insulin Regulation: A Crossover Study 
165 
Comparing Two Automated Insulin Delivery System Algorithms (PID vs. PID + Fuzzy Logic) in 
166 
Individuals with Type 1 Diabetes 
167 
 
168 
Protocol Version/Date: 7.1/ March 17, 2020 
169 
 
170 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, 
171 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
172 
providing the Jaeb Center for Health Research, which serves as the Coordinating Center for the 
173 
protocol, with complete and timely information, as outlined in the protocol. It is understood that 
174 
all information pertaining to the study will be held strictly confidential and that this 
175 
confidentiality requirement applies to all study staff at this site. 
176 
 
177 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
178 
required by the following (use applicable regulations depending on study location and sponsor 
179 
requirements; examples follow): United States (US) Code of Federal Regulations (CFR) 
180 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 
181 
312, and/or 21 CFR Part 812). 
182 
 
183 
For the outside of US sites, the trial will be carried out in accordance with ICH E6 Good Clinical 
184 
Practice (GCP), the Declaration of Helsinki, and specific regulations applicable to the countries 
185 
in which the trial will be conducted. 
186 
 
187 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol will 
188 
take place without prior agreement from the sponsor and documented approval from the 
189 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
190 
to eliminate an immediate hazard(s) to the trial participants. 
191 
 
192 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
193 
completed Human Participants Protection Training and Good Clinical Practice Training. Further, 
194 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
195 
their obligations in meeting the above commitments. 
196 
 
197 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
198 
 
dd 
mon 
yyyy 
199 
Investigator’s Name: ____________________________________ 
200 
 
201 
Site Name/Number: _____________________________________ 
202 
 
203 
 
 
204 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 10 OF 74 
 
Protocol Summary 
205 
PARTICIPANT 
AREA 
DESCRIPTION 
Title 
A Crossover Study Comparing Two Automated Insulin Delivery System 
Algorithms (PID vs. PID + Fuzzy Logic) in Individuals with Type 1 
Diabetes 
(FLAIR- Fuzzy Logic Automated Insulin Regulation) 
Précis 
A randomized crossover trial will compare the efficacy and safety of an 
automated insulin delivery (AID) system with a proportional-integral-
derivative (PID) algorithm versus an automatic insulin delivery (AID) system 
with a PID algorithm enhanced with a Fuzzy Logic algorithm.  
Investigational 
Device 
The Minimed 670G 4.0 Advanced Hybrid Closed-Loop (AHCL) (PID + 
Fuzzy Logic) pump with the Guardian Sensor (3) continuous glucose 
monitoring sensor. 
Objectives 
The objective of the study is to compare the efficacy and safety of AID system 
with PID (Minimed 670G 3.0 HCL) to an AID system with combined PID + 
Fuzzy Logic algorithm (Minimed 670G 4.0 AHCL). In particular, the trial will 
test the hypothesis that the Minimed AHCL can reduce daytime 
hyperglycemia, currently the biggest challenge for AID systems, without 
increasing hypoglycemia. 
Study Design 
Randomized crossover trial with two 12-week crossover periods in auto mode 
preceded by a run-in phase. 
Number of Sites 
Approximately seven sites 
Endpoint 
Primary Efficacy Outcome:  
The co-primary outcomes are differences in CGM-measured metrics between 
periods: 
• 
Superiority for percent of time >180 mg/dL (10.0 mmol/L) from 6AM to 
11:59PM and  
• 
Non-inferiority for percent of time <54 mg/dL (3.0 mmol/L) during the 
entire 24 hour period. 
 
Key Secondary Efficacy Outcomes: 
• 
CGM derived indices over the first 84 days of each treatment period for 24 
hours (excluding time before auto mode is turned on), daytime (6AM-
11:59PM), nighttime (12AM-5:59AM), and for each post-meal period 
(meal starts at the time the carbohydrate is entered), measured for up to 
three hours after a meal (or until another carbohydrate is entered): 
o Mean glucose  
o Coefficient of variation  
o Percentage of sensor glucose readings in the range of 70 to 180 
mg/dL (3.9 to 10.0 mmol/L) and 70 to 140 mg/dL (3.9 to 7.8 
mmol/L) 
o Percentage of sensor glucose readings >180 mg/dL (daytime is a 
co-primary outcome) and >250 mg/dL (10.0 and 13.9 mmol/L, 
respectively) 
o Peak glucose and change in glucose from the start of the meal to 
the peak (only calculated for post-meal periods) 
• 
Amount of total, basal, and bolus daily insulin over the first 84 days of 
each treatment period (excluding time before auto mode is turned on) for 
24 hours, daytime (6AM-11:59PM ), nighttime (12AM-5:59AM ), and for 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 11 OF 74 
 
PARTICIPANT 
AREA 
DESCRIPTION 
each post-meal period (meal starts at the time the carbohydrate is entered), 
measured for up to three hours after a meal (or until another carbohydrate 
is entered) 
• 
HbA1c 
• 
BMI 
 
Key Safety Outcomes 
• 
Percentage of sensor glucose readings <54 mg/dL (overall is a co-primary 
outcome) and <70 mg/dL (3.0 and 3.9 mmol/L, respectively) 
• 
DKA events  
• 
Severe hypoglycemia events 
 
Other Outcomes 
• 
Amount of total basal and bolus insulin at daytime, nighttime, and post-
meal analyzing both total units and units/kg 
• 
Human Factors and Diabetes Technology Attitude and Human Factors 
questionnaires  
Population 
 
 
 
Major Eligibility Criteria 
• 
Type 1 diabetes (T1D) for at least one year, using an insulin pump or 
multiple daily injections of insulin 
• 
Age 14-<30 years 
• 
HbA1c 7.0%-11.0% 
• 
For females, not currently known to be pregnant, be breast-feeding, or 
planning to become pregnant within the planned study duration. 
Major Exclusion Criteria 
• 
Concomitant disease that influences metabolic control or HbA1c 
interpretation  
• 
Use of antidiabetic agents other than insulin 
• 
One or more episodes of severe hypoglycemia (hypoglycemia requiring 
treatment by another person) within the previous 6 months 
• 
One or more episodes of ketoacidosis requiring hospitalization within 6 
months prior to screening 
• 
Clinically significant nephropathy (eGFR <45 mL/min) or on dialysis 
Sample Size 
Enrollment will proceed with the goal of at least 100 participants completing 
the crossover trial. A maximum of 135 individuals may be enrolled and a total 
of approximately 112 are expected to enter the crossover trial. 
Treatment Group 
Random assignment (1:1) ratio to either begin with the PID (670G 3.0 HCL) 
AID system or the PID + Fuzzy Logic (670G 4.0 AHCL) AID system and 
then crossover to the other respective treatment. 
Participant 
Duration 
Approximately 28-36 weeks 
Protocol 
Overview/Synopsis 
Screening and Enrollment 
• 
Informed consent will be signed and eligibility will be assessed 
• 
Medical history and physical examination 
• 
HbA1c measurement  
• 
Urine pregnancy test (if applicable) 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 12 OF 74 
 
PARTICIPANT 
AREA 
DESCRIPTION 
• 
Human Factors and Diabetes Technology Attitude Surveys 
 
Run-In Period (2-8 weeks) 
Pump Run-In (670G 3.0 HCL) 
Eligible participants will use the study 670G 3.0 HCL pump during the run-
in. Participants who were pump users at screening may skip the Pump Run-
In period (but must participate in the Pump+CGM Run-In period) per 
investigator discretion. 670G auto mode users may use the 670G pump in 
auto mode. 
 
Standardized pump training will be provided to study participants and their 
diabetes care partners (for participants <18 years old). The study team will 
assist the participant in study pump infusion site initiation and will start the 
participant on the study pump. For current pump users, the study pump will 
be programmed with the participant’s usual basal rates and pump 
parameters. The participant’s personal pump will be removed. Participants 
may continue to use their personal CGM if applicable. 
 
The pump will be used for at least two weeks during Pump Run-In, with the 
option of repeating Pump Run-In for an additional two weeks per 
investigator discretion. Contact will be made each week with additional 
contacts as needed. Prior to each contact, participants will be asked to 
upload device data for study staff to review. 
 
After completion of Pump Run-In, participants will proceed to use the study 
CGM along with the study 670G 3.0 HCL pump during the Pump+CGM 
Run-In period. 
 
Pump+CGM Run-In (670G 3.0 HCL + Guardian Sensor (3)) 
All participants must complete a two-week run-in period with the use of the 
study pump and CGM before being randomized into the crossover trial. 
During Pump+CGM Run-In, the predictive low glucose suspend feature will 
be turned on and auto mode will be off (i.e. manual mode). Participants who 
were 670G auto mode users at screening may use the pump in auto mode. 
 
Standardized device training will be provided to study participants and their 
diabetes care partners (for participants <18 years old). Personal pumps and 
CGMs will be removed during the Pump+CGM Run-In period as applicable. 
 
Contact will be made each week with additional contacts as needed. Prior to 
each contact, participants will be asked to upload device data for study staff to 
review. 
 
Run-In Assessment 
Successful completion of Pump Run-In is per investigator discretion. Pump 
Run-In may be repeated once. 
 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 13 OF 74 
 
PARTICIPANT 
AREA 
DESCRIPTION 
Successful completion of the Pump+CGM Run-In requires CGM data to be 
collected on at least 80% of the possible time in the prior 14 days of use. An 
average of at least three blood glucose meter (BGM) tests per day will also be 
required. If these are not achieved, the Pump+CGM Run-In period may be 
repeated once. 
 
Randomization into the Crossover Trial 
Eligible participants who successfully complete the Pump+CGM Run-In will 
be randomly assigned to begin with one Automated Insulin Delivery (AID) 
system during Period 1 and then crossover to the other AID system during 
Period 2. The two study AID systems (treatments) are: 
• 
670G 3.0 Hybrid Closed-Loop (HCL) (PID) insulin pump + Guardian 
Sensor (3) CGM 
• 
670G 4.0 Advanced Hybrid Closed-Loop (AHCL) (PID + Fuzzy Logic) 
insulin pump + Guardian Sensor (3) CGM 
 
Home Use of AID System during the Crossover Trial 
Period 1 (~13 weeks) 
Participants and their diabetes care partners (for participants <18 years old) 
will be trained by qualified personnel on the use of the assigned pump and on 
auto mode feature use including meal announcement, meal bolusing, and 
exercise. 
 
Training will also be provided in performing specific tasks including the 
following: 
• 
Confirming pump parameters 
• 
When not to use or rely on auto mode particularly during significant 
illness or acetaminophen use 
• 
CGM calibration instructions 
• 
Meal bolus procedures 
• 
What to do when exercising while using the system 
• 
How to react to safety/alert notifications 
• 
How to perform fingerstick blood glucose measurements in accordance 
with the labeling of the study CGM device 
• 
When and how to contact study staff to ask questions during the study 
 
Study staff will discuss the visit and contact schedule with the participant and 
will make arrangements for follow-up appointments. Participants will be asked 
to upload data before each contact and at least every two weeks. 
 
After auto mode training has been completed, participants will proceed with 
home use of the AID system (meaning free-living use at work, home, etc.) 
during Period 1 with either the 670G 3.0 HCL or 670G 4.0 AHCL pump. The 
predictive low glucose suspend feature will be on. 
 
The system will initially be used with auto mode deactivated (except for 670G 
auto mode users at screening who may activate auto mode if using the 670G 
3.0 HCL pump) until participants are contacted 6-10 days into Period 1 with 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 14 OF 74 
 
PARTICIPANT 
AREA 
DESCRIPTION 
instructions to activate auto mode. Participants will then continue using the 
AID system for 12 weeks after auto mode is initialized. 
 
Participants will be expected to use auto mode at all times at home with some 
exceptions (e.g. times of illness, acetaminophen use). 
 
HbA1c, C-peptide, and glucose levels will be collected for central lab analysis 
at the beginning of Study Period 1. Human Factors and Diabetes Technology 
Attitude Surveys will be administered at the end of Study Period 1. 
 
Period 2 (~13 weeks) 
At the beginning of Period 2, a urine pregnancy test will be completed as 
applicable. Eligible participants will then use the other AID system during 
Period 2. The procedures in Period 1 will be repeated in Period 2. At the end 
of the 12-weeks of AID use in auto mode at home, the participant will 
complete a final study visit which may be conducted at home or remotely, if 
an in-clinic visit is not possible. 
 
206 
 
 
207 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 15 OF 74 
 
Schematic of Study Design 
208 
 
209 
Figure 1. Schematic of Study Design 
210 
 
 
211 
 
212 
 
213 
 
214 
 
 
215 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 16 OF 74 
 
Schedule of Study Visits and Procedures 
216 
 
217 
Table 1. Schedule of Visits and Procedures during Screening and Run-In 
218 
 
Screening/Start of 
Run-In5 
Pump Run-In1 
Pump+CGM Run-In1 
1 week after 
screening (±2d) 
2 weeks after 
screening (+3d) 
1 week after screening 
or end of pump run-in  
(±2d) 
2 weeks after screening 
or end of pump run-in 
(+3d) 
Visit (V) or Contact (C) 
V 
C 
V 
C 
V (Same as Rand Visit) 
Informed Consent  
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Medical history/physical exam 
X 
 
 
 
 
Height, weight, blood pressure 
X 
 
 
 
 
HbA1c – point-of-care or local lab 
X 
 
 
 
 
Study pump training 
X2 
 
 
 
 
Study CGM training 
X3 
 
X 
 
 
Questionnaires - Diabetes Tech 
Attitude + Human Factors 
X 
 
 
 
 
AE Assessment 
 
X 
X 
X 
X 
Upload device data from home 
 
X 
 
X 
 
Upload device data at clinic visit 
 
 
X 
 
X 
Review blood sugars and make 
insulin adjustments as needed 
 
X 
X 
X 
X 
Pregnancy test4 
X 
 
 
 
 
1Run-in periods may be repeated once. 
2Pump training will occur after participant is determined to be eligible. 
3Current pump users at screening may skip Pump Run-In and proceed directly to Pump+CGM Run-In at investigator’s discretion. CGM training will occur 
after participant is determined to be eligible. 
4Additional pregnancy tests to be performed any time pregnancy is suspected. 
5The Screening and start of run-in training visits may occur on the same day or separate days but no more than 14 days apart. 
 
219 
 
220 
 
 
221 

FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 17 OF 74 
 
 
222 
Table 2. Schedule of Visits and Procedures During the Crossover Trial 
223 
 
Randomization 
Crossover Period 1 (P1) 
Crossover Period 2 (P2) 
Auto 
Mode 
Initiation 
Time from Auto Mode Initiation 
Auto 
Mode 
Initiation 
Time from Auto Mode Initiation 
-6-10d1 
0d1,4 
244 
hours 
5d4 ± 
2d  
2w 
± 
4d 
4w 
± 
4d 
6w 
± 
4d 
9w 
± 
4d 
12w + 7d 
(and -6-
10d from 
P21) 
0d1,4 
244 
hours 
5d4 ± 
2d  
2w 
± 
4d 
4w 
± 
4d 
6w 
± 
4d 
9w 
± 
4d 
12w 
+ 7d 
Visit (V) or Contact (C) 
V 
C 
C 
C 
V 
C 
V 
C 
V 
C 
C 
C 
V 
C 
V 
C 
V/C 
Re-review of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment visit 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
Height, weight, blood 
pressure 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central lab – HbA1c 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Central lab – random 
C-peptide and glucose 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Auto mode training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Turn auto mode on 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Setpoint evaluation2 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
Questionnaires - 
Diabetes Tech Attitude 
+ Human Factors 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Upload device data 
from home 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Upload device data at 
clinic visit 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
Review glucose patterns 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Auto mode initiation will begin 6-10 days after Randomization and after end of Period 1. All follow-up visits are relative to the day auto mode is initialized. 
2Setpoint evaluation will occur for 670G 4.0 AHCL users 
3Additional pregnancy tests to be performed any time pregnancy is suspected 
4Contacts must be completed by phone. 
224 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 18 OF 74 
 
 Background Information 
225 
 
226 
 Introduction 
227 
Type I diabetes (T1D) causes autoimmune pancreatic beta cell destruction and lifelong 
228 
dependency on exogenous insulin. Subsequently, patients with T1D are at risk for long-term life-
229 
threatening microvascular and macrovascular complications that can be abated by aiming to 
230 
achieve near-normal blood glucose. However, this tight control is associated with a threefold 
231 
increase in the risk of severe hypoglycemic events, one of the most feared and dangerous events 
232 
for patients and their parents or caregivers.1 Therefore, the ultimate goal in diabetes care is to 
233 
keep blood glucose in a narrow desired range with minimal hypoglycemic events. Over the past 
234 
decade, the use of insulin pumps and sensors and their combination (sensor-augmented pumps) 
235 
have shown advances towards improving glucose control.2-4 However, recent data from diabetes 
236 
centers in Europe and the United States (US) indicate that the glycemic control achieved is still 
237 
not satisfactory and is complicated by the risk of hypoglycemia,5, 6 despite the use of the 
238 
advanced technological tools now available.7 Some progress is being made with the introduction 
239 
of the threshold suspend or low glucose suspend (LGS) sensor and pump systems in the United 
240 
States. We now need to combine predictive features with LGS features to minimize 
241 
hyperglycemia as well,8 without causing anxiety and burden for patients and caregivers due to 
242 
the demand for continual attention to how well the systems cover meals, snacks and periods of 
243 
illness. This is especially true in adolescents and some young adults whose compliance with 
244 
treatment can be low, with 50% omitting or delaying insulin boluses needed for meals.9 
245 
Automated decision support systems, and ultimately, full automated management solutions, are 
246 
strongly desired by patients with T1D and their caregivers to improve metabolic control and 
247 
relieve them of the stress and burden of daily treatment of this chronic disease. 
248 
 
249 
 Background: Studies descriptions below include data from PID, MD-Logic, and the 
250 
combined algorithms: 
251 
Automated insulin-delivery systems have been a focus of diabetes research during the past two 
252 
decades. Several prototypes of control algorithms have evolved and been tested over the world. 
253 
Two commonly used algorithms have been the proportional-integral-derivative (PID) and model 
254 
predictive controller (MPC).10-13 These two systems of control use mathematical models that link 
255 
insulin delivery with glucose excursions. A third approach to algorithms uses fuzzy logic 
256 
algorithms (such as the MD-Logic) to modulate insulin delivery based on a set of rules that 
257 
imitates the line of reasoning of diabetes practitioners, which in turn are based on common 
258 
medical knowledge and the experience of traditional treatment.14 The MD-Logic controller 
259 
applies a basal-bolus approach of insulin delivery with event-driven treatment (i.e., meals and 
260 
exercise) and a personalized system setting, learning capacity, and safety alerts and embedded 
261 
insulin-safety layers.15 The controller algorithms combine control to range and control to target 
262 
and makes MD-Logic use intuitive for the patient and easy to transfer from pump therapy 
263 
treatment to closed-loop. Over the past 8 years, the MD-Logic system has been tested in several 
264 
clinical studies: in research centers, diabetes camps, and at patients’ homes in Israel and Europe. 
265 
In 2012 the system was the first to be studied for home use and, most importantly, was found to 
266 
be safe in daily routine use.16 Since then, the system has been evaluated in several home studies, 
267 
in free-living conditions, and for longer durations: 4 nights, 6 weeks, and recently, 3 months 
268 
overnight use. These extensive studies showed that MD-Logic is safe for home use and effective 
269 
in reducing the occurrence, duration, and severity of hypoglycemia while improving metabolic 
270 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 19 OF 74 
 
control by automating the delivery of insulin.17 The MD-Logic closed-loop software received a 
271 
CE Mark in Europe for the overnight algorithm, the first in the world to receive regulatory 
272 
approval. The well tested enhanced bolus features of the MD-Logic algorithm was combined 
273 
with the safe and effective Medtronic HCL PID platform and proven in in-silico testing to be 
274 
safe and further reduce hyperglycemia compared to either system alone. 
275 
 
276 
 Pre-Clinical Testing of MD-Logic Algorithms  
277 
The MD-Logic algorithm was tested using an in-silico model, FDA-approved UVA simulator in 
278 
300 children, adolescents, and adults.11, 19 The algorithm was effective in characterizing the 
279 
patient profile from open-loop data. The simulations showed that the use of the MD-logic 
280 
algorithm reduced the risk of hypoglycemia and improved glycemic control. In addition, the 
281 
algorithm was useful in adjusting treatment to provide better glycemic control during closed-loop 
282 
operation.11, 15 
283 
 
284 
 Clinical Studies using MD-Logic Systems 
285 
A stepwise approach to studies was used to test MD-Logic System in different settings. During 
286 
these studies, described in greater detail below, the study duration also was gradually increased, 
287 
with the final test of the system at home for day and night use: The first feasibility clinical 
288 
studies using MD-Logic were conducted in 2009 in 7 adults with T1D, aged 19 to 30 years. All 
289 
study participants underwent 14 full, closed-loop control sessions of 8 hours (fasting and meal 
290 
challenge conditions) and 24 hours of full closed-loop control with three meals. During the 24-
291 
hour control, 73% of the sensor values ranged from 70 to 180 mg/dL (3.9-10.0 mmol/L), 27% 
292 
were >180 mg/dL(10.0 mmol/L), and none were <70 mg/dL (3.9 mmol/L). There were no events 
293 
of symptomatic hypoglycemia during any of the trials. During the overnight period, 91% of the 
294 
time glucose concentrations were within 70-140mg/dL (3.9-7.8 mmol/L), and mean glucose was 
295 
112 ± 5 mg/dL (6.2 ± 0.3 mmol/L) with no episodes of hypoglycemia below 63 mg/dL (3.5 
296 
mmol/L).20  
297 
 
298 
Next, the system was tested with and without evening exercise in three adolescents and four 
299 
adults who underwent two sessions with the MD-Logic: one started at dinner alone and the other 
300 
one at dinner time following exercise. These sessions were compared with data derived from 
301 
nights spent at home with SAP in a similar scenario to this proposed study protocol. The mean 
302 
percentage of time spent in the target range of 63-140 mg/dL (3.5-7.8 mmol/L) was 85% (78% to 
303 
92%) for the MD-Logic sessions compared with 27% (6% to 57%) using SAP, respectively 
304 
[median (interquartile range -IQR)]. During the overnight closed-loop sessions at dinner alone, 
305 
92±9% of the sensor values ranged within target, compared with 73±19% for the sessions 
306 
following exercise (P=0.03). No hypoglycemic events occurred during the closed-loop sessions. 
307 
This study demonstrated the ability of the system to cope with evening exercise and to "support" 
308 
meal insulin delivery (i.e., the system gave correction boluses or lowered basal insulin as needed 
309 
to cope with the meal).21 
310 
 
311 
Next was a multicenter, multinational study conducted in Slovenia, Israel, and Germany in 
312 
an inpatient setting in 12 children, adolescents, and young adults randomly assigned to 
313 
participate in two sequential overnight sessions: one using insulin pump treatment and the other 
314 
MD-Logic closed-loop insulin delivery. Results showed that three events of nocturnal 
315 
hypoglycemia occurred during control nights and none during MD-Logic nights (P=0.18).The 
316 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 20 OF 74 
 
percentage of time spent in the target range of 63-140 mg/dL (3.5-7.8 mmol/L) was significantly 
317 
higher during MD-Logic nights 76% (54% to 85%) compared with 29% (11% to 44%) during 
318 
insulin pump nights, P=0.02 [median (IQR)].The mean glucose level overnight was reduced by 
319 
36 mg/dL (2 mmol/L) with the use of MD-Logic (P=0.02), with significantly less glucose 
320 
variability than that of the pump therapy (P<0.001).22  
321 
 
322 
The subsequent study transitioned use of the device to the outpatient setting in a 
323 
multicenter, multinational, randomized, crossover trial in which the short-term safety and 
324 
efficacy of the MD-Logic System was assessed for nocturnal glucose control in 56 children and 
325 
adolescents with T1D at a diabetes camp who participated in two consecutive overnight sessions, 
326 
one night with MD-Logic and the second night with SAP therapy, with the order of nights 
327 
randomly assigned. The primary endpoints were overnight hypoglycemia (measured two ways, 
328 
number of sensor readings below 63 mg/dL (3.5 mmol/L) and a more complex measure of 
329 
episodes of hypoglycemia with several consecutive glucoses below 60 mg/dL(3.3 mmol/L) and 
330 
mean overnight glucose concentrations. On MD-Logic system nights, compared with SAP 
331 
nights, there were significantly fewer episodes of glucose concentrations below 63 mg /dL(3.5 
332 
mmo/l) (7 vs. 22) and significantly shorter periods or episodes when glucose levels were below 
333 
60 mg/dL (3.3 mmol/L) (P=0.003 and P=0.02, respectively). Median values for individual mean 
334 
overnight glucose concentrations were 126.4 mg/dL (7.0 mmol/L) (IQR- 115.7 to 139.1 mg/dL) 
335 
with MD-Logic and 140.4 mg/dL (7.8 mmol/L) (IQR- 105.7 to 167.4 mg/dL (5.9 to 9.3 
336 
mmol/L)) with SAP therapy. No serious adverse events were reported. This study demonstrated 
337 
the safety and efficacy of short-term use of MD-Logic outside the hospital, during diabetes 
338 
camp, with physical activities, and buffet-served meals. MD-Logic system therapy was found to 
339 
be superior to SAP therapy, with a reduced risk of nocturnal hypoglycemia with tighter glucose 
340 
control.23  
341 
 
342 
Studies next focused on home use of the MD-Logic device for a 4-night duration using a 
343 
single-blind, randomized, multicenter, multinational, crossover study designed to validate the 
344 
feasibility, safety, and efficacy of MD-Logic in T1D at patients’ homes.16 Seventy-five 
345 
participants (aged 10 to 54 years; average HbA1c 7.8±0.7%) were randomly assigned to 
346 
participate in two overnight crossover periods, each including four consecutive nights: one under 
347 
MD-Logic system and the second under SAP therapy at patients’ homes in real-life conditions. 
348 
Investigators were masked to treatment intervention. Primary endpoints were the time spent with 
349 
glucose concentrations below 70 mg/dL (3.9 mmol/L), and the percentage of nights in which the 
350 
mean overnight glucose concentrations were within 90-140 mg/dL (5.0 - 7.8mmol/L). The study 
351 
results showed that on nights in which MD-Logic was used, time spent in hypoglycemia was 
352 
significantly reduced (P=0.004) compared with nights in which SAP therapy was used. The 
353 
percentage of individual nights in which mean overnight glucose concentration was within 90–
354 
140 mg/dL (5.0 – 7.8 mmol/L) was decreased for SAP, with a median (and IQR) of 75 mg/dL 
355 
(4.2 mmo/l) (42, 75), and 50 mg/dL (2.8 mmol/L) (25, 75) for MD-Logic and SAP nights, 
356 
respectively; P=0.008. 16 Exploratory comparisons of the intention-to-treat cohort demonstrate 
357 
the safety and efficacy of MD-Logic in terms of significantly reducing the risk of nocturnal 
358 
hypoglycemia parameters while improving overnight glycemic control and reducing the risk of 
359 
nocturnal hyperglycemia. The same amount of total insulin doses were used during closed-loop 
360 
and control nights. No serious adverse events were reported. Mean overnight glucose 
361 
concentrations were more consistent and converging to a narrow range during closed-loop nights 
362 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 21 OF 74 
 
compared with open-loop nights. In addition, worries about episodes of hypoglycemia were 
363 
significantly reduced using the fear-of-hypoglycemia questionnaire when using the MD-Logic 
364 
System compared with SAP therapy (P=0.017). Perceived ease of use significantly increased 
365 
(P=0.002), and the overall satisfaction mean score after the intervention was 3.02±0.54 (range 0-
366 
4), demonstrating a high level of satisfaction with the system.24  
367 
 
368 
The device was next tested in a randomized crossover study designed to evaluate the safety 
369 
and efficacy of MD-Logic system for overnight use in T1D at patients’ homes for 6 weeks.25 
370 
Twenty-four participants (aged 12 to 43 years; average HbA1c 7.5±0.8%) were randomly 
371 
assigned to participate in two overnight crossover periods, each six weeks of consecutive nights: 
372 
one under MD-Logic and the second under SAP therapy. MD-Logic significantly reduced time 
373 
spent in hypoglycemia at night (P=0.02) and increased the percentage of time spent in the target 
374 
range of 70-140 mg/dL (3.9 – 7.8 mmol/L) (P=0.003) compared with SAP. The time spent in 
375 
substantial hyperglycemia (>240 mg/dL) was reduced by a median of 52.2% (IQR, 4.8-72.9%) 
376 
(P=0.001) under MD-Logic compared with SAP therapy. Total insulin doses were lower in the 
377 
MD-Logic group than in the SAP night group (P=0.04). The average daytime glucose 
378 
concentration after closed-loop operation were reduced by a median of 10.0 mg/dL (0.5 mmol/L) 
379 
(IQR -2.7, 19.2, P=0.017) while lower total insulin doses were used (P=0.038). One severe 
380 
hypoglycemia event was observed during a SAP night and none using MD-Logic. 25 
381 
 
382 
The MD-Logic HCL system was then tested over a weekend at home for 60 hours and glucose 
383 
control was compared to that achieved on SAP therapy. The primary endpoint was the time 
384 
within 70-180 mg/dL (3.9-10.0 mmol/L). Twenty-two patients were evaluated. Preliminary 
385 
unpublished data from the intention-to-treat analysis showed that the time within the desired 
386 
range was increased by a median of 19% during MD-Logic HCL control compared with SAP. 
387 
The time spent in hypoglycemia and the amount of insulin use was the same during MD-Logic 
388 
HCL as with SAP. Time spent in hyperglycemia above 180 mg/dL (10.0 mmol/L) was reduced 
389 
by 32% during the MD-Logic HCL control compared with SAP. 
390 
 
391 
The conclusion from this series of studies is that the MD-Logic (fuzzy logic algorithm) system 
392 
was safe and effective in both inpatient and outpatient settings.  
393 
 
394 
Next the studies using the Medtronic HCL (PID algorithm) system are outlined.  
395 
 
396 
 Medtronic HCL Studies  
397 
The feasibility of the Medtronic HCL algorithm has been proven in pediatric, adolescent, and 
398 
young adult patients.26-32 In a study of eight participants age 14-40 using the Medtronic HCL 
399 
system with PID control algorithms on an android device compared to SAP with LGS, there was 
400 
no significant difference in total time spent in target but hypoglycemia (< 2.8 mmol/L) was all 
401 
but eliminated with HCL (1 vs. 9, p=.04) and no adverse effects were reported.29 In response to 
402 
promising data from these studies, Medtronic incorporated a more adaptive algorithm directly 
403 
into the pump hardware (MiniMed 670G) and this Medtronic HCL platform has just been tested 
404 
in 124 individuals (adolescents and adults at 9 centers in the US and one center in Israel) in a 3 
405 
month pivotal safety trial which concluded in March 2016 and was published in JAMA, 
406 
September 15, 2016. Of the 124 participants (mean age, 37.8years [SD, 16.5]; men, 44.4%), 
407 
mean diabetes duration was 21.7 years, mean total daily insulin dose was 47.5U/d (SD, 22.7), 
408 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 22 OF 74 
 
and mean HbA1c was 7.4% (SD, 0.9). Over 12 389 patient-days, no episodes of severe 
409 
hypoglycemia or ketoacidosis were observed. There were 28 device related adverse events all 
410 
resolved at home (including skin irritation, infusion set malfunction, batteries needing 
411 
replacement and damage to the pump screen). There were 4 SAE’s but none related to the 
412 
system. The system was in closed-loop 87.2% of the time and the MARD of the Guardian Sensor 
413 
(3) was 10.3% (SD 9.0). Efficacy data showed is shown in the table below from Table 2 in the 
414 
JAMA publication shown below: 
415 
 
416 
 
417 
 
418 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 23 OF 74 
 
The 670G hybrid closed loop system was approved by the FDA September 28, 2016 and has 
419 
been marketed for clinical use since the Spring of 2017 in the United States. Eighty percent of 
420 
the 670G pivotal study participants continued in an extension study that has been since 
421 
completed. 
422 
 
423 
Several of the PIs for this study are PIs on this Medtronic pivotal HCL study and are very 
424 
familiar with the system safety and effectiveness, particularly the ability to control blood glucose 
425 
overnight and between meals. However, as with other HCL systems being evaluated, there is still 
426 
potential for improvement in mealtime glycemic control by incorporating the more sensitive 
427 
bolus insulin delivery component of the fuzzy logic algorithm as described in this proposal (such 
428 
as the PID + Fuzzy Logic / Advanced Hybrid Closed-Loop (AHCL) / 670G 4.0 System). The 
429 
room for further glucose control can be appreciated from the 670G pivotal trial CGM profile 
430 
figure below (2). 
431 
 
432 
 
433 
 
434 
Particularly relevant to our proposal is that fact that in the 670G pivotal trial data shown below 
435 
that the percent of time with sensor glucose reading >180 mg/dL (10.0 mmol/L) was higher in 
436 
adolescents than adults and was higher in day time than the night time, therefore confirming 
437 
particular room for improvement in time spent >180 mg/dL (10.0 mmol/L) in adolescents 
438 
during the day while using the 670G system, particularly in adolescents.  
439 
 
440 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 24 OF 74 
 
 
441 
 
442 
 
443 
 
444 
 Integrated Advanced HCL System In-Silico Testing  
445 
The Advanced HCL System has been evaluated with an in-silico (virtual) model and compared 
446 
to the Medtronic HCL under carbohydrate (CARB) estimations that deviated from the actual 
447 
CARB values by plus or minus 50%. Medtronic created the in-silico model of T1D pump users 
448 
to test the effectiveness of insulin dosing algorithms prior to clinical study. A total of 218 virtual 
449 
patients (112 female, median total daily insulin dose =40 units, age 43-55) were created using 
450 
data from Medtronic’s large pool of SAP uploads in Carelink. The model contains mathematical 
451 
predictions of sensor glucose measurements validated using 51 days of Carelink uploads 
452 
comparing model predictions to sensor glucose measurements of time >180 mg/dL (10.0 
453 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 25 OF 74 
 
mmol/L) and < 70 mg/dL (3.9 mmol/L). The model had been used successfully in the 
454 
development of Medtronic’s HCL system.  
455 
 
456 
Table 3. Comparing HCL and Advanced AID System with a constant CARB estimation error (a 
457 
50% underestimation)below summarizes the simulation results of the Advanced HCL system 
458 
when CARB estimation was constantly underestimated by 50%. The simulation results indicate 
459 
that, there is a significant improvement to the efficacy of glycemic control in the Advanced HCL 
460 
system by incorporating the MD-Logic algorithms, especially in the presence of CARB 
461 
estimation inaccuracies. 
462 
 
463 
Table 3. Comparing HCL and Advanced AID System with a constant CARB estimation 
464 
error (a 50% underestimation) 
465 
Parameter 
HCL 
Mean ± SD (Median) 
Adv HCL 
Mean ± SD (Median) 
% Time > 250 mg/dL 
15 ± 9 (14) 
12 ± 8 (12) 
% Time > 180 mg/dL 
37 ± 11 (37) 
33 ± 9 (33) 
% Time < 70 mg/dL 
0 ± 0 (0) 
0 ± 1 (0) 
% Time 70 – 180 mg/dL 
63 ± 11 (63) 
67 ± 9 (67) 
Mean Senor Glucose 
177 ± 19 (175) 
169 ± 14 (168) 
AUC < 70 mg/dL 
0 ± 0 (0) 
0 ± 0 (0) 
AUC > 180 mg/dL 
27 ± 15 (25) 
22 ± 12 (20) 
 
466 
 Further Studies and Updates to the Advanced HCL System:  
467 
Clinical testing to ensure safety of the integrated Advanced HCL (PID and fuzzy logic 
468 
algorithms combined) was conducted in Israel as part of NIDDK bridge grant funding in 
469 
anticipation of this proposal (NIDDK/UC4DK108611, Home Use of MD-Logic Automated 
470 
Insulin Delivery System: Safety and Efficacy, PIs Bergenstal and Phillip) to compare the 
471 
Advanced HCL system to the Medtronic 670G HCL system in a crossover RCT of 20-60 
472 
participants with T1D in a camp setting for 3-5 days.  This study was completed successfully 
473 
showing that the PID and fuzzy logic algorithms could be combined safely and effectively in this 
474 
small pilot study. 
475 
 
476 
Following the successful combination of the PID and fuzzy logic algorithms, Medtronic made a 
477 
few additional adjustments to some software settings for the MiniMed 670G 4.0 AHCL system 
478 
which FLAIR study will be comparing to the 670G 3.0 (commercial) system. These additional 
479 
features that will be present in the 670G 4.0 AHCL system are compared to the current 670 3.0 
480 
system in Table 4 below.  Note in Auto mode the 670G 4.0 AHCL system fine tunes some of the 
481 
features to allow patients to spend more time in auto mode. In addition the glucose target 
482 
setpoint can be set at 100 mg/dL (5.6 mmol/L) or 120 mg/dL (6.7 mmol/L) (the latter of which is 
483 
like the 670G 3.0 HCL). The FLAIR protocol will start with a set point of 120 mg/dL (6.7 
484 
mmol/L) for all participants and move to 100 mg/dL (5.6 mmol/L) as long as there is no data 
485 
indicating an undue risk of hypoglycemia after review of glucose/insulin data reports. An 
486 
additional optional feature of auto correction boluses is present in the 670G 4.0 AHCL system (a 
487 
function of the fuzzy logic algorithm component).  Table 4 outlines a few other safety features 
488 
that are added to the 670G 4.0 AHCL system including the ability for the software to reduce a 
489 
meal bolus if based on the current glucose readings there would be an increased risk of 
490 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 26 OF 74 
 
hypoglycemia and a correction bolus is allowed based on sensor glucose readings if a glucose 
491 
meter BG is not available.  
492 
 
493 
These updates to the 670G 4.0 AHCL system have been tested in an inpatient and outpatient 
494 
setting (in Australia) then fine-tuned and tested again in an inpatient (stress testing: meals, 
495 
exercise and testing glucose excursions) and outpatient setting in Israel. After final adjustments 
496 
and reviewing the safety and efficacy parameters the configuration of the 670G 4.0 AHCL was 
497 
determined to be ready for comparing to the 670G 3.0 HCL version in FLAIR.  
498 
 
499 
 
500 
Table 4. 670G 3.0 HCL vs 670G 4.0 AHCL 
501 
 
MiniMed 670G 3.0 (MMT-1780, MMT-1781, 
MMT-1782) 
MiniMed 670G 4.0 (MMT-1741, MMT-1742) 
Manual Mode
Continuous delivery of basal insulin and delivery of user activated insulin boluses. 
When used with Continuous glucose monitoring (CGM), the sensor signals are converted by the compatible 
transmitter to sensor glucose values (based on calibration values from a blood glucose meter) which are transmitted 
to the pump for display to the user. 
MiniMed 670G 3.0  (MMT-1780, MMT-1781, 
and MMT-1782) allows the user to enable one of 
the following features to suspend delivery of 
insulin as follows:  
 
“Suspend on Low” will suspend when sensor 
glucose falls below the predefined threshold value 
 
“Suspend Before Low” will suspend delivery of 
insulin when the sensor glucose is predicted to the 
fall below predefined threshold values. 
The MiniMed 670G 4.0 (MMT-1741, MMT-1741) allows the 
user to enable the following feature to suspend delivery of 
insulin as follows:  
 
“Suspend on Low” will suspend when sensor glucose falls 
below the predefined threshold value 
 
 
“Suspend Before Low” will suspend delivery of insulin when 
the sensor glucose is predicted to the fall below predefined 
threshold values. 
Auto Mode
Automatically adjusts basal insulin using the control algorithm of PID-IFB (Proportional integral derivative 
controller with insulin feedback) to regulate the user’s sensor glucose levels 
Temporary target (user settable) remains unchanged with a setpoint of 150 mg/dL. 
Target Setpoint of 120 mg/dL (6.7 mmol/L) 
Target Setpoint of 100 mg/dL or 120 mg/dL (5.6 mmol/L or 
6.7 mmol/L, respectively) 
Correction bolus target is 150mg/dL (8.3 
mmol/L) 
Correction bolus target is 120 mg/dL (6.7 mmol/L) 
Safeguards in Auto Mode include the following:  
 
• 
Min insulin delivery timeout 2.5 hours 
 
Safeguards in Auto Mode are being fine-tuned to allow more 
time in Auto mode.  
 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 27 OF 74 
 
• 
Max insulin delivery timeout 4 hours 
• 
Sensor integrity check logic to allow into 
Auto Mode 
 
• 
Safe basal will not exceed 90 min 
• 
Model Supervisor detects under read (30 
min) 
• 
Missed Transmission switches to safe basal 
if there is a missed transmission 
• 
Low Glucose Alert will be a mandatory alert 
when the user is 50 mg/dL. 
• 
High Glucose Alert will alert and kick user 
out of Auto Mode when they are  > 250 
mg/dL for 3 hours and alert when the user is 
> 300 mg/dL for 1 hour. 
• 
Min insulin delivery timeout 3-6 hours (dependent on the 
insulin on board)  
• 
Max insulin delivery timeout 7 hours  
• 
Sensor integrity check modified to use sensor calibration 
logic to allow into Auto mode 
 
 
 
 
• 
Safe basal will not exceed 4 hours  
• 
Model Supervisor detects under-read (2 hrs.) 
• 
Missed Transmission switch to safe basal if there is a 
missed transmission 
• 
Low Glucose Alert will be a mandatory alert when the 
user is 50 mg/dL. 
• 
High Glucose Alert will alert but not kick the user out 
of Auto Mode when they are > 250 mg/dL for 3 hours. 
The alert for > 300 mg/dL for 1 hour is being removed. 
N/A 
Auto Correction Bolus is an optional feature (user enabled) to 
deliver correction boluses automatically without any user input 
or acknowledgement. 
N/A 
Safe Meal Bolus has the ability to further reduce the amount of 
a meal bolus if it is predicted to increase the risk of post-
prandial hypoglycemia 
N/A 
Non-Adjunctive capabilities permits correction boluses to use 
sensor glucose values if a meter BG is not available. All other 
correction bolus calculations, including the application of the 
Safe Correction Bolus logic, remain the same. 
 
502 
The updated 670G 4.0 system has features designed to address post-meal hyperglycemia, which 
503 
is the biggest area where the initial 670G trials have shown there is room for improvement in 
504 
glucose control.  Next we selected the patient population previously shown to be have the most 
505 
room for improvement in glucose control as defined by HbA1c levels.  
506 
 
507 
 Rationale 
508 
While AP technology could potentially benefit many people with T1D, it could benefit young 
509 
patients the most because this population has the greatest gap between desirable outcomes and 
510 
those achieved, as shown in data from the T1D Exchange (Figure 2. T1D Exchange data 
511 
showing relationship between age and glycemic control below).5 This population has a higher 
512 
risk of short- and long-term diabetes complications with evidence suggesting that metabolic 
513 
memory of periods of suboptimal control can contribute to increased risk of complications later 
514 
in life.18 Avoidance of suboptimal control in this population could significantly reduce the 
515 
treatment burden on healthcare facilities in years to come and reduce the number, severity, and 
516 
duration of hypoglycemic and diabetic ketoacidosis events and related hospitalizations both now 
517 
and in the future.  
518 
 
519 
The investigators and research teams collaborating on this project have strong international 
520 
expertise in diabetes research and closed-loop technology. The objective of this study is to 
521 
combine and test the best of two AP approaches (PID and MD-Logic/fuzzy logic algorithms) in 
522 
an integrated Advanced HCL System (670G 4.0 AHCL) in order to provide important data on 
523 
the safety and efficacy of this promising AP system. If outcomes are positive, it will help 
524 
promote the recognition of such systems as an effective and safe T1D management solution that 
525 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 28 OF 74 
 
may address some of the gaps in glucose control (e.g., meals, snacks, illness) not adequately 
526 
addressed by the HCL systems tested to date. In addition, this trial is one of first to screen 
527 
patients for entry into the study who are managing their glucose control by a very wider variety 
528 
of diabetes management strategies, with multiple daily injections or insulin pumps for insulin 
529 
delivery and SMBG or CGM for glucose monitoring. This will help the findings of the trial have 
530 
broad generalization.  
531 
 
532 
 
533 
Figure 2. T1D Exchange data showing relationship between age and glycemic control 
534 
 
535 
 
536 
 Automated Insulin Delivery System Description 
537 
The FLAIR study will compare two hybrid closed loop systems, the Minimed 670G 3.0 HCL 
538 
(PID) and the Minimed 670G 4.0 Advanced Hybrid Closed-Loop AHCL (PID + Fuzzy Logic) 
539 
pump. The sensor and infusion set will be the same in both systems. A schematic of the system 
540 
hardware components of the closed loop system is depicted in Figure 3. Schematic of system 
541 
hardware components below. 
542 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 29 OF 74 
 
Figure 3. Schematic of system hardware components 
543 
 
544 
 
545 
 Potential Risks and Benefits of the Investigational Device 
546 
Study System 
547 
Even though the study system has been tested prior to this study, there is still a risk that parts of the 
548 
system may not function properly. The following are possible reasons the system may deliver too 
549 
much insulin or incorrectly stop insulin delivery: 
550 
• CGM sensor reads higher or lower than the actual glucose level which increases risk for 
551 
hypoglycemia and hyperglycemia with automated insulin delivery system; 
552 
• Acetaminophen interference causing the CGM sensor to read high than actual glucose 
553 
levels; 
554 
• Device malfunctions that could produce a suspension of insulin delivery or over delivery of 
555 
insulin. 
556 
 
557 
Potential risks associated with insulin pump therapy include: 
558 
• Slight discomfort at the time of insertion of the insulin delivery cannula (common) 
559 
• Slight bruising at the site of insertion (common) 
560 
• Infusion set and cannula occlusions (common) resulting in hyperglycemia or DKA 
561 
• Insulin pump malfunction and mechanical problems (common) 
562 
• Lipodystrophy/lypoatrophy (common) 
563 
• Bleeding at insertion site (rare) 
564 
• Infection at the site of insertion (rare) 
565 
• Allergy to the insulin delivery cannula or adhesive (rare) 
566 
• Allergy to insulin (very rare) 
567 
 
568 
Continuous Glucose Monitoring 
569 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 30 OF 74 
 
Potential risks associated with CGM: 
570 
• Slight discomfort at the time of insertion of CGM (common) 
571 
• Slight bruising at the site of insertion (unlikely) 
572 
• Bleeding at insertion site (common) 
573 
• Infection at the site of insertion (rare) 
574 
• Allergic reaction to the CGM sensor adhesive material (common) 
575 
 
576 
If a skin reaction is classified as severe (the observation is noticeable and bothersome to 
577 
participant and may indicate infection or risk of infection or potentially life-threatening allergic 
578 
reaction), an adverse event form will be completed. 
579 
 
580 
Risks with Infusion Sets 
Prevention and Mitigation 
Risks with infusion sets may include:  
• Localized infection 
• Skin irritation/redness 
• Bruising 
• Discomfort/pain 
• Bleeding 
• Irritation 
• Rash 
• Hyperglycemia secondary to infusion set 
occlusion or infusion site failure 
• Hyperglycemia secondary to site falling 
off 
• Anxiety associated with insertion 
Prevention and mitigation include: 
• 
Follow the provided user guides 
for insertions and care of infusion 
sets. 
• 
If an infusion site becomes 
irritated or inflamed, the infusion 
set should be removed and another 
placed in a new location.  
• 
In case of hyperglycemia 
secondary to infusion set 
occlusion, remove current infusion 
set and replace with new infusion 
set and give correction insulin if 
directed with syringe.  
• 
Follow the provided user guides 
for insulin pump management.  
• 
Training prior to study on device 
use and diabetes management 
principles and told to call with 
problems.  
Risks with Insulin Administration and Pumps 
Prevention and Mitigation 
Risks with the use of an insulin infusion pump 
may include the risk of malfunction of the 
components of the system (pump, software, 
infusion set and reservoir) as well as the risk of 
use error during use of the system. Device 
deficiencies or use errors can result in 
administration of too much or too little insulin 
which can lead to the following clinical 
consequences: 
 
• Hypoglycemia 
• Hyperglycemia 
• Diabetic ketoacidosis (DKA) 
Prevention and mitigation include: 
• Follow the provided user guides 
for insulin pump management.  
• Training prior to study on device 
use and diabetes management 
principles and told to call with 
problems.  
• Check SMBG 4-6 times a day and 
also before driving (as applicable) 
or monitor the CGM.  
• Instructed to have glucose on hand 
for hypoglycemia 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 31 OF 74 
 
• Severe hypoglycemia with or without 
associated seizure, coma or death 
• Kinked cannula leading to hyperglycemia  
• Infusion set disconnection from pump 
leading to hyperglycemia  
• Dislodged cannula leading to 
hyperglycemia 
• A pump error may lead to under delivery 
or over-delivery of insulin 
• Battery failure – no insulin delivered 
leading to hyperglycemia 
• Insulin deterioration leading to 
hyperglycemia 
• Incomplete priming; fails to prime tubing 
and/or cannula, leading to hyperglycemia 
• Remove a reservoir, without suspending 
and reconnecting after a while resulting in 
hyperglycemia  
• Patient not filling pump reservoir when 
needed leading to hyperglycemia 
• Magnetic Resonance Imaging resulting in 
pump/Guardian Link 3 Transmitter 
malfunction 
• Inaccurate insulin delivery due to sudden 
altitude changes. 
• Hypoglycemia or hyperglycemia from 
manual bolus 
• Hypoglycemia or hyperglycemia from 
computer hacking  
• Change infusion set if suspected 
catheter occlusion or administer 
insulin with syringe for persistent 
hyperglycemia especially if 
ketones develop.  
• Parent(s)/guardian(s) of 
participants <18 years old) will be 
present at night with participants 
and will be trained on study device 
and diabetes management 
principles.  
 
Risks with hyperglycemia may include  
• 
DKA 
• 
Symptomatic ketosis 
• 
Cardiovascular event  
• 
Dehydration  
• 
Potassium and sodium imbalance 
• 
Shock 
• 
Altered mental status  
• 
Coma  
• 
Acidosis 
Prevention and mitigation include: 
• 
Follow the provided user guides 
for insulin pump management.  
• 
Parent(s)/guardian(s)for 
participants <18 years old will be 
present at night with participants 
and will be trained on study device 
and diabetes management 
principles and told to call with 
problems.  
• 
Training prior to study on device 
use and diabetes management 
principles. 
• 
Check SMBG 4-6 times a day or 
monitor the CGM.  

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 32 OF 74 
 
• 
Alternative method of managing 
glucose levels should be available 
(insulin and syringe for example) 
Risks with hypoglycemia may include: 
• Seizure  
• Coma  
• Altered mental status  
• Loss of consciousness  
• Cardiovascular event  
• Death  
• Risk of rebound hyperglycemia with 
ketosis 
Prevention and mitigation include: 
• 
Follow the provided user guides 
for insulin pump management.  
• 
Parent(s)/guardian(s) of 
participants <18 years old will be 
present at night with participants 
and will be trained on study device 
and diabetes management 
principles and told to call with 
problems.  
• 
Training prior to study on device 
use and diabetes management 
principles. 
• 
Check SMBG 4-6 times a day or 
monitor the CGM. 
• 
Instructed to have glucose on hand 
for hypoglycemia 
Risk with Sensors  
Prevention and Mitigation 
Risks with Sensors may include: 
• Skin irritation or reaction to adhesives 
• Bruising 
• Discomfort 
• Redness 
• Excessive bleeding due to anticoagulants 
• Bleeding 
• Pain 
• Rash 
• Infection 
• Irritation from tapes used with glucose-
sensing products 
• Raised bump 
• Appearance of a small "freckle-like" dot 
where needle was inserted 
• Allergic reaction 
• Syncopal episode secondary to needle 
insertion 
• Soreness or tenderness 
• Swelling at insertion site 
• Sensor fracture, breakage or damage 
• Minimal blood splatter associated with 
sensor needle removal 
• Residual redness associated with adhesive 
Prevention and mitigation include: 
• 
Follow the provided user guides 
for insertions and care of sensors. 
• 
If a sensor site becomes infected or 
inflamed, the sensor should be 
removed and another placed in a 
new location 
• 
Base diabetes management on 
fingerstick readings and not sensor 
glucose values. 
 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 33 OF 74 
 
and or tapes 
• Scarring 
• Scab 
• Blister 
• Itchiness 
• Inflammation 
• Anxiety 
• Incorrect sensor glucose reading results in 
incorrect diabetes management 
• Participant over-treating secondary to 
alarms which can result in hyperglycemia 
or hypoglycemia 
• Anxiety associated with insertion 
Risks with Serter 
Prevention and Mitigation 
Risks with Serters may include: 
• Improper insertion may lead to device 
performance issue or hyperglycemia  
Prevention and mitigation include: 
• Follow the provided user guides 
for insertions and care of Serters. 
• Training on proper use of the 
Serter and skin preparation prior to 
insertion. 
Risks with Finger Sticks 
Prevention and Mitigation 
Risks with frequent finger stick testing may 
include: 
• Potential risks associated with frequent 
meter testing of blood glucose and blood 
ketones include discomfort and 
ecchymosis at tips of fingers 
Potential risks associated with drawing blood 
include discomfort and bruising 
Prevention and mitigation include: 
• Follow the provided user guides 
for use of meter with fingerstick 
testing. 
• Training on proper use of the 
meter and fingerstick testing. 
 
Risks with AHCL 
Prevention and Mitigation 
Risks with AHCL include: 
Prevention and mitigation include: 
• Follow the provided user guides 
for insulin pump management. 
• Training prior to study on device 
use and diabetes management 
principles and told to call with 
problems. 
• Check SMBG 4-6 times a day. 
• Instructed to have glucose on hand 
for hypoglycemia. 
• Subjects will be asked to avoid the 
use of products containing 
Acetaminophen 
• If Acetaminophen is taken, 
subjects will be instructed to use 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 34 OF 74 
 
• Hypoglycemia 
• Severe hypoglycemia 
• Hyperglycemia 
• DKA 
• User Entry Error 
o Patient administering boluses by 
entering false carb doses leading 
to hypoglycemia or 
hyperglycemia 
o Patient entering false glucose 
values for any reason leading to 
hypoglycemia and hyperglycemia 
o Patient entering false BG values 
for calibration leading to 
hypoglycemia or hyperglycemia 
• Sensor failure resulting from patient 
failure to calibrate leading to 
hypoglycemia or hyperglycemia 
• Sensor over-reading resulting in 
hypoglycemia 
• Sensor under-reading resulting in 
hyperglycemia 
• Sensor missed transmission, or any other 
fault resulting in no SG value, leading to 
hyperglycemia or hypoglycemia 
• Voluntary insulin delivery (with the pump 
or with a syringe) immediately prior to 
entering Auto Mode may result in severe 
hypoglycemia despite shutting down 
insulin delivery by the algorithm 
• Patient takes insulin via injection while in 
Closed Loop 
• Hypoglycemia or hyperglycemia related 
to entering or exiting Closed Loop 
• Insulin over-delivery due to 
Acetaminophen 
 
 
 
additional BG meter readings (they 
are not to calibrate with those 
readings) to verify their glucose 
levels. 
• If Acetaminophen is taken, 
subjects should consider exiting 
Auto Mode. 
 
Potential risks with acetaminophen may include: 
• False elevation of sensor glucose 
readings. The level of inaccuracy depends 
on the amount of acetaminophen active in 
subject’s body and may be different for 
each subject. 
Prevention and mitigation include: 
• Follow the user guide 
• Where possible, subjects should 
avoid the use of Acetaminophen 
• If Acetaminophen is taken, 
subjects should use additional BG 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 35 OF 74 
 
 
meter readings (they are not to 
calibrate with those readings) to 
verify their glucose levels 
• Subjects should consider exiting 
AutoMode 
 
 
581 
 Risk Assessment 
582 
Based on the facts that (1) adults and adolescents with diabetes experience mild hypoglycemia 
583 
and hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
584 
intervention involves periodic automated insulin dosing that may increase the likelihood of 
585 
hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the 
586 
likelihood of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies 
587 
using the investigational device system in the home setting, that limit the likelihood of excessive 
588 
insulin dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and 
589 
hyperglycemia can be achieved, it is the assessment of the investigators that this protocol falls 
590 
under DHHS 46.405 which is a minor increase over minimal risk. 
591 
 
592 
 Known Potential Benefits 
593 
It is expected that this protocol will yield increased knowledge about using an automated closed-
594 
loop to control the glucose level. This research is a definitive step on the path towards 
595 
development of a fully closed-loop system. In addition, it is the belief of the investigators that 
596 
this study also presents prospect of direct benefit to the participants and general benefit to others 
597 
with diabetes. 
598 
 
599 
 General Considerations 
600 
The study is being conducted in compliance with the policies described in the study policies 
601 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
602 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
603 
Data will be collected in electronic or physical case report forms, either of which will be 
604 
considered the source data when directly used. 
605 
 
606 
The protocol is considered a significant risk device study, due to the fact that the PID +fuzzy 
607 
logic algorithm is experimental. Therefore, an investigational device exemption (IDE) from the 
608 
U.S. Food and Drug Administration (FDA) is required to conduct the study in the US. As the 
609 
device is also investigational in Europe and Israel, approvals from the regulatory authorities in 
610 
the countries where the study is being conducted will also be required as applicable. 
611 
 
612 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 36 OF 74 
 
 Study Enrollment and Screening 
613 
 
614 
 Participant Recruitment and Enrollment 
615 
Enrollment will proceed with the goal of at least 100 participants completing the crossover trial. 
616 
A maximum of 135 individuals may be enrolled and a total of approximately 112 are planned to 
617 
enter the crossover trial. Participants who have signed consent and started the screening process 
618 
will be permitted to continue into the crossover trial, if eligible, even if the crossover trial 
619 
randomization goal has been reached. 
620 
 
621 
Study participants will be recruited from approximately seven clinical centers. All eligible 
622 
participants will be included without regard to sex, gender, race, or ethnicity. All sites are 
623 
experienced in either adult or pediatric endocrinology, or both, and are established research 
624 
centers with proven recruitment track records. 
625 
 
626 
The recruitment goal for each site is the same (approximately 15-16 participants per site); 
627 
however, certain sites may recruit additional participants if necessary for the study to meet the 
628 
overall recruitment goal. 
629 
 
630 
In order to have a broad representation of individuals, there will be the following recruitment 
631 
goals: 
632 
• 
Minimum of  25% of participants entering RCT who at screening were on MDI therapy 
633 
• 
Minimum of  25% of participants entering RCT who at screening were on Pump therapy 
634 
• 
Minimum of  25% of participants entering RCT who at screening were on CGM therapy 
635 
• 
Minimum of  25% of participants entering RCT who at screening were not on CGM therapy 
636 
• 
Minimum of  25% of participants entering RCT who at screening had a POC HbA1c from 
637 
7.0 - 8.5%  
638 
• 
Minimum of  25% of participants entering RCT who at screening had a POC HbA1c from 
639 
8.6 - 11.0%  
640 
• 
Maximum of 25% of participants entering RCT who at screening had a POC HbA1c from 7.0 
641 
-7.4%  
642 
• 
Maximum of 25% of participants entering RCT who at screening were on the MiniMed 670G 
643 
system 
644 
 
645 
Potential eligibility may be assessed as part of a routine-care examination. Prior to completing 
646 
any procedures or collecting any data that are not part of usual care, written informed consent 
647 
will be obtained. For potential study participants >18 years old, the study protocol will be 
648 
discussed with the potential study participant by study staff. The potential study participant will 
649 
be given the Informed Consent Form to read and will be given the opportunity to ask questions. 
650 
Potential study participants will be encouraged to discuss the study with family members and 
651 
their personal physicians(s) before deciding whether to participate in the study. 
652 
 
653 
For potential participants under 18 years of age, a parent/legal guardian (referred to subsequently 
654 
as “parent”) will be provided with the Informed Consent Form to read and will be given the 
655 
opportunity to ask questions. Potential participants meeting the minimum age of assent will be 
656 
given a Child Assent Form to read and discuss with their parents and study personnel. If the 
657 
parent and child agree to participate, the Informed Consent Form and Child Assent Form will be 
658 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 37 OF 74 
 
signed. A copy of consent forms will be provided to the participant and their parent and another 
659 
copy will be added to the participant’s study record. 
660 
 
661 
As part of the informed consent process, each adult participant or parent will be asked to sign an 
662 
authorization for release of personal information. The investigator, or their designee, will review 
663 
the study-specific information that will be collected and to whom that information will be 
664 
disclosed. After speaking with the participant and parent (if applicable), questions will be 
665 
answered about the details regarding authorization. 
666 
 
667 
A participant is considered enrolled when the informed consent form, and assent form if 
668 
applicable, has been signed. 
669 
 
670 
 Participant Inclusion Criteria 
671 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
672 
in the study: 
673 
1. Type 1 diabetes mellitus (as diagnosed clinically) with a duration of at least one year 
674 
2. Age 14 - <30 years 
675 
3. For females, not currently known to be pregnant, be breast-feeding, or planning to 
676 
become pregnant within the planned study duration. 
677 
If female of child-bearing potential and sexually active, must agree to use a form of 
678 
contraception to prevent pregnancy while a participant in the study. A negative serum 
679 
or urine pregnancy test will be required for all females of child-bearing potential. 
680 
Participants who become pregnant will be discontinued from the study. Also, 
681 
participants who during the study develop and express the intention to become 
682 
pregnant within the timespan of the study will be discontinued. 
683 
4. Multiple daily injections (MDI) of insulin or an insulin pump user  
684 
a. Participant must be able to obtain U-100 rapid acting insulin analogues, Aspart or 
685 
Lispro, for use during the study (since these are the only insulins approved for the 
686 
study pump and the study is not supplying insulin) 
687 
b. MDI users must be on a basal/bolus regimen 
688 
c. Participants must have a minimum total daily dose (TDD) of at least eight units 
689 
5. HbA1c from an approved local HbA1c point of care analyzer with an HbA1c value of 
690 
7.0-11.0% 
691 
6. Willingness or ability to do carbohydrate counting 
692 
7. In the investigator’s judgment, participant is able to understand and likely to be adherent 
693 
to the protocol 
694 
8. For participants <18 years old, living with one or more diabetes care partners (i.e. a 
695 
parent/legal guardian) of whom at least one is committed to participating in study training 
696 
for emergency procedures for severe hypoglycemia and able to contact the participant in 
697 
case of an emergency 
698 
9. Have adequate internet access and computer system for uploading data 
699 
10. For participants currently using CGM or insulin pump, willingness to discontinue 
700 
personal CGM and pump when using the study CGM and pumps (note: including 
701 
implantable CGMs) 
702 
  
703 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 38 OF 74 
 
 Participant Exclusion Criteria 
704 
Individuals meeting any of the following exclusion criteria at screening will be excluded from 
705 
study participation: 
706 
1. Concomitant disease that influences metabolic control or HbA1c interpretation (e.g. anemia, 
707 
significantly impaired hepatic function, confirmed gastroparesis, renal failure, history of 
708 
adrenal insufficiency, sickle cell disease, haemoglobinopathy, or has received red blood cell 
709 
transfusion or erythropoietin within three months prior to time of screening) or other medical 
710 
condition which, in the Investigator’s opinion, may compromise patient safety, affect 
711 
outcome assessments, or affect the participant’s ability to follow the protocol 
712 
2. Oral or parenteral glucocorticoids taken within 1 month prior to enrollment, or plans to take 
713 
oral or parenteral glucocorticoids within the planned study duration. Exceptions: Short term 
714 
oral or parenteral glucocorticoids up to seven days 
715 
3. Use of antidiabetic agents other than insulin 
716 
4. Use of other medications, which in the judgment of the investigator would be a 
717 
contraindication to participation in the study 
718 
5. One or more episodes of severe hypoglycemia (hypoglycemia requiring treatment by another 
719 
person) within the previous six months 
720 
6. Known allergy to medical grade adhesives 
721 
7. Participation in another study of a medical device or drug that could affect glucose 
722 
measurements or glucose management or receipt of any investigational medical product 
723 
within 1 month prior to enrollment  
724 
8. Current eating disorder such as anorexia or bulimia 
725 
9. Currently abusing illicit drugs, marijuana, prescription drugs, or alcohol 
726 
10. Visual impairment or hearing loss, which may compromise the participant’s ability to 
727 
perform all study procedures safely, as determined by the investigator 
728 
11. One or more episodes of diabetic ketoacidosis (DKA) requiring hospitalization within six 
729 
months prior to screening 
730 
12. Working night shifts 
731 
13. Untreated celiac disease, hyperthyroidism, or hypothyroidism 
732 
14. Clinically significant nephropathy (eGFR <45 mL/min) or on dialysis 
733 
• Creatinine to determine eGFR must have been obtained as part of usual care within 12 
734 
months prior to enrollment (if not available, at time of enrollment, screening can proceed 
735 
but it must be available prior to randomization) 
736 
 
737 
 Screening Procedures 
738 
After informed consent has been signed, a potential participant will be evaluated for study 
739 
eligibility through the elicitation of a medical history, performance of a physical examination by 
740 
study personnel, and local laboratory testing if needed to screen for exclusionary medical 
741 
conditions. 
742 
 
743 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
744 
date per investigator discretion. Individuals who do meet eligibility criteria will proceed to the 
745 
Run-In period, which will be expected to start on the same day as screening, or up to 14 days 
746 
thereafter. 
747 
 
748 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 39 OF 74 
 
 Data Collection and Testing 
749 
A standard physical exam (including vital signs and height and weight measurements) will be 
750 
performed by the study investigator or qualified designee (e.g. a physician, fellow, nurse 
751 
practitioner, or a physician assistant). 
752 
 
753 
The following procedures will be performed/data collected/eligibility criteria checked and 
754 
documented: 
755 
• Inclusion and exclusion criteria assessed 
756 
• Demographics (socioeconomic status, date of birth, sex, race, and ethnicity) 
757 
• Contact information (retained at the site and not entered into study database) 
758 
• Medical history 
759 
• Diabetes history 
760 
• Concomitant medications 
761 
• Physical examination to include: 
762 
o Weight, height 
763 
o Vital signs including measurement of blood pressure and pulse 
764 
• Blood draw for: 
765 
o HbA1c level measured using the DCA Vantage or similar point-of-care device or 
766 
local lab (used to assess eligibility)  
767 
• Urine pregnancy test for all females of child-bearing potential  
768 
 
769 
Screening procedures may last approximately 1-2 hours. 
770 
 
771 
 Questionnaires 
772 
The following questionnaires will be completed by adult and adolescent participants at 
773 
Screening, End of Period 1, and End of Period 2: 
774 
• Diabetes Distress Scale 
775 
• Glucose Monitoring Satisfaction Survey 
776 
• Hypoglycemia Confidence 
777 
• Diabetes Technology Attitudes 
778 
• INSPIRE Survey (only collected at End of Periods 1 and 2) 
779 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 40 OF 74 
 
 
780 
 Run-in Phase 
781 
 Introduction 
782 
There are two parts of the run-in phase:  
783 
1) Pump Run-In (670G 3.0 HCL) 
784 
2) Pump+CGM Run-In (670G 3.0 HCL + Guardian Sensor (3)) 
785 
 
786 
The length of the run-in phases may vary depending on prior experience with a 670G pump, the 
787 
number of CGM hours collected during run-in, and how quickly participants become 
788 
comfortable using the study pump and CGM according to Table 5. Pump and CGM Run-In 
789 
Criteria below. 
790 
 
791 
Table 5. Pump and CGM Run-In Criteria 
792 
 
Pump Run-In: 
-670G 3.0 HCL 
-Two weeks, repeat if needed 
 
Pump+CGM Run-In: 
-670G 3.0 HCL + Guardian Sensor (3) 
-Two weeks, repeat if needed 
-Auto mode off for non-670G auto mode users, PLGS on 
Pump Users 
Optional  
(Complete per investigator discretion) 
 
 
Required 
Must have CGM data for at least 
80% of the possible time during 
the prior 14 days and average 
BGM test 3x/day. 
 
 
Non-Pump 
Users 
Required 
Required 
Must have CGM data for at least 
80% of the possible time during 
the prior 14 days and average 
BGM test 3x/day. 
 
 
 
793 
 Pump Run-In – 670G 3.0 HCL 
794 
Eligible participants will use the study 670G 3.0 HCL pump during the Pump Run-In period. 
795 
Participants who were current pump users at screening may skip the Pump Run-In period per 
796 
investigator discretion. Participants using the 670G in auto mode at screening may use the 670G 
797 
3.0 HCL pump in auto mode. 
798 
 
799 
Standardized pump training will be provided using a training checklist to study participants and 
800 
their diabetes care partners (for participants <18 years old). Additional topics may include but 
801 
are not limited to: infusion site initiation, cartridge/priming procedures, setting up the pump, 
802 
changing batteries, and navigation through menus. The study team will assist the participant in 
803 
study pump infusion site initiation and will start the participant on the study pump. For current 
804 
pump users, the study pump will be programmed with the participant’s usual basal rates and 
805 
pump parameters. Additionally, important differences between the study pump and personal 
806 
pumps such as calculation of insulin on board and correction boluses will also be discussed. The 
807 
participant’s personal pump will be removed. Participants may continue to use their personal 
808 
CGM if applicable. 
809 
 
810 
The pump will be used for at least two weeks during the Pump Run-In, with the option of 
811 
repeating the Pump Run-In for an additional two weeks per investigator discretion. A contact 
812 
will be made each week with additional contacts as needed. Prior to each contact, participants 
813 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 41 OF 74 
 
will be asked to upload device data for study staff to review. The visit and contact schedule 
814 
during the run-in is summarized in Table 1. Schedule of Visits and Procedures during Screening 
815 
and Run-In. 
816 
 
817 
After completion of the Pump Run-In, participants will proceed to use the study CGM along with 
818 
the study 670G 3.0 HCL pump during the Pump+CGM Run-In period on the same day. 
819 
 
820 
 Pump+CGM Run-In – 670G 3.0 HCL + Guardian Sensor (3) 
821 
All participants must complete a two-week run-in period with the use of the study pump and 
822 
CGM before being randomized into the crossover trial. During the Pump+CGM Run-In, the 
823 
predictive low glucose suspend feature will be turned on and auto mode will be turned off (i.e. 
824 
manual mode). Participants who were 670G auto mode users at screening may use the pump in 
825 
auto mode. 
826 
 
827 
Standardized device training will be provided using a training checklist to study participants and 
828 
their diabetes care partners (for participants <18 years old) if not already provided during pump 
829 
run-in. Personal pumps and CGMs will be removed during the Pump+CGM Run-In period as 
830 
applicable. 
831 
 
832 
A contact will be made each week with additional contacts as needed. Prior to each contact, 
833 
participants will be asked to upload device data for study staff to review. 
834 
 
835 
 Visit and Contact Schedule 
836 
All participants will be contacted by study staff at least once during the first seven days (7±2 
837 
days), followed by a clinic visit after 14 days (14+3 days) for each run-in period. If any run-in 
838 
periods are repeated, the same contact schedule will be followed. 
839 
 
840 
Table 2. Schedule of Visits and Procedures During the Crossover Trial lists the visit and contact 
841 
schedule during run-in. Contacts may be substituted for a visit. Additional contacts or visits may 
842 
be done as needed. 
843 
 
844 
 Run-In Assessments 
845 
Device data will be downloaded by study staff at each clinic visit during Run-In. 
846 
 
847 
Successful completion of the Pump Run-In is per investigator assessment. 
848 
 
849 
Successful completion of the Pump+CGM Run-In requires that CGM data be collected for at 
850 
least 80% of the possible time during the prior 14 days in addition to having an average of at 
851 
least three blood glucose meter tests per day. If this is not achieved the Pump+CGM Run-In may 
852 
be repeated once. If the participant does not complete the Pump+CGM Run-In the second time, 
853 
the participant will be dropped. 
854 
 
855 
 Device Data Uploads 
856 
In addition to device data downloads performed at each clinic visit, participants will be 
857 
instructed to upload device data before each scheduled contact and at least every two weeks for 
858 
study staff review.
859 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 42 OF 74 
 
 Randomization Visit 
860 
 
861 
Once a study participant is randomized, that participant will be counted regardless of whether 
862 
the assigned treatment is received. Thus, the investigator must not proceed to randomize an 
863 
individual until they are convinced that the participant is eligible and will accept assignment 
864 
to either of the two treatment orders. 
865 
 
866 
 Randomization Visit 
867 
The randomization visit is expected to begin on the same day the Pump+CGM Run-In period is 
868 
completed. Eligibility criteria from screening will be reviewed again and if the participant is no 
869 
longer eligible based on these criteria, the participant will be dropped from the study. 
870 
 
871 
 Randomization 
872 
Eligible participants will be randomly assigned to use the study pumps (along with the study 
873 
CGM) in one of the following orders: 
874 
1. 670G 3.0 HCL during Period 1 then switch to the 670G 4.0 AHCL during Period 2; or 
875 
2. 670G 4.0 AHCL during Period 1 then switch to the 670G 3.0 HCL during Period 2 
876 
 
877 
Participant randomization assignment is determined after the Randomization Visit data on the 
878 
study website are entered. The data from this visit and where applicable, prior visits, are assessed 
879 
to verify eligibility prior to the randomization process being completed. 
880 
 
881 
 HbA1c, C-peptide, and Glucose 
882 
After the participant is randomized, a blood sample will be drawn to send to the central laboratory 
883 
for baseline HbA1c determination to be used in outcome analyses and may be either venous or 
884 
capillary. Blood samples will also be drawn to send to the central lab for random C-peptide and 
885 
glucose levels. 
886 
 
887 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 43 OF 74 
 
 Crossover Trial  
888 
 
889 
 Study Procedures and Schedule during the Crossover Trial 
890 
 AID System Training 
891 
Automated insulin delivery (AID) training can occur on the same day or extend up to one 
892 
additional day if needed from randomization. AID training includes auto mode training and will 
893 
be provided at the beginning of each crossover period. 
894 
 
895 
The participant and care partner will be trained by qualified study staff regarding auto mode 
896 
including meal announcement, meal bolusing, and exercise. For participants <18 years old, the 
897 
diabetes care partner will be trained on severe hypoglycemia emergency procedures including 
898 
removal of the study pump and administration of glucagon, and on all other training procedures. 
899 
 
900 
Participants will be provided with Hypoglycemia, Hyperglycemia, and Ketone Guidelines for 
901 
when their glucose levels are ≥250 mg/dL (13.9 mmol/L) for more than two hours, or ≥300 
902 
mg/dL (16.7 mmol/L) for over 1 hour or >400 mg/dL (22.2 mmol/L) at any time or <70 mg/dL 
903 
(3.9 mmol/L) or ketones ≥0.6 mmol/L. 
904 
 
905 
Study team members will train the participant and care partner in performing specific tasks 
906 
including the following: 
907 
• The study team will confirm the pump parameters entered in the system 
908 
• When not to use or rely on auto mode particularly during significant illness 
909 
• CGM calibration instructions 
910 
• Meal bolus procedures 
911 
• What to do when exercising while using the system. 
912 
• The participant and care partner will be assessed for understanding how to react to 
913 
safety/alert notifications 
914 
• Participants will be reminded to perform fingerstick blood glucose measurements in 
915 
accordance with the labeling of the study CGM device 
916 
• Participants will be instructed when to contact study staff and provided with contact 
917 
information to ask any questions they may have during the study 
918 
 
919 
Study staff will discuss the visit schedule with the participant and will make arrangements with 
920 
the participant for the contacts. If the participant cannot be reached, the participant’s other 
921 
contact methods will be utilized. 
922 
 
923 
 Home Use of AID System during Study Period 1 
924 
After AID training has been completed, participants will proceed with home use of the AID 
925 
system (meaning free-living use at work, home, etc.) during Study Period 1 with either the 670G 
926 
3.0 HCL or 670G 4.0 AHCL pump as determined by the randomization order. The predictive 
927 
low glucose suspend feature will be turned on. Participants starting with the 670G 4.0 AHCL 
928 
pump will return the 670G 3.0 HCL pump used during Run-In. 
929 
 
930 
The system will initially be used with auto mode deactivated (except for 670G auto mode users 
931 
at screening who may activate auto mode if using the 670G 3.0 HCL pump) until participants are 
932 
contacted 6-10 days into Study Period 1 with instructions to ensure auto mode is initialized. 
933 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 44 OF 74 
 
Participants will also be instructed to ensure a new sensor is inserted 24 hours prior to initializing 
934 
auto mode. Participants will then continue using the AID system for 12 weeks after auto mode is 
935 
initialized. Participants will be expected to use auto mode at all times at home with some 
936 
exceptions (e.g. times of illness, acetaminophen use). 
937 
 
938 
 Home Use of AID System during Study Period 2 
939 
There will be no washout period. Participants will proceed with home use of the AID system 
940 
(meaning free-living use at work, home, etc.) during Study Period 2 with either the 670G 3.0 
941 
HCL or 670G 4.0 AHCL pump as determined by the randomization order. Week 12 of Crossover 
942 
Period 1 will be the 1st day of Crossover Period 2. 
943 
 
944 
The system will initially be used with auto mode deactivated (except for 670G auto mode users 
945 
at screening who may activate auto mode if using the 670G 3.0 HCL pump) until participants are 
946 
contacted 6-10 days into Study Period 2 with instructions to ensure auto mode is initialized. 
947 
Participants will also be instructed to ensure a new sensor is inserted 24 hours prior to initializing 
948 
auto mode. Participants will then continue using the AID system for 12 weeks after auto mode is 
949 
initialized. Participants will be expected to use auto mode at all times at home with some 
950 
exceptions (e.g. times of illness, acetaminophen use). 
951 
 
952 
 Visit and Phone Contact Schedule during Study Periods 1 and 2 
953 
During each of the two study periods, visits and contacts will be scheduled as outlined below. 
954 
Additional contacts or visits may occur as needed: 
955 
• Study Period begins 
956 
o 6-10 days – participants will be contacted by phone to ensure auto mode is 
957 
initialized 
958 
• Auto mode is initialized (remaining visits and contacts are relative to the day auto mode 
959 
is confirmed to be initialized by site staff) 
960 
o 24-hour contact (Contact must be completed by phone)  
961 
o 5-day contact (±2 days) = 3-7 days (Contact must be completed by phone) 
962 
o 2-week visit (±4 days) = 10-18 days 
963 
o 4-week contact (±4 days) = 24-32 days 
964 
o 6-week visit (±4 days) = 38-46 days 
965 
o 9-week contact (±4 days) = 59-67 days 
966 
o 12-week visit/contact (+7 days) = 84-91 days (end of study period) 
967 
 
968 
The goal will be for all participants to complete all scheduled visits. However, participants who 
969 
(because of unforeseen circumstances) are unable or unwilling to return for all follow-up visits 
970 
will be permitted to return for key visits only as an alternative to withdrawal from the study.  
971 
When a participant is placed into this status, missed visits will not be recorded as protocol 
972 
deviations (since they would not be recorded as protocol deviations if the participant was 
973 
dropped from the study). 
974 
 
975 
 Procedures During Study Periods 
976 
5.1.5.1 Procedures performed during each contact 
977 
• The participant will be asked to upload device data for study staff review 
978 
• Assessment of compliance with study device use 
979 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 45 OF 74 
 
• Answer questions about using the AID system 
980 
• Assessment of adverse events, adverse device effects, and device issues 
981 
• Review of glycemic control 
982 
 
983 
5.1.5.2 Procedures performed during each follow-up visit 
984 
• Assessment of compliance with study device use 
985 
• Retraining on system use as needed 
986 
• Assessment of adverse events, adverse device effects, and device issues 
987 
• Download of AID system and study meter data (BG and ketone data) 
988 
• All study blood glucose and ketone meters will be quality control (QC) tested with 
989 
the available concentration(s) of control solution if the meters are available during all 
990 
office visits 
991 
• Venous or capillary collection of a blood sample to send to the central laboratory for 
992 
HbA1c determination at the beginning and end of Periods 1 and 2 
993 
• Urine pregnancy test for females of child-bearing potential at the beginning of Period 
994 
2  
995 
• Participant weight, height, and blood pressure will be measured at the beginning and 
996 
end of Periods 1 and 2. 
997 
• Completion of questionnaires at the end of Periods 1 and 2  
998 
• Review of glycemic control 
999 
At the Final Visit, participants will return study systems and be placed back on their pre-study 
1000 
insulin delivery method and glucose monitoring method. If the participant desires a change (e.g. 
1001 
prior MDI user who wants to use a pump, non-CGM user who wants to use CGM), this will be 
1002 
handled as part of usual care. The Final Visit may be completed in-person in clinic or in an 
1003 
alternate location such as the participant’s home.  If this is not possible, the study visit may occur 
1004 
remotely via phone or videoconferencing.  Certain procedures such as the measurement of 
1005 
height, weight, vitals, and collection of the central HbA1c sample may be missed if the visit is 
1006 
not completed in-person. Participants requiring a remote final visit will be transitioned off of the 
1007 
study device during the remote contact and an arrangement will be made between site staff and 
1008 
the participant to return all required study devices either in-person or via mail. 
1009 
 
1010 
5.1.5.3 Setpoint adjustments during 670G 4.0 AHCL use 
1011 
All participants in the 670G 4.0 AHCL arm will start with an auto mode target glucose set point 
1012 
of 120 mg/dL (6.7 mmol/L). At the auto mode initiation contact, participants will be reminded to 
1013 
obtain an overnight fingerstick blood glucose measurement (between 2-3AM) for 2-3 nights 
1014 
following auto mode initiation and if SMBG is <70 mg/dL to treat with carbohydrate, 
1015 
discontinue closed loop mode, and notify the investigator or designee the next day for advice. 
1016 
Study staff will inquire about the fingersticks and reinforce the importance of these fingersticks 
1017 
at both the 24-hour and 3-7 day follow-up phone calls. At the 2-week assessment visit the target 
1018 
glucose set point should be lowered to 100 mg/dL (5.6 mmol/L) if the participant meets the 
1019 
criteria listed below since the previously scheduled visit or contact and the site investigators have 
1020 
no other clinical reason not to reduce the setpoint: 
1021 
• No severe hypoglycemia; AND 
1022 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 46 OF 74 
 
o No more than 1% of sensor glucose readings <54 mg/dL (3.0 mmol/L) for the 
1023 
24-hour time period based on review of CGM download AND no sensor 
1024 
glucose readings less than 54 mg/dL from Midnight to 6AM; OR 
1025 
o No more than 3% of sensor glucose readings less than 70 mg/dL (3.9 mmol/L) 
1026 
for 24 hours 
1027 
 
1028 
If the participant does not meet these criteria the setpoint should remain at 120 mg/dL (6.7 
1029 
mmol/L) and the participant should be reevaluated at 4, 6, and 9 weeks to see if the setpoint can 
1030 
be reduced to 100 mg/dL (5.6 mmol/L) using the same criteria.  When the setpoint is lowered, 
1031 
the same requirement as above will be provided regarding overnight fingersticks. 
1032 
 
1033 
The setpoint may be adjusted at any time if clinically appropriate per investigator’s opinion.  
1034 
 
1035 
 Device Data Uploads During the Crossover Trial 
1036 
Device data will be collected by clinic staff during each follow-up visit. In between clinic visits, 
1037 
device data will be uploaded remotely by participants before each scheduled contact and at least 
1038 
every two weeks. 
1039 
 
1040 
 Early Termination Visit  
1041 
If a participant discontinues the study early, an attempt will be made to have the participant come 
1042 
to the clinic for a visit to return study devices and supplies, to record any adverse events or 
1043 
device issues that have occurred, complete final questionnaires, and collect a final HbA1c. 
1044 
 
1045 
 Unscheduled Visits 
1046 
An Unscheduled Visit form will be completed for any contact the participant has with the site for 
1047 
significant protocol-related issues/questions outside the visit schedule.
1048 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 47 OF 74 
 
 Study Devices and Safety 
1049 
 
1050 
 Description of the Study Devices 
1051 
 Insulin Pumps 
1052 
One insulin pump used in the study is the Minimed 670G 3.0 HCL insulin pump, which is an 
1053 
FDA-approved and CE-marked device system with no changes to its hardware or firmware 
1054 
components (MMT-1780 in the United States, MMT-1781 and MMT-1782 outside the United 
1055 
States). The 670G 4.0 AHCL insulin pump will also be used and is an investigational product 
1056 
(MMT-1740 in the United States, MMT-1741 and MMT-1742 outside the United States). The 
1057 
670G 4.0 AHCL pump is the same as the 670G 3.0 HCL pump except the AHCL pump includes 
1058 
the Fuzzy Logic algorithm software. 
1059 
 
1060 
 Continuous Glucose Monitoring 
1061 
The study sensor is the Guardian Sensor (3) (MMT-7020). This is an FDA-approved and CE-
1062 
marked device system with no changes to its hardware or firmware components. The CGM 
1063 
sensor will be connected to a Guardian Link (3) transmitter (MMT-7811) and the sensor will be 
1064 
replaced in accordance with manufacturer labeling (e.g. at least once every seven days). This 
1065 
device is not investigational. 
1066 
 
1067 
 Blood Glucose Meter and Strips 
1068 
Blood glucose levels will be measured and the CGM device will be calibrated using the Contour 
1069 
Next Link 2.4 meter (MMT-1152 or MMT-1352) (or equivalent meter, such as the Contour plus 
1070 
Link) and test strips in accordance with manufacturer labeling. 
1071 
 
1072 
 Ketone Meter and Strips 
1073 
Blood ketone levels will be measured using the Abbott Precision Xtra (or equivalent meter, such 
1074 
as the Optium Neo) meter and strips in accordance with manufacturer labeling. The blood 
1075 
glucose meter component of ketone meters will not be used. 
1076 
 
1077 
 Study Device Accountability Procedures 
1078 
Good clinical research practice requires that investigators and research teams ensure accurate 
1079 
accountability for any investigational device used in a research trial. It is expected that all 
1080 
investigational devices or approved devices used outside their approved intended use will be 
1081 
used in the manner intended during the study, that they will be stored under appropriately 
1082 
controlled conditions, and that they will be used only by (on) participants who have consented to 
1083 
participate in the research study. 
1084 
 
1085 
Any investigational device or approved devices used outside their approved intended use being 
1086 
used in clinical research must be strictly accounted for and will not be shipped to any site unless 
1087 
all of the necessary approvals (e.g. Regulatory, IRB/EC) have been received. This includes 
1088 
keeping records of: 
1089 
1. Center receipt and inventory management 
1090 
2. Storage  
1091 
3. Participant Disbursement  
1092 
4. Return (by Participants and Center) and/or disposal  
1093 
 
1094 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 48 OF 74 
 
US: Investigational devices or approved devices used outside their approved intended use will be 
1095 
labeled “Investigational Device” in accordance with 21 CFR Part 812.140.  
1096 
EMEA: In accordance with the MDD directive, the investigational devices for EMEA will be 
1097 
labeled “Exclusively for Clinical Investigations” 
1098 
 
1099 
During the conduct of the study the investigational center staff will account for, and document, 
1100 
the Device accountability procedures as detailed in the site procedures manual. 
1101 
 
1102 
 Blood Glucose Meter Testing 
1103 
• Participants will be provided with instructions to perform quality control (QC) testing per 
1104 
manufacturer guidelines. Participants will be instructed to contact study staff for a 
1105 
replacement of the meter, test strips, and control solution if a meter fails QC testing at 
1106 
home. 
1107 
• A tested meter will not be used in a study if it does not read within the target range at 
1108 
each concentration per manufacturer labeling.  
1109 
• Participants will be reminded to use the study blood glucose meter for all fingerstick 
1110 
blood glucose measurements 
1111 
• Participants will be asked to perform fingerstick blood glucose measurements in 
1112 
accordance with the labeling of the study CGM device. 
1113 
 
1114 
 Blood Ketone Testing 
1115 
• Participants will be provided with instructions to perform quality control (QC) testing per 
1116 
manufacturer guidelines. The participant will be instructed to contact study staff for a 
1117 
replacement of the meter, test strips, and control solution if a meter fails QC testing at 
1118 
home. 
1119 
• All study blood ketone meters will be QC tested with the available concentration(s) of 
1120 
control solution if the meter is available during all office visits. A tested meter will not be 
1121 
used in a study if it does not read within the target range at each concentration per 
1122 
manufacturer labeling.  
1123 
• Participants will be instructed on how to perform blood ketone testing 
1124 
• Participants will be given guidelines for treatment of elevated blood ketones 
1125 
 
1126 
 Safety Measures  
1127 
 CGM Calibration 
1128 
Throughout the study, participants will be instructed to calibrate the study CGM in accordance 
1129 
with manufacturer labeling. 
1130 
 
1131 
 Pump Failure 
1132 
In the event of a pump failure, the participant will be instructed to use their personal insulin 
1133 
regimen until the problem can be resolved. Reportable events are described in Chapter 8:. 
1134 
 
1135 
 Hypoglycemia Threshold Alarm and Safety Protocol  
1136 
During the course of the study, participants will be permitted to change the low glucose threshold 
1137 
alarm setting, but it is recommend to set it to 70 mg/dL (3.9 mmol/L). Participants will be 
1138 
encouraged to be consistent with their use of any such features between the two periods of the 
1139 
crossover study. 
1140 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 49 OF 74 
 
 
1141 
If a participant receives a CGM hypoglycemia threshold alarm or notes that the CGM glucose is 
1142 
below the hypoglycemia threshold alarm value, confirmatory fingerstick testing will be 
1143 
performed if required by CGM labelling and the participant will be instructed to treat 
1144 
hypoglycemia with ~15 grams of fast-acting oral glucose. 
1145 
 
1146 
 Hyperglycemia Threshold Alarm and Safety Protocol  
1147 
During the course of the study, participants will be permitted to change the high glucose 
1148 
threshold alarm setting, but it is recommend to set it to 300 mg/dL (16.7 mmol/L). Participants 
1149 
will be encouraged to be consistent with their use of any such features between the two periods 
1150 
of the crossover study. 
1151 
 
1152 
If a participant receives a CGM hyperglycemia threshold alarm or notes that the CGM glucose is 
1153 
above the hyperglycemia threshold alarm value, confirmatory fingerstick testing will be 
1154 
performed if required by CGM labelling. 
1155 
 
1156 
During the time period when auto mode is operational and active, if a participant’s CGM reading 
1157 
is >300 mg/dL (16.7 mmol/L) for over one hour or ≥400 mg/dL (22.2 mmol/L) at any point, the 
1158 
participant will be instructed to take the following steps: 
1159 
• Perform a blood glucose meter check. 
1160 
o If the blood glucose is >300 mg/dL (16.7 mmol/L), check for blood ketones with 
1161 
the study ketone meter. 
1162 
▪ If the ketone level is >0.6 mmol/L, contact study staff for further 
1163 
instructions, which may include replacing the insulin infusion set. 
1164 
 
1165 
 Safety Measures Specific to AID system use 
1166 
6.3.5.1 Insulin Dosing 
1167 
In auto mode, all dosing is supervised by the AID system. Insulin injection for meal boluses must 
1168 
be performed using the pump bolus calculator. 
1169 
 
1170 
 Safety Measures for Open-Loop (Manual Mode) CGM Use 
1171 
These measures apply when the AID system (auto mode) is not being used or is not 
1172 
communicating with the CGM device. 
1173 
 
1174 
6.3.6.1 Hypoglycemia Safety Protocol 
1175 
If a participant receives a CGM hypoglycemia threshold or predictive alarm or notes that the 
1176 
CGM glucose is below the hypoglycemia threshold alarm value, confirmatory fingerstick testing 
1177 
will be performed if required by CGM labeling and the participant will be instructed to treat 
1178 
hypoglycemia with ~15 grams of fast-acting oral glucose. 
1179 
 
1180 
6.3.6.2 Hyperglycemia Safety Protocol 
1181 
If a participant receives a CGM hyperglycemia threshold alarm or notes that the CGM glucose is 
1182 
above the hyperglycemia threshold alarm value, confirmatory fingerstick testing will be 
1183 
performed if required by CGM labeling.
1184 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 50 OF 74 
 
 Laboratory Testing and Questionnaires 
1185 
 
1186 
 Laboratory Testing 
1187 
HbA1c: 
1188 
• Performed locally at the Screening visit. 
1189 
• Collected for central lab analysis at Randomization, and at the beginning and end of each 
1190 
study period during the crossover trial. Final HbA1c may also be collected for participants 
1191 
who withdraw from the study. 
1192 
 
1193 
Random C-Peptide and Glucose: 
1194 
• Collected at Randomization for central lab analysis  
1195 
 
1196 
Urine Pregnancy:  
1197 
• Performed locally for females of child-bearing potential at Screening and at the beginning of 
1198 
each study period during the crossover trial. This test may also be performed at any time 
1199 
pregnancy is suspected. 
1200 
 
1201 
Local laboratory testing will be performed if needed to screen for exclusionary medical 
1202 
conditions. Normal creatinine levels must have been obtained within 12 months prior to 
1203 
enrollment (if not available, at time of enrollment, screening can proceed but it must be available 
1204 
prior to randomization). 
1205 
 
1206 
 Questionnaires 
1207 
The following questionnaires will be completed at Screening and at the end of each period 
1208 
during the crossover trial (except that the INSPIRE survey will not be administered at 
1209 
Screening). Final questionnaires may also be collected for participants who withdraw from the 
1210 
study. 
1211 
 
1212 
Each questionnaire is described briefly in Table 6. Questionnaires below. The procedures for 
1213 
administration are described in the study procedures manual. 
1214 
 
1215 
Table 6. Questionnaires 
1216 
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) 
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; only 
collected at end of periods 1 and 2) 
1217 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 51 OF 74 
 
  Adverse Events, Device Issues, and Stopping 
1218 
Rules 
1219 
 
1220 
 Adverse Events 
1221 
 Definitions 
1222 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
1223 
relationship between the adverse event and the device(s) under investigation (see Section 8.1.2 
1224 
for reportable adverse events for this protocol). 
1225 
 
1226 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
1227 
• Results in death. 
1228 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, 
1229 
might have become life-threatening, is not necessarily considered a serious 
1230 
adverse event). 
1231 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
1232 
• Results in persistent or significant disability/incapacity or substantial disruption of 
1233 
the ability to conduct normal life functions (sight threatening). 
1234 
• Is a congenital anomaly or birth defect. 
1235 
• Is considered a significant medical event by the investigator based on medical 
1236 
judgment (e.g., may jeopardize the participant or may require medical/surgical 
1237 
intervention to prevent one of the outcomes listed above). 
1238 
 
1239 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
1240 
any life-threatening problem or death caused by, or associated with, an investigational device, if 
1241 
that effect, problem, or death was not previously identified in nature, severity, or degree of 
1242 
incidence in the investigational plan or application (including a supplementary plan or 
1243 
application), or any other unanticipated serious problem associated with a device that relates to 
1244 
the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
1245 
 
1246 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
1247 
the device may have caused or to which the device may have contributed (Note that an Adverse 
1248 
Event Form is to be completed in addition to a Device Deficiency or Issue Form unless excluded 
1249 
from reporting as defined in Section 8.2). For reporting purposes, the ADE definition will be 
1250 
used to define reportable AEs for the commercially available system (670G 3.0) as well as the 
1251 
investigational system (AHCL). 
1252 
 
1253 
Device Complaints and Malfunctions: A device complication or complaint is something that 
1254 
happens to an investigational device or related to device performance, whereas an adverse event 
1255 
happens to a participant. A device complaint may occur independently from an AE, or along 
1256 
with an AE. An AE may occur without a device complaint or there may be an AE related to a 
1257 
device complaint. A device malfunction is any failure of a device to meet its performance 
1258 
specifications or otherwise perform as intended. Performance specifications include all claims 
1259 
made in the labeling for the device. The intended performance of a device refers to the intended 
1260 
use for which the device is labeled or marketed. (21 CFR 803.3). Note: for reporting purposes, 
1261 
sites will not be asked to distinguish between device complaints and malfunctions. 
1262 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 52 OF 74 
 
 
1263 
 Reportable Adverse Events 
1264 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
1265 
meets one of the following criteria:  
1266 
1. An SAE  
1267 
2. An ADE as defined in Section 8.1.1, unless excluded from reporting in Section 8.2 
1268 
3. An AE as defined in Section 8.1.1 occurring in association with a study procedure  
1269 
4. An AE as defined in Section 8.1.1 which leads to discontinuation of a study device for two or 
1270 
more hours 
1271 
5. Hypoglycemia meeting the definition of severe hypoglycemia as defined below  
1272 
6. Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, hyperglycemia or 
1273 
ketosis event meeting the criteria defined below 
1274 
 
1275 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
1276 
events unless associated with an Adverse Device Effect. Skin reactions from sensor adhesive 
1277 
placement are only reportable if severe and/or required treatment.  
1278 
 
1279 
Pregnancy occurring during the study will be reported as an AE (see Section 8.3). 
1280 
 
1281 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
1282 
during questioning, or detected through physical examination, laboratory test, or other means—
1283 
will be reported on an AE form online. Each AE form is reviewed by the Medical Monitor to 
1284 
assess safety and to verify the coding and the reporting that is required. 
1285 
 
1286 
8.1.2.1 Hypoglycemic Events 
1287 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1288 
event when the following definition for severe hypoglycemia is met: the event required 
1289 
assistance of another person due to altered consciousness, and required another person to actively 
1290 
administer carbohydrate, glucagon, or other resuscitative actions. This means that the participant 
1291 
was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable 
1292 
to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure 
1293 
or loss of consciousness. These episodes may be associated with sufficient neuroglycopenia to 
1294 
induce seizure or loss of consciousness. If plasma glucose measurements are not available during 
1295 
such an event, neurological recovery attributable to the restoration of plasma glucose to normal 
1296 
is considered sufficient evidence that the event was induced by a low plasma glucose 
1297 
concentration. 
1298 
 
1299 
8.1.2.2 Hyperglycemic/Ketotic Events 
1300 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1301 
event when one of the following four criteria is met:  
1302 
• the event involved DKA, as defined by the Diabetes Control and Complications Trial 
1303 
(DCCT) and described below 
1304 
• evaluation or treatment was obtained at a health care provider facility for an acute event 
1305 
involving hyperglycemia or ketosis 
1306 
• blood ketone level ≥1.0 mmol/L and communication occurred with a health care provider 
1307 
at the time of the event 
1308 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 53 OF 74 
 
• blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
1309 
provider 
1310 
 
1311 
Hyperglycemic events are classified as DKA if the following are present: 
1312 
• Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
1313 
• Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
1314 
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1315 
• Treatment provided in a health care facility 
1316 
 
1317 
 Relationship of Adverse Event to Study Device 
1318 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1319 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1320 
by the study device.  Note that this assessment will be made for both the investigational device 
1321 
(AHCL system) and the commercially available system (670G 3.0). 
1322 
 
1323 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1324 
following general guideline when determining whether an adverse event is related: 
1325 
• Unrelated: The AE is clearly not related to a study drug/device and a likely alternative 
1326 
etiology exists such as an underlying disease, environmental or toxic factors or other 
1327 
therapy. 
1328 
• Unlikely Related: The AE does not follow a reasonable temporal sequence during or 
1329 
after use of study drug/device and a more likely alternative etiology exists such as an 
1330 
underlying disease, environmental or toxic factors, or other therapy. 
1331 
• Possibly Related: The AE occurred in a reasonable time during or after use of study 
1332 
drug/device; but could be related to another factor such as an underlying disease, 
1333 
environmental or toxic factors, or other therapy; and there is a possible, though weak, 
1334 
scientific basis for establishing a causal association between the AE and the study 
1335 
drug/device. 
1336 
• Probably Related: The AE occurred in a reasonable time during or after use of study 
1337 
drug/device; is unlikely to be related to another factor such as an underlying disease, 
1338 
environmental or toxic factors, or other therapy; and there is a plausible, though not 
1339 
strong, scientific basis for establishing a causal association between the AE and the study 
1340 
drug/device. 
1341 
• Definitely Related: The AE occurred in a reasonable time during or after use of study 
1342 
drug/device; cannot be explained by another factor such as an underlying disease, 
1343 
environmental or toxic factors, or therapy; and there is a strong scientific basis for 
1344 
establishing a causal association between the AE and the study drug/device.  
1345 
• Not Assessable: Causality of an adverse event cannot be judged because information is 
1346 
insufficient or contradictory, and which cannot be supplemented or verified. 
1347 
 
1348 
 Intensity of Adverse Event 
1349 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or 
1350 
(3) severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse 
1351 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
1352 
may not be clinically serious. 
1353 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 54 OF 74 
 
• 
MILD: Usually transient, requires no special treatment, and does not interfere with the 
1354 
participant’s daily activities. 
1355 
• 
MODERATE: Usually causes a low level of inconvenience or concern to the 
1356 
participant and may interfere with daily activities, but is usually ameliorated by simple 
1357 
therapeutic measures. 
1358 
• 
SEVERE: Interrupts a participant’s usual daily activities and generally requires 
1359 
systemic drug therapy or other treatment. 
1360 
 
1361 
 Coding of Adverse Events 
1362 
Adverse events will be coded using the MedDRA dictionary. The Medical Monitor will review 
1363 
the investigator’s assessment of causality and may agree or disagree. Both the investigator’s and 
1364 
Medical Monitor’s assessments will be recorded. The Medical Monitor will have the final say in 
1365 
determining the causality. 
1366 
 
1367 
 Outcome of Adverse Event 
1368 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1369 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without 
1370 
sequelae.  Record the AE/SAE stop date. 
1371 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
1372 
without change in the event anticipated.  Record the AE/SAE stop date. 
1373 
• FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event 
1374 
that was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at 
1375 
the time of death; however, were not the cause of death, will be recorded as “resolved” at 
1376 
the time of death. 
1377 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined 
1378 
as the event was ongoing with an undetermined outcome. 
1379 
 An ongoing outcome will require follow-up by the site in order to determine the final 
1380 
outcome of the AE/SAE. 
1381 
 The outcome of an ongoing event at the time of death that was not the cause of death, 
1382 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1383 
date. 
1384 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant or 
1385 
the participant’s records to determine the outcome (for example, a participant that was lost 
1386 
to follow-up). 
1387 
If any reported adverse events are ongoing when a participant completes the study (or 
1388 
withdraws), adverse events classified UADEs will be followed until they are either resolved, 
1389 
or have no prospect of improvement or change, even after the subject has completed all 
1390 
applicable study visits/contacts. For all other adverse events, data collection will end at the 
1391 
time the participant completes the study. Note: participants should continue to receive 
1392 
appropriate medical care for an adverse event after their participation in the study ends. 
1393 
 
1394 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 55 OF 74 
 
 Reportable Device Issues 
1395 
All UADEs and ADEs as defined in Section 8.1.1 will be reported on both a device issue form 
1396 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1397 
placement that are not severe and/or require treatment. 
1398 
 
1399 
Device complaints and device malfunctions for the investigational device will be reported except 
1400 
in the following circumstances. These occurrences are expected and will not be reported on a 
1401 
Device Issue Form assuming criteria for a UADE or ADE have not been met: 
1402 
• CGM sensor lasting fewer days than expected per manufacturer 
1403 
• CGM tape adherence issues 
1404 
• Pump infusion set occlusion (including tubing and cartridge) not leading to ketosis ≥0.6 
1405 
mmol/L or in the absence of checking for blood ketones, blood glucose >350 mg/dL 
1406 
(19.4 mmol/L); and not requiring an intervention other than replacing the tubing and/or 
1407 
cartridge 
1408 
• Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
1409 
• Intermittent device component disconnections/communication failures not requiring 
1410 
system replacement or workaround/resolution not specified in user guide/manual. 
1411 
• Device issues clearly addressed in the user guide manual that do not require additional 
1412 
troubleshooting 
1413 
 
1414 
 Pregnancy Reporting 
1415 
If pregnancy occurs, the participant will be discontinued from the study. The occurrence of 
1416 
pregnancy will be reported on an AE Form. 
1417 
 
1418 
 Timing of Event Reporting 
1419 
SAEs possibly related to an investigational device or study participation and UADEs must be 
1420 
reported to the Coordinating Center within 24 hours of the site becoming aware of the event. 
1421 
This can occur via phone or email, or by completion of the online serious adverse event form and 
1422 
device issue form if applicable. If the form is not initially completed, it should be competed as 
1423 
soon as possible after there is sufficient information to evaluate the event. All other reportable 
1424 
ADEs and other reportable AEs should be submitted by completion of the online form within 
1425 
seven days of the site becoming aware of the event. 
1426 
 
1427 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1428 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
1429 
Center becomes aware of the event.  
1430 
 
1431 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1432 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1433 
Ethics Committee. 
1434 
 
1435 
Upon receipt of a UADE report, the Coordinating Center will investigate the UADE and if 
1436 
indicated, report the results of the investigation to the sites’ IRBs, and the FDA within ten 
1437 
working days of the Coordinating Center becoming aware of the UADE per 21CFR 812.46(b) 
1438 
(2). The Medical Monitor must determine if the UADE presents an unreasonable risk to 
1439 
participants. If so, the Medical Monitor must ensure that all investigations, or parts of 
1440 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 56 OF 74 
 
investigations presenting that risk, are terminated as soon as possible but no later than 5 working 
1441 
days after the Medical Monitor makes this determination and no later than 15 working days after 
1442 
first receipt notice of the UADE. 
1443 
 
1444 
Device malfunctions will be handled by the Coordinating Center.  
1445 
 
1446 
 Stopping Criteria 
1447 
 Participant Discontinuation of Investigational Device 
1448 
Rules for discontinuing investigational device use are described below. 
1449 
 
1450 
• 
The investigator believes it is unsafe for the participant to continue on the intervention. 
1451 
This could be due to the development of a new medical condition or worsening of an 
1452 
existing condition; or participant behavior contrary to the indications for use of the device 
1453 
that imposes on the participant’s safety 
1454 
• 
The participant requests that the treatment be stopped 
1455 
• 
Two distinct episodes of DKA (as defined in section 8.1.2) unrelated to infusion set 
1456 
failure 
1457 
• 
A single episode of severe hypoglycemia (as defined in section 8.1.2.1) or DKA (as 
1458 
defined in section 8.1.2.2) for which use of the investigational device (AHCL system) is 
1459 
considered by either the Medical Monitor or DSMB to be the cause of the event (ie, there 
1460 
is not another plausible assignable cause) in the absence of a device malfunction (e.g., 
1461 
software bug) for which the automated insulin delivery algorithm is temporarily or 
1462 
permanently discontinued for all subjects 
1463 
• 
Two distinct severe hypoglycemia events (as defined in Section 8.1.2.1) 
1464 
 
1465 
Even if the investigational device system is discontinued, the participant will be encouraged to 
1466 
remain in the study through the final study visit. If the investigational device (ie. AHCL system) 
1467 
is discontinued for safety reasons, the investigator with concurrence of the Medical Monitor can 
1468 
switch the participant to either use the 670G 3.0 HCL system in closed loop (if the participant 
1469 
entered the trial on 670G 3.0 HCL using closed loop) or to 670G 3.0 HCL system but in open 
1470 
loop only. 
1471 
 
1472 
 Criteria for Suspending or Stopping Overall Study 
1473 
In the case of an unanticipated system malfunction of the investigational device resulting in a 
1474 
severe hypoglycemia or DKA event (both defined in Section 8.1), use of the investigational 
1475 
device system will be suspended while the problem is diagnosed. 
1476 
 
1477 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1478 
study device requires stoppage of device use for safety reasons (e.g. product recall). The affected 
1479 
study activities may resume if the underlying problem can be corrected by a protocol or system 
1480 
modification that will not invalidate the results obtained prior to suspension. 
1481 
 
1482 
The study Medical Monitor will be informed of all adverse events and adverse device events that 
1483 
are reported during the study and will review compiled safety data at periodic intervals 
1484 
(generally timed to the review of compiled safety data by the DSMB). The Medical Monitor may 
1485 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 57 OF 74 
 
request suspension of study activities or stoppage of the study if deemed necessary based on the 
1486 
totality of safety data available. 
1487 
 
1488 
 Independent Safety Oversight 
1489 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data at periodic 
1490 
intervals (typically every six months). In addition, the DSMB will review all DKA and severe 
1491 
hypoglycemia events irrespective of relatedness to study device use, and all serious events 
1492 
(including UADEs) related to the study device use at the time of occurrence. The DSMB also 
1493 
will be informed of any ADEs not meeting criteria for a UADE if the Medical Monitor requests 
1494 
the DSMB review. The DSMB can request modifications to the study protocol or suspension or 
1495 
outright stoppage of the study if deemed necessary based on the totality of safety data available. 
1496 
Details regarding DSMB review will be documented in a separate DSMB document. 
1497 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 58 OF 74 
 
 Miscellaneous Considerations 
1498 
 
1499 
 Drugs Used as Part of the Protocol 
1500 
U-100 rapid acting insulin analogues, Aspart or Lispro, will be used during the study since these 
1501 
are the only insulins approved for the study pumps. 
1502 
 
1503 
 Collection of Medical Conditions and Medications 
1504 
Pre-Existing Condition: Any medical condition that is either present at screening, a chronic 
1505 
disease, or a prior condition that could impact the participant’s health during the course of the 
1506 
study (e.g., prior myocardial infarction or stroke). 
1507 
Medical Conditions during the study: In addition to conditions meeting the reporting 
1508 
requirements for an adverse event or device issues as described in Section 8.1 and Section 8.2, 
1509 
the following medical conditions should also be reported: (1) new diagnosis of a chronic disease 
1510 
(not present at the time of enrollment); and (2) any medical condition that could affect the 
1511 
participant’s ability to carry out any aspect of the protocol or could affect an outcome 
1512 
assessment. 
1513 
Medications: All medication for the treatment of chronic pre-existing conditions, medical 
1514 
conditions, and/or adverse events that the participant is currently taking at screening and during 
1515 
the course of the study should be recorded. Nutraceuticals and preventative treatment also should 
1516 
be recorded. 
1517 
 Prohibited Medications, Treatments, and Procedures 
1518 
Acetaminophen/Paracetamol may cause unreliable glucose sensor readings. If possible, 
1519 
participants should avoid taking medications with acetaminophen while in Auto Mode. If 
1520 
acetaminophen is taken, participants will be instructed to turn off auto mode and use BG meter 
1521 
readings to follow glucose levels. Additional BG meter readings should not be used to calibrate 
1522 
the sensor. Auto mode should be restarted when BG meter and CGM readings are consistently in 
1523 
close agreement which may take up to 8-12 hours. 
1524 
 
1525 
Exclusionary medications are: 
1526 
• Oral or parenteral glucocorticoids taken within 1 month prior to enrollment, or plans to take 
1527 
oral or parenteral glucocorticoids within the planned study duration. Exceptions: Short term 
1528 
oral or parenteral glucocorticoids up to 7 days 
1529 
• Any antidiabetic agents other than insulin 
1530 
 
1531 
 Participant Compensation 
1532 
Participant compensation will be specified in the informed consent form. 
1533 
 
1534 
 Participant Withdrawal 
1535 
Participation in the study is voluntary, and a participant may withdraw at any time. For 
1536 
participants who withdraw, their data will be used up until the time of withdrawal. An early 
1537 
termination visit may be completed to collect final study data. 
1538 
 
1539 
If participants wish to discontinue using the study device without withdrawing, participants will 
1540 
be encouraged to remain in the study through the final study visit. 
1541 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 59 OF 74 
 
 
1542 
 Confidentiality 
1543 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1544 
used instead of their name. Protected health information gathered for this study will be shared 
1545 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
1546 
participant information may also be provided to research sites involved in the study. 
1547 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 60 OF 74 
 
 Statistical Considerations 
1548 
 
1549 
 Statistical and Analytical Plans 
1550 
The approach to sample size and statistical analyses are summarized below. A detailed statistical 
1551 
analysis plan will be written and finalized prior to the completion of the study. The analysis plan 
1552 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
1553 
 
1554 
 Statistical Hypotheses 
1555 
The co-primary outcomes are CGM-measured metrics over 12-week periods (excluding time 
1556 
before auto mode is turned on): 
1557 
• Superiority in percent time >180 mg/dL (10.0 mmol/L) from 6AM to 11:59PM  
1558 
• Non-inferiority in CGM-measured time <54 mg/dL (3.0 mmol/L) calculated over the full 24 
1559 
hours of the day 
1560 
 
1561 
The study hypotheses can be stated as follows: 
1562 
 
1563 
Hyperglycemic Outcome: 
1564 
• Null Hypothesis: There is no difference in the percentage of time spent with sensor 
1565 
glucose levels above 180 mg/dL between the two treatments during the daytime for the 
1566 
entire study population.  
1567 
• Alternative Hypothesis: There is a nonzero difference in the percentage of time spent 
1568 
with sensor glucose levels above 180 mg/dL between the two treatments during the 
1569 
daytime for the entire study population. 
1570 
Hypoglycemic Outcome: 
1571 
• Null Hypothesis: There is a mean difference of at least 2% in the percentage of time spent 
1572 
with sensor glucose levels below 54 mg/dL between the AHCL system and the 670G 3.0 
1573 
system over the full 24 hours of the day for the entire study population. 
1574 
• Alternative Hypothesis: There is a mean difference of less than 2% in the percentage of 
1575 
time spent with sensor glucose levels below 54 mg/dL between the AHCL system and the 
1576 
670G 3.0 system over the full 24 hours of the day for the entire study population. 
1577 
 
1578 
 Sample Size 
1579 
The sample size calculation is detailed in a separate document and summarized below. 
1580 
For computing sample size, estimates of the standard deviation (SD) for time spent in 
1581 
hypoglycemia and hyperglycemia were made based on data from previous studies, Medtronic 
1582 
670G Pivotal Trial 1, DIAMOND2, JDRF CGM RCT3, and REPLACE-BG4. 
1583 
 
1584 
Analyses of both primary outcomes must have a significant result (p < 0.05) to declare benefit of 
1585 
the intervention. The two co-primary outcomes therefore do not inflate the type 1 error, but 
1586 
requiring both to be significant can inflate the type 2 error. A Bonferroni correction was 
1587 
therefore applied to the power calculations by adding the type 2 error rate (i.e., 100% minus 
1588 
power) for the two analyses. This represents a conservative estimate for composite power as the 
1589 
probability that both tests will reject the null hypothesis. 
1590 
 
1591 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 61 OF 74 
 
The total sample size was computed to be 65 for the following assumptions (1) 90% power, with 
1592 
adjustment to account for the two co-primary analyses, (2) a 5% absolute reduction in time >180 
1593 
mg/dL (10.0 mmol/L) with a standard deviation of paired differences of 12%, and a 2-sided type 
1594 
1 error rate of 5%, and (3) a non-inferiority limit of 2% for the treatment group comparison of 
1595 
time <54 mg/dL (3.0 mmol/L) with an SD of paired differences of 1.3% and 1-sided type 1 error 
1596 
of 2.5%. 
1597 
 
1598 
A sample size of 100 completing the trial has been selected to provide increased precision for 
1599 
safety analyses and subgroup analyses. With a sample size of 100 participants completing the 
1600 
crossover trial, the primary analysis will have 98% power. 
1601 
 
1602 
 Outcome Measures 
1603 
All CGM derived indices will be calculated over the first 84 days of each period. The beginning 
1604 
of the period is defined as the time that auto mode is first turned on, which per protocol is 6-10 
1605 
days after the period starts.  A post-meal period is defined as follows: meal starts at the time the 
1606 
carbohydrate is entered and post-meal period ends at three hours after a meal unless another 
1607 
carbohydrate is entered  <3 hours, which is then considered the end of the post-meal period. 
1608 
 
1609 
Hypoglycemia metrics are considered both safety and efficacy outcomes. 
1610 
 
1611 
The following co-primary outcomes will be compared between the two treatment arms in this 
1612 
crossover trial (PID algorithm vs. PID + Fuzzy logic algorithm): 
1613 
• The percent time spent with sensor glucose >180 mg/dL (10.0 mmol/L) during the day 
1614 
(6AM – 11:59 PM) 
1615 
• Non-inferiority for CGM time <54 mg/dL (3.0 mmol/L) over 24 hours 
1616 
 
1617 
The secondary efficacy analyses will include treatment comparisons for the following outcomes: 
1618 
• CGM derived indices for the full 24-hour day, during daytime (6AM-11:59PM), during 
1619 
nighttime (12AM-5:59AM), and for each post-meal period: 
1620 
o Mean glucose  
1621 
o Coefficient of variation  
1622 
o Percentage of sensor glucose from 70 to 180 mg/dL (3.9 to 10.0 mmol/L) and 70 
1623 
to 140 mg/dL (3.9 to 7.8 mmol/L) 
1624 
o Percentage of sensor glucose > 180 (daytime is a co-primary outcome) and >250 
1625 
mg/dL (10.0 and 13.9 mmol/L, respectively) 
1626 
o Peak glucose and change from the start of the meal to the peak (only calculated 
1627 
for post-meal periods) 
1628 
• Amount of total, basal and bolus daily insulin for the full 24 hour, daytime (6AM-
1629 
11:59PM), nighttime (12AM-5:59AM), and for each post-meal period (both total units and 
1630 
units/kg). 
1631 
• HbA1c 
1632 
• BMI 
1633 
 
1634 
Additionally, summary statistics will be reported (but treatment arm comparisons will not be 
1635 
done) for the following outcomes: 
1636 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 62 OF 74 
 
• CGM-derived indices over the first 84 days of each treatment period for 24 hours 
1637 
(excluding time before auto mode is turned on), daytime (6AM-11:59PM), nighttime 
1638 
(12AM-5:59AM), and for each post-meal period (meal starts at the time the carbohydrate 
1639 
is entered), measured for up to three hours after a meal (or until another carbohydrate is 
1640 
entered): 
1641 
o Percentage of sensor glucose <50 and <60 mg/dL (2.8 and 3.3 mmol/L 
1642 
respectively) 
1643 
o Glucose area under the curve >180 mg/dL (10.0 mmol/L) 
1644 
o Glucose area over the curve <70 mg/dL (3.9 mmol/L) 
1645 
o Percentage of sensor glucose >300 mg/dL (16.7 mmol/L) 
1646 
o Glucose standard deviation 
1647 
• Three level variables denoting change in total insulin, basal insulin, and bolus insulin 
1648 
(increase by >10%, decrease by >10%, or in between) 
1649 
• Binary HbA1c variables: 
1650 
o Improvement ≥0.5% and ≥1.0% 
1651 
o Relative reduction ≥10% 
1652 
o Proportion of participants achieving HbA1c <7.0% 
1653 
 
1654 
 Analysis Cohorts 
1655 
Intent to treat 
1656 
The co-primary analyses will follow the intention-to-treat principle. They will include all 
1657 
randomized participants, and data will be analyzed based on the treatment sequence assigned 
1658 
from randomization regardless of the actual treatment received. Data will not be truncated due to 
1659 
protocol deviations. No imputation will be made for missing data. 
1660 
 
1661 
Per-protocol 
1662 
A per-protocol analysis for the co-primary outcomes also will be conducted by limiting to those 
1663 
participants who used the CGM at least 80% of the time in both periods and who used the auto 
1664 
mode feature for at least 80% of the time in both treatment periods, unless the N for the analysis 
1665 
is >95% of the N in the primary intent-to-treat analysis. 
1666 
 
1667 
Safety 
1668 
All participants will be included in safety analyses. 
1669 
 
1670 
 Analysis of the Primary Efficacy Endpoints 
1671 
For each co-primary outcome, a single value will be calculated for each participant during each 
1672 
period. Details regarding the primary analysis cohorts, handling of missing data, and protocol 
1673 
deviations are discussed in Section 10.5. Mean ± SD or percentiles appropriate to the distribution 
1674 
will be reported for each co-primary outcome by treatment period. A repeated measures least 
1675 
squares regression model with an unstructured covariance structure will be fit for the two co-
1676 
primary outcomes to compare the two treatments adjusting for period, pre-study 670G system 
1677 
use, and HbA1c at randomization as fixed effects. In order to declare benefit of the intervention, 
1678 
both outcomes must be significant based on these models. 
1679 
 
1680 
Time >180 mg/dL (10.0 mmol/L) (superiority) 
1681 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 63 OF 74 
 
A 95% confidence interval will be reported for the difference between the two treatment arms 
1682 
based on the least squares model. Residual values will be examined for an approximate normal 
1683 
distribution. If values are highly skewed, then a transformation or nonparametric method will be 
1684 
used instead. Based on previous data, we do not expect that a transformation will be necessary. A 
1685 
two-sided p-value will be reported, and a 5% significance level will be used to declare statistical 
1686 
significance. 
1687 
 
1688 
Time <54 mg/dL (3.0 mmol/L) (non-inferiority) 
1689 
A two-sided 95% confidence interval will be reported for the difference between the two 
1690 
treatment arms based on the least squares model. Non-inferiority will be assessed by comparing 
1691 
the upper limit of this confidence interval to a non-inferiority limit of 2% (approximately 30 
1692 
minutes per day). This limit was selected solely based on clinical judgment. The non-inferiority 
1693 
limit corresponds to the difference between the 670G 4.0 AHCL system (which is the 
1694 
experimental treatment) and the 670G 3.0 HCL system (which is the active control). Residual 
1695 
values will be examined for an approximate normal distribution. If values are highly skewed, 
1696 
then a transformation or nonparametric method will be used instead. A two-sided p-value will be 
1697 
reported, and a 5% significance level will be used to declare statistical significance. 
1698 
 
1699 
Since non-inferiority is typically framed in terms of a one-sided test, it is worth noting that the 
1700 
left half of a two-sided test at alpha = 0.05 gives the same rejection region as a one-sided test at 
1701 
alpha = 0.025. Therefore, reporting a two-sided 95% confidence interval will provide flexibility 
1702 
to test for inferiority if non-inferiority cannot be declared while maintaining the overall type 1 
1703 
error rate at 5%. Figure 4 below shows the inference to be drawn for various scenarios of the 
1704 
two-sided 95% confidence interval: 
1705 
 
1706 
Figure 4. Non-Inferiority and Superiority 
1707 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 64 OF 74 
 
 
1708 
 
1709 
Monthly trends for the co-primary outcomes will also be evaluated using boxplots. Summary 
1710 
statistics also will be displayed by treatment arm for each hour of the day. 
1711 
 
1712 
The co-primary analyses will also be performed after omitting the first 4 weeks of each of the 
1713 
crossover periods. 
1714 
 
1715 
 Analysis of the Secondary Endpoints 
1716 
Secondary CGM-measured glycemic metrics will be calculated in the same way as the co-
1717 
primary outcomes. 
1718 
 
1719 
Mean ± SD or percentiles appropriate to the distribution for above secondary outcomes will be 
1720 
reported by treatment period. For each secondary CGM metric, a repeated measures least squares 
1721 
regression model with an unstructured covariance structure will be fit to compare the two 
1722 
treatments by adjusting for period, pre-study 670G system use, and HbA1c at randomization as 
1723 
fixed effects. For those metrics which have highly skewed distribution, a ranked normal score 
1724 
transformation of outcome data will be applied in the regression model. 
1725 
 
1726 
For comparing changes in HbA1c and BMI over each treatment period, the least squares 
1727 
regression models will adjust for period, pre-study 670G system use, and HbA1c at 
1728 
randomization. The model for BMI will additionally adjust for baseline value, age, and sex.  
1729 
 
1730 
Monthly trends for selected secondary outcomes will be evaluated using boxplots. 
1731 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 65 OF 74 
 
 
1732 
 Safety Analyses 
1733 
All reportable adverse events will be tabulated by treatment group from the time of enrollment 
1734 
through the last study visit.  Events will be separately listed in detail and tabulated for the pre-
1735 
randomization period and each study period. Coding will use the Medical Dictionary for 
1736 
Regulatory Activities (MedDRA). 
1737 
 
1738 
In addition, the following will be tabulated by treatment arm: 
1739 
• 
Number of adverse events/ participants with at least one event 
1740 
o Number of events meeting definition of ADE 
1741 
• 
Number of serious adverse events/participants with at least one event 
1742 
o Number of SAEs meeting definition of UADE 
1743 
• 
Listing of hospitalizations and reasons for the hospitalization 
1744 
• 
Severe Hypoglycemic Events 
1745 
o Number of severe hypoglycemic events as defined in the protocol/number of 
1746 
participants with an event 
1747 
o Number of severe hypoglycemic events associated with seizure or loss of 
1748 
consciousness/number of participants with at least one event 
1749 
• 
Diabetic Ketoacidosis 
1750 
o Number of diabetic ketoacidosis events, as defined in the protocol/number of 
1751 
participants with an event 
1752 
 
1753 
If there are enough observed events to allow formal statistical modelling the following analyses 
1754 
will be conducted for severe hypoglycemia and diabetic ketoacidosis events outcomes. For binary 
1755 
variables, repeated measures logistic regression which adjust for period, pre-study 670G system 
1756 
use, HbA1c at randomization, and whether the participant experienced any events in the 12 months 
1757 
prior to enrollment as fixed effects will be used to compare treatment groups. For counts, such as 
1758 
the number of severe hypoglycemic or diabetic ketoacidosis events per participant, data will be 
1759 
compared using repeated measures Poisson regression with period, pre-study 670G system use,  
1760 
HbA1c at randomization, and whether the subject experienced any events in the 12 months prior 
1761 
to enrollment as fixed effects adjusted in the model. All participants will be included in these 
1762 
analyses. 
1763 
 
1764 
 Adherence and Retention Analyses 
1765 
Tabulations and figures by treatment period to assess protocol adherence will include: 
1766 
• Flowchart showing any dropouts prior to and post randomization and treatment arm 
1767 
completion  
1768 
• Visit completion rates for each follow up visit 
1769 
• Protocol deviations 
1770 
• Numbers and reasons for unscheduled visits and phone calls 
1771 
 
1772 
 Baseline Descriptive Statistics 
1773 
Baseline demographic and clinical characteristics will be tabulated by randomization group. 
1774 
 
1775 
 Planned Interim Analyses 
1776 
No formal interim analyses or stopping guidelines are planned for this study. 
1777 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 66 OF 74 
 
 
1778 
The DSMB will review data for safety per the DSMB Standard Operating Procedures 
1779 
approximately every six months. The data to be reviewed will include information regarding 
1780 
adverse events, device issues, and protocol adherence/deviations as they may relate to participant 
1781 
safety. 
1782 
 
1783 
 Sub-Group Analyses 
1784 
Exploratory subgroup analyses/assessments of effect modification (interaction) will be 
1785 
conducted for each of the two primary outcomes. Interpretation of the analyses will be made with 
1786 
caution, particularly in the absence of an overall difference. The general approach for these 
1787 
exploratory analyses will be to add an interaction term for the subgroup factor by treatment into 
1788 
the model used for the primary analysis. 
1789 
 
1790 
The following baseline factors will be assessed: 
1791 
• Age: as a continuous variable and in two age groups: 14-<21 and 21-<30 years old 
1792 
• Baseline HbA1c: as a continuous variable and in two groups: HbA1c ≤8.5% and ≥8.6% 
1793 
• Insulin method/CGM: 670G user, injection user with CGM, injection user without CGM, 
1794 
pump user with CGM, pump user without CGM 
1795 
• T1D duration as a continuous variable 
1796 
• Sex 
1797 
• Race/ethnicity 
1798 
• Random C-peptide level 
1799 
Beyond above assessment for interactions, the primary and secondary analyses also will also be 
1800 
conducted separately in the two age groups and the two HbA1c groups, in addition to the CGM 
1801 
metrics considered as safety outcomes. Analyses will only be replicated within these subgroups 
1802 
for efficacy outcomes where p-values are being computed.  
1803 
 
1804 
 Multiple Comparison/Multiplicity 
1805 
For the primary analyses, the intervention will be deemed effective only if the null hypotheses 
1806 
for both co-primary outcomes are rejected. The type 1 error is therefore not inflated and there 
1807 
will be no correction for multiple comparisons. 
1808 
 
1809 
For the secondary analyses, the false discovery rate will be controlled using the adaptive Two 
1810 
Stage Benjamini-Hochberg procedure with <0.05 as the threshold for statistical significance. 
1811 
 
1812 
 Additional Tabulations and Analyses 
1813 
  Device Issues and Tabulations 
1814 
All reported device issues will be tabulated regardless of whether they were associated with 
1815 
adverse events. 
1816 
 
1817 
Detailed tabulations will include frequency of use of the system, discontinuation rate, and reasons 
1818 
for discontinuation. 
1819 
 
1820 
The amount of auto mode system use and CGM use will be calculated over each treatment 
1821 
period. Similar repeated measures least squares regression models as described for the co-
1822 
primary outcomes will be used to compare the percentage of time of CGM use and auto mode 
1823 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 67 OF 74 
 
use between the two periods. Monthly values for auto mode use and CGM use also will be 
1824 
reported.  
1825 
 
1826 
 Analysis of Quality of Life Data 
1827 
Quality of life data collected during study assessments will be scored based on established 
1828 
procedures and descriptive statistics (e.g., mean, range) will be calculated for each questionnaire 
1829 
at each time point and across treatment groups. Similar models as described above for the 
1830 
primary analysis will be used to compare the questionnaire scores between the two treatments. 
1831 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 68 OF 74 
 
 Data Collection and Monitoring 
1832 
 
1833 
 Case Report Forms and Device Data 
1834 
The main study data are collected through a combination of electronic case report forms (eCRFs) 
1835 
and electronic device data files obtained from the study software and individual hardware 
1836 
components. These electronic device files and electronic CRFs from the study website are 
1837 
considered the primary source documentation. If paper source documentation is used to initially 
1838 
collect data, this will be considered the source. 
1839 
 
1840 
When data are directly collected in electronic case report forms, this will be considered the 
1841 
source data. Each participating site will maintain appropriate medical and research records 
1842 
for this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
1843 
protection of confidentiality of participants. 
1844 
 
1845 
 Study Records Retention 
1846 
Study documents should be retained for a minimum of two years after the last approval of a 
1847 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1848 
applications in an ICH region or until at least two years have elapsed since the formal 
1849 
discontinuation of clinical development of the investigational product. These documents should 
1850 
be retained for a longer period, however, if required by local regulations. No records will be 
1851 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
1852 
sponsor to inform the investigator when these documents no longer need to be retained. 
1853 
 
1854 
 Quality Assurance and Monitoring 
1855 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1856 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1857 
conducted and data are generated, documented and reported in compliance with the protocol, 
1858 
Good Clinical Practice (GCP) and the applicable regulatory requirements. Adverse events will be 
1859 
prioritized for monitoring. 
1860 
 
1861 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1862 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1863 
Investigations – A Risk-Based Approach to Monitoring” (August 2013). Study conduct and 
1864 
monitoring will conform to 21 Code of Federal Regulations (CFR) 812. 
1865 
 
1866 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1867 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1868 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1869 
verity and completeness of the key site data. Elements of the RBM may include: 
1870 
 
1871 
• Qualification assessment, training, and certification for sites and site personnel 
1872 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
1873 
procedures 
1874 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1875 
review of entered data and edits, statistical monitoring, study closeout 
1876 
• On-site monitoring (site visits): source data verification, site visit report 
1877 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 69 OF 74 
 
• Device accountability 
1878 
• Communications with site staff 
1879 
• Participant retention and visit completion 
1880 
• Quality control reports 
1881 
• Management of noncompliance 
1882 
• Documenting monitoring activities 
1883 
• Adverse event reporting and monitoring 
1884 
 
1885 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1886 
order to maintain current and personal knowledge of the study through review of the records, 
1887 
comparison with source documents, observation and discussion of the conduct and progress of 
1888 
the study. 
1889 
 
1890 
 Protocol Deviations 
1891 
A protocol deviation is any action that departs from the established policies and procedures, 
1892 
formal documents or processes, Good Clinical Practice, federal or state laws, or regulations 
1893 
applicable to the conduct of the research. 
1894 
 
1895 
A significant protocol deviation is any deviation that departs from the established materials in 
1896 
such a way that it poses an increase in the risk to the participant, adversely affects the welfare, 
1897 
rights, or safety of the research subjects, or negatively influences the scientific study integrity. 
1898 
  
1899 
Noncompliance with the clinical trial protocol, GCP, or procedure requirements may be either on 
1900 
the part of the participant, the investigator, or the study site staff. As a result of deviations, 
1901 
corrective actions may be developed by the site and implemented promptly. 
1902 
 
1903 
The site PI/study staff is responsible for knowing and adhering to their IRB/EC requirements for 
1904 
reporting. Further details about the handling of protocol deviations will be included in the 
1905 
monitoring plan. 
1906 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 70 OF 74 
 
 Ethics/Protection of Human Participants 
1907 
 
1908 
 Ethical Standard 
1909 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1910 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1911 
21 CFR Part 56, and/or the ICH E6. 
1912 
 
1913 
 Institutional Review Board (IRB) (or Ethics Committee (EC)) 
1914 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1915 
be submitted to the IRB/EC for review and approval. Approval of both the protocol and the 
1916 
consent form must be obtained before any participant is enrolled. Any amendment to the 
1917 
protocol will require review and approval by the IRB/EC before the changes are implemented to 
1918 
the study. All changes to the consent form will be IRB/EC approved; a determination will be 
1919 
made regarding whether previously consented participants need to be re-consented. 
1920 
 
1921 
 Informed Consent Process 
1922 
 Consent Procedures and Documentation 
1923 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1924 
the study and continues throughout the individual’s study participation. Extensive discussion of 
1925 
risks and possible benefits of participation will be provided to the participants and their families. 
1926 
Consent forms will be IRB/EC-approved and the participant will be asked to read and review the 
1927 
document. The investigator will explain the research study to the participant and answer any 
1928 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
1929 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1930 
research participants. Participants will have the opportunity to carefully review the written 
1931 
consent form and ask questions prior to signing. 
1932 
 
1933 
The participants should have the opportunity to discuss the study with their surrogates or think 
1934 
about it prior to agreeing to participate. The participant will sign the informed consent document 
1935 
prior to any procedures being done specifically for the study. The participants may withdraw 
1936 
consent at any time throughout the course of the trial. A copy of the informed consent document 
1937 
will be given to the participants for their records. The rights and welfare of the participants will 
1938 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1939 
affected if they decline to participate in this study. 
1940 
 
1941 
 Participant and Data Confidentiality 
1942 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1943 
and the Coordinating Center(s) and their agents. This confidentiality is extended to cover testing 
1944 
of biological samples in addition to the clinical information relating to participants. Therefore, 
1945 
the study protocol, documentation, data, and all other information generated will be held in strict 
1946 
confidence. No information concerning the study or the data will be released to any unauthorized 
1947 
third party without prior written approval of the Steering Committee. 
1948 
 
1949 
The study monitor, other authorized representatives of the Coordinating Center, representatives 
1950 
of the IRB/EC or device company supplying study product may inspect all documents and 
1951 
records required to be maintained by the investigator, including but not limited to, medical 
1952 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 71 OF 74 
 
records (office, clinic, or hospital) for the participants in this study. The clinical study site will 
1953 
permit access to such records. 
1954 
 
1955 
The study participant’s contact information will be securely stored at each clinical site for 
1956 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1957 
secure location for as long a period as dictated by local IRB and Institutional/national 
1958 
regulations. 
1959 
 
1960 
Study participant research data, which is for purposes of statistical analysis and scientific 
1961 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research (JCHR) in 
1962 
Tampa, FL, USA. This will not include the participant’s contact or identifying information. 
1963 
Rather, individual participants and their research data will be identified by a unique study 
1964 
identification number. The study data entry and study management systems used by clinical sites 
1965 
and by the JCHR research staff will be secured and password protected. At the end of the study, 
1966 
all study databases will be de-identified and archived at the JCHR in Tampa, FL. 
1967 
 
1968 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1969 
obtained from the NIH. This certificate protects identifiable research information from forced 
1970 
disclosure. It allows the investigator and others who have access to research records to refuse to 
1971 
disclose identifying information on research participation in any civil, criminal, administrative, 
1972 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
1973 
researchers and institutions from being compelled to disclose information that would identify 
1974 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1975 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1976 
 
1977 
 CareLink Clinical System 
1978 
The CareLink Clinical system uses standard Transport Layer Security (TLS) technology. TLS 
1979 
transmission invokes encryption on both ends of the transmissions and is the standard for all 
1980 
security-based systems. The encryption remains in effect whether the data are moving to and 
1981 
from the client and server in the United States, or to and from a client in another country to the 
1982 
United States. The data are secure behind a three-tier industry standard architecture, which 
1983 
places the database behind three different firewalls, where each firewall separates a tier: 
1984 
• The internet to the web server; 
1985 
• Web server to the application server; 
1986 
• Application server to the database server.
1987 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 72 OF 74 
 
 References 
1988 
 
1989 
1. 
Reichard P., B. Y. Nilsson, U. Rosenqvist. The effect of long-term intensified insulin 
1990 
treatment on the development of microvascular complications of diabetes mellitus. The New 
1991 
England journal of medicine. Jul 29 1993;329(5):304-309. 
1992 
2. 
Pickup J. C. Insulin-pump therapy for type 1 diabetes mellitus. The New England journal 
1993 
of medicine. Apr 26 2012;366(17):1616-1624. 
1994 
3. 
Phillip M., T. Danne, S. Shalitin, B. Buckingham, L. Laffel, W. Tamborlane, T. 
1995 
Battelino. Use of continuous glucose monitoring in children and adolescents (*). Pediatr 
1996 
Diabetes. May 2012;13(3):215-228. 
1997 
4. 
Bergenstal R. M., W. V. Tamborlane, A. Ahmann, J. B. Buse, G. Dailey, S. N. Davis, C. 
1998 
Joyce, T. Peoples, B. A. Perkins, J. B. Welsh, S. M. Willi, M. A. Wood. Effectiveness of sensor-
1999 
augmented insulin-pump therapy in type 1 diabetes. The New England journal of medicine. Jul 
2000 
22 2010;363(4):311-320. 
2001 
5. 
Beck R. W., W. V. Tamborlane, R. M. Bergenstal, K. M. Miller, S. N. DuBose, C. A. 
2002 
Hall. The T1D Exchange clinic registry. The Journal of clinical endocrinology and metabolism. 
2003 
Dec 2012;97(12):4383-4389. 
2004 
6. 
Mortensen H. B. Findings from the Hvidore Study Group on Childhood Diabetes: 
2005 
metabolic control and quality of life. Horm Res. 2002;57 Suppl 1:117-120. 
2006 
7. 
McKnight J. A., S. H. Wild, M. J. Lamb, M. N. Cooper, T. W. Jones, E. A. Davis, S. 
2007 
Hofer, M. Fritsch, E. Schober, J. Svensson, T. Almdal, R. Young, et al. Glycaemic control of 
2008 
Type 1 diabetes in clinical practice early in the 21st century: an international comparison. Diabet 
2009 
Med. Dec 15 2014. 
2010 
8. 
Bergenstal R. M., D. C. Klonoff, S. K. Garg, B. W. Bode, M. Meredith, R. H. Slover, A. 
2011 
J. Ahmann, J. B. Welsh, S. W. Lee, F. R. Kaufman. Threshold-based insulin-pump interruption 
2012 
for reduction of hypoglycemia. The New England journal of medicine. Jul 18 2013;369(3):224-
2013 
232. 
2014 
9. 
Burdick J., H. P. Chase, R. H. Slover, K. Knievel, L. Scrimgeour, A. K. Maniatis, G. J. 
2015 
Klingensmith. Missed insulin meal boluses and elevated hemoglobin A1c levels in children 
2016 
receiving insulin pump therapy. Pediatrics. Mar 2004;113(3 Pt 1):e221-224. 
2017 
10. 
Steil G. M., K. Rebrin, C. Darwin, F. Hariri, M. F. Saad. Feasibility of automating insulin 
2018 
delivery for the treatment of type 1 diabetes. Diabetes. Dec 2006;55(12):3344-3350. 
2019 
11. 
Doyle F. J., 3rd, L. M. Huyett, J. B. Lee, H. C. Zisser, E. Dassau. Closed-loop artificial 
2020 
pancreas systems: engineering the algorithms. Diabetes Care. 2014;37(5):1191-1197. 
2021 
12. 
Russell S. J., F. H. El-Khatib, M. Sinha, K. L. Magyar, K. McKeon, L. G. Goergen, C. 
2022 
Balliro, M. A. Hillard, D. M. Nathan, E. R. Damiano. Outpatient glycemic control with a bionic 
2023 
pancreas in type 1 diabetes. The New England journal of medicine. Jul 24 2014;371(4):313-325. 
2024 
13. 
Thabit H., A. Lubina-Solomon, M. Stadler, L. Leelarathna, E. Walkinshaw, A. Pernet, J. 
2025 
M. Allen, A. Iqbal, P. Choudhary, K. Kumareswaran, M. Nodale, C. Nisbet, et al. Home use of 
2026 
closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-
2027 
week, multicentre, randomised crossover study. The lancet. Diabetes & endocrinology. Sep 
2028 
2014;2(9):701-709. 
2029 
14. 
Atlas E., R. Nimri, S. Miller, E. A. Grunberg, M. Phillip. MD-logic artificial pancreas 
2030 
system: a pilot study in adults with type 1 diabetes. Diabetes Care. May 2010;33(5):1072-1076. 
2031 
15. 
Miller S., R. Nimri, E. Atlas, E. A. Grunberg, M. Phillip. Automatic learning algorithm 
2032 
for the MD-logic artificial pancreas system. Diabetes Technol Ther. Oct 2011;13(10):983-990. 
2033 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 73 OF 74 
 
16. 
Nimri R., I. Muller, E. Atlas, S. Miller, O. Kordonouri, N. Bratina, C. Tsioli, M. A. 
2034 
Stefanija, T. Danne, T. Battelino, M. Phillip. Night glucose control with MD-Logic artificial 
2035 
pancreas in home setting: a single blind, randomized crossover trial-interim analysis. Pediatr 
2036 
Diabetes. Mar 2014;15(2):91-99. 
2037 
17. 
Nimri R. The DREAM CONSORTIUM: Integration of the MD-Logic into daily 
2038 
management of diabetes. Paris, France: 8th Advanced Technologies and Treatments for 
2039 
Diabetes; 2015. 
2040 
18. 
Nathan D. M., M. Bayless, P. Cleary, S. Genuth, R. Gubitosi-Klug, J. M. Lachin, G. 
2041 
Lorenzi, B. Zinman. Diabetes control and complications trial/epidemiology of diabetes 
2042 
interventions and complications study at 30 years: advances and contributions. Diabetes. Dec 
2043 
2013;62(12):3976-3986. 
2044 
19. 
Kovatchev B. P., M. Breton, C. D. Man, C. Cobelli. In silico preclinical trials: a proof of 
2045 
concept in closed-loop control of type 1 diabetes. J Diabetes Sci Technol. Jan 2009;3(1):44-55. 
2046 
20. 
Atlas E., R. Nimri, S. Miller, E. A. Grunberg, M. Phillip. MD-logic artificial pancreas 
2047 
system: a pilot study in adults with type 1 diabetes. Diabetes Care. May 2010;33(5):1072-1076. 
2048 
21. 
Nimri R., E. Atlas, M. Ajzensztejn, S. Miller, T. Oron, M. Phillip. Feasibility study of 
2049 
automated overnight closed-loop glucose control under MD-logic artificial pancreas in patients 
2050 
with type 1 diabetes: the DREAM Project. Diabetes Technol Ther. Aug 2012;14(8):728-735. 
2051 
22. 
Nimri R., T. Danne, O. Kordonouri, E. Atlas, N. Bratina, T. Biester, M. Avbelj, S. Miller, 
2052 
I. Muller, M. Phillip, T. Battelino. The "Glucositter" overnight automated closed loop system for 
2053 
type 1 diabetes: a randomized crossover trial. Pediatr Diabetes. May 2013;14(3):159-167. 
2054 
23. 
Phillip M., T. Battelino, E. Atlas, O. Kordonouri, N. Bratina, S. Miller, T. Biester, M. A. 
2055 
Stefanija, I. Muller, R. Nimri, T. Danne. Nocturnal glucose control with an artificial pancreas at 
2056 
a diabetes camp. The New England journal of medicine. Feb 28 2013;368(9):824-833. 
2057 
24. 
Ziegler C., R. Nimri, I. Muller, S. Klemencic, N. Bratina, S. Blasig, K. Remus, M. 
2058 
Phillip, T. Battelino, O. Kordonouri, T. Danne, K. Lange. Reduced worries of hypoglycaemia, 
2059 
high satisfaction and increased perceived ease of use after experiencing four nights of MD-Logic 
2060 
artificial pancreas at home (DREAM 4). Journal of Diabetes Research. In Press 2015. 
2061 
25. 
Nimri R., I. Muller, E. Atlas, S. Miller, A. Fogel, N. Bratina, O. Kordonouri, T. Battelino, 
2062 
T. Danne, M. Phillip. MD-Logic overnight control for 6 weeks of home use in patients with type 
2063 
1 diabetes: randomized crossover trial. Diabetes Care. Nov 2014;37(11):3025-3032. 
2064 
26. 
Weinzimer S. A., G. M. Steil, K. L. Swan, J. Dziura, N. Kurtz, W. V. Tamborlane. Fully 
2065 
automated closed-loop insulin delivery versus semiautomated hybrid control in pediatric patients 
2066 
with type 1 diabetes using an artificial pancreas. Diabetes Care. May 2008;31(5):934-939. 
2067 
27. 
Buckingham B. A., R. W. Beck, K. J. Ruedy, P. Cheng, C. Kollman, S. A. Weinzimer, L. 
2068 
A. DiMeglio, A. A. Bremer, R. Slover, M. Cantwell. The effects of inpatient hybrid closed-loop 
2069 
therapy initiated within 1 week of type 1 diabetes diagnosis. Diabetes Technol Ther. May 
2070 
2013;15(5):401-408. 
2071 
28. 
O'Grady M. J., A. J. Retterath, D. B. Keenan, N. Kurtz, M. Cantwell, G. Spital, M. N. 
2072 
Kremliovsky, A. Roy, E. A. Davis, T. W. Jones, T. T. Ly. The use of an automated, portable 
2073 
glucose control system for overnight glucose control in adolescents and young adults with type 1 
2074 
diabetes. Diabetes Care. Nov 2012;35(11):2182-2187. 
2075 
29. 
de Bock M. I., A. Roy, M. N. Cooper, J. A. Dart, C. L. Berthold, A. J. Retterath, K. E. 
2076 
Freeman, B. Grosman, N. Kurtz, F. Kaufman, T. W. Jones, E. A. Davis. Feasibility of Outpatient 
2077 
24-Hour Closed-Loop Insulin Delivery. Diabetes Care. Nov 2015;38(11):e186-187. 
2078 

 
FLAIR CLINICAL TRIAL PROTOCOL V7.1 2020-03-17_CLEAN 
PAGE 74 OF 74 
 
30. 
Buckingham B., R. W. Beck, K. J. Ruedy, P. Cheng, C. Kollman, S. A. Weinzimer, L. A. 
2079 
DiMeglio, A. A. Bremer, R. Slover, W. V. Tamborlane. Effectiveness of early intensive therapy 
2080 
on beta-cell preservation in type 1 diabetes. Diabetes Care. Dec 2013;36(12):4030-4035. 
2081 
31. 
Grosman B., J. Ilany, A. Roy, N. Kurtz, D. Wu, N. Parikh, G. Voskanyan, N. Konvalina, 
2082 
C. Mylonas, R. Gottlieb, F. Kaufman, O. Cohen. Hybrid Closed-Loop Insulin Delivery in Type 1 
2083 
Diabetes During Supervised Outpatient Conditions. J Diabetes Sci Technol. Feb 15 2016. 
2084 
32. 
Ly T. T., A. Roy, B. Grosman, J. Shin, A. Campbell, S. Monirabbasi, B. Liang, R. von 
2085 
Eyben, S. Shanmugham, P. Clinton, B. A. Buckingham. Day and Night Closed-Loop Control 
2086 
Using the Integrated Medtronic Hybrid Closed-Loop System in Type 1 Diabetes at Diabetes 
2087 
Camp. Diabetes Care. Jul 2015;38(7):1205-1211. 
2088 
33. 
Garg SK, Weinzimer SA, Tamborlance WV, et al. Glucose outcomes in the in-home use 
2089 
of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes. 
2090 
Diabetes Technol Ther. 19(3):155-163; 2017; doi:10.1089/dia.2016.0421. 
2091 
34. 
Bergenstal RM, Garg S, Weinzimer SA, Buckingham BA, Bode BW, Tamborlane WV, 
2092 
Kaufman FR. Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 
2093 
Diabetes. JAMA. 2016;316(13):1407–1408. doi:10.1001/jama.2016.11708. 
2094 
35. 
Premarket Approval (PMA).” U S Food and Drug Administration Home Page, 28 Sept. 
2095 
2016, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P160017.  
2096 
36. 
Beck RW, Riddlesworth T, Ruedy K, Ahmann A, Bergenstal R, Haller S, Kollman C, 
2097 
Kruger D, McGill JB, Polonsky W, Toschi E, Wolpert H, Price D. Effect of continuous glucose 
2098 
monitoring on glycemic control in adults with type 1 diabetes using insulin injections: The 
2099 
DIAMOND randomized clinical trial. JAMA 2017;317(4):371-8. 
2100 
37. 
The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study 
2101 
Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 
2102 
2008;359(14):1464-1476. 
2103 
38. 
The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study 
2104 
Group. The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes 
2105 
Care. 2009;32(8):1378-1383. 
2106 
39. 
Aleppo G, Ruedy KJ, Riddlesworth TD, et al. REPLACE-BG: A randomized trial 
2107 
comparing continuous glucose monitoring with and without routine blood glucose monitoring in 
2108 
well-controlled adults with type 1 diabetes. Diabetes Care 2017; 40(4):538-45. 
2109 
 
2110 
 
2111