An Exploratory 16-Week Pilot Study of the Effect and Safety of a Novel CGM-Based Titration Algorithm for Basal Insulin, With or Without Non-Insulin Antidiabetic Drugs, in Type 2 Diabetes Mellitus Participants Treated With Basal Insulin.
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: University of Virginia

 
 
 
 
 
 
 
 
 
School of Medicine 
Center for Diabetes Technology 
 
An Exploratory 16-Week Pilot Study Of The Effect And Safety Of A Novel CGM-
Based Titration Algorithm For Basal Insulin, With Or Without Non-Insulin 
Antidiabetic Drugs, In T2DM Participants Treated With Basal Insulin 
 
 
 
 
RUNNING TITLE:   CGM-DTx Degludec 
 
 
 
 
 
 
 
 
 
NCT#06111508 
Version Number: v.3.3 
19-Feb-2024 
 

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KEY ROLES 
 
NAME, DEGREE 
INSTITUTION NAME  
Grant Principal Investigator / 
IDE Sponsor 
Marc Breton, PhD 
University of Virginia  
Center for Diabetes 
Technology 
Charlottesville, VA  
Protocol Chair 
Ralf M. Nass, MD 
University of Virginia 
Division of Endocrinology 
and Metabolism 
Charlottesville, VA 
Site Principal Investigator 
Carol Levy, MD, CDE 
Icahn School of Medicine at 
Mount Sinai 
New York, NY 
 
 

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PROTOCOL VERSION HISTORY 
Version 
Number 
Author(s) 
Approver 
Effective Date 
Revision Description 
1.0 
Mary Oliveri, Ralf 
Nass 
Marc Breton 
Ralf Nass 
08/29/2023 
Original Protocol 
2.0 
Mary Oliveri,  
Ralf Nass 
Ralf Nass 
08/31/2023 
Removed redundancies, added 
Statistical Consideration Section 
2.1 
Mary Oliveri, 
Ralf Nass 
Marc Breton 
Marc Breton 
09/11/2023 
Final read through, streamline 
language, and update outcomes 
3.0 
Mary Oliveri 
Ralf Nass 
Marc Breton 
Marc Breton, Ralf 
Nass 
09/12/2023 
FDA submission 
3.1 
Mary Oliveri 
Ralf Nass 
09/24/2023 
FDA edits:  
• Added Exclusion criteria 
(section 3.2) 
• Fasting SMBGs collected each 
day in both EXP & CTR 
Groups (section 4.4) 
• Weekly dose recommendations 
will be confirmed within 24 
hours of receipt (sections 6.1 
and 6.2) 
• Added CTR Safety Assessment 
(section 6.4) 
• Modified Participant Stopping 
Criteria (section 11.8.1) 
3.2 
Mary Oliveri 
Ralf Nass 
11/03/2023 
Clarification of protocol 
discrepancies: 
• replace a narrative description 
of study events to a bulleted 
description throughout 
document 
• clarified study endpoints 
(section 1.8 and 13.3) 
3.3 
Mary Oliveri 
Ralf Nass 
02/19/2024 
Study Team modifications:  
• Increased screen failure rate 
• Clarified that CGM Run-In 
phase may be extended, not 
just repeated, at MD discretion 
(section 5.2) 
 
 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: An Exploratory 16-Week Pilot Study of the Effect and Safety of a Novel CGM-
Based Titration Algorithm for Basal Insulin, With or Without Non-Insulin Antidiabetic Drugs, in 
T2DM Participants Treated with Basal Insulin 
Running Title:  CGM-DTx Degludec 
Protocol Version/Date: v.3.3  19-Feb-2024 
 
I have read the protocol specified above.  In my formal capacity as a 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:  ___________________________________________________________________ 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AP 
Artificial Pancreas 
BG 
Blood Glucose 
CDCES 
Certified Diabetes Care and Education Specialist 
CDT  
Center for Diabetes Technology 
CGM 
Continuous Glucose Monitoring 
CIQ 
Control-IQ AP system, Tandem Diabetes Care, San Diego, CA 
CSII 
Continuous Subcutaneous Insulin Injection 
DCCT 
Diabetes Control and Complications Trial 
DiAs 
Diabetes Assistant – the UVA algorithm prototyping system 
DKA 
Diabetic Ketoacidosis 
DM 
Diabetes Mellitus  
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HHS 
Hyperosmolar Hyperglycaemic State 
iDCL 
International Diabetes Closed-Loop trial 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
NIDDK 
National Institute for Diabetes and Digestive and Kidney Diseases 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
POC 
Point-of-Care 
SAE 
Serious Adverse Event 
S.C. 
Subcutaneous 
SMBG 
Self-Monitoring Blood Glucose 
T1D 
Type 1 Diabetes 
TAE 
Treatment Emergent Adverse Event 
TAR 
Time above range, above 180 mg/dL 
TBR 
Time below range, below 70 mg/dL 
TGL 
Titration Glucose Level  
TIR 
Time within the range 70-180 mg/dL  
UADE 
Unanticipated Adverse Device Effect 
UVA 
University of Virginia 
 
 

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PROTOCOL SUMMARY 
Protocol section 
Description 
Title 
An Exploratory 16-Week Pilot Study of the Effect and Safety of a Novel 
CGM-Based Titration Algorithm for Basal Insulin, With or Without Non-
Insulin Antidiabetic Drugs, in T2DM Participants Treated with Basal Insulin 
Investigational Devices 
CGM-based titration of basal insulin module as implemented in DiAs Cloud 
platform and partner applications  
Study Medication 
FDA approved insulin degludec (Tresiba) (used according to labelling) 
Objectives 
The primary objective of the study is to compare the effect of a CGM 
(Dexcom G6) based once weekly titration algorithm versus a standard 
titration by self-monitoring blood glucose (SMBG) on glycemic control in T2 
DM participants. 
Study Design 
Multicenter, randomized, parallel group, active-comparator clinical trial of 
CGM based titration of insulin degludec vs. standard titration by SMBG. The 
study includes: 
• Screening Visit 
• 2-week blinded CGM Run-In Phase  
• 16-week Intervention Phase 
• 3 Check-In Visits 
• Study End Visit 
• Follow-up Visit about 48 hours after Intervention Phase  
Number of Sites 
Two clinical sites  
Endpoint 
The primary objective of the pilot study is to compare CGM-based titration 
versus standard SMBG-based titration of insulin degludec, both treatment 
arms with or without non-insulin anti-diabetic drugs, in terms of glycemic 
control measured by change in time in range (70-180 mg/dL) from baseline (-
2 to 0 weeks) to week 14-16 in insulin experienced participants with T2DM. 
The secondary objective of the study is to explore other parameters of safety, 
efficacy and feasibility when using CGM-based titration of insulin degludec 
in insulin-experienced participants with T2DM.  
Population 
Type 2 Diabetes Mellitus (T2DM) 
Sample Size  
Up to 60 enrolled participants may sign consent with the enrollment goal of 
completing 30 participants at 2 centers  
Treatment Groups 
• Experimental (EXP) Arm:  CGM based titration algorithm group 
• Control (CTR) Arm:  SMBG titration algorithm group 
Participant Duration 
Approximately 18 weeks (2-week CGM Run-In Phase + 16-week 
Intervention Phase)  
Protocol Overview/Synopsis 
This is a ~18-week study designed to investigate the effect of a CGM based 
titration algorithm versus a standard titration by SMBG on glycemic control in 
T2DM participants using the insulin degludec. After 2 weeks of blinded CGM 
baseline observation, participants are randomized 2:1 to CGM-based titration 
or standard titration by SMBG for 16 weeks; all titrated doses will be reviewed 
by a study physician. All participants (both study groups) will be supplied with 
insulin degludec 100 units/ml, s.c, solution for injection, 3 mL prefilled pen-
injector. After completion of the 16-week titration participants are followed up 
for 2 days. Participants in the standard SMBG based titration group will wear 
a blinded CGM during the whole study. Participants will be stratified related 
to use of sulfonylureas or glinides with a maximum cap of 9 participants being 
treated with sulfonylureas or glinides to complete the study. 

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STUDY VISITS AND PROCEDURES SCHEDULE  
 
Consent 
Screening 
Training 
CGM Run-
In Phase 
Randomiz
ation 
 
Check-In 
Visit 
 
Check-In 
Visit 
 
Check-In 
Visit 
 
Study End  
Visit 
Post-Study 
Check-In 
Location 
(VC=video 
conference) 
Clinic 
or VC 
Clinic or 
VC 
Clinic 
or VC 
Home 
x 2 
weeks 
Clinic/ 
Phone/ 
VC 
 
Clinic/ 
Phone/ 
VC 
 
Clinic/ 
Phone/ 
VC 
 
Clinic/ 
Phone/ 
VC 
 
Clinic/ 
Phone/ 
VC 
Clinic/ 
Phone/ 
VC 
Visit 
1 
2 
3 
4 
5 
 
6 
 
7 
 
8 
 
9 
10 
Intervention 
Phase (week) 
 
 
 
-2 - 0 
0 
1-3 
4 
5-7 
8 
9-11 
12 
13-15 
16 
Post 
Day 2-7 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c – 
Central Lab 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HbA1c – Local 
Lab  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
testing (CMP & 
TSH ) if needed 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(if applicable) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
(height/weight) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
Survey 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CGM Training 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
DiAs Training 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 

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Insulin 
Degludec 
(Tresiba) Pen 
Training 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review of 
CGM data 
(EXP only) & 
SMBG data for  
hypo-and 
hyperglycemic 
events & AEs 
(EXP/CTR) 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Insulin dosing 
changes once 
per week at Day 
7 in both groups 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Chapter 1 Background and Synopsis ...................................................................15 
1 
1.1 Introduction ......................................................................................................................... 15 
2 
1.2 Device Description.............................................................................................................. 15 
3 
1.3 Study Objective ................................................................................................................... 16 
4 
1.4 Study Design ....................................................................................................................... 17 
5 
1.5 Study Enrollment ................................................................................................................ 17 
6 
1.6 Clinical Sites ....................................................................................................................... 17 
7 
1.7 Study Visits ......................................................................................................................... 17 
8 
1.8 Study Endpoints .................................................................................................................. 18 
9 
1.8.1 Primary Endpoint ......................................................................................................... 18 
10 
1.8.2 Secondary Endpoints ................................................................................................... 18 
11 
Chapter 2 Study Consent Visit .............................................................................20 
12 
2.1 Participant Recruitment and Enrollment ............................................................................. 20 
13 
2.2 Informed Consent................................................................................................................ 20 
14 
Chapter 3 Screening Visit .....................................................................................21 
15 
3.1 Participant Inclusion Criteria .............................................................................................. 21 
16 
3.2 Participant Exclusion Criteria ............................................................................................. 21 
17 
3.3 Screening Procedures .......................................................................................................... 22 
18 
3.4 Demographic Data Survey .................................................................................................. 23 
19 
Chapter 4 Training Visit .......................................................................................25 
20 
4.1 Algorithm Description ........................................................................................................ 25 
21 
4.2 Study App ........................................................................................................................... 25 
22 

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4.3 Continuous Glucose Monitor .............................................................................................. 26 
23 
4.4 Blood Glucose Meter and Strips ......................................................................................... 26 
24 
4.5 Study Medication ................................................................................................................ 27 
25 
4.6 Additional Medication ........................................................................................................ 27 
26 
4.7 Hemoglobin A1c Kit ........................................................................................................... 28 
27 
4.8 Glycemic Treatment Guidelines ......................................................................................... 28 
28 
4.9 Glucagon Emergency Kit .................................................................................................... 28 
29 
4.10 Study Accountability Procedures ...................................................................................... 28 
30 
Chapter 5 Continuous Glucose Monitor Run-In Phase .....................................29 
31 
5.1 CGM Run-In Phase ............................................................................................................. 29 
32 
5.2 Successful Completion of Run-in Phase ............................................................................. 29 
33 
Chapter 6 Randomization Visit ............................................................................30 
34 
6.1 CGM Based Titration Algorithm ........................................................................................ 30 
35 
6.2 Safety Assessment .............................................................................................................. 32 
36 
6.3 Standard Titration Algorithm .............................................................................................. 32 
37 
6.4 Safety Assessment .............................................................................................................. 33 
38 
6.5 Hemoglobin A1c Collection – Central Lab ........................................................................ 34 
39 
6.6 Internet Disconnection ........................................................................................................ 34 
40 
Chapter 7 Intervention Phase ...............................................................................35 
41 
7.1 4-Week Check-In Visits ...................................................................................................... 35 
42 
7.2 8-Week Check-In Visit ....................................................................................................... 35 
43 
7.3 12-Week Check-In Visit ..................................................................................................... 35 
44 
7.4 Study End Visit -16-Week .................................................................................................. 35 
45 

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7.5 Post-Study Check-In Visit .................................................................................................. 36 
46 
7.6 Early Termination Visit (If Applicable) ............................................................................. 36 
47 
7.7 Unscheduled Visits ............................................................................................................. 36 
48 
Chapter 8 Testing Procedures ..............................................................................37 
49 
8.1 Hemoglobin A1c ................................................................................................................. 37 
50 
8.1.1 Local Laboratory .......................................................................................................... 37 
51 
8.1.2 Central Laboratory ....................................................................................................... 37 
52 
8.2 Comprehensive Metabolic Panel ........................................................................................ 37 
53 
8.3 Thyroid Stimulating Hormone ............................................................................................ 37 
54 
8.4 Pregnancy Test .................................................................................................................... 37 
55 
8.5 Demographic Data Survey .................................................................................................. 38 
56 
Chapter 9 Glycemic Treatment Guidelines .........................................................39 
57 
9.1 Hypoglycemia Protocol ...................................................................................................... 39 
58 
9.2 Hyperglycemia Protocol ..................................................................................................... 39 
59 
9.3 Study Support...................................................................................................................... 39 
60 
Chapter 10 Risks Associated with Clinical Trial ................................................40 
61 
10.1 Potential Risks and Benefits ............................................................................................. 40 
62 
10.1.1 Venipuncture Risks .................................................................................................... 40 
63 
10.1.2 Fingerstick Risks ........................................................................................................ 40 
64 
10.1.3 CGM Sensor Needle Risks ........................................................................................ 40 
65 
10.1.4 Risks of Hypoglycemia .............................................................................................. 41 
66 
10.1.5 Risks of Hyperglycemia ............................................................................................. 41 
67 
10.1.6 Risks of Device Reuse or Exposure to Used Device ................................................. 41 
68 

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10.1.7 Risk Related Use of the Algorithm ............................................................................ 41 
69 
10.1.8 Risk of Using Degludec ............................................................................................. 42 
70 
10.1.9 Missing Insulin Doses ................................................................................................ 42 
71 
10.1.10 Internet Disconnection ............................................................................................. 42 
72 
10.1.11 Risk of Loss of Confidentiality ................................................................................ 42 
73 
10.1.12 Other Risks............................................................................................................... 42 
74 
10.1.13 Known Potential Benefits ........................................................................................ 42 
75 
10.1.14 Risk Assessment ...................................................................................................... 43 
76 
10.2 General Considerations ..................................................................................................... 43 
77 
Chapter 11 Adverse Events, Device Issues, and Stopping Rules.......................44 
78 
11.1 Definitions......................................................................................................................... 44 
79 
11.1.1 Adverse Events (AE) ................................................................................................. 44 
80 
11.1.2 Serious Adverse Event (SAE) .................................................................................... 44 
81 
11.1.3 Unanticipated Problem (UP) ...................................................................................... 45 
82 
11.1.4 Adverse Reaction (AR) .............................................................................................. 45 
83 
11.1.5 Serious Adverse Reaction (SAR)............................................................................... 45 
84 
11.1.6 Suspected Unexpected Serious Adverse Reactions (SUSAR): ................................. 45 
85 
11.1.7 Unanticipated Adverse Device Effect (UADE) ......................................................... 46 
86 
11.1.8 Adverse Device Effect (ADE) ................................................................................... 46 
87 
11.1.9 Device Complaints and Malfunctions ........................................................................ 46 
88 
11.2 Reportable Events ............................................................................................................. 46 
89 
11.2.1 Hypoglycemia Event .................................................................................................. 46 
90 
11.2.2 Hyperglycemia Events (HHS)/Diabetes Ketoacidosis (9) ......................................... 47 
91 

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11.3 Relationship of Adverse Events to Study Device ............................................................. 47 
92 
11.4 Intensity of Adverse Event................................................................................................ 48 
93 
11.5 Outcome of Adverse Events ............................................................................................. 48 
94 
11.6 Reportable Device Issues .................................................................................................. 49 
95 
11.7 Timing of Event Reporting ............................................................................................... 49 
96 
11.7.1 Data and Safety Monitoring ....................................................................................... 50 
97 
11.8 Stopping Criteria ............................................................................................................... 50 
98 
11.8.1 Participant Discontinuation ........................................................................................ 50 
99 
11.8.2 Suspending/Stopping Overall Study .......................................................................... 50 
100 
11.9 Protocol Deviations ........................................................................................................... 51 
101 
11.10 Definition of a Data Breach ............................................................................................ 51 
102 
Chapter 12 Miscellaneous Considerations ..........................................................52 
103 
12.1 Prohibited Medications, Treatments, and Procedures ....................................................... 52 
104 
12.2 Participant Withdrawal ..................................................................................................... 52 
105 
12.3 Confidentiality .................................................................................................................. 52 
106 
Chapter 13 Statistical Consideration ...................................................................53 
107 
13.1 Design and Randomization ............................................................................................... 53 
108 
13.2 Sample Size ....................................................................................................................... 53 
109 
13.3 Outcome Measures............................................................................................................ 53 
110 
13.3.1 Primary Endpoint ....................................................................................................... 53 
111 
13.3.2 Secondary Endpoints ................................................................................................. 53 
112 
13.4 Criteria for Success ........................................................................................................... 54 
113 
13.5 CGM data treatment .......................................................................................................... 55 
114 

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13.6 Safety Analyses and Participant Feedback ....................................................................... 55 
115 
13.7 Baseline Descriptive Statistics .......................................................................................... 55 
116 
Chapter 14 Data Collection and Monitoring .......................................................56 
117 
14.1 Case Report Forms and Device Data ................................................................................ 56 
118 
14.2 Study Records Retention................................................................................................... 56 
119 
Chapter 15 Ethics/Protection of Human Participants .......................................57 
120 
15.1 Ethics Standard ................................................................................................................. 57 
121 
15.2 Institutional Review Boards .............................................................................................. 57 
122 
15.3 Informed Consent Process ................................................................................................ 57 
123 
15.3.1 Consent Procedures and Documentation ................................................................... 57 
124 
 Participant
 .......................................................................... 58 
125 
Chapter 16 References ...........................................................................................59 
126 
  
 
127 

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Chapter 1  Background and Synopsis 
128 
 
129 
Many people with Type 2 Diabetes Mellitus (T2DM) fail to reach glycemic control target even 
130 
after the initiation of basal insulin [1]. Achieving tight glycemic control early following the 
131 
diagnosis of T2DM is key to optimizing clinical outcomes, yet many patients and clinicians are 
132 
reluctant to initiate and intensify insulin therapy. This arises primarily from a lack of healthcare 
133 
provider (HCP) resources, clinical expertise, and participant understanding [2]. Furthermore, the 
134 
literature indicates that self- titration of insulin could lead to faster glycemic control than 
135 
physician led insulin titration [3]. 
136 
Insulin degludec (degludec) is a daily administered basal insulin with a long duration of action 
137 
(half-life of approximately 25 hours) and a stable profile. Degludec showed improved glycemic 
138 
control with lower frequency of hypoglycemic events when compared to other long-acting 
139 
insulins such as glargine [4]. 
140 
Current safe and effective titration of basal insulins commonly recommends stepwise dose 
141 
adjustments towards an individualized glycemic target (e.g., ADA/EASD recommends a fasting  
142 
blood glucose target of 80-130 mg/dl for many adult participants with diabetes) based on fasting 
143 
blood glucose values measured by Self-Monitoring Blood Glucose (SMBG) or individual 
144 
Continuous Glucose Monitor (CGM) values from CGMs approved for non-adjunctive use [5]. 
145 
Currently a stepwise algorithm using SMBG has been recommended for degludec using a 
146 
starting dose of 10 units once daily for insulin naive participants or a 1:1 conversion for 
147 
participants with T2DM who are already taking basal insulin.   
148 
Since the initial introduction of CGM into clinical practice in 2000, the accuracy and 
149 
sophistication of these devices has progressively increased, resulting in more widespread use of 
150 
CGM systems [6]. This requires availability of a CGM based titration algorithm for long-acting 
151 
insulins.  The expectation is that the automatic processing of CGM data, which is more robust 
152 
and collected continuously, would result in improved titration with potentially more effective 
153 
and safe dose recommendations, compared to standard titration by SMBG. 
154 
 
155 
The titration algorithms (both CGM and SMBG based versions) will run on the Diabetes 
156 
Assistant AWS platform (DiAs-Cloud) – an established prototyping platform that was introduced 
157 
by UVA in 2011 and has been maintained since. DiAs-Cloud enables the seamless integration of 
158 
a smart phone application and AWS server architecture to enable data capture, dose computation, 
159 
review by the clinical team, and communication to study participants. DiAs-Cloud has been used 
160 
in over 25 clinical trials to date. 
161 
The CGM titration module comprises the three following components demonstrated in Figure 1: 
162 

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 Titration glucose level (TGL): The TGL is a daily value derived from CGM data. For a 
163 
given day, the TGL value is the minimum moving average (MA) with a 4-hour window 
164 
across the day. Weekly TGL values (average or minimum) are used to get a dose 
165 
adjustment. 
166 
 Personalized target: The personalization evaluates the risk of hypoglycemia by 
167 
measuring the TGL variability. It personalizes the TGL target range accordingly by 
168 
setting a lower glycemic target for participants with a low TGL variability, and a safer 
169 
glycemic target for participants with a high TGL variability. The TGL variability is based 
170 
on the coefficient of variation (CV) of the latest 14 TGL values. 
171 
 Safety hypoglycemia feature: This module adds a supplementary safety layer by 
172 
ensuring a decrease in insulin dose if in a given week, a daily TGL value is under 80 
173 
mg/dL, or if any hypoglycemic event has been self-reported by the user or if the percent 
174 
time of CGM below range reaches predetermined thresholds. In the case where 
175 
hypoglycemia has been reported, this feature will overrule the TGL-based titration by 
176 
suggesting a decrease in dose. 
177 
 
178 
Figure 1:  CGM-Based titration module review 
179 
 
180 
The primary objective of the pilot study is to compare CGM-based titration versus standard  
181 
SMBG-based titration of insulin degludec, both treatment arms with or without non-insulin anti-
182 
diabetic drugs, in terms of glycemic control measured by change in time in range (70-180 
183 
mg/dL) from baseline (-2 to 0 weeks) to week 14-16 in insulin experienced participants with 
184 
T2DM. The secondary objective of the study is to explore other parameters of safety, efficacy 
185 

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and feasibility when using CGM-based titration of insulin degludec in insulin-experienced 
186 
participants with T2DM. 
187 
 
188 
This is a randomized, parallel group, multi-center trial. After two weeks of blinded CGM 
189 
baseline observation, participants are randomized to CGM-based titration or standard titration by 
190 
SMBG for 16 weeks. Participants in the standard SMBG based titration group will wear a 
191 
blinded CGM during the whole study. The total daily basal insulin dose will be converted 1:1 to 
192 
degludec.  Dose changes will be made once weekly. Participants will be stratified related to use 
193 
of sulfonylureas or glinides (either alone or in combination with other OADs) with a maximum 
194 
cap of 9 participants (3 in the control arm and 6 in the experimental arm) being treated with 
195 
sulfonylureas or glinides to complete the study.  
196 
 
197 
Figure 2: Study Diagram 
198 
 
199 
Approximately 60 participants will be screened to complete 30 participants. This enrollment 
200 
includes an estimated 50% for screen failures, dropouts, and withdrawal. 
201 
 
202 
The study will be performed at the following clinical sites:  
203 
• University of Virginia (Charlottesville, VA) 
204 
• Mt. Sinai (New York, NY) 
205 
 
206 

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Clinic visits, videoconferences, or phone calls will be the preferred method of communication 
207 
with study participants, but email and text communication will be used as needed. Additional 
208 
clinic visits may occur as needed. The study physician may require participants to attend onsite 
209 
visits as needed.    
210 
 
211 
1.8.1 Primary Endpoint 
212 
Change in CGM-measured time in range 3.9-10.0 mmol/L (70-180 mg/dL) from baseline (-2 to 
213 
0, 2 weeks) to weeks 14-16 (2 weeks), compared between CTR and EXP arm. 
214 
1.8.2 Secondary Endpoints 
215 
With the exception of Device Deficiencies (DD), and acceptance rates, the secondary endpoints 
216 
will be compared between EXP and CTR arm with correction of multiple comparisons if 
217 
applicable. Refer to Chapter 13for more details. 
218 
Title 
Time frame 
Unit 
Change in HbA1c 
From baseline (week 0) to week 16 
Percentage 
point 
Change in time in tight range 3.9-
7.8 mmol/L (70-140 mg/dL) 
From baseline (week -2-0) to week 14-
16 
% of time 
Change in Time spent > 10.0 
mmol/L (180 mg/dL) 
From baseline (week -2-0) to week 14-
16 
% of time 
Change in Time spent > 13.9 
mmol/L (250 mg/dL) 
From baseline (week -2-0) to week 14-
16 
% of time 
Change in Coefficient of variation 
(CV - CGM) 
From baseline (week -2-0) to week 14-
16 
% 
Change in Mean glucose level 
(CGM) 
From baseline (week -2-0) to week 14-
16 
Mmol/L 
Change in Time spent < 3.9 
mmol/L (70 mg/dL) 
From baseline (week -2-0) to week 14-
16 
% of time 
Change in Time spent < 3.0 
mmol/L (54 mg/dL) 
From baseline (week -2-0) to week 14-
16 
% of time 
Number of clinically significant 
hypoglycemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 16 
Number of 
episodes 
Number of serious adverse events 
(SAEs) 
From baseline (week 0) to week 16 
Number of 
events 
Number of treatment emergent 
adverse events (TAEs) 
From baseline (week 0) to week 16 
Number of 
events 
Number of device deficiencies 
(DDs) 
From baseline (week 0) to week 16 
Number of 
events 

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Mean basal daily insulin dose at the 
end of trial. 
Week 16 
Units of 
insulin 
Investigator acceptance rate of 
weekly dose guidance – from CGM 
based titration (EXP arm only) 
 
From baseline (week 0) to week 16 
% 
The investigator changes the dose 
from the recommended or the 
current dose (EXP arm only) 
From baseline (week 0) to week 16 
Number of 
events 
 
 
219 

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Chapter 2 Study Consent Visit  
220 
Visit 1 
221 
 
222 
Before consent has been obtained, participants will be asked inclusion/exclusion criteria 
223 
questions during pre-screening to determine study eligibility. Before completing any procedures 
224 
or collecting any data that are not part of usual care, written informed consent will be obtained. 
225 
Potential eligibility may be assessed as part of a routine-care examination.   
226 
A participant is considered enrolled in the study when the informed consent form has been 
227 
signed by the participant and a member of the study team. 
228 
Consenting procedures and documentation are defined in section 15.3. 
229 
 
230 
After the informed consent has been signed, a potential participant will be evaluated for study 
231 
eligibility through the elicitation of a medical history, performance of a physical examination 
232 
by licensed study personnel, laboratory values, and pregnancy testing (if applicable) to screen for 
233 
exclusionary medical conditions. 
234 
Individuals who do not initially meet study eligibility requirements may be rescreened later per 
235 
investigator discretion. The study physician will have the discretion to exclude or discontinue a 
236 
participant’s enrollment in the trial. 
 
237 

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Chapter 3 Screening Visit 
238 
Visit 2 
239 
 
240 
The participants must meet all of the following inclusion criteria in order to be eligible to 
241 
participate in the study. 
242 
1. Age 18 years or older at signing of informed consent 
243 
2. Diagnosis of T2DM minimum 180 days before the day of screening 
244 
3. HBA1c between 7-9% and measured by local lab at screening 
245 
4. On daily basal insulin for at least 90 days before inclusion into the study 
246 
5. 
Stable dose of oral and injectable (other than insulin) antidiabetic medications for 90 days 
247 
prior inclusion. Acceptable medications include: 
248 
a. Metformin 
249 
b. Sulfonylureas 
250 
c. Meglitinides (glinides) 
251 
d. DPP-4 inhibitors 
252 
e. SGLT2 inhibitors 
253 
f. Thiazolidinediones 
254 
g. Alpha-glucosidase inhibitors 
255 
h. Oral combination products (for the allowed individual oral anti-diabetic drugs) 
256 
i. Oral or injectable GLP-1 Receptor Agonists (RAs) 
257 
j. If on sulfonylureas or glinides, willingness to reduce dose by 50% 
258 
 
259 
The participant must not have any exclusion criteria in order to be eligible to participate in the 
260 
study.  
261 
1. Hypersensitivity to Degludec 
262 
2. Use of an insulin pump  
263 
3. Use of a short-acting insulin 
264 
4. Participation or has participated in another trial within 90 days of the screening visit 
265 
5. Female who is pregnant or intends to become pregnant or is of child-bearing potential 
266 
and not using an adequate contraceptive method 
267 
6. Any disorder, except for conditions associated with T2D, which in the investigator’s 
268 
opinion might jeopardize participant’s safety or compliance with the protocol. 
269 
7. Treatment with any medication for the indication of diabetes or obesity other than stated 
270 
in the inclusion criteria within 90 days of the screening visit 
271 
8. Known skin reactions to CGM adhesives  
272 
9. Current/prior use of CGM within 30 days of the screening visit 
273 

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10. Any planned surgery or procedures where basal insulin would be decreased or held in 
274 
anticipation 
275 
 
276 
Screening procedures will last approximately 1-2 hours. The visit may occur in-person or by 
277 
telecommunication. The following procedures may be performed/data collected/eligibility 
278 
criteria checked and documented:  
279 
1. Inclusion and Exclusion criteria assessed. 
280 
1. Demographics, including: 
281 
a. Date of birth 
282 
b. Gender  
283 
c. Race 
284 
d. Ethnicity 
285 
2. Medical History, including diabetes history  
286 
a. Date of onset if known or duration of disease  
287 
b. History of CGM use 
288 
c. Severe hypoglycemia history 
289 
d. Severe hyperglycemia history 
290 
e. History of seizures  
291 
f. Loss of consciousness 
292 
g. Surgical history 
293 
h. Allergies  
294 
3. Daily sum (24 hour) of previous 7 days of basal insulin: amount and timing of injections 
295 
4. Allergies 
296 
5. Concomitant medications 
297 
6. Physical Examination – A historical history and physical report within 12 months of 
298 
screening appointments may be used but is not required for eligibility. If vitals are not 
299 
available, may include self-reported values.  
300 
a. Weight (may be self-reported) 
301 
b. Height (may be self-reported) 
302 
c. Blood pressure 
303 
d. Temperature (if available) 
304 
e. Heart Rate 
305 
7. Screening Labs 
306 

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a. Hemoglobin A1c (serum) at screening 
307 
b. Comprehensive Metabolic Panel (defined in Section 8.2) and Thyroid Stimulating 
308 
Hormone within 14 days of screening 
309 
c. Urine or serum pregnancy test for all women of childbearing potential (this test 
310 
can be done remotely with results sent to the study team) 
311 
Any labs required may be obtained at a laboratory (e.g., LabCorp) convenient to the participant. 
312 
The study physician or physician designee will have the discretion to repeat screening tests. 
313 
This study is not meant to find out if the participant has any other disease or problem. The study 
314 
leaders will alert the participant if any of the research results are important to his/her health 
315 
during the study. The participant may have a copy of the screening tests to discuss with the 
316 
personal physician. When the blood tests are completed, any blood left over will be thrown 
317 
away. It will not be stored for any future testing. 
318 
The study physician or physician designee will have the discretion to repeat screening tests. The 
319 
repeat screening tests may be conducted locally (e.g., LabCorp). The participant may request a 
320 
copy of any of the results from the screening evaluation to review with their primary care 
321 
provider.  
322 
Participants may be re-screened at another time if their clinical situation changes as determined 
323 
by the study physician. 
324 
 
325 
The study team has expanded the demographic questionnaire to include additional questions 
326 
regarding race/ethnicity and socio-economic status (SES). This is in response to the growing 
327 
body of research in diabetes treatment and technology revealing significant disparities in 
328 
minoritized population’s representation in clinical trials and access to devices/treatments that 
329 
improve diabetes outcomes. Researchers are being asked by NIH and other funding institutions 
330 
to make attempts to reduce this under-representation in clinical trial representation. For this 
331 
reason, collection of detailed demographic data regarding participants in technology trials has 
332 
become essential. This includes data on race/ethnicity, income levels and insurance status, as 
333 
well as education and other variables that describe the study population. However, it is important 
334 
to note that individuals completing demographic questionnaires are clearly instructed that 
335 
responses to these items are not mandatory and will not affect their ability to participate in the 
336 
study. 
337 
The Demographic Data Survey will be electronically administered once eligibility has been met.  
338 
a. Gender 
339 
b. Race 
340 
c. Ethnicity 
341 
d. Marital status  
342 
e. Level of education 
343 

CLINICAL PROTOCOL 
 
              
 
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f. Employment status  
344 
g. Household income 
345 
h. Health insurance status 
 
346 

CLINICAL PROTOCOL 
 
              
 
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Chapter 4 Training Visit 
347 
Visit 3 
348 
 
349 
Two algorithms designed to aid basal insulin titration will be tested in this study: 
350 
• An SMBG-based weekly titration algorithm derived from current standard of care 
351 
• An investigational CGM-based, personalized titration algorithm developed in 
352 
collaboration between the University of Virginia Center for Diabetes Technology and 
353 
Novo Nordisk 
354 
The CGM-based titration algorithm will be tested for effectiveness and safety against the 
355 
standard of care SMBG titration algorithm. The SMBG-based algorithm will be used by 
356 
participants in the Control (CTR) arm and the CGM-based algorithm will be used by participants 
357 
in the Experimental (EXP) arm as further defined in Chapter 6. 
358 
The SMBG-based algorithm is a simple look-up table algorithm advising to maintain, increase, 
359 
or decrease the current basal dose by 3, 6, or 8 Units of insulin based on three (3) fasting SMBG 
360 
taken on the two (2) days prior and the day of titration, see details in Chapter 6.  
361 
All dose computation will be run on the DiAs-Cloud AWS architecture, approved by the clinical 
362 
team, and delivered to the participants via the study app. 
363 
 
364 
All participants will use the investigational study app during the Intervention Period (visit 5-9). 
365 
This app may be placed on the participants personal smartphones, or a study phone as needed. A 
366 
study Dexcom Clarity account will be created for participants in the EXP arm. Participants in the 
367 
CTR arm will use the same sensor technology, but “blinded”, i.e., they will use an app or sensor 
368 
receiver to start and end sensor sessions but will not have access to any CGM measurements or 
369 
alarms. All participants will receive weekly insulin dose recommendations based on the 
370 
algorithm corresponding to their randomization and reviewed (CTR arm) or pre-approved (EXP 
371 
arm) by their site study physician. Dose, date, and time of the dose change will be available via 
372 
the study app. Study participants in the CTR arm will also record self-measured fasting blood 
373 
glucose as measured by SMBGs through the study app. The study physician will be able to 
374 
monitor only the EXP Group CGM data. The CGM data for the CTR Group is blinded to both 
375 
the participant and the study team. The study physician will be able to monitor the insulin dose 
376 
changes of both study groups during the entire study period via the Web portal of the DiAs-
377 
Cloud architecture.  
378 
Qualified study team members will train the participant in performing specific tasks when using 
379 
the study app:   
380 

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• How to view the CGM information including the most recent CGM value, trend arrow, 
381 
and CGM graph (EXP arm only) 
382 
• Low and high threshold alerts will be set. The participant may choose the threshold alert 
383 
values, but the low alert may not be set to less than 70 mg/dl and the high alert may not 
384 
exceed 300 mg/dl (EXP arm only) 
385 
• How to read the insulin dose recommendations approved by the study physician 
386 
• How to record symptomatic hypoglycemic events and associated SMBG values 
387 
• How to record fasting SMBG values  
388 
 
389 
The study will use the Dexcom G6 CGM and/or Dexcom G6 Pro. All participants will be 
390 
introduced to the CGM by a qualified member of the study team. Depending on the participant’s 
391 
prior experience, the study team will demonstrate the following CGM functionality:  
392 
• How to start a new CGM session. 
393 
• How to connect the CGM transmitter as well as troubleshooting techniques for 
394 
reconnecting.  
395 
• For CGM-based titration arm participants: How to view the CGM information including 
396 
the most recent CGM value, trend arrow, and CGM graph.  Low and high threshold alerts 
397 
will be set. The patient may choose the threshold alert values, but the low alert may not 
398 
be set to less than 70 mg/dL and the high alert may not exceed 300 mg/dL. 
399 
With the guidance of the study team, the participant will then insert the sensor and begin wearing 
400 
the CGM. The study team will confirm that the participant understood the training and all 
401 
questions have been answered.  
402 
The participants in the EXP Group will wear a blinded CGM during the CGM Run-In Phase and 
403 
will wear a commercial unblinded CGM during the intervention phase. 
404 
The participants in the CTR Group will wear a blinded CGM during the CGM Run-In Phase and 
405 
during the intervention phase. 
406 
 
407 
All participants will be provided with a study glucometer before the start of the CGM Run-In 
408 
Phase. All study blood glucose meters (BGM) will be QC tested with control solution(s) prior to 
409 
issuing to the participant. A tested meter will not be used in a study if it does not read within the 
410 
target range at each concentration per manufacturer labeling. The BGM will be updated with 
411 
correct local date and time before being provided to the participants 
412 
Study staff will demonstrate proper use of the meter as described in the user manual. The 
413 
participant will be required to demonstrate proficiency in the use of the device. The study team 
414 
will confirm that all questions have been answered and that the participant has understood the 
415 
training.  
416 

CLINICAL PROTOCOL 
 
              
 
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Participants will be reminded to use the study blood glucose meter for all fingerstick BGs during 
417 
the study. Participants will be instructed to perform an SMBG at the following timepoints:   
418 
• fasting, pre-breakfast each day with special importance on collecting the fasting, pre-
419 
breakfast SMBG on Day 5, 6 and 7 after an insulin dose change 
420 
• if experiencing symptoms of hypoglycemia (e.g., dizziness, light-headedness, sweating, 
421 
shaking, trouble concentrating, etc.) 
422 
• if experiencing symptoms of hyperglycemia (e.g., extreme thirst, weakness, frequent 
423 
urination, blurry vision, nausea, etc.) 
424 
• if the CGM alarms (EXP Group only) 
425 
Participants will be instructed to contact study staff for a replacement of the meter, test strips, 
426 
and control solution, if necessary, if a meter fails QC testing at home. 
427 
Raw data from the BGM will be uploaded to the study database as a minimum at study end and 
428 
checked for unreported hypoglycemia (BGM<70mg/dL).  
429 
At the end of trial, the participant BG reporting through the study app will be compared with a 
430 
readout from the BGM.  
431 
 
432 
All participants will be provided with the FDA approved Insulin Degludec (Tresiba) (Novo 
433 
Nordisk) 100 units/ml, subcutaneous. (s.c,) solution for injection, 3 mL prefilled injector-pens 
434 
after randomization for the duration of the Intervention Phase. Conversion with their prior basal 
435 
insulin will follow the approved Tresiba label (1:1 conversion) at the start of the Intervention 
436 
Phase which is in accordance with the drug labelling. Training on the use of the pen will be 
437 
specific to the individual. Participants will receive an electronic copy of the package insert which 
438 
includes Instructions for Use. 
439 
Insulin needles will also be provided for use during the study; however, participants may elect 
440 
not to use this supply.  
441 
Insulin degludec is a daily administered basal insulin with a long duration of action with a half-
442 
life of approximately 25 hours and a stable profile. Degludec results in improved glycemic 
443 
control with lower frequency of hypoglycemic events when compared to other long-acting 
444 
insulins such as glargine [4]. 
445 
Participants and the study physician will discuss missed dose and the proper dosage that should 
446 
be administered. Missed doses will not be recorded as protocol deviations. Remaining degludec 
447 
supplies will be returned to the study team at the conclusion of the study. 
448 
 
449 

CLINICAL PROTOCOL 
 
              
 
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The study team will be informed about any additional medication started during the study. All 
450 
medication that can affect glycemic control must be kept unchanged throughout the trial. New 
451 
such drugs or dose changes of should only be prescribed/ordered, if needed, after review by the 
452 
clinical site PI of the participant. 
453 
 
454 
The study team will review the contents of the HbA1c Capillary Kit with the participants. 
455 
Instructions and the appropriate supplies are provided in each kit. The study team will review the 
456 
proper collection techniques and mailing instructions. Participants will be provided with the 
457 
option of collecting these samples at home or attending in-person clinic appointments.  
458 
 
459 
All participants will be instructed on hypoglycemia and hyperglycemia symptoms and will 
460 
receive a handout on how to treat these symptoms.  
461 
 
462 
A home glucagon emergency kit will be required. Participants who currently do not have one 
463 
will be given a prescription for the glucagon emergency kit.  
464 
 
465 
Device serial numbers will be recorded in a case report form (CRF) and use of equipment will be 
466 
tracked. The pharmacy at each clinical site will oversee drug distribution and maintenance of 
467 
drug accountability logs. 
 
468 

CLINICAL PROTOCOL 
 
              
 
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Chapter 5 Continuous Glucose Monitor Run-In Phase  
469 
Visit 4 
470 
 
471 
Once all screening procedures and all necessary training activities are completed, all participants 
472 
will begin a two-week at home use of a blinded CGM. The Run-In Period starts when the CGM 
473 
is activated by the participant. During this Run-In period, all participants will be asked to follow 
474 
their usual care without any changes in their insulin parameters or glucose lowering drugs.  
475 
Participants will be advised that the CGM equipment will need to be promptly returned to the 
476 
study team to facilitate downloading the data from this equipment. The participant will be 
477 
informed that in order to be eligible for the study, the CGM must be used 10 out of 14 days 
478 
CGM, a day must contain 70% measurements to be counted. 
479 
 
480 
The study team will review the CGM data to determine if 10 out of 14 days of data are available. 
481 
If affirmed, the participant will be randomized into one of the two study arms. The investigator 
482 
will have the discretion to extend or repeat this data collection period as needed.  
483 
484 

CLINICAL PROTOCOL 
 
              
 
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Chapter 6 Randomization Visit 
485 
Visit 5 
486 
Upon the completion of the CGM Run-In Phase, study participants will be randomized 2:1 to one 
487 
of two groups:  
488 
EXPERIMENTAL (EXP) Group – CGM Based Titration  
489 
• Participants will wear an unblinded CGM during the study.  
490 
• Participants will be supplied with Insulin Degludec (Tresiba) 100 units/ml, s.c, solution 
491 
for injection, 3 mL prefilled pen-injector, by Novo Nordisk for the duration of the study. 
492 
• The total daily basal (long and intermediate-acting) insulin dose based on pretrial 24/h 
493 
insulin dose will be converted 1:1 to Insulin Degludec (Tresiba) per FDA labelling. 
494 
• Participants will continue to use the study provided BGM meter (measuring daily fasting 
495 
glucose and confirming symptomatic hypoglycemia). 
496 
• Study team will install the study app and the Dexcom Clarity app on the participant’s 
497 
compatible smartphone or on a study phone provided to participant per participant’s 
498 
request and compatibility of personal device. Study team will set the study app with the 
499 
participant’s study information (e.g., Participant ID) 
500 
CONTROL (CTR) GROUP – Standard SMBG Titration 
501 
• Participants will wear a blinded CGM during the study.  
502 
• Participants will be supplied with Insulin Degludec (Tresiba) 100 units/ml, s.c, solution 
503 
for injection, 3 mL  prefilled pen-injector, by Novo Nordisk for the duration of the study. 
504 
• The total daily basal (long and intermediate-acting) insulin dose based on pretrial 24/h 
505 
insulin dose will be converted 1:1 to Insulin Degludec (Tresiba) per FDA labelling. 
506 
• Participants will continue to use the study provided BGM meter (measuring daily fasting 
507 
glucose and confirming symptomatic hypoglycemia). 
508 
• Study team will install the study app on the participant’s compatible smartphone or on a 
509 
study phone provided to participant per participant’s request and compatibility of 
510 
personal device. Study team will set the study app with the participant’s study 
511 
information (e.g., Participant ID) 
512 
 
513 
• The participant will measure fasting, pre-breakfast SMBG daily, but the insulin dose is 
514 
adjusted based on the CGM.  
515 
• Participants in the CGM-based titration group will get a once weekly insulin dosing 
516 
recommendation displayed on the study app. If the participant wants to deviate from the 
517 
recommended insulin dose, they will be advised to contact the study physician prior to 
518 
changing the dosing recommendation. 
519 

CLINICAL PROTOCOL 
 
              
 
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o The study physician will monitor and approve the dose recommendations 
520 
each week prior to participants notification. The participant’s unblinded 
521 
CGM data is reviewed by the physician as a function of reviewing the 
522 
insulin dosing recommendations.   
523 
o The physician approval will be completed using the DiAs-Cloud 
524 
architecture where the study physician will access the data and 
525 
recommendation via the study Web portal. Study physician will be 
526 
instructed to only deviate from the provided dose if the safety of the 
527 
participant is engaged. 
528 
o Modification of the dose recommendation should occur for safety 
529 
purposes only. If modified, the study physician should document the 
530 
revised dose and the rationale for the change of dose on a study CRF.  
531 
o Once approved, the participants will receive notification in their 
532 
phone/study phone with the new dose.; the recommended dose taken will 
533 
be confirmed once a week (and within 24h of receiving the new dose) by 
534 
the participant into the study app. Dose, date, and time of the dose change 
535 
will be available via the study app.  
536 
• At the end of each week, the participant will be asked to confirm the doses taken during 
537 
the week on a study CRF. 
538 
• Only weekly dose adjustments/titration will be performed unless the insulin dose is 
539 
changed during the week for safety purposes (at which point the participant will be asked 
540 
to enter the new dose in the study app).  
541 
 
542 
 
543 
Figure 3: CGM-Based Titration Flow 
544 
Risk categories are based on the variance of the Titration Glucose Levels (TGL, a CGM-based 
545 
glycemic index) (Table 1) over the past two (2) weeks; dose changes are as follow: 
546 
Low hypo risk 
Avg risk 
High risk 
Dose change 
Min TGL <80* 
Min TGL <80* 
Min TGL < 80* OR 
Avg TGL <98 
-3IU 
80 ≤ Avg TGL < 102 
80 ≤ Avg TGL < 120 
98≤ Avg TGL < 120 
0 IU 

CLINICAL PROTOCOL 
 
              
 
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102 ≤ Avg TGL < 144 
120 ≤ Avg TGL < 144 
120 ≤ Avg TGL < 144 
+ 3IU 
144 ≤ Avg TGL < 162 
144 ≤ Avg TGL < 162 
144 ≤ Avg TGL < 162 
+ 6IU 
Avg TGL ≥162 
Avg TGL ≥162 
Avg TGL ≥162 
+8IU 
* If one TGL is below 80 mg/dL the patient will be down titrated 
547 
Table 1:  Titration Glucose Levels.  
548 
 
549 
• Weekly insulin dose recommendations made by the CGM-based algorithm will be 
550 
approved by the study physician each week.  
551 
• The acceptance of the recommended dose will be entered by the participant into the study 
552 
app Failure to do so within 24h of receiving the titrated dose advice for the week will 
553 
trigger an automated system notification to the study team who will follow up with the 
554 
participant and document an out of cycle visit CRF. 
555 
• Hypoglycemic monitoring and reporting. 
556 
• Systematic collection of insulin dose history: while not available in real-time it can be 
557 
made available to study physicians if necessary for safety 
558 
• Any revised recommended dose changes will be entered into the study app along with the 
559 
date and time.   
560 
 
561 
 The participant will measure fasting, pre-breakfast SMBG daily, but three (3) fasting, 
562 
pre-breakfast SMBGs measured on Day 5, 6 and 7 will be used to titrate the insulin dose; 
563 
if less than three SMBGs are provided, the previous week’s dose will be re-recommended 
564 
or titrated -3IU (if one SMBG is below 80 mg/dL). 
565 
• The dose recommendation will be based on the titration algorithm described in  Table 2 
566 
below based on the three SMBGs. The participant will receive their weekly basal dose 
567 
recommendation via their phone/study phone and will confirm acceptance/receipt of 
568 
recommended dose in the study app. If the participant wants to deviate from the 
569 
recommended insulin dose, they will be advised to contact the study physician prior to 
570 
changing the dosing recommendation. 
571 

CLINICAL PROTOCOL 
 
              
 
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Value to be used 
Pre-breakfast SMBG available (mg/dL) 
Dose change 
Lowest value 
Pre-breakfast SMBG <80 
-3IU 
Mean 
80 ≤ Pre-breakfast SMBG ≤ 130 
0 IU 
130 < Pre-breakfast SMBG < 144 
+3IU 
144 ≤ Pre-breakfast SMBG < 162** 
+6IU 
Pre-breakfast SMBG ≥162** 
+8IU 
Table 2: Standard Algorithm Table 
572 
• Study physician will document review of each dose recommendation via the study web 
573 
portal and document this review on a study case report form (CRF). Study physician will 
574 
be instructed to only follow up with the participant if the safety of the participant is 
575 
engaged. 
576 
• Modification of the dose recommendation by either the participant or study physician 
577 
should occur for safety purposes only. If modified, the study physician should document 
578 
the revised dose and the rationale for the change of dose on a study CRF.  
579 
• At the end of each week, the participant will be asked to confirm the dose taken during 
580 
the week on a study CRF. 
581 
• The physician will contact the study participant in case of safety concerns. 
582 
• Only weekly dose adjustments/titration will be performed unless the insulin dose is 
583 
changed during the week for safety purposes. 
584 
 
585 
 
586 
Figure 4: Standard SMBG Titration Flow 
587 
 
588 
• Fasting, pre-breakfast each day with special importance on collecting a fasting, pre-
589 
breakfast SMBG on Day 5, 6 and 7 after an insulin dose change. 
590 
• Hypoglycemic monitoring and reporting. 
591 
• Systematic collection of insulin dose history: while not available in real-time it can be 
592 
made available to study physicians if necessary for safety. 
593 

CLINICAL PROTOCOL 
 
              
 
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• 
Systematic collection of blinded CGM: while not available in real-time, the CGM data is 
594 
automatically transmitted from the blinded CGM app to our study server, allowing for 
595 
easy unblinding if necessary for safety. 
596 
• 
Study physician will review the dose that the participant has entered into the web portal 
597 
within 24 hours.  
598 
 
599 
All participants will collect a hemoglobin A1c capillary blood sample and will send the sample 
600 
in a provided pre-labeled package to the central laboratory for analysis.   
601 
 
602 
If the participant is without internet service for more than 14 days, participant will be instructed 
603 
to contact the study team to re-establish connectivity. The study team may provide a study phone 
604 
with SIM card. CGM Based Titration Algorithm participants will be asked to maintain their 
605 
current basal dosing until they contact study team or re-establish connectivity, whichever comes 
606 
first. All participants will be instructed to follow Glycemic Treatment Guidelines (Chapter 9) 
607 
regardless of connectivity status. 
 
608 

CLINICAL PROTOCOL 
 
              
 
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Chapter 7 Intervention Phase 
609 
 
610 
Visit 6 
611 
The study team will contact the participant via telephone call or videoconferencing to assess 
612 
adverse events, adverse device effects, and device issues approximately every 2 weeks (+/-3 
613 
days). If the participant chooses, this visit can occur at the clinical site. The study team will 
614 
verify the following information: 
615 
• Inquire about any changes to the participant’s medical history and medication changes 
616 
• Review of CGM data (EXP group only) 
617 
• Review of SMBG 
618 
• Review of hypoglycemic events & confirmation SMBG measurements 
619 
• Review of hyperglycemic events & confirmation SMBG measurements 
620 
• Review of insulin dosing 
621 
• Review proper insulin pen use and injection technique 
622 
• Address any concerns about the algorithm (Standardized Titration and CGM based) 
623 
• Review of any technical complaints expressed by the participant  
624 
• Verify that CGM alarms continue to be set at <70 mg/dL and >300 mg/dL (EXP Group 
625 
only) 
626 
 
627 
Visit 7 
628 
Participants will have a telephone call or videoconference call in Week 8 (+/-3 days). Procedures 
629 
are described in section 7.1. 
630 
All participants will collect a hemoglobin A1c blood sample and will send the sample in a pre-
631 
labeled package to the central laboratory for analysis.  
632 
 
633 
Visit 8 
634 
Participants will have a telephone call or videoconference call in Week 12 (+/-3 days). 
635 
Procedures are described in section 7.1. 
636 
 
637 
Visit 9 
638 

CLINICAL PROTOCOL 
 
              
 
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Participants will have clinic visit, a telephone call, or videoconference call in Week 16 (+/-3 
639 
days). Study participants will be instructed on how to transition back to the home insulins and 
640 
the doses to be used. Participants will be informed that there may be a risk of severe 
641 
hypoglycemia and/or severe hyperglycemia during the transition back to the participant’s usual 
642 
home basal insulin. The study physician will be available for consultation during this transition 
643 
period.   
644 
The study team will verify the following information: 
645 
a. Return of any remaining study supplies (i.e., CGM sensors, transmitter)  
646 
b. Return of unused degludec 
647 
c. Download of glucometer; equipment may be returned to the participant 
648 
d. Review of the CGM data and SMBG data (hypo- and hyperglycemic events) 
649 
e. The participant has collected a hemoglobin A1c blood sample and has sent the 
650 
sample in the pre-labeled package to the central laboratory for analysis. 
651 
f. Assessment of adverse events, adverse device effects, and device issues 
652 
g. Obtain body weight measurement (measured on-site or self-reported) 
653 
 
654 
Visit 10 
655 
Participants will have a telephone call or videoconference call about 2-7 days after completing 
656 
the study. Study participants will be asked about their glycemic control as well as hypo-and 
657 
hyperglycemic events since completing the Intervention Phase (visit 9).  
658 
 
659 
Participants will be asked to attend the Study End Visit (visit 9) in the event of withdrawal or 
660 
early termination. 
661 
 
662 
Participants may have unscheduled visits during the study period if required for additional device 
663 
training or other unanticipated needs per the study investigator discretion. 
 
664 

CLINICAL PROTOCOL 
 
              
 
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Chapter 8 Testing Procedures 
665 
 
666 
8.1.1 Local Laboratory 
667 
A blood sample may be obtained to measure a hemoglobin A1c level at the screening visit. Labs 
668 
may be obtained at the clinical site or a local laboratory (e.g., LabCorp) convenient to the 
669 
participant. 
670 
8.1.2 Central Laboratory 
671 
The hemoglobin A1c level will be based on a capillary sample collected by the participant using 
672 
a kit at home or at an in-person clinic visit if assistance is needed [8]. Collection points will be at 
673 
Randomization (week 0), visit 7 (week 8), and visit 9 (week 16). The participant will collect this 
674 
blood sample and will send the sample in a pre-labeled package to the central laboratory for 
675 
analysis. The same collection kit (ARDL HBA1c collection kit) will be used at all sites.  
676 
 
677 
A blood sample will be obtained at screening to assess kidney and liver functioning. Labs may 
678 
be obtained at the clinical site or a local laboratory (e.g., LabCorp) convenient to the participant. 
679 
Blood test obtained within 14 days prior to enrollment may be used for eligibility purposes. 
680 
CMP Definition: Alanine aminotransferase (ALT/SGPT); albumin:globulin (A:G) ratio; 
681 
albumin, serum; alkaline phosphatase, serum; aspartate aminotransferase (AST/SGOT); 
682 
bilirubin, total; BUN; BUN:creatinine ratio; calcium, serum; carbon dioxide, total; chloride, 
683 
serum; creatinine, serum; eGFR calculation; globulin, total; glucose, serum; potassium, serum; 
684 
protein, total, serum; sodium, serum. 
685 
 
686 
A blood sample will be obtained at screening to assess thyroid function. Labs may be obtained at 
687 
the clinical site or a local laboratory (e.g., LabCorp) convenient to the participant. Blood test 
688 
obtained within 14 days prior to enrollment may be used for eligibility purposes.   
689 
 
690 
A beta HCG or urine pregnancy test will be required for women of childbearing potential at the 
691 
screening appointment. The test must be negative to continue participation in the study. Labs 
692 
may be obtained at the clinical site or a local laboratory (e.g., LabCorp) convenient to the 
693 
participant. A point of care test may also be used to assess pregnancy status. A photograph of the 
694 
test result will serve as source documentation.  
695 

CLINICAL PROTOCOL 
 
              
 
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696 
The Demographic Data Survey will be asked after study eligibility has been met (visit 2).  
697 

CLINICAL PROTOCOL 
 
              
 
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Chapter 9 Glycemic Treatment Guidelines 
698 
 
699 
Hypoglycemic events should be classified as per ADA guidelines and based on SMBG 
700 
confirmatory measurements [5]. Study participants will follow the standard hypoglycemia 
701 
protocol described in the appendix Glycemic Treatment Guidelines in case of a hypoglycemic 
702 
event. Participants will be reminded to obtain a SMBG at the onset of hypoglycemic symptoms. 
703 
All participants will be asked to report symptomatic hypoglycemic events and provide SMBG 
704 
confirmation to the study team via the study app. Mild hypoglycemia (situation where study 
705 
participant is able to treat her/himself) can be treated by oral administration of glucose of 
706 
carbohydrate containing products.  
707 
In case a participant is not able to treat him/herself (level 3 hypoglycemia), treatment will 
708 
escalate to glucagon or glucose given intravenously (see also section “reportable events”). The 
709 
study coordinator and the study physician will be informed of the event by the study participant 
710 
as soon as possible but not later than 12 hours after the event. 
711 
The study participant will record day and time of the hypoglycemic events in a pre-designed 
712 
form via the study app in addition to reporting all relevant data in order to properly classify the 
713 
event. Participant will be instructed to record a confirmation SMBG(s). Study coordinator and 
714 
study physician will report the event if required per protocol. 
715 
 
716 
Study participants will follow the standard hyperglycemia protocol described in the appendix  
717 
Glycemic Treatment Guidelines in case of a hyperglycemic event during both the CGM run-in 
718 
phase and the intervention phase. Participants will be reminded to obtain a SMBG at the onset of 
719 
hyperglycemic symptoms. All participants will be asked to report symptomatic hyperglycemic 
720 
events and provide SMBG confirmation to the study team. The study coordinator and the study 
721 
physician will be informed of the event by the study participant as soon as possible but not later 
722 
than 12 hours after the event.  
723 
The study participant will record day and time of the hyperglycemic events in a pre-designed 
724 
form via the study app in addition to reporting all relevant data in order to properly classify the 
725 
event. Participant will be instructed to record a confirmation SMBG(s). 
726 
 
727 
Participants will receive study staff contact information to ask any questions they may have 
728 
during the study. Additionally, participants will be provided with study contact information for 
729 
technical support with the study app and the study CGM. The participant will be asked to call the 
730 
study team at any time during the study for any health-related issues, including hypoglycemia 
731 
<70 mg/dL or frequent highs >300 mg/dL, as confirmed by an SMBG value. The blood glucose 
732 
value will be confirmed by fingerstick blood glucose measurement. 
 
733 

CLINICAL PROTOCOL 
 
              
 
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Chapter 10 Risks Associated with Clinical Trial 
734 
 
735 
Risks and Benefits are detailed below. Hypoglycemia and hyperglycemia are  a risk in 
736 
participants with type 2 diabetes, and participants will be monitored for these symptoms.  
737 
10.1.1 Venipuncture Risks 
738 
A hollow needle will be placed in the arm for taking blood samples. Blood draws can cause 
739 
common reactions like pain, bruising, or redness at the sampling site. Less common reactions 
740 
include bleeding from the sampling site, formation of a small blood clot or swelling of the vein 
741 
and surrounding tissues, and fainting. 
742 
There is the risk of contamination from blood sampling techniques. Hand washing with either 
743 
soap & water or waterless hand sanitizer will be used prior to caring for the study participant. 
744 
Gloves will be worn during blood sample collection and processing. Medical personnel will 
745 
continue to practice hygiene for the participant’s protection (i.e., hand washing, changing gloves 
746 
frequently, disposing needles properly). Gloves will be removed, and hands washed or sanitized 
747 
prior to leaving and upon return to the participant’s room. Soiled linen will be changed to 
748 
minimize the transfer of pathogenic organisms. 
749 
10.1.2 Fingerstick Risks 
750 
About 2 drops of blood will be removed by fingerstick for measuring blood sugars and 
751 
sometimes HbA1c or other tests. This is a standard method used to obtain blood for routine 
752 
hospital laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small 
753 
amount of bleeding under the skin will produce a bruise. A small scar may persist for several 
754 
weeks. The risk of local infection is less than 1 in 1000. This should not be a significant 
755 
contributor to risks in this study as finger sticks are part of the usual care for people with 
756 
diabetes. 
757 
10.1.3 CGM Sensor Needle Risks 
758 
Participants using the CGM will be at low risk for developing a local skin infection or skin 
759 
reactions at the site of the sensor needle placement. Though approved for 10 days of use, if a 
760 
catheter is left under the skin for more than 24 hours, it is possible to get an infection where it 
761 
goes into the skin, with swelling, redness, and pain. There may be bleeding where the needle is 
762 
inserted and bleeding under the skin causes a bruise (1 in 10 risk). 
763 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
764 
leave a small portion of the needle under the skin that may cause redness, swelling, or pain. The 
765 
participants will be instructed to notify the study coordinator immediately if this occurs. 
766 

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10.1.4 Risks of Hypoglycemia  
767 
As with any person having T2DM and using insulin, there is always a risk of having a low blood 
768 
sugar (hypoglycemia). The frequency of hypoglycemia should be no more and possibly less than 
769 
it would be as part of daily living. Symptoms of hypoglycemia can include sweating, jitteriness, 
770 
and not feeling well. Just as at home, there is the possibility of fainting or seizures (convulsions) 
771 
and subsequently for a few days the participant may not be as aware of symptoms of 
772 
hypoglycemia. There is the risk of false hypoglycemia alarms based on sensor pressure, e.g., 
773 
sleeping on the sensor 
774 
A poorly functioning CGM can periodically display falsely high glucose values, which could 
775 
lead to inappropriate insulin recommendation. 
776 
10.1.5 Risks of Hyperglycemia  
777 
Hyperglycemia could occur if insulin dosage is too low. A poorly functioning CGM can 
778 
periodically display falsely high glucose values, which could lead to inappropriate insulin 
779 
recommendation.  
780 
10.1.6 Risks of Device Reuse or Exposure to Used Device 
781 
Participants will be informed that FDA or relevant national authorities have approved the CGM 
782 
for single use and that by using them among multiple patients, bloodborne pathogens (i.e., 
783 
Hepatitis B) may be spread through the use of multiple users. The sensor (the component of the 
784 
system that enters the skin) will be single use only. The transmitter and receiver may be reused 
785 
during the study after cleaning the device using a hospital-approved cleaning procedure. The 
786 
transmitter is attached to the sensor but does not enter the skin and the receiver, if used, is a 
787 
handheld device.  
788 
CGM cleaning instructions are provided in the Dexcom G4 Platinum (Professional) Cleaning and 
789 
Disinfection manual (current edition) and a similar approach will be applied for the G6 version 
790 
used in this study. 
791 
The study-provided blood glucose meter will be returned to the study participant at the 
792 
conclusion of the study after the study team has confirmed data collection. Cleaning procedures 
793 
will be used if it is necessary to be in physical contact with the equipment to download the 
794 
device.  
795 
10.1.7 Risk Related Use of the Algorithm 
796 
Use of the algorithm may result in hypoglycemia, hyperglycemia, and increased glucose 
797 
variability.  
798 

CLINICAL PROTOCOL 
 
              
 
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10.1.8 Risk of Using Degludec 
799 
The study drug, degludec, may result in hypoglycemia or an allergic reaction.  
800 
10.1.9 Missing Insulin Doses 
801 
All participants will be asked to document missed insulin doses on the CRF completed at the end 
802 
of each week. Study physician may review CRF and contact study participant as needed.  
803 
10.1.10 Internet Disconnection  
804 
An unplanned internet disconnection of >14 days will be considered a device deficiency.  
805 
10.1.11 Risk of Loss of Confidentiality 
806 
Loss of confidentiality is a potential risk. Some people may be uncomfortable with the 
807 
researchers' having such detailed information about their daily diabetes habits. The study team 
808 
will assign a Participant ID number and a code word to each person who signs a consent form. 
809 
Both are entered to record study data in eCRFs. Limited study team members have access to 
810 
identified data. CGM and BGM data are de- stored in a cloud storage in a de-identified format.    
811 
10.1.12 Other Risks  
812 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
813 
the CGM. If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, 
814 
Tegaderm, etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or 
815 
other medication may be required. 
816 
Whenever the skin is broken there is the possibility of an infection. The CGM sites are inserted 
817 
under the skin. It is possible that any part that is inserted under the skin may cause an infection. 
818 
These occur very infrequently, but, if an infection was to occur, oral and/or topical antibiotics 
819 
can be used. The risk of skin problems could be greater if you use a sensor for longer than it is 
820 
indicated for use. Therefore, participants will be carefully instructed about proper use of the 
821 
sensor. 
822 
Participants will be advised that acetaminophen (Tylenol) taken in high doses (e.g., > 1 gram 
823 
every 6 hours in adults) may falsely raise sensor glucose readings.  
824 
10.1.13 Known Potential Benefits  
825 
It is expected that this protocol will yield increased knowledge about using a titration algorithm 
826 
for insulin dosing suggestions. The access to a CGM can provide improvement in diabetic care. 
827 
The individual participant may or may not benefit from study participation. 
828 

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10.1.14 Risk Assessment 
829 
The risk to participants in this study is no higher than the risks associated with type 2 diabetes 
830 
under normal outpatient conditions. This assessment is based on the following facts: (1) adults 
831 
with insulin-treated diabetes experience mild hypoglycemia and hyperglycemia frequently as a 
832 
consequence of the disease and its management, (2) both study interventions involve feedback 
833 
and advice for insulin dosing. Changes in dosing may result in hypoglycemia and hyperglycemia 
834 
symptoms. 
835 
 
836 
The study is being conducted in compliance with the policies described in the study policies 
837 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
838 
the protocol described herein, and in compliance with CFR 21. 
839 
Whenever possible, data will be directly collected in electronic case report forms (eCRFs), which 
840 
will be considered the source data. 
841 
The protocol is considered a significant risk device study since the algorithm used in this study is 
842 
experimental. Therefore, an investigational device exemption (IDE) from the U.S. Food and 
843 
Drug Administration (FDA) is required to conduct the study. 
844 
There is no restriction on the number of participants enrolled by each site towards the overall 
845 
recruitment goal.  
846 
The study is supported by third party collaborators for the provision of study drugs, devices, and 
847 
software. Current study collaborators are:  
848 
• Novo Nordisk (Bagsværd, Denmark) 
849 
• Dexcom Inc. (San Diego, CA) 
 
850 

CLINICAL PROTOCOL 
 
              
 
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Chapter 11 Adverse Events, Device Issues, and Stopping Rules 
851 
 
852 
11.1.1 Adverse Events (AE) 
853 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) 
854 
associated with study procedures or occurring during the course of a study in which a device, 
855 
biologic, or drug is used in humans, including any comparator used, whether or not the event is 
856 
considered related (i.e., irrespective of the relationship between the adverse event and the 
857 
device(s) under investigation).  
858 
For this protocol, an adverse event is considered any untoward medical occurrence, unintended 
859 
disease or injury, or untoward clinically significant clinical sign in a study participant that 
860 
manifests while in the study if it was not present before enrolling in the study, or if present prior 
861 
to enrollment, it has increased in severity, frequency, or type. Adverse Event recording and 
862 
reporting will occur at the onset of the CGM Run-In through post-study check-in visit (visit 4 – 
863 
visit 10).  
864 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
865 
during questioning, or detected through physical examination, laboratory test, or other means—
866 
will be reported on the Adverse Event Form. Adverse Events that are identified during the study 
867 
and defined as related to the study will be followed until their medical outcome is determined or 
868 
until no further change in the condition is expected. 
869 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
870 
events unless associated with an Adverse Device Effect.  
871 
Skin reactions from sensor placement are only reportable if severe and/or required treatment. 
872 
A positive pregnancy test will not be considered an adverse event.  
873 
Treatment Emergent Adverse Event (TAE): An undesirable event that is not present prior to 
874 
medical treatment, and an already present event that worsens either in intensity or frequency 
875 
which occurs between the first dose and the end of follow up visits.  
876 
11.1.2 Serious Adverse Event (SAE) 
877 
Any untoward medical occurrence that: 
878 
• results in death. 
879 
• is life-threatening; (a non-life-threatening event which, had it been more severe, might 
880 
have become life-threatening, is not necessarily considered a serious adverse event). 
881 
• requires inpatient hospitalization or prolongation of existing hospitalization. 
882 
• results in persistent or significant disability/incapacity or substantial disruption of the 
883 
ability to conduct normal life functions (life threatening). 
884 

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• is a congenital anomaly or birth defect. 
885 
• is considered a significant medical event by the investigator based on medical judgment 
886 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
887 
prevent one of the outcomes listed above). 
888 
• Any serious psychological and emotional distress in study participation (suggesting need 
889 
for professional counseling or intervention). 
890 
11.1.3 Unanticipated Problem (UP) 
891 
An unanticipated problem is any event, experience, issue, instance, problem or outcome that 
892 
meets all 3 of the following criteria: 
893 
• Is unexpected in terms of the nature, severity or frequency given the research procedures 
894 
that are described in the protocol –related documents AND in the characteristics of the 
895 
population under study. 
896 
• Is related or possibly related to participation in research.  This means that there is a 
897 
reasonable possibility that the incident may have been caused by the procedures involved 
898 
in the research study. 
899 
• The incident suggests that the research places the participant or others at greater risk of 
900 
harm (physical, psychological, economic or social) than was previously known or 
901 
recognized OR results in actual harm of the participant or others.  An unanticipated 
902 
problem generally required a change in policy or procedure , warrants consideration of 
903 
substantive changes to the protocol/consent or other immediate corrective actions in order 
904 
to reduce the risk or eliminate immediate hazard. 
905 
11.1.4 Adverse Reaction (AR) 
906 
An adverse reaction (AR) is an AE for which the causal relationship between the drug and the 
907 
AE is suspected. The FDA-approved Prescribing Information (PI), also known as United States 
908 
Prescribing Information (USPI), which reflects the FDA’s finding regarding the safety and 
909 
effectiveness of the human prescription drug under the labeled conditions of use, will be 
910 
reviewed in the event of an adverse reaction. In this trial the review will be performed whenever 
911 
an AE is considered related to Insulin Degludec (Tresiba).   
912 
11.1.5 Serious Adverse Reaction (SAR) 
913 
An adverse event which fulfils both the criteria for a serious adverse event and the criteria for an 
914 
adverse reaction. 
915 
11.1.6 Suspected Unexpected Serious Adverse Reactions (SUSAR):  
916 
An SAR which is unexpected and regarded as possibly or probably related to the insulin 
917 
degludec by the investigator.  
918 

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11.1.7 Unanticipated Adverse Device Effect (UADE) 
919 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
920 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
921 
nature, severity, or degree of incidence in the investigational plan or application (including a 
922 
supplementary plan or application), or any other unanticipated serious problem associated with a 
923 
device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
924 
11.1.8 Adverse Device Effect (ADE) 
925 
An adverse event related to the use of an investigational medical device. Any untoward medical 
926 
occurrence in a study participant which the device may have caused or to which the device may 
927 
have contributed per the medical monitor’s assessment, in collaboration with the investigator 
928 
(section 11.7.1) . 
929 
11.1.9 Device Complaints and Malfunctions 
930 
A device complaint is something that happens to a device or related to device performance, 
931 
whereas an adverse event happens to a participant. A device complaint may occur independently 
932 
from an AE, or along with an AE. An AE may occur without a device complaint or there may be 
933 
an AE related to a device complaint. A device malfunction is any failure of a device to meet its 
934 
performance specifications or otherwise work as intended. Performance specifications include all 
935 
claims made in the labelling for the device. The intended performance of a device refers to the 
936 
intended use for which the device is labelled or marketed (21 CFR 803.3).  
937 
 
938 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
939 
meets one of the following criteria: 
940 
11.2.1 Hypoglycemia Event 
941 
Hypoglycemia not associated with an ADE is only reportable as an AE when the following 
942 
definition for severe hypoglycemia is met:   
943 
Level 1 
Glucose <70 mg/dL 
(3.9 mmol/L) and 
glucose ≥54 mg/dL 
(3 mmol/L) 
SMBG 
Not reportable event 
Level 2 
Glucose <54 mg/dL 
(3 mmol/L)  
SMBG 
Reportable event 
Level 3 
Characterized by 
altered mental and/or 
physical status 
requiring assistance 
SMBG if available, 
or without SMBG but 
symptomatic 
Reportable event 

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for treatment of 
hypoglycemia 
11.2.2 Hyperglycemia Events (HHS)/Diabetes Ketoacidosis (9) 
944 
Hyperglycemia not associated with an ADE is only reportable as an AE when one of the 
945 
following is met:  
946 
• The event involved DKA, as defined by the DCCT and described below evaluation or 
947 
treatment was obtained at a health care provider facility for an acute event involving 
948 
hyperglycemia resulting in hyperglycemic hyperosmolar syndrome (HHS) or ketosis 
949 
Hyperglycemic events are classified as HHS if the following are present: 
950 
• Arterial pH >7.3 
951 
• Serum bicarbonate > 18mEq/L 
952 
• Serum beta-hydroxybutyrate < 3 mmol/L 
953 
• Urine or serum ketones normal or small 
954 
Hyperglycemic events are classified as DKA if the following are present: 
955 
• Symptoms such as polyuria, polydipsia, nausea, or vomiting 
956 
• Serum ketones ≥1.5 mmol/L or large/moderate urine ketones 
957 
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15mEq/L 
958 
• Treatment provided in a health care facility 
959 
An adverse event as defined in section above which leads to discontinuation of a study device for 
960 
2 or more hours will be considered a reportable event.  
961 
 
962 
The study investigator will assess whether any AE is related or unrelated by determining if there 
963 
is a reasonable possibility that the adverse event may have been caused by the study device. 
964 
To ensure consistency of adverse event causality assessments, investigators should apply the 
965 
following general guideline when determining whether an adverse event is: 
966 
• Related: There is a plausible temporal relationship between the onset of the adverse event 
967 
and the study device, and the adverse event cannot be readily explained by the 
968 
participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
969 
adverse event follows a known pattern of response to the study intervention; and/or the 
970 
adverse event abates or resolves upon discontinuation of the study intervention or dose 
971 
reduction and, if applicable, reappears upon rechallenge. 
972 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 48 of 59 
  
• Unrelated: Evidence exists that the adverse event has an etiology other than the study 
973 
intervention (e.g., preexisting medical condition, underlying disease, intercurrent illness, 
974 
or concomitant medication); and/or the adverse event has no plausible temporal 
975 
relationship to study intervention. 
976 
 
977 
The intensity of an AE, coded per the UVA IRB website instructions, will be rated on a three-
978 
point scale: (1) mild, (2) moderate, or (3) severe. It is emphasized that the term severe is a 
979 
measure of intensity: thus, a severe AE is not necessarily serious. For example, itching for 
980 
several days may be severe, but may not be clinically serious. 
981 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
982 
participant’s daily activities. 
983 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant 
984 
and may interfere with daily activities but is ameliorated by simple therapeutic measures. 
985 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic 
986 
drug therapy or other treatment. 
987 
 
988 
The outcome of each reportable AE will be classified by the investigator as follows: 
989 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without 
990 
sequelae.  Record the AE/SAE stop date. 
991 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had 
992 
stabilized without change in the event anticipated.  Record the AE/SAE stop date. 
993 
• FATAL – A fatal outcome is defined as SAE resulting in death. Only the event that was 
994 
the cause of death should be reported as fatal.  AEs/SAEs that were ongoing prior to 
995 
death, however, were not the cause of death, will be recorded as “resolved” at the time of 
996 
death. 
997 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined 
998 
as the event was ongoing with an undetermined outcome. 
999 
• An ongoing outcome will require follow-up by the site to determine the final outcome of 
1000 
the AE/SAE. 
1001 
• The outcome of an ongoing event at the time of death that was not the cause of death, 
1002 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1003 
date. 
1004 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant 
1005 
or the participant’s records to determine outcome (e.g., a participant lost to follow-up). 
1006 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
1007 
occurring during the study and continuing at study termination should be followed by the 
1008 
participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
1009 
underlying cause, or resolution. Follow-up information should be recorded on source documents. 
1010 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 49 of 59 
  
If any reported adverse events are present when a participant completes the study, or if a 
1011 
participant is withdrawn from the study due to an adverse event, the participant will be contacted 
1012 
for re-evaluation. If the adverse event has not been resolved, additional follow-up will be 
1013 
performed as appropriate. Every effort should be made by the Investigator or delegate to contact 
1014 
the participant until the adverse event has resolved or stabilized. 
1015 
 
1016 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
1017 
whether an AE occurred, except in the following circumstances. 
1018 
The following device issues are anticipated and will not be reported but will be reported as an 
1019 
AE if the criteria for AE reporting described above are met: 
1020 
• Component disconnections 
1021 
• CGM sensors lasting fewer than the number of days expected per CGM labelling 
1022 
• CGM tape adherence issues 
1023 
• Skin reactions from CGM sensor placement or pump infusion set placement do not meet 
1024 
criteria for AE reporting. 
1025 
 
1026 
• The University of Virginia IRB does not accept reports of adverse events and IND Safety 
1027 
Reports that do not meet the definition of an unanticipated problem or an unexpected and 
1028 
serious adverse event involving risks to participants or others. Internal, serious, and 
1029 
unexpected AEs must be reported to the IRB-HSR within 7 calendar days from the time 
1030 
that the study team received knowledge of the event. These events will be reported using 
1031 
the IRB Online found at http://irb.virginia.edu.  
1032 
• SAEs possibly related to a study device, study drug, or study participation and UADEs 
1033 
and SUSARs must be reported by the investigator to the IDE Sponsor within 24 hours of 
1034 
the site becoming aware of the event. This can occur via phone or email. An Adverse 
1035 
Event Form CRF, and Device Deficiency Reportable Events form if applicable, should be 
1036 
completed. If the form is not initially completed, it should be completed as soon as 
1037 
possible after there is sufficient information to evaluate the event. All other reportable 
1038 
ADEs and other reportable AEs should be submitted by completion CRF within 7 days of 
1039 
the site becoming aware of the event. 
1040 
• The IDE Sponsor will investigate the UADE and if indicated, report the results of the 
1041 
investigation to the IRBs, FDA, and Medical Monitor within 10 working days of the 
1042 
study team becoming aware of the UADE per 21CFR 812.46(b).  
1043 
• The Medical Monitor will determine if the UADE presents an unreasonable risk to 
1044 
participants. If so, the Medical Monitor will must ensure that all investigations, or parts 
1045 
of investigations presenting that risk, are terminated as soon as possible but no later than 
1046 
5 working days after the Medical Monitor will makes this determination and no later than 
1047 
15 working days after first receipt notice of the UADE. 
1048 

CLINICAL PROTOCOL 
 
              
 
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• In the case of a device system component malfunction (e.g., CGM), information will be 
1049 
forwarded to the responsible manufacturer by the study personnel. At a minimum the 
1050 
following should be reported: Study name, Participant Identifier, Event (diagnosis), Trial 
1051 
drug, Reporter, Causality, Outcome. 
1052 
• Other reportable adverse events, device malfunctions (with or without an adverse event) 
1053 
and device complaints must be reported in the yearly IDE progress report. 
1054 
11.7.1 Data and Safety Monitoring 
1055 
A Medical Monitor will review all HHS/DKA and severe hypoglycemia irrespective of 
1056 
relatedness to study device use, and all serious events (including UADEs) related to study device 
1057 
use at the time of occurrence. The Medical Monitor can request modifications to the study 
1058 
protocol or suspension or outright stoppage of the study if deemed necessary based on the 
1059 
totality of safety data available. Details regarding the Medical Monitor review will be 
1060 
documented in a separate Medical Monitor document.   
1061 
The Medical Monitor will review the investigator’s assessment of causality of all SAEs (and 
1062 
derivatives) and may agree or disagree. Both the investigators and Medical Monitor’s 
1063 
assessments will be recorded. The Medical Monitor will have the final say in determining the 
1064 
causality as well as whether an event is classified as a serious adverse event and/or an 
1065 
unanticipated adverse device effect. 
1066 
 
1067 
11.8.1 Participant Discontinuation  
1068 
Rules for discontinuing investigational device use are described below. 
1069 
• The investigator believes it is unsafe for the participant to continue the intervention.  This 
1070 
could be due to the development of a new medical condition or worsening of an existing 
1071 
condition; or participant behaviors contrary to the indications for use of the device that 
1072 
imposes on the participant’s safety 
1073 
• The participant requests that the treatment be stopped 
1074 
• Two events of any kind (e.g., severe hypoglycemia or DKA/HHS events as defined 
1075 
above) 
1076 
11.8.2 Suspending/Stopping Overall Study 
1077 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
1078 
hyperglycemia event, use of the study device system will be suspended while the problem is 
1079 
diagnosed. 
1080 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1081 
study device requires stoppage of device use for safety reasons (e.g., product recall). The 
1082 
affected study activities may resume if the underlying problem can be corrected by a protocol or 
1083 
system modification that will not invalidate the results obtained prior to suspension.  
1084 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 51 of 59 
  
 
1085 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
1086 
Practices (GCP), or procedure requirements. The noncompliance may be either on the part of the 
1087 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
1088 
may be developed by the site and implemented as appropriate. Major deviations will be reported 
1089 
to the IRB-HSR within 7 calendar days of when the study team becomes aware of the event. 
1090 
 
1091 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, 
1092 
access, or use of protected health information (PHI) that compromises the security or privacy of 
1093 
such information.  
 
1094 

CLINICAL PROTOCOL 
 
              
 
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Chapter 12 Miscellaneous Considerations  
1095 
 
1096 
The study device (CGM) must be removed before Magnetic Resonance Imaging (MRI), 
1097 
Computed Tomography (CT) or diathermy treatment. Participants may continue in the trial after 
1098 
temporarily discontinuing use if requiring one of the treatments above. 
1099 
 
1100 
Participation in the study is voluntary. Participant may withdraw at any time.  For participants 
1101 
who do withdraw from the study, the study team will determine if their data will be used in 
1102 
analysis.  
1103 
 
1104 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1105 
used instead of their name.  De-identified participant information may also be provided to 
1106 
collaborators involved in the study after the appropriate research agreement has been executed. 
1107 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 53 of 59 
  
Chapter 13 Statistical Consideration 
1108 
 
1109 
This is an early study intended to pilot test the safety and feasibility of a CGM-based titration 
1110 
algorithm. The study will follow a multisite, unblinded, randomized, parallel arm design with 2:1 
1111 
randomization to either the CTR arm (using a standardized SMBG-based titration) or the EXP 
1112 
arm (personalized CGM-based titration). 
1113 
The primary hypothesis is that personalized CGM-based titration (with unblinded CGM) will 
1114 
lead to non-inferior improvement in time in the 70-180 mg/dL range during week 15 and 16 from 
1115 
baseline as compared to standardized SMBG-titration. A non-inferiority margin of 5% will be 
1116 
adopted per CGM outcomes consensus guidelines [9]. 
1117 
 
1118 
Published results on change in TIR from studies investigating glycaemic control in T2D 
1119 
participants titrating Degludec weekly showed an improvement of 7% with SD of 20% from 
1120 
baseline [8] after 16 weeks.  
1121 
The current sample size is not computed based on a formal power analysis but chosen to provide 
1122 
sufficient system exposure to assess feasibility and estimate effect size. 
1123 
 
1124 
13.3.1 Primary Endpoint 
1125 
The primary endpoint is the change in CGM-measured time in range 3.9-10.0 mmol/L (70-180 
1126 
mg/dL) from baseline (-2 to 0, 2 weeks) to weeks 14-16 (2 weeks), compared between CTR and 
1127 
EXP arm. 
1128 
13.3.2 Secondary Endpoints 
1129 
With the exception of Device Deficiencies (DD) and acceptance rates, the secondary endpoints 
1130 
will be compared between EXP and CTR arm with correction of multiple comparisons if 
1131 
applicable. Secondary endpoints 1 through 12 will be compared between EXP and CTR arm with 
1132 
Benjamini Hochberg correction to control the false discovery rate in the presence of multiple 
1133 
comparisons [10]. Outcomes will be grouped as noted in the table below, and corrected p-values 
1134 
will be reported. 
1135 
Secondary outcomes are listed below: 
1136 
 
 
1137 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 54 of 59 
  
 
1138 
 
1139 
 
1140 
Unpowered study. Not defined. 
1141 
BH 
Group 
Title 
Time Frame 
Unit 
1 
Change in HbA1c 
From week 0 to week 16 Percentage point 
1 
Change in CGM time in tight 
range 3.9-7.8 mmol/L (70-140 
mg/dL) 
From baseline (week -2-
0) to week 14-16 
% of time 
1 
Change in CGM Time spent > 
10.0 mmol/L (180 mg/dL) 
From baseline (week -2-
0) to week 14-16 
% of time 
1 
Change in CGM Time spent > 
13.9 mmol/L (250 mg/dL) 
From baseline (week -2-
0) to week 14-16 
% of time 
1 
Change in Coefficient of variation 
(CV - CGM) 
From baseline (week -2-
0) to week 14-16 
% 
1 
Change in CGM Mean glucose 
level (CGM) 
From baseline (week -2-
0) to week 14-16 
Mmol/L 
1 
Change in CGM Time spent < 3.9 
mmol/L (70 mg/dL) 
From baseline (week -2-
0) to week 14-16 
% of time 
1 
Change in CGM Time spent < 3.0 
mmol/L (54 mg/dL) 
From baseline (week -2-
0) to week 14-16 
% of time 
2 
Number of clinically significant 
hypoglycemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From week 0 to week 16 Number of 
episodes 
2 
Number of serious adverse events 
(SAEs) 
From week 0 to week 16 Number of events 
2 
Number of treatment emergent 
adverse events (TAEs) 
From week 0 to week 16 Number of events 
2 
Mean basal daily insulin dose at 
the end of trial. 
Week 16 
Units of insulin 
NA 
Number of device deficiencies 
(DDs) 
From week 0 to week 16 Number of events 
NA 
Investigator acceptance rate of 
weekly dose guidance – from 
CGM based titration (EXP arm 
only) 
From baseline (week 0) 
to week 16 
% 
NA 
The investigator changes the dose 
from the recommended or the 
current dose (EXP arm only) 
From baseline (week 0) 
to week 16 
Number of events 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 55 of 59 
  
 
1142 
Raw CGM data from the study database will be downloaded for each participant. The 
1143 
approximately two weeks (14 days midnight to midnight) of data between each visit will be used 
1144 
to compute the CGM outcomes. 
1145 
Low and High values in the CGM stream will be replaced by 39 and 401, respectively. 
1146 
Any SMBG entered via the CGM collection app will be removed prior to analysis. 
1147 
Consensus metric will be computed for each available day, if 70% or more of the maximum 
1148 
number of measurements are available (>201values per day), and then averaged over valid days 
1149 
for the period. 
1150 
If more than 7 days have more than 30% of CGM measurements missing, the outcome will be 
1151 
labelled missing. 
1152 
 
1153 
• Number of symptomatic hypoglycemic events  
1154 
• Reported AEs will be used for safety analysis. 
1155 
• Study physician override of automated insulin dose computation in the EXP arm  
1156 
 
1157 
Baseline demographic and clinical characteristics of the cohort of all randomized participants 
1158 
will be summarized in a table using summary statistics appropriate to the distribution of each 
1159 
variable. The following descriptive statistics will be displayed overall and by treatment group: 
1160 
• Age 
1161 
• HbA1c 
1162 
• Gender 
1163 
• Race/ethnicity 
1164 
• Diabetes duration 
1165 
• BMI 
1166 
• Total Daily Insulin 
 
1167 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 56 of 59 
  
Chapter 14  Data Collection and Monitoring 
1168 
 
1169 
Data is collected through a combination of case report forms (electronic and paper) and 
1170 
electronic device data files obtained from the software and individual hardware components. 
1171 
These electronic device files and electronic CRFs are considered the primary source 
1172 
documentation. For any data points for which the eCRF is not considered source, the original 
1173 
source documentation will be maintained in the participant’s study chart or medical record.  
1174 
Electronic reports (e.g., medical records), electronic results (e.g., LabCorp results), or electronic 
1175 
device data files (e.g., software and individual hardware components) will be considered the 
1176 
primary source documentation and stored in the participant study folder or on a highly sensitive 
1177 
UVA local secure drive. 
1178 
HbA1c samples will be sent to the central laboratory for analysis. The results will be transmitted 
1179 
to the University of Virginia. 
1180 
 
1181 
Study documents should be retained for a minimum of 6 years after the study completion, or 
1182 
until at least 2 years have elapsed since the formal discontinuation of development of the 
1183 
investigational product. Documents should be retained for a longer period, if required by local 
1184 
regulations. No records will be destroyed without the written consent of the IDE Sponsor. It is 
1185 
the responsibility of the IDE Sponsor to inform each clinical site if retention of these records will 
1186 
exceed these timelines. 
 
1187 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 57 of 59 
  
Chapter 15  Ethics/Protection of Human Participants 
1188 
 
1189 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1190 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1191 
21 CFR Part 56, and/or the ICH E6. 
1192 
 
1193 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1194 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1195 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1196 
require review and approval by the IRB before the changes are implemented to the study. All 
1197 
changes to the consent form will be IRB approved; a determination will be made regarding 
1198 
whether previously consented participants need to be re-consented. 
1199 
 
1200 
15.3.1 Consent Procedures and Documentation 
1201 
Informed consent is a process that is initiated prior to an individual’s agreement to participate in 
1202 
the study and continues throughout the individual’s study participation. Consent forms will be 
1203 
IRB approved, and the participant will be asked to read and review the document. The 
1204 
investigator or delegate will explain the study to the participant and answer any questions that 
1205 
may arise. All participants will receive verbal explanation in terms suited to their comprehension 
1206 
of the purposes, procedures, and potential risks of the study and of their rights as research 
1207 
participants. Extensive discussion of risks and possible benefits of participation will be provided. 
1208 
The participant will sign the informed consent document prior to any procedures being done 
1209 
specifically for the study.  
1210 
The potential participant will be provided with a short overview of the study including its study 
1211 
goals, study procedures, and study timeline. If the potential participant remains interested, they 
1212 
will be asked permission to review inclusion/exclusion criteria to assess if they are eligible to 
1213 
participate in the study. If permission is granted, the study team will review the 
1214 
Inclusion/Exclusion Questionnaire. If eligible, the study team member will provide a copy of the 
1215 
informed consent form (e.g., Clinic, email, fax, or mail) to the potential participant for their 
1216 
review. Potential participants may also elect to review the informed consent form prior to 
1217 
discussing pre-screening questions.  
1218 
The consenting process will involve discussing the study at length in a phone call/HIPAA 
1219 
compliant telecommunication method for consenting that is not face to face. The potential 
1220 
participant will be given an opportunity to ask the study team questions or may speak directly 
1221 
with the study physician. The potential participant’s understanding of the information presented 
1222 
in the process of consent will be assessed by asking open-ended questions.  
1223 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 58 of 59 
  
The consent form may be signed electronically with the use of the Part 11 compliant version of 
1224 
DocuSign for both in-person and telecommunication screening visits. Note: For potential 
1225 
participants who are not able to use DocuSign, email, fax, or mail will be an option for receipt of 
1226 
the signed consent. A HIPAA compliant video conferencing tool will be utilized during the 
1227 
consenting process of the telecommunication screening visit to facilitate the FDA part 11 
1228 
compliant process of verification of reviewing two forms of identification if signing 
1229 
electronically off site. A copy of the informed consent document will be given to the participant 
1230 
for their records. Study procedures may begin once the consent has been signed by the 
1231 
participant and a member of the study team.  
1232 
The rights and welfare of the participants will be protected by emphasizing to them that the 
1233 
quality of their medical care will not be adversely affected if they decline to participate in this 
1234 
study. 
1235 
 Participant
1236 
The study monitor, representatives of the IRB, the pharmaceutical company, or the device 
1237 
company supplying study product may inspect documents and records required to be maintained 
1238 
by the investigator, for the participants in this study as detailed in the contractual agreements 
1239 
with these sponsors.  
1240 
The study participant’s contact information will be securely stored at the clinical site for internal 
1241 
use during the study. The study team will assign a Participant ID number and a code word to 
1242 
each person who signs a consent form. Both are entered to record study data in eCRFs. Limited 
1243 
study team members have access to identified data. CGM and BGM data are stored in a cloud-
1244 
based storage in a de-identified format. Data are anonymized by CDT personnel before being 
1245 
stored on UVA Office365 OneDrive or a highly sensitive UVA local secure drive. At the end of 
1246 
the study, all records will continue to be kept in a secure location for as long a period as dictated 
1247 
by local IRB and Institutional regulations. 
1248 
Participants’ research data, which is for the purposes of statistical analysis and scientific 
1249 
reporting, will be transmitted to and stored at the UVA CDT. The study data entry and study 
1250 
management systems used by research staff will be secured and password protected. At the end 
1251 
of the study, all study databases may be de-identified and archived at the UVA CDT. 
1252 

CLINICAL PROTOCOL 
 
              
 
 CGM-DTx Degludec v3.3                                        19-Feb-2024                                                           Page: 59 of 59 
  
Chapter 16 References  
1253 
1. M. Mocarski et al., Slow titration and delayed intensification of basal insulin among 
1254 
participants with type 2 diabetes, 2018, J.Manag.Care Spec.Pharm. (4): 390-400. 
1255 
2. K. Khunti and D. Millar-Jones, Clinical inertia to insulin initiation and intensification in the 
1256 
UK: A focused literature review, 2017, Primary Care Diabetes (11): 3-12. 
1257 
3. H. Ishii et al., Comparison of Patient-Led and Physician-Led Insulin Titration in Japanese 
1258 
Type 2 Diabetes Mellitus Participants Based on Treatment Distress, Satisfaction and Self-
1259 
Efficacy: The COMMIT-Patient Study,2021, Diabetes Ther, 12 (2): 595-611. 
1260 
4. RE Ratner et al., Hypoglycemia risk with insulin degludec compared with insulin glargine in 
1261 
type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials, 2012, Diabetes, 
1262 
Obesity and Metabolism, Vol 15, 2, 175-184. 
1263 
5. ADA, Standards of Medical Care in Diabetes-2023 Abridged for Primary Care Providers, Clin 
1264 
Diabetes 2023;41 (1) 
1265 
6. MA Jackson et al., Type 2 Diabetes and the Use of Real-Time Continuous Monitoring, 2021, 
1266 
Diabetes Technol Ther, 23 (Suppl1): S27-S34 
1267 
7. Beck RW, An evaluation of two capillary sample collection kits for laboratory measurement 
1268 
of HBA1c, 2021, Diabetes Technology & Therapeutics, Vol 23 (8),537-545 
1269 
8. Goldenberg RM, Aroda VR, Billings LK, Christiansen AS, Meller Donatsky A, Parvaresh 
1270 
Rizi E, Podgorski G, Raslova K, Klonoff DC, Bergenstal RM. Effect of insulin degludec 
1271 
versus insulin glargine U100 on time in range: SWITCH PRO, a crossover study of basal 
1272 
insulin‐treated adults with type 2 diabetes and risk factors for hypoglycaemia. Diabetes, 
1273 
Obesity and Metabolism. 2021 Nov;23(11):2572-81. 
1274 
9. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, Bosi E, Buckingham 
1275 
BA, Cefalu WT, Close KL, Cobelli C. Clinical targets for continuous glucose monitoring data 
1276 
interpretation: recommendations from the international consensus on time in range. Diabetes 
1277 
care. 2019 Aug 1;42(8):1593-603. 
1278 
10. Benjamini Y, Hochberg Y (1995). "Controlling the false discovery rate: a practical and 
1279 
powerful approach to multiple testing". Journal of the Royal Statistical Society, Series B. 57 
1280 
(1): 289–300.  
1281