SGLT2 Inhibitor Adjunctive Therapy to Closed Loop Control in Type 1 Diabetes Mellitus
Phase: PHASE1
Conditions: Type 1 Diabetes
Sponsor: Ananda Basu, MD

UVA CENTER FOR DIABETES TECHNOLOGY 
SGLT2 Inhibitor Adjunctive Therapy to 
Closed Loop Control in Type 1 Diabetes 
Mellitus 
Protocol Chair 
Ananda Basu, MD FRCP 
University of Virginia 
Center for Diabetes Technology 
Version Number: v1.8 
19-Apr-2021
NCT04201496

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KEY ROLES 
 
Protocol Principal Investigator 
 
Name, degree 
Ananda Basu, MD 
Institution Name 
University of Virginia Center for Diabetes Technology  
 
 

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PROTOCOL VERSION HISTORY 
Version 
Number 
Author(s) 
Approver 
Effective Date 
Revision Description 
1.0 
 
 
 
Original Protocol 
1.1 
Mary Oliveri 
Mary Oliveri 
24-Oct-2019 
FDA Review: 
• Modified Figure 1:  Study Diagram to 
include extra check in visit post CiQ 
training 
• Added to Inclusion Criteria (section 4.4): 
insulin pump use for six months 
• Modified Exclusion Criteria (section 4.5): 
eGFR lab value from below 45 to below 
60 mL/min/1.73 m2 
• Added to Ketoacidosis Management 
(section 6.3): ketone measurement will 
be obtained any symptoms, change of 
conditions, and as described in Glycemic 
Treatment Guidelines 
• Added to Empagliflozin Treatment 
Group (section 9.1.1): Participant will 
meet the following criteria to continue 
study participation after the completion 
of the Run-In phase during the Main 
Study:  
o 
Adherence to study protocol 
o 
Ketone testing at least 2 times 
daily, preferably 4 times, with 
monitored values not greater than 
0.6/mmol on at least two 
successive occasions 
o 
No adverse events relating to 
perineal infections, symptomatic 
postural hypotension, no evidence 
of significant hypoglycemia (< 54 
mg/dl) or any other listed adverse 
effects of medication.  
• Added to Check In visits (section 9.4): 
Two visits will occur after the Control-IQ 
Training Visit. 
• Added to Ketoacidosis Management 
(section 10.5): If ketones > 0.6 mmol/L, 
participants will be advised to stop the 
drug and then recheck ketones in 3-4 
hours. Participants may restart the use 

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of Empagliflozin after the ketone 
measurement if <0.6 mmol/L. All ketosis 
events should be recorded and 
evaluated in participants who are taking 
the study drug.  
• Added to Empagliflozin Adverse 
Reactions (section 12.2.1): Participates 
will also be advised that a majority of 
infections can be prevented by 
maintaining attention to basic hygiene 
include regular washing after urination. 
• Added to Stopping Rules (section 
13.9.2):  In the event that two subjects 
experience urosepsis, AKI, fournier’s 
gangrene, severe genital mycotic 
infections and hypotension requiring 
hospitalization, the study will be paused 
to discuss events with the DSMB. 
1.2 
Mary Oliveri 
Mary Oliveri 
27-Oct-2019 
FDA Review: 
• Added sentence for clarification 
(Chapter 6): Participants will download 
the study equipment approximately one 
time per week or as frequently as 
needed.  
• Added sentence for clarification (section 
9.5): Participants will be instructed to 
download the study devices (i.e. insulin 
pumps, CGM, ketone meters, activity 
tracker, etc…) each week, or as needed, 
to secure data collection, except the 
ketone meter which will assess ketosis 
events). 
• Added to Ketoacidosis Management 
(section 10.5): Experimental participants 
will be advised to check ketones if 
symptoms consistent with ketoacidosis 
occur even if blood glucose is not 
elevated. 
Added to Adverse Event (section 13.1.1): 
now includes study drug in definition. 
Modified sentence (section 13.2.2): Ketosis 
as defined by symptoms and ketones 
regardless of treatment provided in a 
health care facility. 
Modified participants’ stopping rules 
(section 13.9.1):  

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o 
Two distinct episodes of DKA that 
are not attributable to the study 
drug 
o 
One distinct episode of DKA 
directly attributable to the study 
drug  
1.3 
Mary Oliveri 
Mary Oliveri 
30-Oct-2019 
FDA Review: 
• Inserted that study drug is not approved 
for use in T1DM patients (section 1.2).  
• Inserted User Manual language 
regarding the pumps response to 
missing CGM data (section 9.6). 
1.4 
Mary Oliveri 
Mary Oliveri 
01-Nov-2019 
IRB Pre Review Comments from 04-Oct-
2019.  
• Added that Equipment training in the 
Pilot Study is intended to begin 
immediately after screening eligibility 
has been met (section Chapter 6). 
• Clarified sentence to read that staff & 
participants will be at the hotel 
admission (section 7.1). 
1.5 
Laura Kollar 
Mary Oliveri 
24-Mar-2020 
Study Team Modifications:  
• DSMB reduced Empagliflozin from 10 
mg/daily to 5 mg/daily post-pilot study 
review. 
• Empagliflozin dosage instructions 
(section 3.3). 
• The study physician will determined 
screening test(s) needed for pilot 
participants to proceed to the Main 
Study. (section 4.1). 
• Corrections to the Glycemic Treatment 
Guidelines (section 7.5). 
• Virtual study visits may take the place of 
in-person study visits (Chapter 9). 
• Participants will be asked to record two 
days of baseline ketone values before 
initiating the use of the study drug 
(section 9.1.1). 
• 
Ketone meters will no longer be 
downloaded each week (section 
9.5). 

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• 
Study participants will log daily 
ketone values in an online 
resource for ongoing assessment 
purposes (section 9.5). 
• 
Blood glucose check in section 
10.3 conflicts with section 7.4. 
• 
Clarified that Pregnancy will not 
be considered an adverse event 
(section 13.1.1). 
• 
A Data and Safety Monitoring 
Board (DSMB) will review 
compiled safety data after the 
completion of 10 Main Study 
participants. As a safety measure, 
the Board will review if the rate of 
mild ketosis greater than 40% (B-
OH-B level > 0.6 mmol), 20% 
significant ketosis (B-OH-B > 1.5 
mmol) and more than 5% DKA (B-
OH-B > 3 mmol) to be considered 
significant to stop the study 
(section 8.3). 
• 
Other miscellaneous corrections 
throughout document.  
1.6 
Mary Oliveri 
Ralf Nass; Laura 
Kollar 
06-Apr-2020 
Response to FDA questions 03-Apr-2020: 
• 
Clarified the Pilot participants lab 
work needed to proceed into Main 
Study: Pilot participants may 
enroll the Main Study. The study 
physician may request repeat 
laboratory values if values are 
greater than 6 weeks from Pilot 
screening laboratory values. A 
current urine/blood pregnancy 
test will be required prior to 
enrolling into the Main Study 
(section 4.1).  
• 
Added for clarification: Main Study 
participants who did not 
participate in the Pilot Study may 
use historical lab results that are 
dated within 2 weeks of the 
screening appointment (section 
4.6).  
• 
The study physician has the 
discretion to exclude a study 
participant if concerned about 

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their safety in this trial (section 
4.6). 
1.7 
Mary Oliveri  
 
10-Apr-2020 
Response to FDA questions 07-Apr-2020: 
• 
Added: Empagliflozin is available 
only in 10 mg and 25 mg film 
coated unscored tablets. For this 
study, the participants will be 
provided 10 mg tablets and a pill 
splitter. They will be instructed to 
split only 1 tablet at a time and 
take each half tablet (5mg each) 
on subsequent days. Participants 
will be cautioned against spitting 
more than one tablet at a time 
(section 3.3).  
• 
A Data and Safety Monitoring 
Board (DSMB) will review 
compiled safety data after 10 
participants complete 4 weeks of 
the Main Study. Absence of 
serious adverse events related to 
Empaglifozin, the participants will 
continue with study participation 
pending DSMB review (section 
8.3).  
• 
Added: The study team will 
download the ketone meter 
whenever the study subject 
attends an in-clinic visit (section 
9.5). 
1.8 
Mary Oliveri  
 
19-Apr-2021 
Study Team Modifications:  
• 
Remove exclusion criteria of 
’Having a family member(s) 
employed by Tandem Diabetes 
Care, Inc. or having a direct 
supervisor at place of employment 
who is also directly involved in 
conducting the clinical trial (as a 
study investigator, coordinator, 
etc.); or having a first-degree 
relative who is directly involved in 
conducting the clinical trial 
 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
 
Protocol Title:  SGLT2 Inhibitor Adjunctive Therapy to Closed Loop Control in Type 1 Diabetes 
Mellitus 
Protocol Version: v1.8 
Protocol Date:  19-Apr-2021 
I have read the protocol specified above.  In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision.  It 
is understood that all information pertaining to the study will be held strictly confidential and 
that this confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as required 
by the following: United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training.  Further, 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
Investigator’s Signature __________________________________Date: _____ / _____ / _____ 
Investigator’s Name: ________________________________ 
Site Name:  University of Virginia 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADRR 
Average Daily Risk Range 
AP 
Artificial Pancreas 
BiQ 
Tandem t:slim X2 Insulin Pump with Basal-IQ Technology 
BG 
Blood Glucose 
BT/BTLE 
Bluetooth, Bluetooth low energy 
CGM 
Continuous Glucose Monitoring 
CLC 
Closed-Loop Control 
CiQ 
Tandem t:slim X2 Insulin Pump with Control-IQ Technology 
CSII 
Continuous Subcutaneous Insulin Injection 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data Safety Monitoring Board 
EMPA 
Empagliflozin 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBGI 
High Blood Glucose Index  
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
JDRF 
Juvenile Diabetes Research Foundation 
LBGI 
Low Blood Glucose Index  
NIH 
National Institutes of Health 
POC 
Point-of-Care 
SAP 
Sensor-Augmented Insulin Pump  
SGLT2 
Sodium-Glucose Cotransporter 2 
SGLT2-i 
Sodium-Glucose Cotransporter 2-inhibitor 
QC 
Quality Control 
UI 
User Interface 
 
 

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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
SGLT2 Inhibitor Adjunctive Therapy to Closed Loop Control in T1D 
Investigational Device 
Tandem Control-IQ with G6 Continuous Glucose Monitor (CiQ) 
Investigational Medication 
Empagliflozin 5 mg daily 
Objectives 
To evaluate the safety and efficacy of combining SGLT2 inhibitors with closed loop control 
Study Design 
The study is a randomized control trial where approximately 60 participants will be in the trial for 
approximately 10 weeks. A Pilot Study with approximately five (5) participants will use the Basal-IQ insulin 
therapy + Empagliflozin 10 mg daily. These participants will participate in an estimated 36-48 hour hotel 
admission to initiate use of Closed Loop Control (CLC) with the Tandem t:slim X2 with Control-IQ 
Technology (CiQ) with Empagliflozin (CiQ-EMPA). The safety data from the hotel admission will be 
presented to the DSMB for review. Upon DSMB approval, up to 40 participants will be randomized 1:1 to 
(a) CiQ x 4 weeks with or without Empagliflozin 5 mg daily (CiQ-EMPA vs. CiQ-NO EMPA) then Basal-IQ x 
2 weeks with or without Empagliflozin 5 mg daily (BiQ-EMPA vs. BiQ-NO EMPA) or (b) Basal-IQ x 2 weeks 
with or without Empagliflozin (BiQ-EMPA vs. BiQ-NO EMPA) then CiQ x 4 weeks with or without 
Empagliflozin (CiQ-EMPA vs. CiQ-NO EMPA)   
Number of Sites 
1 
Endpoint 
To demonstrate the efficacy of Empagliflozin as adjuvant therapy with Basal-IQ therapy vs a closed loop 
artificial pancreas system (CiQ-EMPA) in patients with T1DM. The primary efficacy outcome variable will 
be time in range (70-180 mg/dl). 
Population 
Key Inclusion Criteria 
• 
Age 18-65 
• 
Diagnosis of Type 1 Diabetes 
Key Exclusion Criteria  
• 
Hemoglobin A1c > 9% 
Sample Size  
• 
 Enrollment for the Pilot Study will proceed with the goal of completing approximately 5 participants 
in the trial. 
• 
Enrollment for the Main Study will proceed with the goal of completing approximately 40 subjects, 10 
subjects in each group. 
Treatment Groups 
With Empagliflozin 5 mg daily: 
• 
CiQ x 4 weeks (CiQ-EMPA) then Basal-IQ x 2 weeks (BiQ-EMPA) 
• 
Basal-IQ x 2 weeks (BiQ-EMPA) then CiQ x 4 weeks (CiQ-EMPA) 
Without Empagliflozin:  
• 
CiQ x 4 weeks (CiQ-NO EMPA) then Basal-IQ x 2 weeks (BiQ-NO EMPA) 
• 
Basal-IQ x 2 weeks (BiQ-NO EMPA) then CiQ x 4 weeks (CiQ-NO EMPA) 
Participant Duration 
Approximately 10 weeks  
Protocol Overview/Synopsis 
Up to five participants will participate in a Pilot Study. These participants will wear the Basal-IQ insulin 
pump, continuous glucose monitor, and take one tab daily of Empagliflozin 10 mg for about 2-3 weeks at 
home. They will then participate in a 36-48 hour hotel admission to begin the use of Control-IQ System 
with Empagliflozin. After DSMB review of safety data, up to 40 participants will be enrolled to begin the 
Main Study where, in a crossover design, participants will use the Control-IQ for 4 weeks and then Basal-
IQ for 2 weeks, with the drug given at the dosage of 5mg per day or without drug.   

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STUDY VISITS AND PROCEDURES SCHEDULE 
 
 
Screening 
Hotel 
Admission 
Randomization 
& Equipment 
Training 
Control-IQ 
Use 
Equipment 
Training 
Basal-IQ 
Use 
Equipment 
Training 
Follow-Up 
Location 
Clinic/Virtual 
about 36-
48 hours 
Clinic/Virtual 
Home x 4 
weeks 
Clinic/Virtual 
Home x 2 
weeks 
Clinic/Virtual 
Home 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
HbA1c  
X 
 
 
 
 
 
 
 
Blood Testing: TSH, CMP (additional 
labs as necessary) 
X 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
Vital Signs (including height/weight) 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Questionnaires  
 
 
X 
Post Use 
 
Post Use 
 
X 
Review diabetes management and 
AEs 
X 
X 
 
X 
 
X 
 
X 

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Table of Contents 
1 
Chapter 1:  Background ....................................................................................................... 17 
2 
1.1 Introduction ........................................................................................................................ 17 
3 
1.2 Empagliflozin (SGLT-2 inhibitor) in TID ............................................................................... 17 
4 
1.3 Artificial Pancreas with Empagliflozin (SGLT2-i) use in T1D ............................................... 18 
5 
1.4 Basal-IQ with Empagliflozin use in T1D............................................................................... 19 
6 
1.5 Study Objective ................................................................................................................... 19 
7 
1.6 Study Design........................................................................................................................ 19 
8 
1.7 Purpose/Objectives of Clinical Study .................................................................................. 22 
9 
1.8 Primary Specific Aim ........................................................................................................... 22 
10 
1.9 Secondary Specific Aim ....................................................................................................... 22 
11 
Chapter 2 Study Devices ...................................................................................................... 23 
12 
2.1 Insulin Pump ....................................................................................................................... 23 
13 
2.2 Continuous Glucose Monitor .............................................................................................. 23 
14 
2.3 Blood Glucose Meter and Strips ......................................................................................... 23 
15 
2.4 Ketone Meter and Strips ..................................................................................................... 23 
16 
2.5 Study Devices Accountability Procedures........................................................................... 23 
17 
2.6 Activity Tracker ................................................................................................................... 23 
18 
Chapter 3 Study Medications ............................................................................................... 24 
19 
3.1 Insulin .................................................................................................................................. 24 
20 
3.2 Empagliflozin – SGLT2-Inbitor ............................................................................................. 24 
21 
3.3 Dosage ................................................................................................................................. 24 
22 
3.4 Drug Accountability and Storage ........................................................................................ 24 
23 
3.5 Documentation ................................................................................................................... 24 
24 
3.6 Storage ................................................................................................................................ 25 
25 
3.7 Compliance and Reconciliation ........................................................................................... 25 
26 
Chapter 4 Study Screening ................................................................................................... 26 
27 

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4.1 Participant Recruitment and Enrollment ............................................................................ 26 
28 
4.2 Informed Consent and Authorization Procedures .............................................................. 26 
29 
4.3 Screening Procedures ......................................................................................................... 26 
30 
4.4 Participant Inclusion Criteria............................................................................................... 27 
31 
4.5 Participant Exclusion Criteria .............................................................................................. 27 
32 
4.6 Eligibility Screening Procedures .......................................................................................... 29 
33 
Chapter 5 Randomization Visit ............................................................................................. 31 
34 
5.1 Pilot Participants ................................................................................................................. 31 
35 
5.2 Main Study Participants ...................................................................................................... 31 
36 
Chapter 6 Study Equipment Training .................................................................................... 32 
37 
6.1 CGM Training ...................................................................................................................... 32 
38 
6.2 Blood Glucose Training ....................................................................................................... 33 
39 
6.3 Blood Ketone Training......................................................................................................... 33 
40 
6.4 Activity Tracker ................................................................................................................... 33 
41 
6.5 Insulin Pump Training ......................................................................................................... 33 
42 
Chapter 7 Pilot Study ........................................................................................................... 36 
43 
7.1 Run-In Phase ....................................................................................................................... 36 
44 
7.2 Qualifications and Role of the Staff .................................................................................... 36 
45 
7.3 Pre-Admission Check-In Visit .............................................................................................. 36 
46 
7.4 Admission Check-In ............................................................................................................. 36 
47 
7.5 Hotel Admission Glycemic Treatment Guidelines .............................................................. 37 
48 
7.6 Study Meals ......................................................................................................................... 38 
49 
7.7 Admission Activities ............................................................................................................ 38 
50 
7.8 Admission Discharge ........................................................................................................... 38 
51 
7.9 Post Admission Check-In Visit ............................................................................................. 38 
52 
Chapter 8 DSMB Review ...................................................................................................... 39 
53 
8.1 DSMB Pilot Study Safety Data Review ................................................................................ 39 
54 

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8.2 DSMB Decisions .................................................................................................................. 39 
55 
8.3 DSMB Main Study Safety Data Review ............................................................................... 39 
56 
Chapter 9 Main Study .......................................................................................................... 40 
57 
9.1 Empagliflozin Treatment Group .......................................................................................... 40 
58 
9.2 Insulin Pump Training Visit ................................................................................................. 40 
59 
9.3 Optimization of Insulin Pump Settings ............................................................................... 40 
60 
9.4 Check-In Visits ..................................................................................................................... 41 
61 
9.5 Study Device Download ...................................................................................................... 41 
62 
9.6 Study System Issues ............................................................................................................ 41 
63 
9.7 Repeating Visits & Unscheduled Visits ............................................................................... 42 
64 
9.8 Equipment Training/Initiation ............................................................................................ 42 
65 
9.9 Study Conclusion Visit ......................................................................................................... 42 
66 
9.10 Post-Study Check-In Visit .................................................................................................. 42 
67 
Chapter 10 Glycemic Treatment Guidelines.......................................................................... 43 
68 
10.1 Hypoglycemia Threshold Alert and Safety Protocol ......................................................... 43 
69 
10.2 Hyperglycemia Threshold Alert and Safety Protocol ........................................................ 43 
70 
10.3 Empagliflozin Randomized Participants............................................................................ 43 
71 
10.4 No Empagliflozin Randomized Participants ...................................................................... 44 
72 
10.5 Ketoacidosis Management ............................................................................................... 44 
73 
Chapter 11 Testing Procedures ............................................................................................ 46 
74 
11.1 Laboratory / Point of Care Testing .................................................................................... 46 
75 
11.2 Questionnaires .................................................................................................................. 46 
76 
Chapter 12 Risks Associated with Clinical Trial ..................................................................... 49 
77 
12.1 Potential Risks and Benefits of the Investigational Device ............................................... 49 
78 
12.2 Potential Risks and Benefits of the Medication ................................................................ 52 
79 
12.3 General Considerations..................................................................................................... 53 
80 
Chapter 13 Adverse Events, Device Issues, and Stopping Rules ............................................. 54 
81 

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13.1 Definitions ......................................................................................................................... 54 
82 
13.2 Reportable Events ............................................................................................................. 55 
83 
13.3 Relationship of Adverse Event to Study Device ................................................................ 56 
84 
13.4 Intensity of Adverse Event ................................................................................................ 57 
85 
13.5 Coding of Adverse Events ................................................................................................. 57 
86 
13.6 Outcome of Adverse Events ............................................................................................. 57 
87 
13.7 Reportable Device Issues .................................................................................................. 58 
88 
13.8 Timing of Event Reporting ................................................................................................ 58 
89 
13.9 Stopping Criteria ............................................................................................................... 59 
90 
13.10 Independent Safety Oversight ........................................................................................ 60 
91 
Chapter 14 Miscellaneous Considerations ............................................................................ 61 
92 
14.1 Prohibited Medications, Treatments, and Procedures .................................................... 61 
93 
14.2 Participant Withdrawal ..................................................................................................... 61 
94 
14.3 Confidentiality ................................................................................................................... 61 
95 
Chapter 15 Statistical Consideration .................................................................................... 62 
96 
15.1 Design and Randomization ............................................................................................... 62 
97 
15.2 Sample Size ....................................................................................................................... 64 
98 
15.3 Outcome Measures ........................................................................................................... 65 
99 
15.4 Safety Analyses ................................................................................................................. 66 
100 
15.5 Baseline Descriptive Statistics ........................................................................................... 66 
101 
15.6 Device Issues ..................................................................................................................... 66 
102 
Chapter 16 Data Collection and Monitoring ......................................................................... 68 
103 
16.1 Case Report Forms and Device Data ................................................................................. 68 
104 
16.2 Study Records Retention .................................................................................................. 68 
105 
16.3 Protocol Deviations ........................................................................................................... 68 
106 
Chapter 17 Ethics/Protection of Human Participants ............................................................ 69 
107 
17.1 Ethics Standard ................................................................................................................. 69 
108 

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17.2 Institutional Review Boards .............................................................................................. 69 
109 
17.3 Informed Consent Process ................................................................................................ 69 
110 
Chapter 18 References ......................................................................................................... 71 
111 
 
112 
 
 
113 

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Chapter 1:  Background 
114 
 
115 
Current automated insulin delivery device systems providing dynamic insulin infusion, while 
116 
improving prandial glucose control compared to conventional open loop therapies, have been 
117 
unable to normalize prandial glucose control in T1DM. Strategies that have been 
118 
used/considered in AP systems to improve prandial control include a) hybrid system that requires 
119 
the patient to announce meals by entering the carbohydrate content; b) system with meal 
120 
announcement that is partially or completely independent of meal carbohydrate content, and c) 
121 
fully automated system with no meal announcement. Notably, a fully automated CLC system 
122 
would lower the significant patient burden linked to prandial glucose control. Postprandial 
123 
glucose control is a key determinant of HbA1c, the clinical gold standard for optimal glucose 
124 
control. While meal carbohydrate content is the major factor for prandial glucose excursions, 
125 
precise determination of meal carbohydrate content (that is associated with better glycemic 
126 
control and lower glucose variability) during free living remains a significant challenge for the 
127 
patients with an average error in carbohydrate counting of ~20% with most patients 
128 
underestimating their carbohydrate content hence leading to increased prevalence of prandial 
129 
hyperglycemia.  
130 
Clinical trials with fully automated AP systems have mostly been in small number of patients and 
131 
in the in-patient settings for short durations [1, 2]. These trials have demonstrated significant 
132 
postprandial hyperglycemia with a risk for late postprandial hypoglycemia. The availability of 
133 
newer antidiabetic drugs provide the opportunity to test these medications as adjuvants 
134 
together with conventional or CLC algorithms, to determine the effects, if any, of combination 
135 
therapy, for improvements in postprandial and overall glucose control in individuals with T1DM. 
136 
The adjuvants that have been tried in very short-term inpatient trials include pramlintide (amylin 
137 
analogue that delays gastric emptying and lowers postprandial glucagon concentrations) [3-5] 
138 
and Glucagon-like-peptide 1 receptor analogues (delays gastric emptying and lowers 
139 
postprandial glucagon concentrations) and GLP-1 receptor agonists [6]. These studies have 
140 
demonstrated modest improvements in CGM parameters (time in range and glucose variability) 
141 
without increasing hypoglycemia in T1DM subjects.  
142 
 
143 
Inhibitors of sodium-glucose cotransporter-2 have been approved for use in type 2 diabetes 
144 
where large clinical trials have demonstrated clinically significant improvements in glucose 
145 
control (viz., HbA1c) and cardiovascular events [7]. While not FDA approved for use in adults with 
146 
Type 1 diabetes subjects, these drugs have also been tested in randomized controlled clinical 
147 
trials in these patients to evaluate their safety and efficacy. The EASE program [8] included two 
148 

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double-blind, placebo-controlled phase 3 trials in > 1700 patients with T1DM. These trials tested 
149 
2.5 mg, 10 mg and 25 mg tablets vs. placebo over 26-52 weeks. The results showed that 
150 
Empagliflozin lowered HbA1c, lowered total daily dose of insulin (by 10-13%) while increasing 
151 
time in range (by up to 12%) without any increase in the frequency or severity of hypoglycemia. 
152 
Simultaneously, there were improvements in body weight (by up to 3.5 Kg), blood pressure and 
153 
glucose variability.  
154 
However, adverse effects pertaining to genital infections, diabetic ketoacidosis, and ketosis 
155 
without acidosis were between 2-3 fold higher with Empagliflozin than placebo. Due to the 
156 
glycosuric effects of this class of drugs, it is noteworthy that the characteristic hyperglycemic 
157 
milieu often seen during classical episodes of diabetic keto-acidosis are not observed in 
158 
ketoacidosis related to SGLT2 drug use where the ambient glucose concentrations are frequently 
159 
< 250 mg/dl. This observation has prompted the creation of the condition of “euglycemic diabetic 
160 
keto-acidosis” associated with SGLT2 drug use. Risks for development of ketosis were deemed to 
161 
be due to concomitant illnesses (viral infections, gastro-enteritis), insulin pump failure, alcohol 
162 
excess, extreme/endurance sports and low carbohydrate diet (< 100 grams/day). Suggestions for 
163 
prevention of ketosis in patients on SGLT2 inhibitor therapy are to avoid use of this class of drugs 
164 
in those with HbA1c > 9%, temporary drug discontinuation for 24-48 prior to planned surgery, 
165 
fasting, intercurrent illnesses or prolonged physical activity, early recognition of symptoms of 
166 
ketosis (malaise, nausea, vomiting, abdominal pain, excess thirst), regular point of care ketone 
167 
monitoring (6-12 hourly) especially if glucose > 9mmol. The putative STICH protocol has recently 
168 
been recommended for management of diabetic ketoacidosis associated with use of SGLT2 
169 
inhibitor therapy [9]. This includes STop drug, Inject bolus insulin (1.5 times the usual correction 
170 
bolus), Consume 30-60 grams of carbohydrate and Hydrate with 200-500 ml of fluids. The above 
171 
sequence needs to be repeated every 1-2 hours with recheck of ketones in 2-4 hours. Medical 
172 
attention should be sought if any of the steps cannot be followed, particularly if fluids cannot be 
173 
maintained or if ketonemia does not resolve within 4-6 hours.   
174 
The increased risk of ketosis and DKA in SGLT2 users with T1DM may not preclude use of this 
175 
class of drugs for the management of T1DM given their clinical benefits in RCTs in T1DM patients 
176 
(described above) and the cardiovascular benefits in T2DM patients. As always, careful patient 
177 
selection, patient education and monitoring strategies need to be developed and tested to 
178 
ensure patient safety. 
179 
 
180 
Adjuvant use of antidiabetic medications in combination with automated insulin delivery systems 
181 
have been tested in short term clinical trials in T1DM. The drugs tested include pramlintide and 
182 
GLP-1 receptor agonists [6]. To the best of our knowledge, there are no published clinical trials 
183 
on the safety and efficacy of combining SGLT2 inhibitors with closed loop control. In contrast to 
184 

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the above trials, where both pramlintide and GLP-1 agonists need to be infused or injected, 
185 
Empagliflozin, an SGLT2 inhibitor, is taken as a once daily oral tablet making it simple, practical 
186 
and not burdensome for patient adherence. Additionally, given its proven benefits on glucose 
187 
control in several large RCTs involving >1700 patients with T1DM, it is necessary to test its efficacy 
188 
and safety, in combination with automated insulin delivery systems, in T1DM subjects as part of 
189 
a clinical trial that we propose. Additionally, albeit the increased prevalence of ketosis with 
190 
empagliflozin use in the published trials, given the accumulated clinical information and 
191 
experience, we will ensure that appropriate precautions including judicious selection of research 
192 
participants (HbA1c of 9% as cutoff for enrollment), educating subjects on avoiding 
193 
circumstances that could predispose to ketosis (intercurrent illnesses, alcohol excess, low carb 
194 
diet etc) and careful monitoring, will prevent and further lower the risks of ketosis during the 
195 
proposed, short term clinical trial.  
196 
 
197 
The Basal-IQ feature in the t:slim insulin pump reduce the frequency and duration of low-glucose 
198 
events by predicting glucose levels 30 minutes ahead and suspending insulin if they are expected 
199 
to drop below 80 mg/dL. Use of Empagliflozin during Basal-IQ phase is to explore its safety and 
200 
feasibility as an adjunctive agent, compare its use vs Control-IQ phase and to gather data on its 
201 
effect on postprandial glucose excursions. 
202 
 
203 
The purpose of this study is to demonstrate the safety and efficacy of the use of Empagliflozin as 
204 
an adjunctive therapy with the Tandem t:slim  X2 insulin pump with Control IQ Technology vs. 
205 
the Tandem t:slim X2 insulin pump with Basal-IQ Technology in T1D participants.  
206 
 
207 
The Main Study is a randomized control trial, aged 18 to 65 y.o. at time of consent, will be in the 
208 
trial for up to 10 weeks. The first five participants will be enrolled in a Pilot Study to use the Basal-
209 
IQ with Empagliflozin 10 mg daily for approximately two weeks. These participants will 
210 
participate in an estimated 36-48-hour hotel admission to initiate use of Closed Loop Control 
211 
(CLC). 
212 
The safety data from the Pilot Study will be presented to the DSMB for review. Upon DSMB 
213 
approval, approximately 40 participants will be randomized 1:1 in a crossover design:  
214 
With Empagliflozin: 
215 
CiQ x 4 weeks (CiQ-EMPA) then Basal-IQ x 2 weeks (BiQ-EMPA) 
216 
Basal-IQ x 2 weeks (BiQ-EMPA) then CiQ x 4 weeks (CiQ-EMPA) 
217 

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Without Empagliflozin:  
218 
CiQ x 4 weeks (CiQ-NO EMPA) then Basal-IQ x 2 weeks (BiQ-NO EMPA) 
219 
Basal-IQ x 2 weeks (BiQ-NO EMPA) then CiQ x 4 weeks (CiQ-NO EMPA)
220 

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221 
Figure 1:  Study Diagram 
222 

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223 
 Study Participants 
224 
Enrollment for the Pilot Study will proceed with the goal of completing approximately 5 
225 
participants in the trial.   
226 
Enrollment in the Main Study will proceed with the goal of completing approximately 40 subjects, 
227 
10 subjects in each group.   
228 
Up to 60 participants may sign the consent form.  
229 
 Clinical Sites 
230 
The study will be performed at the University of Virginia. 
231 
 
232 
CGM-measured time in the target range 70-180mg/dl (TIR) during the day 
233 
 
234 
24/7 CGM time in range <70mg/dl; 24/7 CGM-measured average glucose;  
235 
CGM-measured glucose variability (coefficient of variation, CV) during the day;  
236 
Risks for hypo- and hyperglycemia. 
 
237 

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Chapter 2 Study Devices 
238 
 
239 
The study system will include the Tandem t:slim X2 with Control-IQ Technology and Basal-IQ 
240 
Technology.  
241 
 
242 
The study CGM will include Dexcom G6 transmitter and sensors while using the Tandem t:slim 
243 
insulin pumps. The CGM sensor is viable for 10 days. 
244 
 
245 
Blood glucose levels will be measured using the Bayer Contour Next blood glucose meter 
246 
(glucometer). The CGM device will be calibrated, if needed, using the study glucometer and strips 
247 
in accordance with the manufacturer’s labeling.  
248 
 
249 
Blood ketone levels will be measured using the Abbott Precision Xtra meters and strips in 
250 
accordance with the manufacturer’s labeling. The blood glucose meter component of the 
251 
Precision Xtra Device will not be used.  
252 
 
253 
Device serial numbers will be recorded and use of equipment will be tracked. 
254 
 
255 
All subjects will be asked to wear a commercial activity tracker (e.g. Fitbit).  
 
256 

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Chapter 3 Study Medications  
257 
 
258 
Participants will use either lispro or aspart insulin prescribed by their personal physician. 
259 
Participants should bring their insulin to all study appointments. 
260 
 
261 
Inhibitors of sodium-glucose cotransporter-2 have been approved for use in type 2 diabetes 
262 
where large clinical trials have demonstrated clinically significant improvements in glucose 
263 
control (viz., HbA1c) and cardiovascular events [7, 10]. These drugs have also been tested in 
264 
randomized controlled clinical trials in patients with Type 1 diabetes to evaluate their safety and 
265 
efficacy.  
266 
 
267 
Experimental group participants will be advised to take Empagliflozin (trade name: Jardiance) 5 
268 
mg one time daily, with or without food. Empagliflozin is available only in 10 mg and 25 mg  film 
269 
coated unscored tablets. For this study, the participants will be provided 10 mg tablets and a pill 
270 
splitter. They will be instructed to split only 1 tablet at a time and take each half tablet (5mg each) 
271 
on subsequent days. Participants will be cautioned against spitting more than one tablet at a 
272 
time. Participants will be advised to take the medication only as prescribed. If a dose is missed, it 
273 
should be taken as soon as the participant remembers but will be advised not to double the next 
274 
dose. 
275 
 
276 
Empagliflozin will be provided by a third-party collaborator and delivered to the UVA 
277 
Investigational Pharmacy. The clinical investigator will be responsible for maintaining adequate 
278 
records of the disposition of the drug.  
279 
 
280 
The site will document drug receipt, subject dispensing and return, returns of used and unused 
281 
supplies to a third-party collaborator (or on-site destruction), and will maintain a current 
282 
accounting of all supplies in inventory—that is, a balance-on-hand log. The balance-on-hand, or 
283 
dispensing, log will contain the protocol number, the investigative site(s), the drug name, and the 
284 
medication units).  When dispensing drug to a subject, site personnel will record the date, subject 
285 
number, and amount dispensed. When a subject returns a drug, the amount used and unused 
286 
will be documented, and an explanation for any inadvertent loss or destruction of supplies will 
287 
also be recorded.  
288 

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289 
Participants will be instructed to store Empagliflozin at 25°C (77°F); excursions permitted to 15°-
290 
30°C (59°-86°F). 
291 
 
292 
Site personnel will assess dosing regimen compliance and drug reconciliation in an ongoing 
293 
manner. At each subject visit, subject compliance will be evaluated and documented, including 
294 
calculating the expected amount of consumed drug given the regimen and amount of time 
295 
between visits. This figure will be compared with the amount dispensed minus the amount the 
296 
subject returned. Site personnel will question the subject regarding any discrepancies in these 
297 
amounts and document the explanation.  
 
298 

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Chapter 4 Study Screening 
299 
 
300 
Approximately five subjects will be enrolled into the Pilot Study. The Pilot participants will 
301 
complete use the Basal-IQ Technology with Empagliflozin for 1-3 weeks. They will then 
302 
participate in a 36-48 hour hotel admission where they will use the Control-IQ System with the 
303 
Empagliflozin.  The safety data from this admission will be presented to the DSMB for review 
304 
prior to proceeding to the Main Study.  
305 
Pilot participants may enroll the Main Study. The study physician may request repeat laboratory 
306 
values if values are greater than 6 weeks from Pilot screening laboratory values. A current 
307 
urine/blood pregnancy test will be required prior to enrolling into the Main Study.  
308 
Enrollment in the Main Study will proceed with the goal of completing approximately 40 subjects, 
309 
10 subjects in each group.  Subjects will initially be randomized to Empagliflozin use or NO 
310 
Empagliflozin use during the study.  They will then be randomized to which type of insulin pump 
311 
will be used first.  
312 
Up to 60 participants may sign the consent form.  
313 
 
314 
Before consent has been obtained, participants will be asked inclusion/exclusion criteria 
315 
questions during prescreening to determine study eligibility. Before completing any procedures 
316 
or collecting any data that are not part of usual care, written informed consent will be obtained. 
317 
Potential eligibility may be assessed as part of a routine-care examination.   
318 
A participant is considered enrolled when the informed consent form has been signed by the 
319 
participant and the study team. 
320 
Consenting procedures and documentation is defined in section 17.3. 
321 
 
322 
After informed consent has been signed, a potential participant will be evaluated for study 
323 
eligibility through the elicitation of a medical history, performance of a physical examination 
324 
by licensed study personnel, an ECG, and pregnancy testing (if applicable) to screen for 
325 
exclusionary medical conditions.  
326 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
327 
date per investigator discretion. 
328 

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329 
The participants must meet all of the following inclusion criteria in order to be eligible to 
330 
participate in the study. 
331 
1. Age ≥18.0 and ≤65 years old at time of consent 
332 
2. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year  
333 
3. Currently using an insulin pump for at least six months 
334 
4. Currently using insulin for at least six months  
335 
5. Using insulin parameters such as carbohydrate ratio and correction factors consistently on 
336 
their pump in order to dose insulin for meals or corrections  
337 
6. Access to internet and willingness to upload data during the study as needed  
338 
7. For females, not currently known to be pregnant or breastfeeding 
339 
8. If female and sexually active, must agree to use a form of contraception to prevent pregnancy 
340 
while a participant in the study.  A negative serum or urine pregnancy test will be required 
341 
for all females of childbearing potential. Participants who become pregnant will be 
342 
discontinued from the study. Also, participants who during the study develop and express 
343 
the intention to become pregnant within the timespan of the study will be discontinued. 
344 
9. Willingness to suspend use of any personal CGM for the duration of the clinical trial once the 
345 
study CGM is in use 
346 
10. Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, and to use 
347 
no other insulin besides lispro (Humalog) or aspart (Novolog) during the study 
348 
11. Total daily insulin dose (TDD) at least 10 U/day 
349 
12. Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
350 
trial (including metformin, GLP-1 agonists, pramlintide, DPP-4 inhibitors, biguanides, 
351 
sulfonylureas and naturaceuticals) 
352 
13. Willingness to eat at least 100 grams of carbohydrates per day  
353 
14. An understanding and willingness to follow the protocol and signed informed consent  
354 
15. Pilot Participants:  Agree to hotel/research house admission with other Pilot participants on 
355 
a date selected by the study team.  
356 
 
357 
The participant must not have any exclusion criteria in order to be eligible to participate in the 
358 
study.  
359 
1. Hemoglobin A1c >9% 
360 

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2. History of diabetic ketoacidosis (DKA) in the 12 months prior to enrollment 
361 
3. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior to 
362 
enrollment 
363 
4. Pregnancy or intent to become pregnant during the trial 
364 
5. Currently breastfeeding or planning to breastfeed 
365 
6. Currently being treated for a seizure disorder 
366 
7. Planned surgery during study duration  
367 
8. History of cardiac arrhythmia (except for benign premature atrial contractions and benign 
368 
premature ventricular contractions which are permitted) 
369 
9. Clinically significant electrocardiogram (ECG) abnormality at time of Screening, as interpreted 
370 
by the study medical physician 
371 
10. Use of diuretics (e.g. Lasix, Thiazides) 
372 
11. History of chronic or recurrent genital infections 
373 
12. eGFR lab value below 60 mL/min/1.73 m2 
374 
13. Treatment with any non-insulin glucose-lowering agent (including metformin, GLP-1 agonists, 
375 
pramlintide, 
DPP-4 
inhibitors, 
SGLT-2 
inhibitors, 
biguanides, 
sulfonylureas 
and 
376 
naturaceuticals)  
377 
14. A known medical condition that in the judgment of the investigator might interfere with the 
378 
completion of the protocol such as the following examples: 
379 
a. Severe renal impairment, end-stage renal disease, or dialysis 
380 
b. Inpatient psychiatric treatment in the past six months 
381 
c. Presence of a known adrenal disorder 
382 
d. Abnormal liver function test results (Transaminase>2 times the upper limit of 
383 
normal); testing required for subjects taking medications known to affect liver 
384 
function or with diseases known to affect liver function 
385 
e. Uncontrolled thyroid disease  
386 
15. Severe renal impairment, end-stage renal disease, or dialysis 
387 
16. Use of an automated insulin delivery mechanism that is not downloadable by the subject or 
388 
study team 
389 
17. Current enrollment in another clinical trial, unless approved by the investigator of both 
390 
studies or if clinical trial is a non-interventional registry trial  
391 
18. Alcohol restricted to no more than 2 drinks per night in men and no more than 1 drink per 
392 
night in women 
393 
19. Low carb diet (less than 100g per day) 
394 

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395 
The participant will be evaluated for study inclusion and exclusion eligibility after the informed 
396 
consent form has been signed by the participant and the study team.  
397 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
398 
date per investigator discretion. 
399 
1. Demographics 
400 
a. Date of birth 
401 
b. Gender  
402 
c. Race 
403 
d. Ethnicity 
404 
2. Medical History  
405 
a. Duration of disease (number of years) 
406 
b. Current insulin pump model 
407 
c. History of CGM use 
408 
d. Current treatment 
409 
i. 
Basal rates 
410 
ii. 
Carbohydrate ratios 
411 
iii. 
Insulin sensitivity factors 
412 
iv. 
Target glucose 
413 
v. 
Average daily insulin 
414 
e. History of diabetic ketoacidosis 
415 
f. History of severe hypoglycemia  
416 
g. History of seizures  
417 
h. Loss of consciousness 
418 
3. Surgical history 
419 
4. Allergies 
420 
5. Concomitant medications 
421 
6. Physical Examination – A historical history and physical report within 52 weeks of the 
422 
screening appointment may be used 
423 
a. Weight 
424 
b. Height 
425 
c. Blood pressure 
426 
d. Pulse 
427 
e. Temperature  
428 

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7. Screening Labs – A historical laboratory results within 2 weeks of the screening 
429 
appointment may be used 
430 
a. Hemoglobin A1c 
431 
b. Comprehensive Metabolic Panel  
432 
c. Thyroid functioning test 
433 
d. Urine or serum pregnancy test for all women of childbearing potential 
434 
Screening procedures will last approximately 2 hours. Once all results of the screening 
435 
evaluations are available, a decision will be made to determine the participant’s eligibility for the 
436 
study or if one or more part of the screening will have to be repeated. If at the first screening or 
437 
repeat screening an exclusionary condition is identified, the participant will be excluded from 
438 
participation with follow up and referred to their primary care physician as needed. The study 
439 
physician may elect to rescreen participants and collect additional laboratory values if their 
440 
clinical situation changes. The study physician has the discretion to exclude a study participant if 
441 
concerned about their safety in this trial.  
 
442 

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Chapter 5 Randomization Visit 
443 
Once eligibility is met, the participant may continue with randomization at the conclusion of the 
444 
screening appointment. Screening failures and study dropout participants may be replaced.  
445 
 
446 
Participants will not be randomized in the Pilot Study. 
447 
 
448 
Approximately 40 participants will be randomized to using Empagliflozin 5 mg per day or not 
449 
using the medication.  Participants will then be randomized to the order of the insulin pump.   
450 
With Empagliflozin: 
451 
Group 1:  CiQ x 4 weeks (CiQ-EMPA) then Basal-IQ x 2 weeks (BiQ-EMPA) 
452 
Group 2:  Basal-IQ x 2 weeks (BiQ-EMPA) then CiQ x 4 weeks (CiQ-EMPA) 
453 
Without Empagliflozin:  
454 
Group 3:  CiQ x 4 weeks (CiQ-NO EMPA) then Basal-IQ x 2 weeks (BiQ-NO EMPA) 
455 
Group 4:  Basal-IQ x 2 weeks (BiQ-NO EMPA) then CiQ x 4 weeks (CiQ-NO EMPA) 
456 
Equipment training will be initiated after randomization.  
 
457 

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Chapter 6 Study Equipment Training 
458 
Equipment training in the Main Study may begin immediately after screening eligibility has been 
459 
met or may be deferred for a maximum of 30 days.  Equipment training in the Pilot Study is 
460 
intended to begin immediately after screening eligibility has been met. The study physician may 
461 
elect to delay a participant’s equipment training session if needed.  The purpose of this training 
462 
is to introduce the study insulin pump and study CGM to the participant.  
463 
The participant’s insulin parameters will be programmed into their study insulin pump by two 
464 
research staff. Subjects will then switch to the study insulin pump. The participant’s personal 
465 
pump and infusion site will be removed. 
466 
The participant will have the insulin pump and sensor on them at all times. Study supplied phones 
467 
will be available upon request.  
468 
Participants will download the study equipment approximately one time per week or as 
469 
frequently as needed.  
470 
 
471 
A study CGM will be provided to all participants at the training session. The participants will be 
472 
provided with CGM equipment and instructed to use the study CGM on a daily basis. If the 
473 
participant has prior use of the CGM, re-training will be specific to the individual. The study team 
474 
may elect to have less frequent CGM users watch the Dexcom online training videos 
475 
(https://www.dexcom.com/training-videos) to assist in the training session.  Study staff training 
476 
may include review of study CGM in real-time to make management decisions and how to review 
477 
the data after an upload for retrospective review. Study staff will specifically identify how alarms 
478 
are set using the app and the frequency that these alarms will repeat when  
479 
The participants personal CGM will be discontinued. The participants will be observed placing the 
480 
sensor and will learn/review how to access the CGM trace via the t:slim X2 insulin pump user 
481 
interface. The participants will be asked to perform fingerstick blood glucose measurements (if 
482 
needed) in accordance with the labeling of the study CGM device.  
483 
An electronic copy of the CGM user’s guide will be provided for the participants to take home. 
484 
The study team will be sure that the participants will leave the clinic knowing how to use proper 
485 
use the CGM. The study team will be available for any questions. 
486 
Participants will have the option of using their personal smartphone or receive a study 
487 
smartphone to use in order to collect the data from the devices. If the participant elects to use a 
488 

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personal device, the Dexcom app will be downloaded to their phone in order to monitor the 
489 
participant’s CGM values and alerts in real-time may be used. 
490 
 
491 
Participants will be provided with a study blood glucose meter and test strips to be used at home 
492 
per manufacturer guidelines. 
493 
All study blood glucose meters will be QC tested by study staff with at least two different 
494 
concentrations of control solution, if available.  A tested meter will not be used in a study if it 
495 
does not read within the target range at each concentration per manufacturer labeling.   
496 
Participants will be reminded to use the study blood glucose meter for all fingerstick BGs during 
497 
the study. 
498 
 
499 
Participants will be provided with a study blood ketone meter and test strips to be used at home 
500 
per manufacturer guidelines. 
501 
All study blood ketone meters will be QC tested by study staff with at least two different 
502 
concentrations of control solution, if available.  A tested meter will not be used in a study if it 
503 
does not read within the target range at each concentration per manufacturer labeling.   
504 
Participants will be instructed to perform blood ketone testing at any symptoms, change of 
505 
conditions, and as described in Glycemic Treatment Guidelines (section 10.2). A home glucagon 
506 
emergency kit will be required. Participants who currently do not have one will be given a 
507 
prescription for the glucagon emergency kit. 
508 
 
509 
All subjects will be asked to wear an activity tracker (e.g. Fitbit). Information about movement 
510 
and heart rate will be recorded though not an endpoint in this study. 
511 
 
512 
 Insulin Pump Topics  
513 
The participant will be fully instructed on the study insulin pump. A qualified system trainer will 
514 
conduct the training and in particular discuss differences from their home pump in important 
515 
aspects such as calculation of insulin on board and correction boluses. Additional topics not 
516 
limited to but may include: infusion site initiation, cartridge/priming procedures, setting up 
517 
the pump, charging the pump, navigation through menus, bolus procedures including 
518 
stopping a bolus, etc. 
519 

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The study team will assist the participant in study pump infusion site initiation and will start the 
520 
participant on the study pump. The study pump will be programmed with the participant’s 
521 
usual basal rates and pump parameters. The participant’s personal pump will be removed. 
522 
The participant will be supervised with the study pump during at least one meal or snack bolus 
523 
to ensure participant understanding of the pump features. 
524 
The participant will be encouraged to review the literature provided with the pump and 
525 
infusion sets after the training is completed. Infusion sets manufactured by Tandem will be 
526 
provided to the study subject and a sample list is below and may be provided in different 
527 
cannula lengths (e.g. 6mm or 9mm) and tubing lengths (e.g. 23 or 43 inch): 
528 
 Tandem Autosoft Line  (e.g. Autosoft 30, Autosoft 90, Autosoft XC) 
529 
 Tandem Varisoft 
530 
 Tandem TruSteel  
531 
Insulin pump training specific to the Basal-IQ Technology & Control-IQ Technology functions will 
532 
include: 
533 
How to turn on and off the equipment 
534 
How to understand when the insulin pump is increasing or decreasing basal rates 
535 
How to administer a meal or correction bolus 
536 
How to enable the sleep function and set the sleep schedule 
537 
The participant will be assessed for understanding of the system interface and how to react to 
538 
safety/alert messages 
539 
The participant will be given electronic versions of the user guides as a reference 
540 
 Basal-IQ Training 
541 
Participants will be instructed how the t:slim X2 insulin pump with Basal-IQ technology differs 
542 
from their personal insulin pump. Specifically, participants will be instructed how the technology 
543 
is able to predict glucose levels 30 minutes ahead and will suspend insulin delivery in the event 
544 
of a low glucose event. They will also be advised that the system can turn on and turn off every 
545 
5 minutes and can suspend insulin up to 2 hours when identifying a hypoglycemic trend. While 
546 
the Basal-IQ technology can be on (active) or off when in normal use, participants will be 
547 
instructed to have the Basal-IQ feature “ON” when assigned to the Basal-IQ treatment arm.  
548 
 Control-IQ Training 
549 
The participant will be instructed to how to use the system if insulin is delivered by any means 
550 
other than the study pump (e.g. injection of subcutaneous insulin via syringe in the event of 
551 
infusion site failure). If insulin is delivered by any means other than the study pump, the 
552 
participant will be instructed to turn off Control-IQ for approximately four hours. 
553 

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The participant will be provided with contact information and will be asked to call the study 
554 
clinical staff during periods of illness with an elevated temperature >101.5 degrees Fahrenheit 
555 
(38.6 degrees Celsius), periods of significant illness, or during periods of use of medications such 
556 
as epinephrine for the emergency treatment of a severe allergic reaction or asthma attack in 
557 
addition to use of oral or injectable glucocorticoids to determine if closed-loop use should be 
558 
temporarily discontinued. 
559 
The participant will also be asked to call the study clinical staff for technical issues with t:slim X2 
560 
with Control IQ. The participant should use the study pump without Control-IQ activated and 
561 
study CGM (open loop mode) during periods of component disconnections or technical 
562 
difficulties.  Study staff contact information will be provided to the participant.  
563 
Upon completion of each insulin pump training, study staff will document, using a checklist, that 
564 
the participant is familiar with the function/feature and/or capable of performing each of the 
565 
tasks specified. 
566 
The participant will be provided Glycemic Treatment Guidelines (Chapter 10:) to use at home. 
567 
 Optimization of Insulin Pump Settings 
568 
Data-driven optimization of pump settings can occur any time during the study, particularly if the 
569 
participant contacts the study physician due to concerns about their pump settings due to 
570 
recurring hypo- or hyperglycemia. 
 
571 

CLINICAL PROTOCOL 
 
 
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Chapter 7 Pilot Study 
572 
The Pilot Study will be performed at a local hotel/research house. The duration of the hotel 
573 
admission will be approximately 36-48 hours with the intent of collecting appropriate safety data 
574 
that will be presented to the DSMB for review.  
575 
 
576 
After participant’s eligibility is confirmed, the participant will undergo Study Equipment & 
577 
Medication Training (Chapter 6) and receive education regarding the use of Empagliflozin 
578 
(section 3.2).  
579 
The participant will be on the study equipment and study medication for about 7-14 days prior 
580 
to the hotel admission. The study physician may elect to have the study participant take the 
581 
medication for a shorter or longer period of time, depending on side effects.  Participants of the 
582 
study will stay at the hotel/research house with study staff and other study participants.  
583 
 
584 
There will be at least two study staff present at all times at the study site, at least one of whom 
585 
will be clinical staff (e.g. nurse, physician, nurse practitioner). There will be a physician available 
586 
either on-site or nearby off-site at all times. In addition, one of the study medical physicians and 
587 
one senior engineer will be on call during the entire admission. Glucagon for the emergency 
588 
treatment of hypoglycemia will be available on-site. 
589 
 
590 
Pilot participants will be contacted by the study team approximately 48 hours prior to the hotel 
591 
admission to verify the following information: 
592 
Inquire about any changes to the participant’s medical history 
593 
Study equipment (e.g. insulin pump, CGM, and activity tracker) has occurred 
594 
Determine pump profile(s) the participant uses on certain days 
595 
New CGM sensor has been placed approximately 48-72 hours prior to admission for proper 
596 
warm-up 
597 
Verify with the subject that the goal CGM reading at time of arrival is less than 250 mg/dL  
598 
Should any concerns regarding medical history, pump information, or unforeseen issues arise, 
599 
the admission will be cancelled for that participant at the discretion of the investigator. 
600 
 
601 
Participants will arrive at the hotel on the first day of the admission.  The study team will perform 
602 
vital signs and inquire about any changes to the participant’s medical history.  Any changes to 
603 

CLINICAL PROTOCOL 
 
 
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medical history will be communicated to the medical physician to ensure continued eligibility and 
604 
participation.   
605 
In the event that the participant’s CGM reading is not between 80-250 mg/dL or ketone 
606 
concentration is ≥0.6 mmol/L prior to the Control-IQ initiation, the study physician may 
607 
recommended corrective action as outlined in Chapter 10:. Study physician may elect to cancel 
608 
participant’s participation in the hotel admission if concerned about their medical safety.  This 
609 
participant will not be replaced.  
610 
The participant’s Basal-IQ insulin pump will be discontinued and the Control-IQ insulin pump will 
611 
be initiated.  The study team will ensure the proper function of the CGM, insulin pump, and 
612 
activity tracker. The goal will be to initiate Closed Loop Control by approximately 11 a.m.  
613 
The CGM used in the study is FDA-approved for the non-adjunctive measurement of blood 
614 
glucose (i.e. the CGM reading can be used for insulin dosing decisions). The CGM readings will be 
615 
the primary source of blood glucose values.  There are no protocol fingerstick blood glucose 
616 
measurements other than at times of CGM calibration (if necessary) and if directed by the study 
617 
team.  Glycemic Treatment Guidelines to be used during the hotel admission are defined in 
618 
Chapter 10:. 
619 
 
620 
Upon arrival, the subject will be asked to check the CGM reading and ketone concentration using 
621 
the study ketone meter.  If CGM is <70 mg/dL or >250 mg/dL, or ketone test is >0.6 mmol/L, the 
622 
study physician will suggest appropriate treatment.  The study team may request fingersticks as 
623 
needed. The study subject may continue participation in the trial once CGM is between 70-250 
624 
mg /dL and ketone concentration is ≤0.6 mmol/L. 
625 
If CGM is ≥200mg/dL for more than 2 hours or ≥300 mg/dL at any time for experimental group 
626 
participants, study physician will be notified to suggest appropriate treatment and ketones will 
627 
be checked.  If CGM is ≥300mg/dL for more than 2 hours or ≥400 mg/dL at any time for control 
628 
group participants, study physician will be notified to suggest appropriate treatment and ketones 
629 
will be checked. If ketone concentration is ≥0.6 mmol/L, the study team will check the insulin 
630 
pump infusion site and correction insulin and will consider the proper remedy based on the study 
631 
physician judgement via the subject’s insulin pump.  The study team will monitor CGM changes 
632 
and ketones will be checked every 60 minutes until ketone concentration is <0.6 mmol/L. 
633 
If ketone concentration is ≥3.0 mmol/L, the study physician will recommend the appropriate 
634 
medical treatment.    
635 

CLINICAL PROTOCOL 
 
 
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If CGM ≤60 mg/dL at any time, subjects will be given approximately 16 grams of fast-acting rescue 
636 
carbohydrates.  Study team will monitor CGM rise and will consider treating again if CGM <80 
637 
mg/dL after approximately 20 minutes.  Hypoglycemic treatments can occur at any time per study 
638 
physician request. 
639 
 
640 
Participants may eat freely during the admission, eating a minimum of 100g of carbs per day. The 
641 
estimated time of meals will be 8 a.m., 1 p.m., and 7 p.m.  
642 
 
643 
Participants will be free to engage in low-intensity activity (walking, shopping) during the morning 
644 
and afternoon hours in a group setting. Participants will enjoy quiet activities in the evening. 
645 
 
646 
Discharge will be at approximately7p.m. if the CGM and ketone values are within parameters 
647 
outlined in Chapter 10. A snack will be provided for the participant at the time of discharge. 
648 
Participants will be asked to continue monitoring ketone levels for 24-48 hours after discharge 
649 
from the hotel. 
650 
 
651 
Approximately 48 hours after the hotel admission, the study team will contact the participant via 
652 
phone/email/text to assess: 
653 
adverse events, adverse device effects, and device issues 
654 
Review download of activity tracker, glucometer and ketone meter to assess occurrence of 
655 
glucose values <60 mg/dL and >300 mg/dL 
 
656 

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Chapter 8 DSMB Review 
657 
 
658 
The Data Safety Monitoring Board (DSMB) will be provided all adverse event data from the  onset 
659 
of the Pilot Study through the hotel admission for review.  While approximately 5 participants 
660 
will be scheduled for the hotel admission, the goal is to provide at least 75% of the data to the 
661 
DSMB for review.  Replacing dropped study participants will not be required in the Pilot Study. 
662 
The DSMB will review data related to individual stopping criteria as detailed in the study protocol.   
663 
 
664 
After their review, the DSMB can recommend that the current study continue without 
665 
modification, continue with specified modifications, discontinue one or more arms of the study, 
666 
or halt or modify the study until more information is available. 
667 
The DSMB may recommend modifications to individual stopping rules if additional safety 
668 
concerns arise during from their continuing reviews of the study data.   
669 
The hotel admission will not be repeated unless required by the Data Safety Monitoring Board 
670 
(DSMB).   
671 
 
672 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data after the 
673 
completion of 10 Main Study participants. As a safety measure, the Board will review if the rate 
674 
of mild ketosis greater than 40% (B-OH-B level > 0.6 mmol), 20% significant ketosis (B-OH-B > 1.5 
675 
mmol) and more than 5% DKA (B-OH-B > 3 mmol) to be considered significant to stop the study. 
676 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data after 10 participants 
677 
complete 4 weeks of the Main Study. Absence of serious adverse events related to Empaglifozin, 
678 
the participants will continue with study participation pending DSMB review. The DSMB will 
679 
review compiled safety data after 10 participants complete the trial. In addition, the DSMB will 
680 
review all DKA and severe hypoglycemia irrespective of relatedness to study device use, study 
681 
drug, and all serious events (including UADEs) related to study device use at the time of 
682 
occurrence. The DSMB also will be informed of any ADEs not meeting criteria for a UADE if the 
683 
Study PI requests the DSMB review.  The DSMB can request modifications to the study protocol 
684 
or suspension or outright stoppage of the study if deemed necessary based on the totality of 
685 
safety data available. 
 
686 

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Chapter 9 Main Study 
687 
After DSMB review and approval of the hotel admission safety data, Main Study participants will 
688 
be screened, randomized and trained on the study equipment. Pilot participants may be enrolled 
689 
in the Main Study. Screening and consenting of the Main Study participants may be concurrent 
690 
to the DSMB review. Virtual study visits may take the place of in-person study visits. 
691 
 
692 
 Run-In Phase  
693 
Participants will be asked to record two days of baseline ketone values before initiating the use 
694 
of the study drug. Participant will then be directed to use the study CGM with Empagliflozin for 
695 
1-2 weeks. Proceeding to the pump treatment is dependent upon the participant’s tolerance to 
696 
the medication. The study physician may elect to provide the participant additional time in the 
697 
event of medication side effects.   
698 
Participants will be instructed on the Glycemic Treatment Guidelines with special focus upon 
699 
CGM readings (section 10.3) and Hyperglycemic Management (section 10.5).  
700 
Participant will meet the following criteria to continue study participation:  
701 
o Adherence to study protocol 
702 
o Ketone testing at least 2 times daily, preferably 4 times, with monitored values not 
703 
greater than 0.6/mmol on at least two successive occasions (first measurement should be 
704 
obtained upon waking in a fasting state) 
705 
o No adverse events relating to perineal infections, symptomatic postural hypotension, no 
706 
evidence of significant hypoglycemia (< 54 mg/dl) or any other listed adverse effects of 
707 
medication.  
708 
 
709 
Participants will receive pump training dependent upon the randomization group (i.e. Control-IQ 
710 
pump for 4 weeks then Basal-IQ pump for 2 weeks.)  Training provided is described in Section 
711 
6.5. 
712 
 
713 
Data driven optimization of pump settings can occur any time during the study, particularly if the 
714 
study participant contacts the study physician due to concerns about their pump settings due to 
715 
recurring hypo- or hyperglycemia. 
716 

CLINICAL PROTOCOL 
 
 
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While initiating and maintaining Empagliflozin therapy, the study physician will carefully monitor 
717 
insulin dose reductions, especially basal insulin decreases. 
718 
 
719 
All participants will be contacted by the study team in the week following the Run-In Phase and 
720 
the Basal-IQ Pump Training Visits to address issues relating to the study equipment and side 
721 
effect of the Empagliflozin if randomized to the treatment group. Two check-in visits will occur 
722 
after the Control-IQ Training Visit. Extra contact with subjects will occur as needed. 
723 
 
724 
Participants will be instructed to download the study devices (i.e. insulin pumps, CGM, activity 
725 
tracker, etc…) each week, or as needed, to secure data collection.  Study participants will log daily 
726 
ketone values in an online resource for ongoing assessment purposes. The study team will 
727 
download the ketone meter whenever the study subject attends an in clinic visit. If the subject 
728 
owns a personal laptop device, he/she will be asked to bring it to the visit for the study team to 
729 
download specific software to be used during data collection. If the subject does not own a laptop 
730 
device but owns a desktop computer, he/she will be provided with a memory drive storing the 
731 
appropriate resources to be used at home.  
732 
 
733 
The Basal-IQ Technology will continue working for the first 15 minutes after CGM readings 
734 
become unavailable. The Basal-IQ Technology requires three of the last four data points to make 
735 
a prediction. If connectivity with the CGM is lost during a suspension, the Basal-IQ Technology 
736 
will continue the suspension for 15 minutes. If connectivity is not resolved within 20 minutes, 
737 
Basal-IQ Technology will resume insulin automatically. 
738 
The Control-IQ Technology will continue to operate for the first 15 minutes after CGM readings 
739 
become unavailable. If connectivity is not restored after 20 minutes, the Control-IQ Technology 
740 
will stop operation until CGM readings are available. While the Control-IQ Technology is not 
741 
operating, the participant’s pump will continue to deliver insulin according to the participant’s 
742 
personal profile settings. Once CGM readings are available, the automated insulin delivery 
743 
feature will automatically resume.  
744 
If the study system is unable to activate the Control-IQ Technology for any reason, the pump will 
745 
automatically revert to pre-programmed basal insulin delivery without any need for instruction 
746 
from the user. 
747 

CLINICAL PROTOCOL 
 
 
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If the Control-IQ Technology detects a system error that does not allow the pump to operate, the 
748 
Malfunction Alarm will display and the participant will be instructed to contact Tandem Technical 
749 
Support via the study team. 
750 
 
751 
Participants may have unscheduled visits during the study period if required for additional device 
752 
training or other unanticipated needs per the study investigator discretion. 
753 
 
754 
All participants will complete both the Basal-IQ and Control-IQ insulin pump training at a virtual 
755 
clinic visit prior to using the equipment.  
756 
 
757 
The following procedures will be performed in both groups at the study conclusion visit: 
758 
All study devices and all remaining Empagliflozin supplies, including empty medication bottles 
759 
Study team will download the study equipment 
760 
Blood will be drawn for creatinine, HbA1c, and pregnancy assessment 
761 
Study participants will be instructed on how to transition back to the home insulins and the doses 
762 
to be used. Subjects will be informed that there may be a risk of severe hypoglycemia and/or 
763 
severe hyperglycemia during the transition back to the subject’s usual home basal insulin. The 
764 
study physician will be available for consultation during this transition period.   
765 
 
766 
Approximately 48 hours after the home use of the equipment, the study team will contact the 
767 
participant via phone/email/text to assess: 
768 
Adverse events, adverse device effects, and device issues 
 
769 

CLINICAL PROTOCOL 
 
 
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Chapter 10 Glycemic Treatment Guidelines 
770 
 
771 
During the course of the study, participants will be permitted to change the CGM low glucose 
772 
threshold alert setting on their device or mobile app but will be instructed to choose a value no 
773 
less than 60 mg/dL. 
774 
The t:slim X2 with Control-IQ system will issue a predictive hypoglycemia alert (Control-IQ Low 
775 
Alert) when the system predicts BG <70 mg/dL within the next 15 minutes (<80 mg/dL when 
776 
exercise mode is activated). 
777 
If the participant receives a Control-IQ Low Alert, a message appears on the user interface (UI) 
778 
that is accompanied by vibration followed by vibrations and/or sound if not acknowledged by the 
779 
user in 5 minutes.  This alert remains on the screen until acknowledged by the user. The user is 
780 
prompted to test blood sugar and treat with carbohydrates.  
781 
CGM values are updated every 5 minutes and will be able to see it on the pump and Dexcom 
782 
App. 
783 
CGM alarms on the study team controlled Dexcom App will be set at 70 mg/dl for 30 minutes 
784 
and 300 mg/dl for 60 minutes. 
785 
If CGM < 80 mg/dL during the day, the patient will be treated until CGM reads ≥80 mg/dL. If 
786 
CGM < 70 mg/dL during the night. Hypoglycemia treatment will be provided until CGM reads 
787 
≥ 80 mg/dL.  
788 
 
789 
During the course of the study, participants will be permitted to change the CGM high glucose 
790 
threshold alert setting on their device or mobile app but will be instructed to choose a value no 
791 
greater than 250 mg/dL 
792 
The t:slim X2 with Control-IQ system will issue a predictive hyperglycemia alert (Control-IQ High 
793 
Alert) when the system has increased insulin delivery, but detects a CGM value above 200 mg/dL 
794 
and does not predict the value will decrease in the next 30 minutes. 
795 
If the participant receives a Control-IQ High Alert, a message appears on the UI that is 
796 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user 
797 
in 5 minutes. This alert remains on the screen until acknowledged by the user. The user is 
798 
prompted to check the site for occlusion and test blood glucose. 
799 
 
800 
If a participant’s CGM readings ≥200 mg/dL for over 2 hours or ≥300 mg/dL at any point,  
801 

CLINICAL PROTOCOL 
 
 
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If the CGM is ≥200 mg/dL, check for blood ketones with the study ketone meter 
802 
If the ketone level is ≥0.6 mmol/L, consider correction insulin and/or consider infusion site 
803 
change. Contact study staff. 
804 
If a participant administers correction insulin via insulin syringe, participants will be instructed 
805 
to turn Control-IQ off for approximately four hours 
806 
 
807 
If a participant’s CGM reading is ≥300 mg/dL for over 2 hours or ≥400 mg/dL at any point, the 
808 
participant will be instructed to take the following steps: 
809 
If CGM is ≥300 mg/dL, check for blood ketones with the study ketone meter. 
810 
If the ketone level is ≥0.6 mmol/L, consider correction insulin and/or consider infusion site 
811 
change. Contact study staff. 
812 
If a participant administers correction insulin via insulin syringe, participants will be instructed 
813 
to turn Control-IQ off for approximately four hours. 
814 
 
815 
Due to the higher risk of ketoacidosis while using Empagliflozin, experimental participants will 
816 
be instructed to measure ketone levels at a minimum of 2 times daily but preferable 4 times 
817 
daily. Required measurement upon waking (fasting state) and prior to bedtime. If ketones ≥ 0.6 
818 
mmol/L, participants will be advised to stop the drug and then recheck ketones in 3-4 hours. 
819 
Participants may restart the use of Empagliflozin after the ketone measurement is <0.6 mmol/L. 
820 
All ketosis events should be recorded and evaluated in participants who are taking the study 
821 
drug.   
822 
Experimental participants will be advised to check ketones if symptoms consistent with 
823 
ketoacidosis occur even if blood glucose is not elevated. 
824 
Experimental participants will be instructed on the proper use of the STICH Protocol:  
825 
STop drug, 
826 
Inject bolus insulin (1.5 times the usual correction bolus) 
827 
Consume 30 grams of carbohydrate 
828 
Hydrate with up to 500 ml of water 
829 

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Blood Ketone (BHB) Level 
Remedial Actions 
<0.6 mmol/L (normal) 
No action needed 
0.6-1.5 mmol/L (ketonemia) 
Treat as follows or per clinician instructions:  
• Ingest 30-60g rapidly absorbed carbohydrates and 
maintain fluid consumption (200-500 mL) every 1-2 hours 
• Administer rapid-acting insulin based on carbohydrate 
intake every 1-2 hours 
• Check blood ketones (every 2-4 h) until resolution 
• Check blood glucose frequently to avoid hyperglycemia 
and hypoglycemia  
Seek medical attention if levels persist and symptoms present 
1.6-3.0 mmol/L (impending 
DKA) 
Follow treatment recommendations listed above  
Consider seeking immediate medical attention 
>3.0 mmol/L (probable DKA) 
Seek immediate medical attention 
BHB=β-hydroxybutyrate 
 
*Danne, et al….Diabetes Care v42, June 2019 [11] 
830 
Experimental group participants will be advised to measure ketones in the event of the following 
831 
symptoms/events: 
832 
• Malaise 
833 
• Fatigue 
834 
• Nausea, or vomiting.   
835 
• Infection 
836 
• Injury 
837 
• Occlusion of infusion cannula 
838 
• Pump malfunction 
839 
• Stress 
840 
• Changes in diet 
841 
• Changes in physical activity 
842 
Control participants will be advised to measure and document ketone levels each morning. 
843 
Experimental Participants will also be instructed on the importance of prompt treatment of 
844 
symptoms as recommended in the STICH Protocol. 
 
845 

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Chapter 11 Testing Procedures 
846 
 
847 
 HbA1c  
848 
A blood sample will be obtained at screening to obtain a baseline hemoglobin A1c level. Blood 
849 
test may be obtained within 2 weeks prior to enrollment may be used for eligibility purposes. 
850 
HbA1c level may be measured by study team using the DCA2000, a comparable point of care 
851 
device, at time of screening  
852 
Labs may be obtained at a local laboratory convenient to the participant. 
853 
 Comprehensive Metabolic Panel 
854 
A blood sample will be obtained at screening to assess kidney and liver functioning.  
855 
Specifically, creatinine will be evaluated at the screening visit, at end of study, and if subject has 
856 
nausea, vomiting, diarrhea or intercurrent illnesses during study. 
857 
Labs may be obtained at a local laboratory convenient to the participant. 
858 
 Thyroid Stimulating Hormone (TSH) 
859 
A blood sample will be obtained at screening to assess thyroid functioning. Blood test may be 
860 
obtained within 2 weeks prior to enrollment may be used for eligibility purposes.   
861 
 Pregnancy Test 
862 
Pilot Study Participants: A serum or urine pregnancy test will be required for women of 
863 
childbearing potential at the screening visit, prior to the study equipment training session, 
864 
prior to the start of the hotel admission, and at the end of the study.  Test must be negative 
865 
to participate in the study. 
866 
Main Study Participants: A serum or urine pregnancy test will be required for women of 
867 
childbearing potential at the screening visit, prior to each study equipment training sessions, 
868 
and at the end of the study.  Test must be negative to participate in the study.  
869 
 
870 
Questionnaires are completed as noted below during the Main Study for all participants.  
871 
 Questionnaire Schedule 
872 
Screening:  
873 
Diabetes Distress Scale (DDS) 
874 
Fear of Hypoglycemia Survey (HFS-II) – Adult  
875 
Administration time is approximately 10 minutes. 
876 

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Post Control-IQ Insulin Pump Use: 
877 
Diabetes Distress Scale (DDS) 
878 
Fear of Hypoglycemia Survey (HFS-II) – Adult  
879 
Control-IQ Questionnaire Survey Technology Acceptance 
880 
Post Basal-IQ Insulin Pump Use: 
881 
Diabetes Distress Scale (DDS) 
882 
Fear of Hypoglycemia Survey (HFS-II) – Adult  
883 
Basal-IQ Questionnaire Survey Technology Acceptance 
884 
 
885 
The Diabetes Distress Scale [12] is a measure of diabetes-related emotional distress and consists 
886 
of a scale of 28 items. These include 7 items from each of four domains central to diabetes-related 
887 
emotional distress. Patients rate the degree to which each item is currently problematic for them 
888 
on a 6-point Likert scale, from 1 (no problem) to 6 (serious problem). 
889 
Administration time is approximately 5 minutes. 
890 
 
891 
The Hypoglycemia Fear Survey-II [13] was developed to measure behaviors and worries related 
892 
to fear of hypoglycemia in adults with type 1 diabetes. It is composed of 2 subscales, the Behavior 
893 
(HFS-B) and Worry (HFS-W). HFS-B items describe behaviors in which patients may engage to 
894 
avoid hypoglycemic episodes and/or their negative consequences (e.g., keeping blood glucose 
895 
levels higher, making sure other people are around, and limiting exercise or physical activity). 
896 
HFS-W items describe specific concerns that patients may have about their hypoglycemic 
897 
episodes (e.g., being alone, episodes occurring during sleep, or having an accident). Items are 
898 
rated on a 5-point Likert scale (0=never, 4=always), with higher scores indicating higher fear of 
899 
hypoglycemia.  
900 
Administration time is approximately 10 minutes (both versions). 
901 
 Control-IQ / Basal-IQ Survey Technology Acceptance 
902 
The Technology Acceptance Surveys [14] were developed for a Bionic Pancreas camp study. The 
903 
38 items in the Questionnaire were based on interviews conducted with individuals who had 
904 
participated in previous Bionic Pancreas trials about their experience regarding the Bionic 
905 
Pancreas. It was subsequently adapted to assess these same measures for the inControl closed-
906 
loop system. It assesses both positive and negative experiences with inControl, including blood 
907 
glucose management, device burden, and overall satisfaction. Items were rated on a 5-point 
908 
scale. 
909 

CLINICAL PROTOCOL 
 
 
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Administration time is approximately 10 minutes. 
 
910 

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Chapter 12 Risks Associated with Clinical Trial 
911 
 
912 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are 
913 
handled to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are always a 
914 
risk in participants with type 1 diabetes and participants will be monitored for these symptoms.  
915 
 Venipuncture Risks 
916 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can 
917 
cause some common reactions like pain, bruising, or redness at the sampling site.  Less common 
918 
reactions include bleeding from the sampling site, formation of a small blood clot or swelling of 
919 
the vein and surrounding tissues, and fainting. 
920 
 Fingerstick Risks 
921 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
922 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital 
923 
laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount 
924 
of bleeding under the skin will produce a bruise.  A small scar may persist for several weeks.  The 
925 
risk of local infection is less than 1 in 1000.  This should not be a significant contributor to risks in 
926 
this study as finger sticks are part of the usual care for people with diabetes. 
927 
 Subcutaneous Catheter Risks (CGM) 
928 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
929 
the sensor needle placement.  If a catheter is left under the skin for more than 24 hours it is 
930 
possible to get an infection where it goes into the skin, with swelling, redness and pain.  There 
931 
may be bleeding where the catheter is put in and bleeding under the skin causes a bruise (1 in 10 
932 
risk). 
933 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
934 
leave a small portion of the sensor under the skin that may cause redness, swelling, or pain at 
935 
the insertion site.  The participant should be further instructed to notify the study coordinator 
936 
immediately if this occurs. 
937 
 Risks of Hypoglycemia  
938 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low 
939 
blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and possibly less 
940 
than it would be as part of daily living.  Symptoms of hypoglycemia can include sweating, 
941 
jitteriness, and not feeling well.  Just as at home, there is the possibility of fainting or seizures 
942 

CLINICAL PROTOCOL 
 
 
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(convulsions) and that for a few days the participant may not be as aware of symptoms of 
943 
hypoglycemia.  A CGM functioning poorly and significantly over-reading glucose values could lead 
944 
to inappropriate insulin delivery. 
945 
 Risks of Hyperglycemia  
946 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
947 
extended period or if the pump or infusion set is not working properly.  A CGM functioning poorly 
948 
and significantly under-reading glucose values could lead to inappropriate suspension of insulin 
949 
delivery. 
950 
 Risks of Device Reuse  
951 
Participant will be informed that FDA or relevant national authorities have approved the insulin 
952 
pump, CGM, glucometer and ketone meter for single use and that by using them among multiple 
953 
patients, bloodborne pathogens (e.g. Hepatitis B) may be spread through the use of multiple 
954 
users. 
955 
The study CGM system is labeled for single use only. The sensor (the component of the system 
956 
that enters the skin) will be single use only. The transmitter and receiver may be reused during 
957 
the study after cleaning the device using a hospital-approved cleaning procedure. The transmitter 
958 
is attached to the sensor but does not enter the skin and the receiver, if used, is a hand held 
959 
device.  
960 
The study insulin pumps are labeled for single-patient use. During the study, this device may be 
961 
reused after cleaning adhering to a hospital-approved cleaning procedure. All infusion set 
962 
equipment will be single patient use only (infusion set insertion kits, tubing, cartridges etc.)   
963 
The study blood glucose meter and blood ketone meter are labeled for single-patient use. 
964 
During the study, these devices may be reused after cleaning adhering to a hospital-approved 
965 
cleaning procedure.   
966 
 Device Cleaning Instructions 
967 
CGM cleaning instructions are provided in the Dexcom G4 PLATINUM (Professional) Cleaning and 
968 
Disinfection manual (current edition). The transmitter should be cleaned with Clorox Healthcare® 
969 
Bleach Germicidal Cleaner or any disinfectant product in a spray bottle containing a bleach 
970 
solution of 6500 parts per million with the EPA registration number 56392-7.  The transmitter 
971 
will be submerged in this solution and then placed on an absorbent wipe or clean surface.  Two 
972 
sprays will be dispensed from the Clorox cleaner onto each side of the transmitter. A nylon brush 
973 
will be used to scrub the transmitter on all sides for 30 seconds.  The transmitter will be placed 
974 
in the Clorox Cleaner solution for one minute. Transmitter is then rinsed under flowing tap water 
975 

CLINICAL PROTOCOL 
 
 
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for ten seconds. The transmitter will then be disinfected using a disinfectant product with EPA 
976 
registration number 56392-7 using similar procedures as the cleaning process.   
977 
Per the pump manufacturer, the insulin pump will be cleaned with a damp lint-free cloth. Use of 
978 
household or industrial cleaners, solvents, bleach, scouring pads, chemicals, or sharp instruments 
979 
are prohibited. The pump should never be submerged in water. If needed, use only a very mild 
980 
detergent, such as a bit of liquid soap with warm water. A soft towel will be used to dry the pump.  
981 
The Bayer Contour Next glucometer is cleaned and disinfected with two separate Super Sani-
982 
Cloths (EPA number 9480-4). The entire surface will be cleaned, making sure the surface stays 
983 
wet for 2 minutes. This step is repeated with a clean cloth for disinfecting the device.  
984 
The Precision Xtra User’s Guide suggests that healthcare professionals use 10% bleach, 70% 
985 
alcohol or 10% ammonia to clean the device.  
986 
Equipment that touches intact skin will be cleaned with ethyl or isopropyl alcohol (70-90%), 
987 
quaternary ammonium germicidal detergent (i.e. Cavicide, EPA number 46781) or household 
988 
bleach. The contact time on the surface depends on the method used to clean the equipment. 
989 
Cavicide requires three minutes on the surface of the equipment. Clorox Germicidal Bleach Wipes 
990 
require two minutes on the equipment. The surface should remain wet (i.e. slightly damp) with 
991 
the disinfectant to be considered effective though not wet enough to leave drops of liquid.  
992 
In the event a manufacturer updates cleaning procedures for their device, the study team will 
993 
adhere to the most current recommendations.  
994 
There is the risk of blood sampling collection and contamination from sampling techniques. Hand 
995 
washing with either soap & water or waterless hand sanitizer will be used prior to caring for the 
996 
study subject. Gloves will be worn during blood sample collection and processing. Medical 
997 
personnel will continue to practice hygiene for the subject’s protection (i.e. hand washing, 
998 
changing gloves frequently, disposing needles properly). Gloves will be removed and hands 
999 
washed or sanitized prior to leaving and upon return to the subject’s room. Soiled linen will be 
1000 
changed to minimize the transfer of pathogenic organisms. 
1001 
 Hb1Ac Risk 
1002 
An NGSP Point of Care analyzer (i.e. DCA Vantage Analyzer) will be utilized at the research site to 
1003 
obtain the subject’s HbA1c level. 
1004 
 Other Risks  
1005 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
1006 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
1007 

CLINICAL PROTOCOL 
 
 
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If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
1008 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
1009 
medication may be required. 
1010 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion 
1011 
sites are inserted under the skin.  It is possible that any part that is inserted under the skin may 
1012 
cause an infection.  These occur very infrequently, but, if an infection was to occur, oral and/or 
1013 
topical antibiotics can be used.  The risk of skin problems could be greater if you use a sensor for 
1014 
longer than it is supposed to be used.  Therefore, participants will be carefully instructed about 
1015 
proper use of the sensor. 
1016 
Data downloaded from the CGM, pump, and glucose and ketone meter, if accessible, will be 
1017 
collected for the study as measures of diabetes self-management behaviors.  Some people 
1018 
may be uncomfortable with the researchers' having such detailed information about their daily 
1019 
diabetes habits. 
1020 
 Known Potential Benefits  
1021 
It is expected that this protocol will yield increased knowledge about using an automated 
1022 
closed-loop system with anticipatory action to control glucose levels.  The individual participant 
1023 
may not benefit from study participation. 
1024 
 Risk Assessment 
1025 
Based on the facts that (1) adults and adolescents with diabetes experience mild hypoglycemia 
1026 
and hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
1027 
intervention involves periodic automated insulin dosing that may increase the likelihood of 
1028 
hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the 
1029 
likelihood of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies 
1030 
using the investigational device system in the home setting, that limit the likelihood of excessive 
1031 
insulin dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and 
1032 
hyperglycemia can be achieved, it is the assessment of the investigators that this protocol falls 
1033 
under DHHS 46.405 which is a minor increase over minimal risk. In addition, it is the belief of the 
1034 
investigators that this study also presents prospect of direct benefit to the participants and 
1035 
general benefit to others with diabetes. 
1036 
 
1037 
 Empagliflozin Adverse Reactions 
1038 
The most recognized adverse reactions associated with the use of Empagliflozin are urinary tract 
1039 
infections and mycotic genital infections occurring in both men and women.  
1040 

CLINICAL PROTOCOL 
 
 
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Nausea, vomiting, abdominal pain, generalized malaise, acute febrile illness, reduced caloric 
1041 
intake due to illness or surgery, alcohol abuse, and shortness of breath may result in adverse 
1042 
reactions. The study physician may consider temporarily discontinuing Empagliflozin in any 
1043 
setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as 
1044 
gastrointestinal illness or excessive heat exposure).  
1045 
After initiating therapy, participants will be monitored for increased urination and dehydration. 
1046 
Participants will be informed that dehydration may increase the risk of hypotension and, 
1047 
therefore, will be encouraged to increase their fluid intake while taking the medication. 
1048 
Participates will also be advised that a majority of infections can be prevented by maintaining 
1049 
attention to basic hygiene include regular washing after urination.  
1050 
Ketoacidosis is a common adverse reaction with the use of Empagliflozin.  Ketone measurement 
1051 
instructions are detailed in section 10.5.  
1052 
While very rare, participants treated with Empagliflozin may present with pain or tenderness, 
1053 
erythema, or swelling in the genital or perineal area, along with fever or malaise, and should be 
1054 
assessed for necrotizing fasciitis. If suspected, the study team will assess and refer the participant 
1055 
for appropriate care. Empagliflozin will be discontinued and blood glucose levels will be closely 
1056 
monitored, and provide appropriate alternative therapy for glycemic control. The study physician 
1057 
will contact the participant’s personal physician. 
1058 
 
1059 
The study is being conducted in compliance with the policies described in the study policies 
1060 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
1061 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
1062 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
1063 
considered the source data. 
1064 
The protocol is considered a significant risk device study, due to the fact that the closed loop 
1065 
system is experimental.  Therefore, an investigational device exemption (IDE) from the U.S. Food 
1066 
and Drug Administration (FDA) is required to conduct the study. 
 
1067 

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Chapter 13   Adverse Events, Device Issues, and Stopping Rules 
1068 
 
1069 
 Adverse Events (AE) 
1070 
Any untoward medical occurrence in a study participant, irrespective of the relationship between 
1071 
the adverse event, the study drug, and the device(s) under investigation (section 13.2) for 
1072 
reportable adverse events for this protocol). Pregnancy will not be considered an adverse event. 
1073 
 Serious Adverse Event (SAE) 
1074 
 Any untoward medical occurrence that: 
1075 
Results in death. 
1076 
Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1077 
become life-threatening, is not necessarily considered a serious adverse event). 
1078 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
1079 
Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
1080 
conduct normal life functions (life threatening). 
1081 
Is a congenital anomaly or birth defect. 
1082 
Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1083 
may jeopardize the participant or may require medical/surgical intervention to prevent one 
1084 
of the outcomes listed above). 
1085 
 Unanticipated Adverse Device Effect (UADE) 
1086 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
1087 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
1088 
nature, severity, or degree of incidence in the investigational plan or application (including a 
1089 
supplementary plan or application), or any other unanticipated serious problem associated with 
1090 
a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
1091 
 Adverse Device Effect (ADE) 
1092 
Any untoward medical occurrence in a study participant which the device may have caused or to 
1093 
which the device may have contributed. 
1094 
 Device Complaints and Malfunctions 
1095 
A device complication or complaint is something that happens to a device or related to device 
1096 
performance, whereas an adverse event happens to a participant.  A device complaint may occur 
1097 
independently from an AE, or along with an AE.  An AE may occur without a device complaint or 
1098 
there may be an AE related to a device complaint.  A device malfunction is any failure of a device 
1099 

CLINICAL PROTOCOL 
 
 
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to meet its performance specifications or otherwise perform as intended.  Performance 
1100 
specifications include all claims made in the labeling for the device.  The intended performance 
1101 
of a device refers to the intended use for which the device is labeled or marketed. (21 CFR 803.3).   
1102 
 
1103 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
1104 
meets one of the following criteria: 
1105 
A serious adverse event as defined in section 13.1.2 
1106 
An Adverse Device Effect as defined in section 13.1.4, unless excluded from reporting in section 
1107 
13.7 
1108 
An Adverse Event as defined in section 13.1.4 occurring in association with a study procedure 
1109 
An AE as defined in section 13.1.1 which leads to discontinuation of  a study device  for 2 or 
1110 
more hours 
1111 
Hypoglycemia meeting the definition of severe hypoglycemia as defined in section 13.2.1  
1112 
Diabetic ketoacidosis (DKA) as defined in section 13.2.2 or in the absence of DKA, a 
1113 
hyperglycemic or ketosis event meeting the criteria defined below 
1114 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
1115 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor placement 
1116 
are only reportable if severe and/or required treatment. 
1117 
 Hypoglycemia Event 
1118 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
1119 
when the following definition for severe hypoglycemia is met:   
1120 
The event required assistance of another person due to altered consciousness, and required 
1121 
another person to actively administer carbohydrate, glucagon, or other resuscitative actions;  
1122 
Impaired cognitively to the point that he/she was unable to treat himself/herself, was unable to 
1123 
verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced 
1124 
seizure or coma.  These episodes may be associated with sufficient neuroglycopenia to 
1125 
induce seizure or coma; 
1126 
If plasma glucose measurements are not available during such an event, neurological recovery 
1127 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence 
1128 
that the event was induced by a low plasma glucose concentration. 
1129 
 Hyperglycemia Events/Diabetes Ketoacidosis 
1130 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1131 
event when one of the following four criteria is met:  
1132 

CLINICAL PROTOCOL 
 
 
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The event involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) and 
1133 
described below 
1134 
Evaluation or treatment was obtained at a health care provider facility for an acute event 
1135 
involving hyperglycemia or ketosis 
1136 
Blood ketone level ≥1.5 mmol/L and communication occurred with a health care provider at the 
1137 
time of the event 
1138 
Blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
1139 
provider 
1140 
Hyperglycemic events are classified as DKA if the following are present: 
1141 
Symptoms such as polyuria, polydipsia, nausea, or vomiting 
1142 
Serum ketones ≥1.5 mmol/L or large/moderate urine ketones 
1143 
Ketosis as defined by symptoms and ketones regardless of treatment provided in a health care 
1144 
facility 
1145 
All reportable Adverse Events—whether volunteered by the participant, discovered by study 
1146 
personnel during questioning, or detected through physical examination, laboratory test, or 
1147 
other means—will be reported on an adverse event form online.  Each adverse event form is 
1148 
reviewed by a Study Physician to verify the coding and the reporting that is required. 
1149 
 
1150 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1151 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1152 
by the study device. 
1153 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1154 
following general guideline when determining whether an adverse event is related: 
1155 
There is a plausible temporal relationship between the onset of the adverse event and the 
1156 
study intervention, and the adverse event cannot be readily explained by the participant’s 
1157 
clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event follows 
1158 
a known pattern of response to the study intervention; and/or the adverse event abates or 
1159 
resolves upon discontinuation of the study intervention or dose reduction and, if applicable, 
1160 
reappears upon re-challenge. 
1161 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
1162 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1163 
medication); and/or the adverse event has no plausible temporal relationship to study 
1164 
intervention. 
1165 

CLINICAL PROTOCOL 
 
 
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1166 
The intensity of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, or 
1167 
(3) severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 
1168 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
1169 
but may not be clinically serious. 
1170 
MILD: Usually transient, requires no special treatment, and does not interfere with the 
1171 
participant’s daily activities. 
1172 
MODERATE: Usually causes a low level of inconvenience or concern to the participant and may 
1173 
interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
1174 
SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug 
1175 
therapy or other treatment. 
1176 
 
1177 
Adverse events will be coded per the UVA IRB website instructions (i.e. mild, moderate, severe).  
1178 
The DSMB will review the investigator’s assessment of causality and may agree or disagree.  Both 
1179 
the investigator’s and DSMB’s assessments will be recorded.  The DSMB will have the final say in 
1180 
determining the causality. 
1181 
Adverse events that continue after the participant’s discontinuation or completion of the study 
1182 
will be followed until their medical outcome is determined or until no further change in the 
1183 
condition is expected. 
1184 
 
1185 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1186 
RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae.  Record 
1187 
the AE/SAE stop date. 
1188 
RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized without 
1189 
change in the event anticipated.  Record the AE/SAE stop date. 
1190 
FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event that was 
1191 
the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the time of 
1192 
death; however, were not the cause of death, will be recorded as “resolved” at the time of 
1193 
death. 
1194 
NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as the event was 
1195 
ongoing with an undetermined outcome. 
1196 
An ongoing outcome will require follow-up by the site in order to determine the final outcome 
1197 
of the AE/SAE. 
1198 
The outcome of an ongoing event at the time of death that was not the cause of death, will be 
1199 
updated and recorded as “resolved” with the date of death recorded as the stop date. 
1200 

CLINICAL PROTOCOL 
 
 
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UNKNOWN – An unknown outcome is defined as an inability to access the participant or the 
1201 
participant’s records to determine the outcome (for example, a participant that was lost to 
1202 
follow-up). 
1203 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
1204 
occurring during the study and continuing at study termination should be followed by the 
1205 
participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
1206 
underlying cause, or resolution.  Follow-up information should be recorded on source 
1207 
documents. 
1208 
If any reported adverse events are present when a participant completes the study, or if a 
1209 
participant is withdrawn from the study due to an adverse event, the participant will be 
1210 
contacted for re-evaluation within 2 weeks.  If the adverse event has not resolved, additional 
1211 
follow-up will be performed as appropriate.  Every effort should be made by the Investigator or 
1212 
delegate to contact the participant until the adverse event has resolved or stabilized. 
1213 
 
1214 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
1215 
whether an adverse event occurred, except in the following circumstances. 
1216 
The following device issues are anticipated and will not be reported but will reported as an 
1217 
Adverse Event if the criteria for AE reporting described above are met: 
1218 
Component disconnections 
1219 
CGM sensors lasting fewer than the number of days expected per CGM labeling 
1220 
CGM tape adherence issues 
1221 
Pump infusion set occlusion not leading to ketosis 
1222 
Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
1223 
Intermittent device component disconnections/communication failures not leading to system 
1224 
replacement 
1225 
Device issues clearly addressed in the user guide manual that do not require additional 
1226 
troubleshooting 
1227 
Skin reactions from CGM sensor placement or pump infusion set placement that do not meet 
1228 
criteria for AE reporting 
1229 
 
1230 
UADEs must be reported within 10 working days to the FDA after the sponsor first receives 
1231 
notice of the adverse effect. 
1232 
Other reportable adverse events, device malfunctions (with or without an adverse event) and 
1233 
device complaints should be reported promptly, but there is no formal required reporting 
1234 
period. 
1235 

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The IDE Sponsor will investigate the UADE and if indicated, report the results of the 
1236 
investigation to the IRBs, FDA, and DSMB within 10 working days of the study team 
1237 
becoming aware of the UADE per 21CFR 812.46(b) (2).  
1238 
The DSMB will determine if the UADE presents an unreasonable risk to participants. If so, the 
1239 
DSMB must ensure that all investigations, or parts of investigations presenting that risk, are 
1240 
terminated as soon as possible but no later than 5 working days after the DSMB makes this 
1241 
determination and no later than 15 working days after first receipt notice of the UADE. 
1242 
In the case of a device system component malfunction (e.g. pump, CGM, control algorithm), 
1243 
information will be forwarded to the responsible manufacturer by the study personnel. 
1244 
 
1245 
 Participant Discontinuation  
1246 
Rules for discontinuing study device use are described below. 
1247 
The investigator believes it is unsafe for the participant to continue on the intervention.  This 
1248 
could be due to the development of a new medical condition or worsening of an existing 
1249 
condition; or participant behavior contrary to the indications for use of the device that 
1250 
imposes on the participant’s safety 
1251 
The participant requests that the treatment be stopped 
1252 
Two distinct episodes of DKA that are not attributable to the study drug 
1253 
One distinct episode of DKA directly attributable to the study drug  
1254 
Two distinct severe hypoglycemia events as defined in section 13.2.1. 
1255 
 Suspending/Stopping Overall Study 
1256 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
1257 
hyperglycemia event (as defined in section 13.2), use of the study device system will be 
1258 
suspended while the problem is diagnosed. 
1259 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1260 
study device requires stoppage of device use for safety reasons (e.g. product recall).  The affected 
1261 
study activities may resume if the underlying problem can be corrected by a protocol or system 
1262 
modification that will not invalidate the results obtained prior to suspension. The study Medical 
1263 
Monitor will review all adverse events and adverse device events that are reported during the 
1264 
study and will review compiled safety data at periodic intervals (generally timed to the review of 
1265 
compiled safety data by the DSMB). The DSMB may request suspension of study activities or 
1266 
stoppage of the study if deemed necessary based on the totality of safety data available. 
1267 
In the event that two subjects experience urosepsis, AKI, fournier’s gangrene, severe genital 
1268 
mycotic infections and hypotension requiring hospitalization, the study will be paused to discuss 
1269 
events with the DSMB. 
1270 

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1271 
A DSMB will review all DKA and severe hypoglycemia irrespective of relatedness to study device 
1272 
use, and all serious events (including UADEs) related to study device use at the time of 
1273 
occurrence. The DSMB can request modifications to the study protocol or suspension or outright 
1274 
stoppage of the study if deemed necessary based on the totality of safety data available. Details 
1275 
regarding DSMB review will be documented in a separate DSMB document.   
 
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Chapter 14 Miscellaneous Considerations  
1277 
 
1278 
Participants using glulisine at the time of enrollment will be asked to contact their personal 
1279 
physician to change their prescribed personal insulin to lispro or aspart for the duration of the 
1280 
trial. 
1281 
The study devices (study insulin pump, study CGM) must be removed before Magnetic Resonance 
1282 
Imaging (MRI), Computed Tomography (CT) or diathermy treatment. Participants may continue 
1283 
in the trial after temporarily discontinuing use if requiring one of the treatments above. 
1284 
 
1285 
Participation in the study is voluntary. Participant may withdraw at any time.  For participants 
1286 
who do withdraw from the study, the study team will determine if their data will be used in 
1287 
analysis.  
1288 
 
1289 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
1290 
instead of their name.  Protected health information gathered for this study may be shared with 
1291 
the third party collaborators.  De-identified subject information may also be provided to 
1292 
collaborators involved in the study after the appropriate research agreement has been executed. 
1293 

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Chapter 15 Statistical Consideration 
1294 
 
1295 
As presented in Figure 1, this study uses a randomized controlled design, with participants 
1296 
randomly assigned to four groups as follows: 
1297 
a. Groups 1 and 2 are assigned to Experimental condition – use of SGLT2 inhibitor 
1298 
(Empagliflozin) plus technology (CGM, Basal IQ or Control IQ) 
1299 
b. Groups 3 and 4 are assigned to Control condition – no use of SGLT2 inhibitors; 
1300 
use of technology only (CGM, Basal IQ or Control IQ) 
1301 
All four groups participate in a 1-2 week baseline CGM sessions, after which Groups 1 and 3 begin 
1302 
use of Control IQ, while Groups 2 and 4 begin use of Basal IQ. After using Control IQ or Basal IQ 
1303 
for 4 or 2 weeks, respectively, all groups switch to use of the alternative technology (Figure 1). 
1304 
The primary purpose of this pilot study is to evaluate the safety and efficacy of combining SGLT2 
1305 
inhibitors with closed loop control, and to gauge the effect size of the outcomes listed below. 
1306 
Nevertheless, the projected sample size of N=40 (N= 60 recruited) participants is expected to 
1307 
results in statistically significant differences on some outcomes: 
1308 
Primary Outcome: CGM-measured time in the target range 70-180mg/dl (TIR) during the day; 
1309 
Hierarchical secondary outcomes: 24/7 CGM time in range <70mg/dl; 24/7 CGM-measured 
1310 
average glucose; CGM-measured glucose variability (coefficient of variation, CV) during the day; 
1311 
risks for hypo- and hyperglycemia. 
1312 
Analysis Overview: The overall analysis will follow Intention-to-treat (ITT) approach, with each 
1313 
participant analyzed according to the treatment assigned by initial randomization. The study 
1314 
design includes repeated measures on all outcomes; thus, we will use a linear mixed-effect model 
1315 
that corresponds well to this structure. The mixed model will use “Subject” as a random factor 
1316 
and “Group” as a fixed factor, e.g. using the Linear Mixed Models procedure in SPSS. We should 
1317 
note that similar results may be generated by repeated measures ANOVA, but mixed models 
1318 
handle missing data better (e.g. ANOVA only uses listwise deletion, which could reduce power 
1319 
and introduce bias towards study completers). A mixed model is also more flexible and will allow 
1320 
us to address additional questions, such as clustering of subjects or introducing time between 
1321 
assessments as a continuous variable.  
1322 
Data Sources: Continuous glucose monitoring (CGM) data acquired every 5 minutes during the 
1323 
baseline and throughout the study. CGM data will be used to compute established metrics of 
1324 
glycemic control (e.g. time in ranges), risks for hypo- and hyperglycemia, e.g. the Low and High 
1325 
BG Indices (LBGI/HBGI), and CV, as recommended by the Consensus on Use of CGM, to which our 
1326 
team contributed substantially. 
1327 

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Handling of Missing Data: All randomized participants who have at least 50% of their CGM 
1328 
readings during the study period will be included in the analysis. Occasional missing CGM data 
1329 
do occur during normal CGM use and these values will be ignored when summary CGM metrics 
1330 
(e.g. percent times in range, LBGI, HBGI) are computed. Typically, CGM data are voluminous and 
1331 
the percent of missing values is low; thus no imputation would be required. For example, in the 
1332 
recently completed multi-center Protocol 3 of the International Diabetes Closed Loop Trial, 
1333 
N=168 subjects (of N=168 recruited) completed the entire 6-month protocol, and CGM data were 
1334 
available 96% of the time [15] (Table 1).  
1335 
Safety outcomes will be reported for all enrolled participants, irrespective of whether the 
1336 
subjects were randomized or the study was completed. 
1337 
Data Analysis: The objectives of this study are addressed by different sub-analyses of our general 
1338 
analytical scheme, as follows:   
1339 
Objective 1: Effect of adding Empagliflozin to predictive low glucose suspend (Basal IQ – 2 
1340 
weeks) and closed-loop control (Control IQ – 4 weeks) will be assessed by the study 
1341 
randomized design (Figure 1). In this design we will have N=20 participants on Empagliflozin 
1342 
and N=20 participants off Empagliflozin, beginning with Control IQ and then switching to 
1343 
Basal IQ, or beginning with Basal IQ and then switching to Control IQ. This analysis will be 
1344 
done using the baseline data as covariates in a general linear model. 
1345 
Objective 2: CGM-measured effect of Empagliflozin will be assessed using the baseline CGM 
1346 
data, (between Visits 2 and 3) via direct contrast between the two Experimental and two 
1347 
Control groups (N=20 participants in Groups 1-2 vs 20 participants in Groups 3-4); 
1348 
Objective 3: CGM-measured effects of Empagliflozin added to Basal IQ will be assessed by 
1349 
direct comparison of the Experimental vs Control groups during the Basal IQ sessions (N=20 
1350 
participants per arm will be available to this analysis); 
1351 
Objective 4: CGM-measured effects of Empagliflozin added to Control IQ will be assessed 
1352 
by direct comparison of the Experimental vs Control groups during the Control IQ sessions 
1353 
(N=20 participants per arm will be available to this analysis); 
1354 
To preserve the overall type 1 error, a hierarchical testing procedure will be used: if the primary 
1355 
analysis for CGM-measured TIR 70-180mg/dL during the day is statistically significant (p < 0.05), 
1356 
then testing will proceed to the next outcome metric in the following order: CGM-measured 24/7 
1357 
percent time <70mg/dL; CGM-measured average glucose; CGM-measured CV during the day; 
1358 
LBGI and HBGI. This process will continue iteratively moving to the next variable down on the list 
1359 
until a non-significant result (p ≥ 0.05) is observed, or all variables have been tested. If a non-
1360 
significant result is encountered, then formal statistical hypothesis testing is terminated and any 
1361 
variables remaining on the list become exploratory. 
1362 

CLINICAL PROTOCOL 
 
 
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1363 
Sample Size Determination is based on data from our Protocol 3 of the recently completed iDCL 
1364 
Trial (Table 1) conducted with the same algorithm in the same population. The Pre-Post changes 
1365 
in TIR in Table 1indicate effect size of >0.7 of Control IQ compared to SAP. Knowing the action of 
1366 
Basal IQ and Control IQ, and the action of Empagliflozin, we can assume that Empagliflozin will 
1367 
double the effect of Basal IQ and Control IQ during the day and will preserve their benefits 
1368 
overnight. This, a 1:1 randomization into two Experimental vs. two Control groups and N=20 
1369 
participants per study arm, yields a sample size on N=40 subjects to complete the study. This 
1370 
sample size was computed using the G*Power 3 software under the assumptions of power=90% 
1371 
and type 1 error α=0.01, further reinforcing the feasibility of the hierarchical analyses described 
1372 
above. In our experience with long-term AP studies, we observe attrition rate of 20%, with most 
1373 
dropouts occurring during the baseline prior to randomization. Thus, the recruitment sample size 
1374 
was increased to N=60 to accommodate up to 20% attrition rate without sacrificing statistical 
1375 
power. We should also note that technology improvement appears to increase the retention rate 
1376 
in recent large-scale trials. For example, it the iDCL protocol 3, only 2 out of 170 recruited 
1377 
participants dropped out and all 168 randomized participants completed the 6-month study. 
1378 
Table 1: Glycemic control 
results from Protocol 3: 
N=168 patients who used 
Control IQ for 6 months 
Baseline (2 weeks) 
Post-Randomization (26 weeks) 
CLC 
SAP 
CLC 
SAP 
Differenc
e 
p value 
CGM use during the 
study 
 
 
97% 
96% 
 
 
Percent below 70 
mg/dL 
3.59 ± 
3.39% 
2.82 ± 
2.53% 
1.59 ± 
1.15% 
2.25 ± 
1.46% 
-0.88% 
<0.0001 
Percent 70-180 mg/dL 
(study primary 
outcome) 
60 ± 17% 
59 ± 14% 
71 ± 12% 
59 ± 15% 
+11% 
<0.0001 
Percent above 180 
mg/dL 
36 ± 19% 
38 ± 15% 
27 ± 12% 
39 ± 15% 
-10% 
<0.0001 

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Overall, the studies using the AP algorithm originally developed at the University of Virginia, have 
1379 
logged >65,000 days of use to date, in 31 clinical trials enrolling over 600 children and adults with 
1380 
type 1 diabetes at 15 clinical centers in the U.S. and Europe (Table 1). Control IQ is the third 
1381 
commercial-grade generation of this algorithm, which will be used in this study. 
1382 
 
1383 
 Primary Efficacy Endpoint  
1384 
To demonstrate the efficacy of Empagliflozin as adjuvant therapy added to a closed loop artificial 
1385 
pancreas system (AP-EMPA) in patients with T1DM. The primary efficacy outcome variable will 
1386 
be time in range (70-180 mg/dl). Secondary efficacy outcomes will be: time below 70 mg/dl, time 
1387 
above 180 mg/dl, time between 70-140 mg/dl 5 hours postprandial, glucose variability indices 
1388 
(HBGI, LBGI, ADRR). The corresponding variables obtained from the NO-AP-EMPA arm will be the 
1389 
comparator.  
1390 
 Secondary Outcome 
1391 
To evaluate the safety of Empagliflozin as adjuvant therapy added to a closed loop artificial 
1392 
pancreas system (AP-EMPA) in subjects with T1DM by monitoring: 
1393 
Episodes of diabetic ketoacidosis (DKA) 
1394 
Episodes of severe hypoglycemia (glucose <50 mg/dl) 
1395 
Genital infections (balanitis, urethritis, vulvar infections, Fournier’s gangrene)  
1396 
Urinary tract infections 
1397 
Other AE CGM based LBGI & HBGI 
1398 
Furthermore, we will compute 
1399 
Total amount of insulin used 
1400 
Number of hyperglycemic episodes as defined by contiguous CGM above 300mg/dL 
1401 
Percent above 250 
mg/dL 
12.4 ± 
12.8% 
11.9 ± 9.9% 7.0 ± 6.7% 
12.4 ± 
10.3% 
-5.5% 
<0.0001 
HbA1c 
7.4% 
7.4% 
7.06% 
7.4% 
-0.33% 
=0.0014 
Mean glucose [mg/dL] 
166 ± 32 
169 ± 25 
156 ± 19 
170 ± 25 
-13 
<0.0001 
Coefficient of 
Variation 
37 ± 6% 
36 ± 5% 
34 ± 5% 
36 ± 5% 
-3% 
<0.0001 

CLINICAL PROTOCOL 
 
 
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Page 66 of 72 
 
 
1402 
All randomized participants will be included in these analyses and the circumstances of all 
1403 
reportable cases of the following will be summarized and tabulated by treatment group: 
1404 
Severe hypoglycemia 
1405 
Diabetic ketoacidosis 
1406 
Other serious adverse events and serious adverse device events 
1407 
Unanticipated adverse device effects 
1408 
 
1409 
Baseline demographic and clinical characteristics of the cohort of all randomized participants will 
1410 
be summarized in a table using summary statistics appropriate to the distribution of each 
1411 
variable. Descriptive statistics will be displayed overall and by treatment group. 
1412 
Will include: 
1413 
Age 
1414 
HbA1c 
1415 
Gender 
1416 
Race/ethnicity 
1417 
CGM use before enrollment 
1418 
Diabetes duration 
1419 
BMI 
1420 
 
1421 
The following tabulations and analyses will be performed by treatment group to assess device 
1422 
issues: 
1423 
Device malfunctions requiring study team contact and other reported device issues 
1424 
Sensor performance metrics (difference, absolute relative difference, and International 
1425 
Organization for Standardization criteria) – if applicable, by sensor version. 
1426 
% time CGM data available - overall and by month 
1427 
The following tabulations will be performed for the Experimental arm only: 
1428 
Performance metrics, describing the CLC system and its components like: 
1429 
a. % time CGM data were available to the CLC system – overall and by month 
1430 
b. % time in different operational modes per week - overall and by month  
1431 
c. Rate of different failure events and alarms per 48 hours recorded by the CLC 
1432 
system – overall and by month 
1433 

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Rationale for sample size determination: Use of Empagliflozin could potentially ‘double the 
1434 
effect’ of Basal-IQ and Control IQ during the day by lowering postprandial glucose concentrations 
1435 
based on the following rationale.  
1436 
a. Studies have demonstrated reduced hepatic glycogen synthesis resulting in 
1437 
reduced net hepatic glycogen content in poorly controlled T1D compared to 
1438 
nondiabetic controls [16]. In contrast, in well controlled T1DM subjects, initial 
1439 
splanchnic glucose uptake was not reduced when compared to matched 
1440 
nondiabetic controls [17]. Taken together, assuming usual daily carbohydrate 
1441 
intake of ~ 180 grams (i.e., 60 grams per main meal) in an adult with T1DM, and a 
1442 
net splanchnic extraction of ingested carbohydrates of ~ 25% [17], ~ 75% of 
1443 
ingested carbohydrates (~ 135 grams) would appear daily into the circulation. 
1444 
Given a relatively conservative estimate that ~ half the ingested carbohydrates 
1445 
are taken up by the peripheral tissues, that leaves ~ 70 grams of ingested 
1446 
carbohydrates/day to contribute to postprandial glucose excursions.   
1447 
b. Based on data obtained from the prescribing information of Empagliflozin that 10 
1448 
mg of Empagliflozin results in net urinary loss of 64 grams of glucose per day [18], 
1449 
it is reasonable to assume that adjuvant use of this medication with Control-IQ or 
1450 
Basal-IQ would at least “double the effects” of lowering postprandial glucose 
1451 
concentrations in this clinical trial.   
 
1452 

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Chapter 16  Data Collection and Monitoring 
1453 
 
1454 
The study data are collected through a combination of case report forms (electronic and paper) 
1455 
and electronic device data files obtained from the software and individual hardware 
1456 
components.  These electronic device files and electronic CRFs are considered the primary source 
1457 
documentation. 
1458 
When data are directly collected in electronic case report forms, this will be considered the 
1459 
source data.  Records will be maintained in accordance with ICH E6 and institutional regulatory 
1460 
requirements for the protection of confidentiality of participants. 
1461 
 
1462 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1463 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1464 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1465 
discontinuation of clinical development of the investigational product.  These documents should 
1466 
be retained for a longer period, however, if required by local regulations.  No records will be 
1467 
destroyed without the written consent of the sponsor, if applicable.  It is the responsibility of the 
1468 
sponsor to inform the investigator when these documents no longer need to be retained. 
1469 
 
1470 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practices 
1471 
(GCP), or procedure requirements.  The noncompliance may be either on the part of the 
1472 
participant, the investigator, or the study site staff.  As a result of deviations, corrective actions 
1473 
may be developed by the site and implemented as appropriate.  Major deviations will be reported 
1474 
to the IRB-HSR within 7 calendar days of when the study team becomes aware of the event.  
1475 

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Chapter 17 Ethics/Protection of Human Participants 
1476 
 
1477 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1478 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
1479 
CFR Part 56, and/or the ICH E6. 
1480 
 
1481 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1482 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1483 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1484 
require review and approval by the IRB before the changes are implemented to the study.  All 
1485 
changes to the consent form will be IRB approved; a determination will be made regarding 
1486 
whether previously consented participants need to be re-consented. 
1487 
 
1488 
 Consent Procedures and Documentation 
1489 
Informed consent is a process that is initiated prior to an individual’s agreement to participate in 
1490 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1491 
risks and possible benefits of participation will be provided.  Consent forms will be IRB approved 
1492 
and the participant will be asked to read and review the document.  The investigator or their 
1493 
delegate will explain the research study to the participant and answer any questions that may 
1494 
arise.  All participants will receive a verbal explanation in terms suited to their comprehension of 
1495 
the purposes, procedures, and potential risks of the study and of their rights as research 
1496 
participants.  Participant will have the opportunity to carefully review the written consent form 
1497 
and ask questions prior to signing. 
1498 
The participant will sign the informed consent document prior to any procedures being done 
1499 
specifically for the study. A copy of the informed consent document will be given to the 
1500 
participant for their records.  The rights and welfare of the participants will be protected by 
1501 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
1502 
decline to participate in this study. 
1503 
 Participant and Data Confidentiality 
1504 
The study monitor, representatives of the IRB or device company supplying study product may 
1505 
inspect all documents and records required to be maintained by the investigator, including but 
1506 
not limited to, medical records (office, clinic, or hospital) for the participants in this study.   
1507 

CLINICAL PROTOCOL 
 
 
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The study participant’s contact information will be securely stored at the clinical site for internal 
1508 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
1509 
location for as long a period as dictated by local IRB and Institutional regulations. 
1510 
Study participant research data, which is for purposes of statistical analysis and scientific 
1511 
reporting, will be transmitted to and stored at the University of Virginia Center for Diabetes 
1512 
Technology.  The study data entry and study management systems used by research staff will be 
1513 
secured and password protected.  At the end of the study, all study databases may be de-
1514 
identified and archived at the University of Virginia Center for Diabetes Technology. 
1515 

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Chapter 18 References  
1516 
1. Thabit, H., Hartnell, S., Allen, J. M., Lake, A., Wilinska, M. E., Ruan, Y., Evans M.L., Coll A.P., 
1517 
Hovorka, R. (2017). Closed-loop insulin delivery in inpatients with type 2 diabetes: a 
1518 
randomised, 
parallel-group 
trial. 
Lancet 
Diabetes 
Endocrinol, 
5(2), 
117-124. 
1519 
doi:10.1016/S2213-8587(16)30280-7. PMID: 27836235. 
1520 
2. Boughton, C. K., Bally, L., Martignoni, F., Hartnell, S., Herzig, D., Vogt, A., Wertli, M.M., 
1521 
Wilinska, M.E., Evans, M.L., Coll, A.P., Stettler, C., Hovorka, R. (2019). Fully closed-loop insulin 
1522 
delivery in inpatients receiving nutritional support: a two-centre, open-label, randomised 
1523 
controlled trial. Lancet Diabetes Endocrinol, 7(5), 368-377. doi:10.1016/S2213-
1524 
8587(19)30061-0. PMID: 30935872; PMCID: PMC6467839. 
1525 
3. Renukuntla, V. S., Ramchandani, N., Trast, J., Cantwell, M., & Heptulla, R. A. (2014). Role of 
1526 
glucagon-like peptide-1 analogue versus amylin as an adjuvant therapy in type 1 diabetes in 
1527 
a closed loop setting with ePID algorithm. J Diabetes Sci Technol, 8(5), 1011-1017. 
1528 
doi:10.1177/1932296814542153. PMID: 25030181:  PMCID: PMC4455387. 
1529 
4. Riddle, M. C., & Cefalu, W. T. (2018). SGLT Inhibitors for Type 1 Diabetes: An Obvious Choice 
1530 
or Too Good to Be True? Diabetes Care, 41(12), 2444-2447. doi:10.2337/dci18-0041. PMID: 
1531 
30459245. 
1532 
5. Heptulla, R. A., Rodriguez, L. M., Mason, K. J., & Haymond, M. W. (2009). Twenty-four-hour 
1533 
simultaneous subcutaneous Basal-bolus administration of insulin and amylin in adolescents 
1534 
with type 1 diabetes decreases postprandial hyperglycemia. J Clin Endocrinol Metab, 94(5), 
1535 
1608-1611. doi:10.1210/jc.2008-2580. PMID: 19190104: PMCID: PMC2684475. 
1536 
6. Sherr, J. L., Boyle, C. T., Miller, K. M., Beck, R. W., Tamborlane, W. V., & Network, T. D. E. C. 
1537 
(2016). No Summer Vacation From Diabetes: Glycemic Control in Pediatric Participants in the 
1538 
T1D Exchange Registry Based on Time of Year. Diabetes Care, 39(12), e214-e215. 
1539 
doi:10.2337/dc16-1522. PMID: 27703027; PMCID: PMC5321252. 
1540 
7. Zinman, B., Warner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, 
1541 
T., Johansen, O.E., Woerle, H.J., Broedl, C., Inzucci, S.E., for the EMPA-REG OUTCOME 
1542 
Investigators. (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 
1543 
Diabetes. NEJM 373: 2117-2128. doi: 10.1056/NEJMoa1504720. PMID: 31163986. 
1544 
8. Famulla, S., Pieber, T.R., Eibracht, J., Neubacher, D., Soleymanlou, N., Woerle, H.J., Broedl, 
1545 
U.C., Kaspers, S. (2017) Glucose Exposure and Variability with Empagliflozin as Adjunct to 
1546 
Insulin in Patients with Type 1 Diabetes:  Continuous Monitoring Data from a 4-week, 
1547 
Randomized, Placebo-Controlled Trial (EASE-1). Diabetes Technol Ther, 19(1), 49-60. 
1548 
Doi:10.1089/dia.2016.0261. PMID: 27929674 
1549 
9. Garg, S.K., Peters, A.L., Buse, J.B., Danne, T. (2018). Strategy for mitigating DKA risk in patients 
1550 
with type 1 diabetes on adjunctive treatement with SGLT inhibitors: a STICH protocol. 
1551 
Diabetes Technol Ther, 20:571-575. PMID: 301299772. 
1552 

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10. Wanner, C., Silvio, E., Inzucchi, M.D., Lachin, J.M., Fitchett, D., von Eynatten, M., Mattheus, 
1553 
M., Johansen, O.E., Woerle, H.J., Broedl, U.C., Zinman, B. (2016) Empagliflozin and 
1554 
Progression of Kidney Disease in Type 1 Diabetes. NEJM. 375:323-334. Doi: 
1555 
10.1056/NEJMMoal515920.  
1556 
11. Danne, T., Garg, S., Peters, A.L., Buse, J.B., Mathieu, C., Pettus, J.H., Alexander, C.M., 
1557 
Battelino, T., Ampudia-Biasco, F.J., Bode, B.W., Cariou, B., Close, K.L., Dandona, P., Dutta, S., 
1558 
Ferrannini, E., Fourlanos, S., Grunberger, G., Heller, S.R., Henry, R.R., Kurian, M.J., Kushner, 
1559 
J.A., Oron, T., Parkin, C.G., Pieber, T.R., Robard, H.W., Schatz, D., Skyler, J.S., Tamborlane, 
1560 
W.V. Yokote, K., Phillip, M. (2019) International Consensus on Risk Management of Diabetic 
1561 
Ketoacidosis in Patients with Type 1 Diabetes Treated with Sodium-Glucose Cotransporter 
1562 
(SGLT) Inibitors. Diabetes Care 42(6): 1147-1154. DOI:10.2337.  PMID: 30728224. 
1563 
12. Polonsky WH, Fisher L, Earles J, Dudl RJ, Lees J, Mullan J, Jackson RA.  (2005) Assessing 
1564 
psychosocial distress in diabetes: development of the diabetes distress scale. Diabetes Care 
1565 
28:626-631. PMID: 15735199. 
1566 
13. Gonder-Frederick LA, Schmidt KM, Vajda KA, Greear ML, Singh H, Shepard JA, Cox DJ. (2011) 
1567 
Psychometric properties of the hypoglycemia fear survey-ii for adults with type 1 diabetes. 
1568 
Diabetes Care 34:801-806.  
1569 
14. Weissberg-Benchell J, Hessler D, Polonsky WH, Fisher L. (2016) Psychosocial Impact of the 
1570 
Bionic Pancreas During Summer Camp. J Diabetes Sci Technol. 10(4):840-844. PMID: 
1571 
26993252; PMCID: PMC4928236.  
1572 
15. Brown S. Clinical Acceptance of the Artificial Pancreas: Glycemic Outcomes from a 6-month 
1573 
Multicenter RCT. American Diabetes Association 79th Scientific Sessions, San Francisco, CA, 
1574 
2019. 
1575 
16. Hwang, J.H., Perseghin, G., Rothman, D.L., Cline, G.W., Magnusson, I., Peterson, K.F., and 
1576 
Shulman, G.I. (1995) Impaired Net Hepatic Glycogen Synthesis in Insulin-Depedent Diabetic 
1577 
Subjects During Mixed Meal Ingestion.  A 13C Nuclear Magnetic Resonance Spectroscopy 
1578 
Study. J Clin Invest 95(2): 783-7. doi: 10.1172/JCI117727.  PMID: 7860761; PMCID: 
1579 
PMC295553.  
1580 
17. Vella, A., Shah, P., Basu, R., Basu, A., Camilleri, M., Schwenk, W.F., Rizza. R.A. (2001) Type 1 
1581 
Diabetes Mellitus Does Not Alter Initial Splanchnic Glucose Extraction or Hepatic UDP-
1582 
Glucose Flux During Enteral Glucose Administration. Diabetologia 44(6):729-37.  doi: 
1583 
10.1007/s00125005162. PMID: 11440366.  
1584 
18. Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim 
1585 
Pharmaceuticals, Inc.; 2018. 
1586