Continuous Glucose Monitoring Versus Blood Glucose Monitoring to Optimize Glycemic Outcomes in People With Type 2 Diabetes Following the Virta Treatment Program" (IGNITE: Impact of Glucose moNitoring and nutrItion on Time in rangE Study)
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: HealthPartners Institute

 
Official Title: Continuous Glucose Monitoring Versus Blood Glucose Monitoring to Optimize Glycemic 
Outcomes in People With Type 2 Diabetes Following the Virta Treatment Program" (IGNITE: Impact of 
Glucose moNitoring and nutrItion on Time in rangE Study) 
Brief Title: IGNITE (Impact of Glucose moNitoring and nutrItion on Time in rangE)   
Clinical Trials Number: NCT05516797 
Date: 03Jan2023  

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 1 of 34 
 
Continuous Glucose Monitoring versus Blood Glucose Monitoring to Optimize Glycemic Outcomes in 
People with Type 2 Diabetes Following the Virta Treatment Program   
 
Study Name: IGNITE (Impact of Glucose moNitoring and nutrItion on Time in rangE) 
ClinicalTrials.gov number: Pending, will be submitted upon Institutional Review Board (IRB) approval 
Protocol Version Number: 2.0 
Protocol Version Date: 06Dec2022 
Funding Mechanism: Investigator Initiated Study 
Industry Funding Provided by: Abbott Diabetes Care 
 
Principal Investigator: Holly Willis, PhD, RDN, CDCES 
 
Phone: 952-993-3219 
 
E-mail: holly.willis@parknicollet.com  
Co-Investigator: Richard M. Bergenstal, MD 
Phone: 952-993-1913 
Email: richard.bergenstal@parknicollet.com  
Co-Investigator: Amy McKenzie, PhD 
Phone: 765413-6171 
Email: amy@virtahealth.com  
Co-Investigator: Caroline Roberts, MD 
Phone: 443-904-5290 
Email: caroline@virtahealth.com  
Co-Investigator: Brittanie Volk, PhD, RD 
Phone: 765-418-2814 
Email: brittanie@virtahealth.com  
Co-Investigator: Rebecca Adams, PhD 
Phone: 415-513-3639 
Email: rebecca@virtahealth.com  
 
CONFIDENTIAL 
This document is confidential and the property of International Diabetes Center and Virta Health. No 
part of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
 
Revision 
Date 
Summary of Change 
Ver 1.0 
20Jun2022 
Original Protocol 
Ver 2.0 
06Dec2022 
● Inclusion criteria changed 
to include: HbA1c between 
7.0%- 11.5% documented 
within 180 days prior to 
consent, Stable diabetes 
medication regimen and 
lifestyle patterns (eating 
and activity) within 
approximately 30 days prior 
to consent, and Confirmed 
download of FreeStyle Libre 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 2 of 34 
 
2 app on smartphone with 
regular WiFi or cellular data 
access 
● ASA24 version 2020 
updated to indicate version 
2020 or later 
● Additional language to 
describe repeat sensor 
wear scenarios at baseline, 
month 3, and 6 
● Clarification for when IDC 
may contact participants; 
the updated protocol 
language clarified to match 
the consent 
Minor clarifying and formatting 
edits 
TABLE OF CONTENTS  
Contents 
1 
List of Abbreviations 
3 
2 
Protocol Summary 
4 
3 
Background/Rationale and Purpose 
5 
3.1 
     5 
3.2 
     7 
4 
Objectives 
7 
4.1 
     8 
4.2 
     8 
4.2.1 
Primary Outcome Measures 
8 
4.2.2 
Secondary Outcome Measures 
9 
4.2.3      Exploratory Outcome Measures 
9 
5 
Study Design 
11 
6 
Study Partcipant Selection 
11 
6.1 
12 
6.2 
12 
7 
Study Procedures and Intervention 
12 
7.1 
13 
7.2 
13 
8       Study Intervention 
14 
8.1           Ongoing Study Procedures 
15 
8.2 
16 
8.3 
16 
8.4     Contact schedule 
17 
9        Early Termination and Participant Withdrawal 
19 
10      Lost to Follow-Up 
19 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 3 of 34 
 
11      Protocol Deviation 
20 
12      Potential Risks and Benefits 
20 
12.1        Risks 
20 
12. 2       Potential Benefits 
21 
12.3        Analysis of Risks in Relation to Benefits 
21 
13      Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
21 
13.1        Definitions 
21 
13.2        Safety Review 
22 
13.3        Reporting Plans 
23 
13.4        Stopping Rules and Study Suspension or Termination 
23 
14 
Data Management and Record Keeping 
23 
14.1        Data Monitoring 
24 
14.2        Confidentiality 
24 
14.3        Records Retention 
24 
15 
Statistical Plan 
25 
15.1        Analysis of Primary Endpoint 
25 
15. 2       Analysis of Secondary Endpoints 
25 
15.3        Analysis of Exploratory Endpoints 
26 
15.4        Study Hypotheses 
26 
15.5        Sample Size Determination 
26 
16 
Ethics/Protection of Human Subjects 
27 
16.1       Informed Consent and HIPAA Authorization 
27 
16.2        Conflict of Interest 
27 
17        Appendices 
27 
17.1        Appendix A. Study Schematic 
28 
17.2        Appendix B. Study Periods and Assessments 
29 
17.3        Appendix C. Participant-Facing Materials 
30 
18       References 
31 
 
 
1 
List of Abbreviations 
 
Abbreviation 
Abbreviation definition 
AE 
Adverse event 
ADA 
American Diabetes Association 
ASA24 
Automated Self-Administered 24-Hour Dietary Assessment Tool 
BGM 
Blood glucose monitoring 
BHB 
Beta-hydroxybutyrate 
BMI 
Body mass index 
CGM 
Continuous glucose monitoring 
CI  
Confidence interval 
CIRBI 
Center for IRB Intelligence 
CLIA 
Clinical Laboratory Improvement Amendments 
DKA 
Diabetic ketoacidosis 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 4 of 34 
 
EMR 
Electronic medical record 
HbA1c 
Glycated hemoglobin 
HCP 
Healthcare provider 
HHS 
Hyperosmolar hyperglycemic syndrome 
HIPAA 
Health Insurance Portability and Accountability Act 
IRB 
Institutional Review Board 
ICF 
Informed consent form 
ID 
Identification 
IDC 
International Diabetes Center 
IGNITE 
Impact of Glucose moNitoring and nutrItion on Time in rangE  
MES 
Medication effect score 
NGSP 
National Glycohemoglobin Standardization Program 
PRO 
Patient reported outcome 
PWD 
People with diabetes 
SAE 
Serious adverse event 
SOC  
Standards of Medical Care 
SOP 
Standard operating procedure 
T2D 
Type 2 diabetes 
TIR 
Time in range 
TITR 
Time in tight range 
UAE 
Unanticipated event 
UPIRTSO 
Unanticipated Problems Involving Risks to Subjects or Others 
WFKD 
Well-formulated ketogenic diet 
 
2 
Protocol Summary  
 
Title: 
Continuous Glucose Monitoring versus Blood Glucose Monitoring 
to Optimize Glycemic Outcomes in People with Type 2 Diabetes 
Following the Virta Carbohydrate-Restricted Treatment Program 
(IGNITE Study) 
Population: 
N=150; Adults >18 years with T2D who are enrolled in the Virta 
Treatment  
Intervention: 
Use of CGM during participation in the Virta Treatment 
Objectives: 
Primary: Difference in change in 14-day CGM-derived TIR (% time 
with glucose 70‑180 mg/dL) from Baseline to 3-month Post-Dietary 
Change period between participants with T2D who are randomized 
to use either BGM or CGM as part of Virta Treatment. 
 
Secondary:  
● Difference in 90-day mean blood ketone levels between 
BGM and CGM arms 
● Difference in changes in other CGM-derived metrics from 
Baseline to 3-month Post-Dietary Change period between 
BGM and CGM arms 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 5 of 34 
 
● Difference in percent of participants reaching CGM-derived 
consensus targets at the end of the 3-month Post-Dietary 
Change period between BGM and CGM arms 
● Difference in Change in HbA1c from Baseline to the end of 
the 3-month Post-Dietary Change period between BGM and 
CGM arms 
Design/Methodology: 
Non-pivotal, randomized, parallel group, two-arm, prospective 
study. 1:1 randomization to either BGM or CGM during Baseline 
assessment period. 
 
See Appendix A for a study schematic and Appendix B for a table of 
study periods and assessments. 
Total Study Duration: 
Approximately 24 months 
Subject Participation 
Duration: 
Approximately 7-8 months 
 
 
 
 
 
3 
Background/Rationale and Purpose 
 
3.1 
Background Information 
 
More than 37 million people in the United States have diabetes, and type 2 diabetes (T2D) accounts for 
90-95% of all diagnosed cases. The number of adults diagnosed with diabetes has more than doubled in 
the last 20 years, which creates significant burdens for the economy, healthcare system, and families 
affected by the disease. Options to help manage T2D are more important than ever before.1 
 
Nutrition-related interventions have long been recognized as a critical component of diabetes care and 
management. Current guidance from the American Diabetes Association (ADA) Standards of Medical 
Care (SOC) states there is no “one-size-fits-all” eating pattern, or ideal macronutrient distribution, that 
works for all people with diabetes.2 A variety of eating patterns (e.g., Mediterranean, very-low-
carbohydrate, vegetarian) have demonstrated good efficacy for people with diabetes (PWD). However, 
evidence suggests all healthy eating patterns should emphasize non-starchy vegetables, minimal added 
sugars and refined grains, and whole foods over highly processed foods whenever possible. Reducing 
overall carbohydrate intake has demonstrated the most evidence for improving glycemia in people with 
T2D and should be considered with emphasis on the aforementioned components of healthy eating 
pattern.2 
 
People with T2D often learn about how their food choices impact their glucose by performing 
intermittent fingersticks, which is also called blood glucose monitoring (BGM). Continuous glucose 
monitoring (CGM), which tracks glucose continually over time is also an option. However, as of 2022, 
CGM is only recommended in the ADA SOC for PWD who require insulin.    
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 6 of 34 
 
Several studies in PWD who use insulin suggest that CGM may lead to greater improvements in glycated 
hemoglobin (HbA1c) compared to usual care, which is often BGM.3,4 CGM studies in PWD who do not 
use insulin are sparse; however, Jackson et al conducted a review of the available data and reported 
CGM may improve glycemic outcomes in PWD not using insulin and may have the potential to improve 
lifestyle changes and adherence to diabetes treatments.5 Wright and Subramanian, also suggest there is 
evidence that CGM provides benefits to PWD who are treated with less-intensive therapies; they 
present data showing that behavioral interventions that use CGM improve dietary habits, physical 
activity, bodyweight, and problem-solving skills.6  
 
One of the key benefits of CGM is the ability to see granular changes in glycemia over time. While HbA1c 
has long been the gold-standard for assessing glycemia, the HbA1c does not provide a clear picture of 
glucose variability or the patterns of hyper- and/or hypo-glycemia. The 2022 ADA SOC recognizes that 
CGM can provide better insights into more personalized diabetes care, and they call out ten core metrics 
that should be considered when evaluating CGM data. There is specific emphasis on time in range (TIR), 
the goal of which for most PWD is 70% of time in the target glucose range of 70-180mg/dL.7 A 14-day 
TIR has been shown to correlate well with HbA1c8 and emerging data suggest TIR is also correlated with 
risk of diabetes-related complications.9  
 
Two recent randomized controlled trials in PWD who were treated with basal insulin10 or less intensive 
therapies11 showed that use of CGM improves TIR by about 15%, which is noteworthy when considering 
a 5% improvement in TIR is considered clinically meaningful.12 CGM’s immediate feedback on current 
glucose levels and the retrospective review of glucose patterns from CGM reports may help optimize 
diabetes therapy, including dietary changes. The value of CGM for making nutrition and lifestyle 
modifications has strong potential, but it needs further research, which could lead to expanded 
indications for CGM for people with T2D.  
 
Very few nutrition intervention studies have used CGM technology to guide the intervention in people 
with T2D. Griauzde et al provided intermittent access to CGM as part of a low-carbohydrate intervention 
(< 100 g carbohydrate per day) and found that HbA1c decreased by 0.4% more than a comparison group 
who received usual care without CGM; they also showed that TIR increased by almost 18% over 12 
months in the group that was using CGM.13 Similarly, Oser et al showed that CGM was an effective 
educational and motivational tool in a study of 17 people with newly diagnosed T2D who used CGM as 
part of a nutrition-focused lifestyle intervention that emphasized carbohydrate restriction to minimize 
glycemic excursions.14 In this study, 67% of participants achieved HbA1c < 6.5% without diabetes 
medications and 80% of the participants showed an HbA1c reduction of 2.3% + 1.3%. While both studies 
appear promising, neither are randomized controlled trials with an adequate comparison group and 
neither of these studies evaluated TIR as a primary outcome. 
 
All people with T2D are encouraged to adopt lifestyle modifications focusing on eating patterns, physical 
activity, and weight management to improve their health. Treatment for people with T2D at Virta Health 
includes an individualized, remotely delivered, lifestyle-based intervention emphasizing a carbohydrate-
restricted diet to induce nutritional ketosis.  
 
Enrollment in the Virta Treatment is contingent on medical approval from the Virta HCP. Upon 
enrollment, participants receive introductory educational resources and an appointment with a health 
coach. Treatment at Virta includes guidance on the use of a well-formulated, ketogenic diet (WFKD), 
biometric feedback, behavior change support, optional peer support, and medication management 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 7 of 34 
 
(referred to as the “Virta Treatment”). The WFKD is a carbohydrate-restricted, moderate-protein, 
nutrient-dense eating pattern that emphasizes whole foods, including a variety of low-carbohydrate 
vegetables.  Health coaches provide frequent nutritional guidance and troubleshooting while healthcare 
providers (HCPs), physicians and nurse practitioners, provide medication management and medical 
oversight. As participants begin dietary changes, blood glucose declines and diabetes medications are 
titrated to match emerging glycemic patterns; this typically occurs within the first three months. 
 
In response to carbohydrate restriction with moderate protein intake, blood ketones rise, and a state of 
nutritional ketosis can be achieved. Blood ketones, therefore, serve as a marker of carbohydrate and 
protein intake and can be utilized as a marker of adherence to a carbohydrate-restricted, ketogenic 
diet.15 Blood ketones can be utilized by most tissues as a source of energy and can serve as a metabolite 
with recognized signaling properties.16 Further, greater blood ketone concentrations as a result of a 
ketogenic diet have been associated with better health outcomes such as greater weight loss.17 
 
The impact of Virta Treatment has been evaluated in a non-randomized, controlled intervention trial. In 
brief, 262 adults with a mean age of 54 years, a mean time with T2D of 8.4 years, and a mean baseline 
A1c of 7.5% underwent Virta’s nutrition intervention and continuous care plan. The comparison group 
received usual diabetes care, including standard dietary advice, outside of Virta. The trial showed that 
the impact of Virta’s intervention on diabetes-related health parameters is rapid, with an average of 1% 
reduction in HbA1c, a reduction in or elimination of diabetes medications, and a clinically meaningful 
weight loss for most participants at 10 weeks.18 Importantly, HCP oversight allowed for diabetes 
medication changes to reduce the risk of hypoglycemia in patients taking medications that are prone to 
hypoglycemia. Of those taking insulin or sulfonylureas at baseline, 87% and 93%, respectively, had 
medications either stopped or doses reduced by 10-weeks. Similar or improved results persisted after 
one19 and two20 years of trial participation. Notably, the retention rate throughout the trial was high: 
91% at 10-weeks, 83% at 1-year, and 74% at 2-years.  
 
Similar to most lifestyle modification programs for PWD, the Virta Treatment relies on BGM by 
fingerstick; however, dietary adoption and adherence to the Virta Treatment may be enhanced by the 
timely feedback of CGM data. Therefore, the following protocol describes a randomized, controlled trial 
intended to assess whether the addition of CGM into Virta’s clinical care plan improves TIR, glycemia, 
and adherence to nutrition therapy as evidenced by blood ketone monitoring.   
 
3.2 
Rationale and Purpose  
 
The purpose of this three-month, randomized, controlled trial is to compare the difference in change in 
14-day CGM-derived TIR (% time with glucose 70‑180 mg/dL) from Baseline to 3-months Post-Dietary 
Change in participants with T2D who are assigned to use either BGM or CGM. The difference in mean 
blood ketone levels and additional glycemic endpoints will also be compared, and several exploratory 
endpoints, including medication changes, dietary intake, and body weight will be described.  
 
The study also includes a three-month Follow-Up period (months three to six), where participants will 
remain using their randomly assigned glucose monitoring modality (e.g., BGM or CGM); this period will 
help assess durability of the results found during the intervention.    
 
This study will provide insights into how continuous feedback from CGM affects glycemic outcomes, 
such as TIR and HbA1c, compared to the standard method of BGM. It is important to understand if the 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 8 of 34 
 
methods of glucose monitoring differ, because greater TIR and lower HbA1c are associated with reduced 
risk of diabetes complications.  
 
While many studies have compared the differences in glycemic outcomes between BGM and CGM, this 
study would be one of the first-of-its kind to compare differences between the two glucose monitoring 
methods as part of a randomized, controlled nutrition intervention in people with T2D. It would also be 
one of the first-of-its kind to use TIR as a primary endpoint in a nutrition-focused program. Further, it is 
possible that this study will help demonstrate whether the continuous feedback provided by CGM 
influences adherence to dietary guidance.  
 
4 
Objectives 
 
4.1 
Study Objectives  
 
The primary objective of this study is to compare the difference in change in 14-day CGM-derived TIR (% 
time with glucose 70‑180 mg/dL) during Baseline and 3-month Post-Dietary Change periods between 
participants with T2D who are randomized to use either BGM or CGM to guide dietary and diabetes 
medication adjustments as part of the Virta Treatment.  
 
The secondary objectives of this study are to compare: 
1. Difference in 90-day mean blood ketone levels between BGM and CGM arms 
2. Difference in changes in other CGM-derived metrics from Baseline to 3-month Post-Dietary 
Change period between BGM and CGM arms 
3. Difference in percent of participants reaching CGM-derived consensus targets at the end of the 
3-month Post-Dietary Change period between BGM and CGM arms 
4. Difference in Change in HbA1c from Baseline to the end of the 3-month Post-Dietary Change 
period between BGM and CGM arms 
 
The exploratory objectives of this study are to describe: 
1. Change in CGM-derived TIR during Baseline and 6-month Follow-Up period 
2. Change in other CGM-derived metrics during Baseline and 6-month Follow-Up period  
3. Percent reaching CGM-derived consensus targets during 6-month Follow-Up period 
4. Change in A1c from Baseline to 6-month Follow-Up period  
5. Change in diabetes medication use  
6. Change in dietary intake  
7. Change in body mass index (BMI) and body weight  
8. Percent reaching blood ketone targets > 0.5mM  
9. Mean blood ketone levels  
10. Change in CGM-derived ‘time in tight range’ (TITR; glucose 70-140 mg/dL)  
11. Absolute values in CGM-derived metrics 
12. Number of contacts between participants and Virta care team   
13. Change in mean scores on patient-reported outcome (PRO) surveys 
 
4.2 
Study Outcome Measures 
 
For all CGM-related outcome measures, data will be assessed in the following ways: 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 9 of 34 
 
● Baseline CGM data for both study arms will come from the 14-day, blinded, FreeStyle Libre Pro 
sensors and readers using the Libre 2 algorithm  
● 3-month Post-Dietary Change CGM data (end of month three data) will come from: 
● CGM Arm: 14-day, FreeStyle Libre 2 data download from LibreView 
● BGM Arm: 14-day, blinded, FreeStyle Libre Pro sensors and readers using the Libre 2 
algorithm  
● 6-month Follow-Up period CGM data (end of month six data) will come from: 
● CGM Arm: 14-day, FreeStyle Libre 2 data download from LibreView 
● BGM Arm: 14-day, blinded, FreeStyle Libre Pro sensors and readers using the Libre 2 
algorithm  
 
The blinded FreeStyle Libre Pro reader used for collecting outcome measures data will use the Libre 2 
algorithm to keep outcome measure data comparable between study arms.  
 
4.2.1 Primary Outcome Measures 
 
Outcome 
Assessment Method 
Change in 14-day CGM-derived TIR (% of time with glucose 
70‑180 mg/dL) from Baseline to 3-month Post-Dietary Change 
period  
See CGM-related outcome 
measures described above 
 
4.2.2 Secondary Outcome Measures 
 
Outcome 
Assessment Method 
1. Mean of all blood ketone levels from day 0 to day 90 
BHB levels as tested by Precision 
Xtra Blood Glucose & Ketone 
Monitoring System; ketones 
requested twice daily 
throughout study 
2. Change in other CGM-derived metrics from Baseline to 3-
month Post-Dietary Change period: 
a. Time above range >180 mg/dL 
b. Time above range >250 mg/dL  
c. Time below range <70 mg/dL 
d. Time below range <54 mg/dL  
e. Mean sensor glucose 
f. % Coefficient of variation  
g. Mean amplitude of glucose excursion   
See CGM-related outcome 
measures described above 
3. Reaching CGM-derived consensus targets in the 3-month Post-
Dietary Change period (yes/no): 
● Time >250 mg/dL <5% 
● Time >180 mg/dL <25% 
● Time 70-180 mg/dL >70% 
● Time <70 mg/dL <4% 
● Time range <54 mg/dL <1% 
● Time 70-180 mg/dL >70% AND Time <70 mg/dL <4% 
See CGM-related outcome 
measures described above  

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 10 of 34 
 
● Time 70-180 mg/dL >70% AND Time <54 mg/dL <1% 
4. Change in HbA1c from Baseline to 3-month Post-Dietary 
Change period  
HbA1c assessed at Virta-
approved, CLIA-certified 
laboratory using NGSP HbA1c 
method 
 
4.2.3        Exploratory Outcome Measures 
 
Outcome 
Assessment Method 
1. Change in CGM-derived TIR (glucose 70-180 mg/dL) from 
Baseline to 6-month Follow-Up period 
See CGM-related outcome 
measures described above 
2. Change in other CGM-derived metrics from Baseline to 6-month 
Follow-Up period: 
● Time above range >180 mg/dL 
● Time above range >250 mg/dL  
● Time below range <70 mg/dL 
● Time below range <54 mg/dL  
● Mean sensor glucose 
● % Coefficient of variation  
● Mean amplitude of glucose excursion   
See CGM-related outcome 
measures described above  
3. Reaching CGM-derived consensus targets in the 6-month 
Follow-Up period (yes/no): 
● Time >250 mg/dL <5% 
● Time >180 mg/dL <25% 
● Time 70-180 mg/dL >70% 
● Time <70 mg/dL <4% 
● Time range <54 mg/dL <1% 
● Time 70-180 mg/dL >70% AND Time <70 mg/dL <4% 
● Time 70-180 mg/dL >70% AND Time <54 mg/dL <1% 
See CGM-related outcome 
measures described above 
 
4. Change in HbA1c from Baseline to 6-month Follow-Up period 
 
HbA1c assessed at Virta-
approved, CLIA-certified, 
laboratory using NGSP HbA1c 
method 
5. Change in medication use, as described by class, dose, and 
medication effect score (MES),21 from Baseline to end of Month 1, 
2, 3, and 6 
Medication name, class, dose, 
and frequency will be extracted 
from the participant’s medical 
record; MES will be calculated 
for each period  
6. Change in dietary intake from Baseline to end of month 1, 2, 3, 
and 6 
● Total energy intake 
● Total macronutrients and fiber (including type of fats) 
● Select micronutrients 
● Healthy Eating Index score 
● Food group equivalents  
Dietary intake based on a single 
Automated Self-Administered 
24-hour (ASA24®) diet recall 
(Version 2020 or later) collected 
via web-based survey 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 11 of 34 
 
7. Change in BMI and body weight from Baseline to month 1, 2, 3, 
and 6 
 
Cellular-connected BodyTrace 
body weight scale (BodyTrace, 
New York, New York, USA); 
Self-reported height; 
BMI calculated from measured 
weight and self-reported height 
8. Reaching blood ketone targets > 0.5mM based on the mean of 
all blood ketone levels in month 1 (0-30 days), 2 (31-60 days), 3 
(61-90 days), and 6 (150-180 days and 0-180 days) (yes/no) 
BHB levels as tested by Precision 
Xtra Blood Glucose & Ketone 
Monitoring System; ketones 
requested twice daily 
throughout study 
9. Mean blood ketone levels during month 1 (0-30 days), 2 (31-60 
days), 3 (61-90 days), and 6 (150-180 days and 0-180 days) 
 
BHB levels as tested by Precision 
Xtra Blood Glucose & Ketone 
Monitoring System; ketones 
requested twice daily 
throughout study 
10. Change in CGM-derived ‘time in tight range’ TITR (glucose 70-
140 mg/dL) during Baseline, 3-month Post-Dietary Change period, 
and 6-month Follow-Up period 
See CGM-related outcome 
measures described above 
11. Absolute values in CGM-derived metrics during 3-month Post-
Dietary Change period and 6-month Follow-Up period 
● Time >250 mg/dL 
● Time >180 mg/dL  
● Time 70-180 mg/dL 
● Time 70-140 mg/dL 
● Time <70 mg/dL  
● Time range <54 mg/dL 
● Mean sensor glucose 
● % coefficient of variation  
● Mean amplitude of glucose excursion 
See CGM-related outcome 
measures described above 
12. Number of contacts between participants and Virta care team 
during month 1 (0-30 days), 2 (31-60 days), 3 (61-90 days), and 6 
(150-180 days and 0-180 days) 
Absolute count of non-
automated messages exchanged 
between participants and Virta 
care team  
13. Patient-reported outcomes (PROs)  
● Diabetes Distress Scale-1722 at Baseline, end of month 3, 
and end of month 6 
● Lifestyle change survey (study-specific) end of month 3 
and end of month 6 
● CGM arm only: CGM Satisfaction Survey23 at end of month 
3 
All surveys administered via 
REDCap 
 
5 
Study Design 
 
This is a non-pivotal, randomized, parallel group, two-arm, prospective study. This 3-month intervention 
with a 3-month follow-up at 6 months will evaluate the impact of BGM and CGM as tools to guide 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 12 of 34 
 
dietary and diabetes medication adjustments during Virta Treatment. Participants will be randomized 
1:1 to either a BGM or CGM arm, with approximately seventy-five participants per arm.  
 
The intervention phase is defined as the “Post-Dietary Change” period and it occurs Day 0 through the 
end of the Month 3 assessments, approximately Day 90 to 104.  The “Follow-Up” period begins 
immediately following the Month 3 assessments and runs through the end of the Month 6 assessments, 
approximately Day 180 to 194.  
  
Appendix A provides an overview of the study design and Appendix B provides an overview of study 
periods and assessments. 
 
6 
Study Partcipant Selection 
 
6.1 
Participant Inclusion Criteria 
 
To be eligible to participate in this study, an individual must meet all the following criteria: 
1. Age > 18 years  
2. U.S. residence with plans to remain in the U.S. for study duration (for shipping purposes)  
3. Diagnosis of T2D  
4. HbA1c between 7.0-11.5% documented within 180 days prior to consent 
5. Stable diabetes medication regimen and lifestyle patterns (eating and activity) within 
approximately 30 days prior to consent 
6. Using at least one glucose-lowering medication (oral or injectable) for diabetes management at 
the time of consent; if using insulin, this may include up to a total of three or fewer insulin 
injections per day (e.g., once or twice daily basal insulin, once or twice daily basal insulin plus 
one prandial insulin dose, once or twice daily pre-mix insulin, or another combination etc.)  
7. English language comprehension 
8. Confirmed download of FreeStyle Libre 2 app on personal smartphone with regular WiFi or 
cellular data access 
9. Willing and able to record study data using smartphone, tablet, and/or computer 
10. Willing to wear and use study-provided CGM devices for up to 7 months 
11. Willing to perform fingersticks to test blood glucose 
12. Willing to perform fingersticks to test blood ketones twice daily 
13. Eligible to initiate and intention to participate in the dietary changes required as part of the Virta 
Treatment for at least 7 months 
 
6.2 
Participant Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Type 1 diabetes  
2. Currently using an insulin pump or multiple daily injection insulin therapy with >3 insulin 
injections per day or using bolus injections to cover every meal 
3. Currently following a self-reported, very low-carbohydrate eating pattern 
4. Currently using a personal CGM or plans to use a personal CGM during the study period 
5. Advanced-stage renal, cardiac, hepatic, or other chronic disease 
6. History of ketoacidosis 
7. Pregnant, lactating, or planned pregnancy 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 13 of 34 
 
8. Allergy to medical grade adhesive or isopropyl alcohol used to disinfect skin 
9. Participation in another interventional trial at the time of enrollment or during the study period 
10. Participant is unsuitable for participation due to any cause as determined by Investigators 
 
7 
Study Procedures and Intervention  
 
7.1 
Pre-Study Staff Training 
 
The site may include up to 10 total IGNITE study staff, from Virta and IDC, for a FreeStyle Libre 2 training 
experience. This training will provide the opportunity for study staff to participate in hands-on, 
experiential learning using the commercially approved, 14-day FreeStyle Libre 2 system. This experience 
is for educational purposes only and provides study staff with the opportunity to practice using the Libre 
2 and to troubleshoot potential device issues prior to the enrollment of participants in the study. This 
training will occur after IRB protocol approval, but prior to the enrollment of any participants in the 
study described by this protocol.  
 
Training participants will have the opportunity for a group-training session lasting approximately 60 
minutes or have the option to independently read the FreeStyle Libre 2 product instructions and 
complete a product experience on their own. Participants from IDC and Virta will sign a participant 
training waiver, and they will be able to participate in training if they meet the self-assessed eligibility 
criteria.  The self-assessed inclusion/exclusion criteria will be included in the training waiver.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 
Recruitment, Screening, and Randomization Procedure 
 
Prospective study participants include any person with T2D who seeks treatment in the Virta Treatment 
program. Prospective participants will be identified through screening during a Virta pre-enrollment 
period. As part of the normal Virta enrollment process, all people complete an online health assessment 
with a medical provider. People who meet initial study criteria will be approached by a Virta HCP during 
the routine new-patient visit and further screened for exclusions, such as currently eating a self-
reported very-low carbohydrate diet or currently using a personal CGM. Those who continue to meet 
inclusion/exclusion criteria and who express interest in study participation will be contacted by 
members of the Virta research team who will explain the study in further detail, complete additional 
screening questions, answer questions, and obtain informed consent as appropriate.  
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 14 of 34 
 
Up to 2,000 free-living adults with T2D may be invited to participate in this study, and approximately 
200 participants will be consented; this is based on the following assumptions 1) approximately 10% of 
people choose to volunteer to participate in research 2) some participants (estimate up to 50 people) 
will consent, but may withdraw before being randomized and therefore will need to be replaced and 3) 
approximately 15% attrition is expected for the randomized participants within the 3-month study 
intervention period. Therefore, to meet the sample size calculation requirements, 150 qualifying 
participants need to be randomized to obtain 126 participants with evaluable data. Evaluable data is 
defined as participants with at least five days of blinded Libre Pro CGM data at baseline. 
 
All participants must obtain Virta’s standard medical approval from a Virta HCP and meet all eligibility 
criteria, as defined in Section 6, to participate in the study. Once the informed consent form (ICF) has 
been signed, the participant is formally enrolled in the study and a participant ID number will be 
assigned and recorded in the shared Virta and IDC study database (REDCap). Participants will be 
randomized 1:1 to either the BGM or CGM arm (Table 1) once a minimum of five days of blinded Libre 
Pro CGM data is confirmed by the participant. Of note, the blinded Libre Pro CGM system provides a 
way for the participant to see the number of days of data recording while the sensor is in use. If a 
participant wears a blinded Libre Pro CGM at baseline that does not capture at least 5 days of data, the 
participant will be provided the option to wear a repeat blinded CGM or choose to exit the study. 
Participants who capture five or six days of blinded CGM data may also be provided an option to wear a 
repeat blinded CGM to collect additional blinded CGM data. 
 
Blinding procedures are not described since blinding is not possible in a study comparing two different 
methods of glucose monitoring (BGM versus CGM); the participants will know which arm they are 
assigned to in order to conduct the appropriate monitoring. 
 
Given that enrolling participants takes several months to complete, a block randomization scheme will 
be used to ensure that participants are assigned to BGM and CGM arms in approximately equal 
proportions each month. The participant randomization schedule will be generated by the study 
statistician using the random number generator in SAS. Participants will remain in their assigned study 
arm throughout the intervention and follow-up period (day 0 to day 194). 
 
Table 1. Randomization arms and associated study-arm devices 
Study Arm 
Devices Used 
Blood Glucose Monitoring (BGM) Arm 
Commercially approved FreeStyle Libre Pro Sensor 
and Reader (blinded CGM) 
 
Commercially approved Precision Xtra Blood Glucose 
& Ketone Monitoring System for glucose and ketone 
monitoring; used in accordance with package inserts. 
Continuous Glucose Monitoring (CGM) Arm 
Commercially approved FreeStyle Libre Pro Sensor 
and Reader (blinded CGM for baseline assessment 
only) 
 
Commercially approved 14-day, personal FreeStyle 
Libre 2 system and associated phone-based app; used 
in accordance with package inserts. 
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 15 of 34 
 
Commercially approved Precision Xtra Blood Glucose 
& Ketone Monitoring System used for  fingerstick 
ketone monitoring and as indicated for glucose 
monitoring; used in accordance with package inserts. 
 
8        Study Intervention 
 
The intervention will compare the impact of two glucose monitoring methods, BGM or CGM, as part of 
Virta Health’s diabetes care program. All care and education are provided via telemedicine (i.e., 
virtually) and with the use of web-based software applications for biomarker reporting, monitoring, and 
communication with Virta’s care team.  
 
As part of standard Virta Treatment, participants will receive continuous coaching from the Virta care 
team that focuses on modifying daily nutrition choices to achieve and sustain nutritional ketosis as 
measured by blood BHB 0.5-3.0 mmol/L. The care team includes health coaches for day-to-day program 
guidance and HCPs for medication management and clinical oversight. Virta HCPs review glucose values 
reported by participants in the Virta app. HCPs make proactive and reactive medication dose 
adjustments to prevent hypoglycemia while participants are experiencing metabolic improvements. 
Care for Virta participants is provided continuously and is not limited by specific time milestones (e.g., 
appointments are not at scheduled timepoints).  
 
The current Virta Treatment relies on BGM for glucose assessment and does not supply CGMs as part of 
routine care. Thus, the intervention under study is use of CGM compared to BGM (Virta’s current 
standard care) for glucose monitoring. 
 
In the BGM arm, participants, health coaches, and Virta HCPs will use BGM and ketone data to guide 
medication management decisions and to encourage program adherence, per their usual practices. The 
blinded Libre Pro CGM data collected at baseline and during the intervention and follow-up periods will 
not be available to participants or the Virta care team; however, data from the blinded Libre Pro CGM 
assessments can be made available to BGM arm participants after study completion, upon request from 
the participant. BGM and ketone data will be used to help determine which foods, behaviors, and 
medications sustain nutritional ketosis. Typical BGM assessment in the Virta Treatment includes one to 
two fingerstick glucose tests per day depending on the participant’s medication regimen. Fingerstick 
data is reported in the Virta app by the participant. 
   
In the CGM arm, participants receive Virta’s usual care except instead of using BGM, participants, health 
coaches, and Virta HCPs will use real-time and retrospective CGM and ketone data to guide medication 
management decisions and to encourage program adherence. Emphasis will be placed on guiding 
participants to use the CGM device and its associated data to determine which foods, behaviors, and 
medications help them achieve CGM glucose targets and sustain nutritional ketosis. Glucose target 
ranges will be individualized for each participant and use of CGM alarms to alert participants of high or 
low glucose will be individualized based on a shared decision-making approach that aligns with current 
guidance on providing technology-enabled diabetes care. Virta Health coaches will consider CGM data 
during participant contact as needed, and HCPs will systematically assess CGM data during the defined 
Contact Periods and at any point throughout the study as indicated by clinical care. IDC will provide 
minimal participant support for technical CGM-related issues.  
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 16 of 34 
 
8.1           Ongoing Study Procedures 
 
Study duration is expected to be approximately 215 days, an approximately 21-day baseline assessment 
period plus a 194-day Post-Dietary Change intervention and Follow-Up period. Throughout the study, 
participant communication with Virta staff will occur via phone, secured email, and chat messages 
within the Virta app, which feed into the Virta electronic medical record (EMR).   
 
8.2           Baseline Assessments 
 
After signing the ICF, demographic and anthropometric information will be assessed to describe the 
participants. Age at enrollment, race, ethnicity, income, education, marital status, year of type 2 
diagnosis, gender identity, biological sex, weight, height, etc. will be collected at baseline. 
 
Baseline assessments also include a 14-day, blinded CGM assessment using the FreeStyle Libre Pro 
system. The FreeStyle Libre Pro system (sensor and reader) is commercially available and will be used 
according to user manual instructions; however, the system will be started at home by the participant 
instead of in a clinic with an HCP. The sensor will be returned to the clinical site for data download. A 
minimum of five days of blinded Libre Pro CGM sensor data must be obtained for randomization. 
Participants will use the provided reader to confirm adequate days of data recording during the Baseline 
assessment period. 
 
All 14-day, blinded, FreeStyle Libre Pro sensors will be returned via mail. Data will be uploaded with a 
FreeStyle Libre Pro reader using the Libre 2 algorithm and then downloaded to secure study computer. 
Blinded FreeStyle Libre Pro sensors will be tracked by linking sensor serial numbers with study 
participant ID numbers.  
 
Once baseline assessments are complete, the study intervention (use of CGM vs. BGM) begins 
concurrently with the initiation of the WFKD (Day 0). 
 
8.3        Outcome Assessments 
 
Outcome-related measures will be assessed at Baseline, Month 1, Month 2, Month 3, and Month 6. 
Primary and secondary outcome assessments will occur after the intervention, the “Post-Dietary 
Change” period, which is approximately Day 90 to 104.  Additional secondary and exploratory outcome 
assessments will occur after “Follow-Up” period, which is approximately Day 180 to 194.  
 
The study will include five defined Contact Periods between study staff (Virta and IDC) and study 
participants (“Baseline”, “Month 1”, “Month 2”, “Month 3”, and “Month 6”). Each Contact Period will 
last approximately two to three weeks, to accommodate the 14-day sensor wear. Required assessments 
can take place anytime during the Contact Period. Each Contact Period includes a plus or minus 10 or 14 
day window, depending on the period; however, this should minimally impact the length of study 
participation since assessment windows are set according to initiation of the WFKD at Day 0. For 
example, assessment activities during Contact Period Two could start as early as day 20 or end as late as 
Day 54 and be in-window; and the target start date for Contact Period Three would remain at Day 90 
regardless of when Contact Period Two was completed.   
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 17 of 34 
 
Outcome measures will be assessed using study-specific glucose and ketone testing supplies, which will 
be provided by Abbott Diabetes Care, the manufacturer of these products. Supplies will be mailed to 
each participant from the IDC after consent is signed and throughout the study as needed. All 
application and start-up of the FreeStyle Libre Pro and FreeStyle Libre 2 systems will be done 
independently by the participant with manufacturer- and study-provided resources for support.  
 
Participant supplies include: 
● Blinded 14-day FreeStyle Libre Pro system with sensors and reader 
● Personal 14-day FreeStyle Libre 2 system with the associated phone-based Libre 2 app 
● Precision Xtra Blood Glucose & Ketone Monitoring System with glucose and ketone test strips 
● Lancing devices with lancets 
● Supply return kits 
 
Personal 14-day Libre 2 data will be collected at multiple assessment points throughout the study for 
CGM arm participants. The 14-day Libre 2 data are retrieved electronically from the FreeStyle Libre2 
app, which is sent to the LibreView website. Data is automatically uploaded to LibreView when the 
subject’s smartphone is connected to the internet. Data will be downloaded from LibreView by staff at 
the specified intervals for outcome assessment purposes.  
 
Participants will be instructed to contact the Virta care team for study-related questions, healthcare-
related questions, and any adverse events. Care related to the treatment of adverse events associated 
with study-supplied devices may be recommended. Medical care that does not pertain to diabetes 
management will not be provided to study participants as a part of this protocol. Participants will be 
instructed to contact IDC for problems related to study-provided monitoring supplies. IDC may contact 
participants directly for device-related issues and for questions/issues related to outcome assessments 
(e.g. survey data, blinded sensor data, etc.). IDC will maintain accountability records for study-specific 
glucose and ketone monitoring supplies including dates and quantity of product issued to participants.    
 
8.4          Contact Schedule 
 
Contact period 
Key tasks 
#1: Baseline Assessments: 
Day -21 to -1   
● Eligibility confirmed and consent conducted and documented 
● Participant receives baseline study supplies and instructions for 
completing baseline assessments, including HbA1c, in the mail  
● Participant is randomized once they confirm that the minimum 
of five days of Libre Pro CGM data has been recorded. If a 
participant is not able to obtain a minimum of five days of 
blinded CGM data, they will be provided an option to repeat the 
blinded sensor wear period or choose to withdraw. 
● Participants who capture five or six days of blinded CGM data on 
the first sensor may be provided an option to wear a repeat 
blinded CGM sensor to collect additional blinded CGM data. 
Wearing a repeat sensor, if 5 or 6 days of blinded sensor data 
was obtained on first sensor, is not required for randomization. 
● Participant continues wearing 14-day blinded CGM sensor and 
promptly mails sensor(s) back for data capture 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 18 of 34 
 
o Note: Participants randomized to the CGM arm will be 
instructed to return the blinded CGM sensor(s) and the 
associated reader. 
● Plan initiation of the WFKD 
● Participant receives study supplies according to randomization 
assignment in preparation for initiation of study intervention 
● Baseline assessments are documented 
 
Note: There may be several days between Day -1 and Day 0 to account 
for participant readiness to begin the program; final clearance by the 
Virta care team (i.e. standard process); supply shipping issues; or 
personal factors for the participant (e.g. scheduling, medication 
adjustment, CGM wear issues). In other words, Day –21 to Day -1 will 
include initiation of baseline assessments, and Day 0 will mark the actual 
start of the program. All baseline assessments must be completed 
before Day 0. The difference between Day -1 and Day 0 will be as short 
as possible; Investigator discretion will be used to determine an 
inappropriate delay between study Day -1 and Day 0. 
#2: Month 1 Assessment: 
Day 30 to 44 with up to 
+/- 10 days 
 
Intervention Period 
● Participants complete month 1 assessments 
● BGM group: 
o Prompted to apply and start Libre Pro CGM for 14-day 
wear 
o Participant confirms five days of blinded CGM data has 
been recorded. If a participant is not able to obtain a 
minimum of five days of blinded CGM data, they will be 
provided an option to repeat the blinded sensor wear 
period. 
o Participant promptly mails blinded CGM sensor back for 
data capture 
● CGM group: 
o Maintains consistent personal Libre 2 use for 14 days 
o HCP documents CGM data review and shares learnings 
with participant asynchronously 
● Additional glucose and ketone monitoring supplies sent as 
needed 
● Month 1 assessments are documented 
#3: Month 2 Assessment: 
Day 60 to 74 with up to 
+/- 10 days 
 
Intervention Period 
 
● Participants complete month 2 assessments 
● BGM group: 
o Prompted to apply and start Libre Pro CGM for 14-day 
wear 
o Participant confirms five days of blinded CGM data has 
been recorded. If a participant is not able to obtain a 
minimum of five days of blinded CGM data, they will be 
provided an option to repeat the blinded sensor wear 
period. 
o Participant promptly mails blinded CGM sensor back for 
data capture 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 19 of 34 
 
● CGM group: 
o Maintains consistent personal Libre 2 use for 14 days 
o HCP documents CGM data review and shares learnings 
with participant asynchronously 
● Additional glucose and ketone monitoring supplies sent as 
needed 
● Month 2 assessments are documented 
#4: Month 3 Assessment: 
Day 90 to 104 with up to 
+/- 10 days 
 
Intervention Period 
 
● Participants complete month 3 assessments, including HbA1c 
● BGM group: 
o Prompted to apply and start Libre Pro CGM for 14-day 
wear 
o Participant confirms five days of blinded CGM data has 
been recorded.  
o If a participant captures less than 7 days of blinded CGM 
data, they will be provided an option to wear a repeat 
blinded CGM to collect additional blinded CGM data. 
o Participant promptly mails blinded CGM sensor(s) back 
for data capture 
● CGM group: 
o Maintains consistent personal Libre 2 use for 14 days 
o HCP documents CGM data review and shares learnings 
with participant asynchronously 
● Additional glucose and ketone monitoring supplies sent as 
needed 
● Month 3 assessments are documented 
#5: Month 6 Assessment: 
Day 180 to 194 with up to 
+/- 14 days 
 
Follow-Up Period 
 
● Participants complete month 6 assessments, including HbA1c 
● BGM group: 
o Prompted to apply and start Libre Pro CGM for 14-day 
wear 
o Participant confirms five days of blinded CGM data has 
been recorded.  
o If a participant captures less than 7 days of blinded CGM 
data, they will be provided an option to wear a repeat 
blinded CGM to collect additional blinded CGM data. 
o Participant promptly mails blinded CGM sensor(s) back 
for data capture 
● CGM group: 
o Maintains consistent personal Libre 2 use for 14 days 
o HCP documents CGM data review and shares learnings 
with participant asynchronously 
● Month 6 assessments are documented 
 
Note: The month 6 assessment is the final study contact. Participants in 
the BGM arm will be required to return all blinded Libre Pro CGM 
sensors and the associated reader promptly after study completion. 
Participants will not be required to return any other study-provided 
glucose or ketone monitoring supplies at the end of the study. 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 20 of 34 
 
 
9        Early Termination and Participant Withdrawal 
 
A participant can choose to terminate study participation and exit the study at any time and for any 
reason. A participant can be withdrawn from the study without their consent if deemed necessary based 
on adverse event(s) or for any other reason deemed appropriate by Investigators, such as non-
compliance with study instructions. If a participant chooses early termination or is withdrawn, the 
Investigators will decide whether the participant could be eligible to complete a final assessment.  
 
Participants will be asked their reason for early withdrawal and reason for CGM discontinuation if 
applicable. Participants who terminate or are withdrawn early will be required to return used blinded 
Libre Pro CGM sensors and the associated Libre Pro reader promptly after study exit; they will not be 
required to return any other study-provided glucose or ketone monitoring supplies. Early termination or 
participant withdrawal will not impact participation in the Virta Treatment.  
 
10        Lost to Follow-Up 
 
Multiple attempts will be made to contact participants who become lost to follow-up. Investigator 
discretion will determine whether a participant should be withdrawn if reasonable attempts for contact 
are unsuccessful.    
 
11        Protocol Deviation 
 
A protocol deviation occurs when the study is not conducted according to this protocol. All deviations 
will be documented in study deviation log. Investigators will not knowingly deviate from this protocol 
except in the cases of protecting participant safety. The delegated Investigator will notify the IRB of 
protocol deviations in accordance with IRB policies and procedures. 
    
12       Potential Risks and Benefits 
 
12.1    Risks 
 
Blood draws 
 
Blood draw by venipuncture for HbA1c at Baseline, month 3, and month 6 is a standard care procedure 
which would occur regardless of participation in this study. Blood draws may cause discomfort and 
bruising at the puncture site. Participants may also experience lightheadedness or fainting during the 
blood draw and there is a slight risk of infection. The total blood volume needed for each HbA1c test is 
less than 5 mL. 
 
Capillary (fingerstick) blood glucose and ketone testing 
 
BGM by fingerstick is a standard care procedure for PWD. Participants will follow Virta’s usual frequency 
recommendations for BGM. Fingerstick ketone monitoring is a routine procedure for Virta participants 
and uses the same technique as BGM. Study subjects will be asked to monitor and log fingerstick 
ketones twice daily; this is more than Virta’s usual recommendation of once daily. Risks arising from 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 21 of 34 
 
fingerstick testing are minimal and may include pain, bruising, or the infrequent occurrence of skin 
infection.  
 
CGM use 
 
CGM use is a routine part of the care for many PWD. CGM users usually report less pain or discomfort 
with CGM than with capillary blood glucose testing. Mild pain on insertion of CGM may be experienced 
by subjects at low frequency. Known allergies to medical grade adhesives is an exclusion from 
participation. Cutaneous complications of CGM use are typically wear-related erythema, itching, and 
induration. The incidence of these complications is expected to be low, 0.13 to 0.15 events per week of 
wear-time, with the majority (79%) being mild. Study discontinuation rate due to skin reactions is 
expected to be very low.24  
 
Privacy 
 
The study requires use of web-based applications, which include providing personal information and 
personal health information. There is always some risk that data will be compromised, and that personal 
information will become available to unexpected parties. Several mechanisms are in place to protect 
personal information, including use of de-identified participant identification (ID) numbers whenever 
possible.  
 
Surveys 
 
Surveys will be used to collect information on food intake and other PROs. Sometimes survey questions 
can trigger uncomfortable feelings. Participants will be informed that they are not required to respond 
to questions that make them uncomfortable for whatever reason. 
 
12.2        Potential Benefits 
 
Participants in both arms of the study may benefit from the additional monitoring they are requested to 
complete as part of the study. For example, this study requests two blood ketone tests per day for 6-7 
months, which is more than what participants are requested to do in the usual Virta Treatment. The 
additional monitoring information collected may be useful for helping participants and providers 
manage diabetes care.      
  
Participants assigned to the CGM arm may benefit from access to continuous glucose data and the use 
of the FreeStyle Libre 2 app. Use of FreeStyle Libre 2 and the associated app may aid in a better 
understanding of which foods and behaviors keep glucose and ketones in target ranges.   
  
Additionally, information from this study could lead to new and more effective methods for helping 
people with T2D manage their glucose and diabetes or adhere to nutrition therapies. 
 
12.3          Analysis of Risks in Relation to Benefits 
 
In this study, risks posed beyond standard care are minimal. The rationale for exposing study 
participants to the minor risks associated with blood draws, capillary glucose and blood ketone testing, 
and CGM use, is that these components of usual diabetes care are outweighed by the potential benefit 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 22 of 34 
 
to patients if this study can help define whether method of glucose testing may impact health-
outcomes.   
 
13     Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
13.1   Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the intervention, regardless of whether it is considered 
related to the intervention.  
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the participant's health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition.  
 
Life-threatening means the event places the subject at immediate risk of death from the event as it 
occurred.  
 
Unanticipated Event (UAE) is defined as an event, experience or outcome that meets all three of the 
following criteria:  
● 
is unexpected; AND 
● 
is related or possibly related to participation in the research; AND 
● 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
● the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in the protocol-related documents, such as the IRB-approved research 
protocol, the ICF, and/or other relevant sources of information, such as product labeling and 
package inserts 
● the expected natural progression of any underlying disease, disorder, or condition for the 
participant experiencing the adverse event, and/or the participant’s predisposing risk factor 
profile for the adverse event. 
 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) means: 
● any problem or event which in the opinion of the Investigator was unanticipated, serious; AND  
● at least possibly related to the research procedures   
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 23 of 34 
 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research. 
 
Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily encountered in daily life or during 
the performance of routine physical or psychological examinations or tests.  
 
Severity of events will be defined as: 
• 
Mild requires minimal or no treatment and does not interfere with the participant’s daily 
activities.  
• 
Moderate results in a low level of inconvenience or concern with therapeutic measures. 
Moderate events may cause some interference with the participant’s functioning. 
• 
Severe interrupts a participant’s usual daily activity and may require systemic drug therapy or 
other treatment.  
 
13.2     Safety Review 
 
Risks described in section 12.1, AEs, SAEs, and UAEs will be monitored continuously throughout the 
study by study staff. 
 
13.3     Reporting Plans 
 
The delegated Investigator will report all reportable AEs, SAEs, UAEs, and UPIRTSOs to Advarra in 
accordance with IRB policies. 
 
AE’s are considered reportable if they meet any of the following: 
● Severe sensor-related reactions or infections requiring in-person medical care 
● Severe hypoglycemia defined as requiring assistance of another person due to altered 
consciousness, and requiring another person to actively administer carbohydrate, glucagon, or 
other resuscitative actions. 
● Severe hyperglycemia if the event involves diabetic ketoacidosis (DKA) or hyperosmolar 
hyperglycemic state (HHS), as defined in Kitabchi et al.25  
 
Reportable AEs and all SAEs will be recorded within an adverse event log with a description including the 
nature of the event, the date and time of onset and/or frequency, determination of non-serious versus 
serious, intensity (mild, moderate, severe), duration of the event, relationship to the intervention, the 
expectedness, and outcome of the event. 
 
This study does not include an independent monitoring committee (e.g., no Data Safety Monitoring 
Board). Since the study procedures are of minimal risk, SAEs are not expected. If any UAEs related to the 
research and involving risks to subjects or others happen during this study (including SAEs), they will be 
reported to the IRB in accordance with Advarra IRB standard operating procedure (SOP).  
 
13.4    Stopping Rules and Study Suspension or Termination 
 
This study will be stopped prior to completion if information becomes available during the study that 
indicates a stop, which may include information related to adverse events or the potential for adverse 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 24 of 34 
 
events. The study may also be stopped prior to completion if recruitment challenges or retention issues 
will impact the ability to properly analyze defined endpoints or for other reasons determined by the 
Investigator.    
 
14      Data Management and Record Keeping 
 
Data for the study will be collected and documented: 1) verbally and electronically from participants by 
Virta and IDC staff, 2) in Virta’s HIPAA compliant EMR and patient-facing app (the mobile interface 
where patients interact with the care team), 3) from the Libre Pro reader and LibreView website , 4) in 
REDCap, 5) via the web-based ASA24 and 6) in electronic files on secured, password protected 
institutional computers.  
 
CGM-related data will either be uploaded directly from the blinded Libre Pro reader and then 
downloaded to an institutional computer or downloaded from the LibreView website (for participants 
assigned to the CGM arm). CGM data will be saved on password-protected computers, which are backed 
up to a secure server. Participants assigned to the CGM arm will need to create a personal account in 
order to access the phone-based app associated with the FreeStyle Libre 2 system. Data in the app is 
secure to the extent provided by the manufacturer.  
 
Participant and study-related data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system that is licensed to IDC. REDCap includes password protection and internal quality checks, 
including field validation to help identify inconsistent, incomplete, or inaccurate data. Data entered into 
REDCap will come directly from the original source data; or in some cases REDCap will serve as the 
source data (e.g. protocol deviations; tracking participant phone calls between participants and IDC 
staff; when participants respond to surveys directly in REDCap; etc.). REDCap maintains a built-in audit 
trail that logs all user activity and all pages viewed by every user, this includes entering data, exporting 
data, modifying a field, running a report, or add/modifying a user, etc. 
 
Participants will complete surveys directly in REDCap and directly in ASA24. ASA24 is a free, web-based 
dietary assessment tool that is run by the National Institutes of Health. ASA24 data is associated with 
study ID and does not capture any personally identifiable information from participants. All completed 
surveys will be retained in the web-based server as a source document and will also be downloaded 
from the servers and stored as .CSV or similar files throughout the study.   
 
This trial will be registered at ClinicalTrials.gov once the protocol has been approved by the IRB; trial 
results will be added to the ClinicalTrials.gov after study completion. 
 
14.1       Data Monitoring 
 
Investigators and study staff will periodically monitor data for completeness and quality as specified in 
data-sharing contracts and to provide the opportunity to address any concerns. 
 
14.2      Confidentiality  
 
Participants will be assigned a unique ID number at the time of enrollment. Whenever possible, 
participant records and datasets will contain the unique ID only. The participant will be informed during 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 25 of 34 
 
the study screening process and via the ICF that their personal study-related data will be accessible by 
both Virta and the IDC throughout the duration of the study. Participant data and any related records 
may also be made accessible to regulatory authorities or as required by law.  
 
The confidentiality of all participant information and data are protected to the extent allowed by law. 
Records will be kept confidential in accordance with HIPAA privacy regulations. Investigators and 
personnel will not use data or records for any purpose other than conducting the study; however, 
deidentified participant data may be used for educational purposes and shared in medical journals, at 
scientific meetings, or in similar settings. No identifiable data will be used for future study without first 
obtaining IRB approval. In the case a limited data set is needed for future study, a data use agreement 
will be utilized.  
 
14.3      Records Retention 
 
Clinical research records, including IRB records and records related to the study will be stored in a 
manner that ensures privacy, confidentiality, security, and accessibility when the clinical research is 
being conducted and after the study is completed. Based on regulatory requirements, Advarra will retain 
study records for at least 3 years after the last site reviewed by the IRB has terminated. Any hardcopy 
documents will be moved to the Advarra archive files at termination. After the record retention period 
has been met, all study-related materials are destroyed. Once a study is terminated in CIRBI (Center for 
IRB Intelligence), the study is automatically archived in the system for the retention period noted above. 
Prior to purging study documentation/information from CIRBI (i.e., studies that have met the retention 
period), CIRBI sends out an automated notification to the study contacts. The notification instructs the 
study contacts to log in to CIRBI and retrieve any documentation/information needed within 30 days of 
the notification. After the 30-day period, all documentation/information is purged from CIRBI. 
 
All HIPAA-related documents containing PHI collected by the IDC, will be retained for at least six years 
after completion of the study. Physical documents will be consolidated and stored in boxes in a secure 
location after study completion and electronic documents will be maintained in designated research 
study folders on the institutional drive in accordance with the HealthPartners data retention guidelines. 
 
15 
Statistical Plan  
 
15.1       Analysis of Primary Endpoint 
 
Summary statistics (including number, mean, median, standard deviation, minimum and maximum) for 
percentage (%) of TIR (glucose 70 - 180 mg/dL), based on 14-day CGM assessments, will be calculated by 
treatment and period. 
 
The primary endpoint will be analyzed using a linear mixed model with treatment (BGM or CGM), period 
(Baseline (period A) and Post-Dietary Change (period B)), and interaction between treatment and period 
as fixed effects, and patient as random effect. The model will be fitted to all the data simultaneously and 
from this model the relevant treatment differences will be estimated. Adjusted mean estimates for each 
treatment with standard errors, the adjusted estimate of treatment mean difference with standard 
error and a 95 % confidence interval for the treatment mean difference will be provided. The statistical 
test will be two-sided tests at a nominal 5% significance level. 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 26 of 34 
 
Enrolled participants without adequate Baseline blinded Libre Pro CGM data will not be included in the 
analysis.  Adequate Baseline blinded CGM data is defined as a minimum of 5 days of sensor data. In 
cases where two blinded sensors are worn in the same contact period, sensor data may be combined.  
15.2      Analysis of Secondary Endpoints 
 
Summary statistics (including number, mean, median, standard deviation, minimum and maximum for a 
continuous variable, or % at each level for a categorical variable) of each secondary endpoint, will be 
calculated by treatment and period. 
 
Mean blood ketone levels at month 3: Mean blood ketone levels at month 3 will be calculated as 
average of all fingerstick BHB levels from day 0 to 90. Mean blood ketones levels will be analyzed using a 
linear regression model with treatment (BGM or CGM) as the effect variable. 
 
Change in other CGM-derived metrics and A1c: These metrics include percent (%) of time with glucose 
above 180 mg/dL, above 250 mg/dL, below 70 mg/dL, and below 54 mg/dL based on 14-day CGM during 
Baseline (period A) and Post-Dietary Change (period B). These metrics also include measures of mean 
and variation in glucose profiles: mean glucose, % coefficient of variation, mean amplitude of glucose 
excursion (MAGE) based on 14-day CGM during Baseline (period A) and Post-Dietary Change (period B). 
Change in A1c during Baseline and Post-Dietary Change period is also included and evaluated here. 
 
All secondary endpoints will be analyzed using linear mixed models with treatment (BGM or CGM), 
period (Baseline (period A) and Post-Dietary Change (period B)), and interaction between treatment and 
period as fixed effects, and patient as random effect. Analyses of such models are similar to the analysis 
for the primary endpoint. 
 
Reaching CGM-derived consensus targets at month 3: This includes percent (%) of time with glucose 
>250 mg/dL <5% (yes/no); percent (%) of time in glucose >180 mg/dL <25% (yes/no); percent (%) of time 
in glucose 70-180 >70% (yes/no); percent (%) of time in glucose <70 mg/dL <4% (yes/no); percent (%) of 
time in glucose <54 mg/dL <1% (yes/no); percent (%) of time in glucose 70-180 AND percent (%) of time 
in glucose <70 mg/dL <4% (yes/no); percent (%) of time in glucose 70-180 AND percent (%) of time in 
glucose <54 mg/dL <1% (yes/no) based on 14-day at Post-Dietary Change (period B). 
 
Since each endpoint is a dichotomous variable indicating if a patient reaches the consensus target goal 
at month 3 (yes/no), they will be analyzed using logistic regression models with treatment (BGM or 
CGM) as the effect variable. 
 
15.3     Analysis of Exploratory Endpoints 
 
Analysis of exploratory endpoints is descriptive (including number, mean, median, standard deviation, 
minimum and maximum for a continuous variable, or % at each level for a categorical variable). A 95% 
confidence interval (CI) will be calculated for each endpoint, but no hypothesis testing or inferential 
analysis will be conducted due to the exploratory nature of these variables. 
 
15.4    Study Hypotheses 
 
Alternative primary hypothesis: CGM will lead to greater improvements in TIR at month three compared 
to BGM in people with T2D who participate in the Virta Treatment. 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 27 of 34 
 
 
Alternative secondary hypotheses: 
● CGM will lead to greater blood ketone levels at month three (a presumed marker of adherence 
to the Virta dietary plan) compared to BGM in people with T2D who participate in the Virta 
Treatment. 
● CGM will lead to greater improvements in other glycemic markers at month three compared to 
BGM in people with T2D who participate in the Virta Treatment. 
 
15.5    Sample Size Determination 
 
The sample size estimation is based on the following assumptions: 
● 80% power (at 0.05 significance level) to test the primary hypothesis, which is the difference in 
TIR between BGM and CGM arms 
● anticipated mean difference in TIR between CGM and BGM = 10%  
● anticipated standard deviation of TIR in each arm = 20%  
 
The two-sided t-test suggests N=63 for each arm. Assuming an 85% retention rate at the end of the 3-
month Post-Dietary Change period brings the required sample size to approximately N=75 per arm; or 
N=150 randomized participants with adequate Baseline data.  
 
Consented participants who are not randomized do not count toward the 150 total participants; these 
participants may be replaced. 
 
16 
Ethics/Protection of Human Subjects 
 
This protocol and any amendments will be submitted to Advarra for formal approval of the study 
conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
Investigator. A copy of the initial IRB approval letter will be provided to the study funder (Abbott 
Diabetes Care) before commencement of this study.  
 
This study will be conducted in full accordance with all applicable Federal and state laws and regulations 
including 45 CFR, and the HIPAA Privacy Rule. Any episodes of non-compliance will be documented. The 
Investigators will perform the study in accordance with this protocol, will obtain consent, and will report 
unexpected problems in accordance with IRB policies and procedures. Collection, recording, and 
reporting of data will be accurate and will ensure the privacy, health, and welfare of research 
participants during and after the study. 
 
16.1     Informed Consent and HIPAA Authorization 
 
Interested participants will be asked to electronically sign a combined ICF and HIPAA authorization form 
that will be sent to participants from Virta staff via DocuSign. Participants will be enrolled in the study 
after signing the ICF. The ICF will describe the purpose of the study, the procedures to be followed, and 
the risks and benefits of participation. A copy of the informed consent and HIPAA authorization will be 
emailed to each participant.   
 
16.2      Conflict of Interest 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 28 of 34 
 
 
Study personnel from Virta Health have been offered stock options in Virta Health and therefore have 
the potential for a significant financial interest in the company. The intervention being tested in the 
present investigation, however, is the utilization of a commercially available continuous glucose monitor 
from Abbott Diabetes Care, to which Virta Health study personnel have no conflict. The ICF and any 
publications resulting from this study will reflect these potential perceived conflicts of interest.  
 
17        Appendices 
 
Appendix A. Study Schematic  
Appendix B. Study Periods and Assessments 
Appendix C. Participant-Facing Materials 
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 28 of 34 
 
17.1     Appendix A. Study Schematic  
 
 
 
 
 
 
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 29 of 34 
 
17.2     Appendix B. Study Periods and Assessments  
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 30 of 34 
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 30 of 34 
 
17.3    Appendix C. Participant-Facing Materials – See attached document 
o Questionaries to be administered via REDCap 
▪ 
Demographic Survey – REDCap Distribution 
▪ 
Diabetes Distress Scale-17 (DDS-17) – REDCap Distribution 
▪ 
CGM Satisfaction Survey – REDCap Distribution 
▪ 
Lifestyle change survey – CGM Arm (study-specific) – REDCap Distribution 
▪ 
Lifestyle change survey – BGM Arm (study-specific) – REDCap Distribution 
▪ 
Reasons for CGM Discontinuation (CGM ARM if applicable) – REDCap 
Distribution 
o Materials to be distributed by postal mail and e-mail 
▪ 
IGNITE Study Overview and Instructions 
▪ 
FreeStyle Libre Pro Blinded CGM Instructions  
▪ 
IGNITE Study CGM Group Instructions  
▪ 
IGNITE Study BGM Group Instructions 
▪ 
Returning your FreeStyle Libre Pro Blinded Reader  
 
 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 31 of 34 
 
18       References 
 
1. 
CDC.gov. Diabetes Fast Facts. https://www.cdc.gov/diabetes/basics/quick-facts.html. Upadated 
December 17, 2021. Accessed June 07, 2022. . 
2. 
American Diabetes Association. 5. Facilitating Behavior Change and Well-being to Improve 
Health Outcomes: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022;45(Suppl. 
1):S60–S82. 
3. 
Maiorino MI, Signoriello S, Maio A, et al. Effects of Continuous Glucose Monitoring on Metrics of 
Glycemic Control in Diabetes: A Systematic Review With Meta-analysis of Randomized 
Controlled Trials. Diabetes Care. 2020;43(5):1146-1156. 
4. 
Park C, Le QA. The Effectiveness of Continuous Glucose Monitoring in Patients with Type 2 
Diabetes: A Systematic Review of Literature and Meta-analysis. Diabetes Technol Ther. 
2018;20(9):613-621. 
5. 
Jackson MA, Ahmann A, Shah VN. Type 2 Diabetes and the Use of Real-Time Continuous Glucose 
Monitoring. Diabetes Technol Ther. 2021;23(S1):S27-s34. 
6. 
Wright EE, Subramanian S. Evolving Use of Continuous Glucose Monitoring Beyond Intensive 
Insulin Treatment. Diabetes Technol Ther. 2021;23(S3):S12-s18. 
7. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes—
2022. Diabetes Care 2022;45(Suppl. 1):S83–S96. 
8. 
Beck RW, Bergenstal RM, Cheng P, et al. The Relationships Between Time in Range, 
Hyperglycemia Metrics, and HbA1c. J Diabetes Sci Technol. 2019;13(4):614-626. 
9. 
Raj R, Mishra R, Jha N, Joshi V, Correa R, Kern PA. Time in range, as measured by continuous 
glucose monitor, as a predictor of microvascular complications in type 2 diabetes: a systematic 
review. BMJ Open Diabetes Res Care. 2022;10(1). 
10. 
Martens T, Beck RW, Bailey R, et al. Effect of Continuous Glucose Monitoring on Glycemic 
Control in Patients With Type 2 Diabetes Treated With Basal Insulin: A Randomized Clinical Trial. 
JAMA. 2021;325(22):2262-2272. 
11. 
Grace T, Salyer J. Use of Real-Time Continuous Glucose Monitoring Improves Glycemic Control 
and Other Clinical Outcomes in Type 2 Diabetes Patients Treated with Less Intensive Therapy. 
Diabetes Technol Ther. 2022;24(1):26-31. 
12. 
Battelino T, Danne T, Bergenstal RM, et al. Clinical Targets for Continuous Glucose Monitoring 
Data Interpretation: Recommendations From the International Consensus on Time in Range. 
Diabetes Care. 2019;42(8):1593-1603. 
13. 
Griauzde DH, Ling G, Wray D, et al. Continuous Glucose Monitoring With Low-Carbohydrate 
Nutritional Coaching to Improve Type 2 Diabetes Control: Randomized Quality Improvement 
Program. J Med Internet Res. 2022;24(2):e31184. 
14. 
Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall AL, Cox DJ. An Innovative Lifestyle 
Intervention to Reduce Glucose Excursions with the Use of Continuous Glucose Monitoring to 
Educate, Motivate, and Activate Adults with Newly Diagnosed Type 2 Diabetes: A Paradigm shift. 
JMIR Diabetes. 2022;7(1):e34465. 
15. 
Harvey C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction 
on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in 
healthy adults: A randomized clinical trial. Nutrition. 2019;67-68s:100005. 
16. 
Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1-22. 
17. 
McKenzie AL, Athinarayanan SJ, Adams RN, Volk BM, Phinney SD, Ratner R. 307-OR: Mean Blood 
Beta-Hydroxybutyrate Predicts Clinically Significant Weight Loss following 90 Days 
Carbohydrate-Restricted Nutrition Therapy. Diabetes. 2021;70(Supplement_1). 

CGM vs. BGM to Optimize Glycemic Outcomes in T2D Following the Virta Treatment Ver. 2.0 06Dec2022 
 
Page 32 of 34 
 
18. 
McKenzie AL, Hallberg SJ, Creighton BC, et al. A Novel Intervention Including Individualized 
Nutritional Recommendations Reduces Hemoglobin A1c Level, Medication Use, and Weight in 
Type 2 Diabetes. JMIR Diabetes. 2017;2(1):e5. 
19. 
Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and Safety of a Novel Care Model for 
the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled 
Study. Diabetes Ther. 2018;9(2):583-612. 
20. 
Athinarayanan SJ, Adams RN, Hallberg SJ, et al. Long-Term Effects of a Novel Continuous Remote 
Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year 
Non-randomized Clinical Trial. Front Endocrinol (Lausanne). 2019;10:348. 
21. 
Alexopoulos AS, Yancy WS, Edelman D, et al. Clinical associations of an updated medication 
effect score for measuring diabetes treatment intensity. Chronic Illn. 2021;17(4):451-462. 
22. 
Polonsky WH, Fisher L, Earles J, et al. Assessing psychosocial distress in diabetes: development 
of the diabetes distress scale. Diabetes Care. 2005;28(3):626-631. 
23. 
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Validation 
of measures of satisfaction with and impact of continuous and conventional glucose monitoring. 
Diabetes Technol Ther. 2010;12(9):679-684. 
24. 
Asarani NAM, Reynolds AN, Boucher SE, de Bock M, Wheeler BJ. Cutaneous Complications With 
Continuous or Flash Glucose Monitoring Use: Systematic Review of Trials and Observational 
Studies. J Diabetes Sci Technol. 2020;14(2):328-337. 
25. 
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with 
diabetes. Diabetes Care. 2009;32(7):1335-1343.