Ketone Monitoring Approaches for Diabetic Ketoacidosis Risk Mitigation in People With T1D on Adjunctive SGLT2 Inhibitors
Phase: PHASE2
Conditions: Type 1 Diabetes, Type 2 Diabetes
Sponsor: AdventHealth Translational Research Institute

 
 
 
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Study Protocol Title: 
Ketone Monitoring Approaches for Diabetic Ketoacidosis Risk Mitigation     
in People with T1D on Adjunctive SGLT-2 Inhibitors (KARMA) 
 
Study Sponsor:   
AdventHealth  
 
Principal Investigator: 
Richard E. Pratley, MD 
Senior Investigator and Diabetes Program Lead 
AdventHealth Translational Research Institute  
301 E. Princeton Street 
Orlando, Florida, 32804 
Phone 407-303-2519 
Email: Richard.Pratley.MD@AdventHealth.com 
 
Funded by:  
National Institute of Diabetes and Digestive and Kidney Diseases / National 
Institute of Health 
 

 
 
 
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List of Abbreviations: 
ADA 
American Diabetes Association 
ASA-24 
Automated Self-Administered 24-hour dietary assessment tool 
BMI 
Body mass index 
BOHB 
Beta-hydroxybutyrate 
CBC 
Complete blood count 
CGM 
Continuous glucose monitor 
CKM 
Continuous ketone monitor 
CMP 
Comprehensive metabolic panel 
DGK 
Dual Glucose / Ketone Monitoring system 
DKA 
Diabetic ketoacidosis 
eGFR 
Estimated glomerular filtration rate 
FDA 
U.S. Food and Drug Administration 
HbA1c 
Hemoglobin A1c/ Glycated hemoglobin 
IPAQ 
International Physical Activity Questionnaire 
IWT 
Insulin Withdrawal Test 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
RFA 
Request for applications 
SGLT-2i 
Sodium-glucose co-transporter-2 inhibitors 
T1D 
Type 1 diabetes 
TSH 
Thyroid stimulating hormone 
UACR 
Urine albumin creatinine ratio 
 
 
 

 
 
 
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Contents 
List of Abbreviations: ..................................................................................................................... 2 
Introduction ..................................................................................................................................... 5 
Background Information and Scientific Rationale ......................................................................... 5 
Overarching Aim ........................................................................................................................ 5 
Primary Objective/Aim/Goal/Hypothesis ................................................................................... 6 
Secondary Objective/Aim/Goal/Hypothesis ............................................................................... 6 
Study Design ................................................................................................................................... 7 
Research Design.......................................................................................................................... 7 
Research Intervention Description .............................................................................................. 8 
Study Site(s)/Location(s) and Number of Subjects .................................................................. 11 
Multi-Site Research Logistics/Communication Plan ................................................................ 11 
Research Conducted in a Foreign Country ............................................................................... 11 
Community-Based Participatory Research ............................................................................... 11 
Subject Selection ........................................................................................................................... 12 
Vulnerable Populations (if applicable) ..................................................................................... 12 
Inclusion Criteria ...................................................................................................................... 12 
Exclusion Criteria ..................................................................................................................... 12 
Resources Available...................................................................................................................... 13 
Study Procedures .......................................................................................................................... 14 
Subject Recruitment and Screening .......................................................................................... 14 
Consent Process ........................................................................................................................ 14 
Subjects who are not yet adults (infants, children, teenagers) .................................................. 14 
Cognitively Impaired Adults ..................................................................................................... 14 
Adults Unable to Consent ......................................................................................................... 14 
Documentation of Informed Consent Process .......................................................................... 15 
Waiver of Written Documentation of Consent or Waiver of Consent ...................................... 15 
Non-English-Speaking Subjects ............................................................................................... 15 
Randomization .......................................................................................................................... 15 
Study Visits ............................................................................................................................... 15 
Study Duration .......................................................................................................................... 28 
Materials of Human Origin:  Collection, Preparation, Handling and Shipping........................ 29 
Study Outcome Measures (Endpoints) ......................................................................................... 29 

 
 
 
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Data Management and Quality Plan ............................................................................................. 31 
Data De-identification ............................................................................................................... 31 
Data Confidentiality, Storage, and Retention ........................................................................... 32 
Data Quality .............................................................................................................................. 32 
Data Sharing.............................................................................................................................. 33 
Sample Size Determination........................................................................................................... 33 
Statistical Analysis Plan ................................................................................................................ 33 
Primary Objective Analysis ...................................................................................................... 33 
Secondary Objective Analysis .................................................................................................. 33 
Potential Risks and Benefits ......................................................................................................... 34 
Potential Benefits ...................................................................................................................... 34 
Potential Risks .......................................................................................................................... 34 
Mitigation of Risks ................................................................................................................... 35 
Provisions to Protect the Privacy Interest of Subjects .............................................................. 39 
Early Withdrawal of Subjects ....................................................................................................... 39 
Investigator Withdrawal of Subjects ......................................................................................... 39 
Subject Request for Withdrawal from Study ............................................................................ 40 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 40 
Adverse Events - Recording and Reporting.................................................................................. 40 
Safety Monitoring Plan ................................................................................................................. 40 
Safety Monitoring ..................................................................................................................... 40 
Data and Safety Monitoring Board (DSMB) or Equivalent ..................................................... 44 
Ethical Considerations .................................................................................................................. 45 
Funding Source ............................................................................................................................. 45 
Subject Stipends or Payments ....................................................................................................... 45 
Publication Plan ............................................................................................................................ 46 
 
 
 

 
 
 
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Introduction 
This document is a protocol for a human research study. This study is to be conducted 
in accordance with AH and FDA institutional research requirements and Good Clinical 
Practices (GCP) International Conference on Harmonization (ICH) Guidelines (E6) for 
GCPs standard. 
 
Background Information and Scientific Rationale 
 
SGLT-2 inhibitors were originally approved by the FDA to improve glycemic control in 
people with type 2 diabetes (T2D), in whom they provide additional clinical benefits – 
including decreasing risk of hospitalization for heart failure, slowing of the progression of 
chronic kidney disease, and decreasing the risk of major adverse cardiovascular events 
(1, 2). Although these additional benefits would provide great value for patients with 
type 1 diabetes (T1D), the FDA did not approve use of SGLT-2 inhibitors as adjunctive 
treatments for T1D because of an increased in the risk of diabetic ketoacidosis (DKA) 
observed in phase 3 clinical trials (3). Published phase 3 clinical trials for SGLT-2 
inhibitors in T1D all included self-monitoring of plasma beta-hydroxybutyrate (BOHB), 
but this type of intermittent monitoring of BOHB levels failed to completely prevent what 
the FDA viewed as an unacceptable increase in the risk of severe adverse DKA events. 
Recent technological advances have enabled continuous monitoring of BOHB levels in 
interstitial fluid – raising the possibility that continuous monitoring of BOHB levels could 
more effectively mitigate the increased risk of DKA in SGLT-2 inhibitor-treated patients 
with T1D. NIDDK created an RFA to support pragmatic research to investigate 
continuous ketone monitoring (CKM) technology with the objective of increasing safety 
of SGLT-2 inhibitors in patients with T1D. The next step to progress the field is to 
develop and test pragmatic risk mitigation strategies that clinically integrate continuous 
Ketone Monitoring (CKM) technology with SGLT-2 inhibitor use. To achieve this 
objective, we propose addressing three critical questions required to implement an 
effective risk mitigation strategy based on continuous BOHB monitoring in adults with 
T1D:  
a) What BOHB levels indicate increased risk of developing ketoacidosis? 
b) What intervention(s) should be triggered in response to BOHB levels 
indicating increased risk? 
c) Is it possible to design an effective “one-size-fits-all” approach for risk  
mitigation with SGLT-2 use or is it preferable to individualize the approach to 
account for variation among individual patients?  
 
Overarching Aim  
To develop a risk mitigation strategy employing continuous ketone monitoring that will 
allow SGLT-2 inhibitors to be safely used in patients with T1D to reduce risk for chronic 
kidney disease progression and cardiovascular disease.  

 
 
 
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Overarching Hypothesis: A novel risk mitigation strategy accounting for the 
physiological effects of SGLT-2 inhibitors on the development and resolution of ketosis 
will be effective at reducing the number and severity of ketosis events.  
We will test this hypothesis by completing two specific aims in a clinical study. The 
specific aims of the clinical study are:  
 
Primary Objective/Aim/Goal/Hypothesis 
Aim 1 of the clinical study is to determine how adjunctive SGLT-2 inhibitor use affects 
the development and resolution of ketosis and ketoacidosis in adults with T1D by 
comparing, in a highly controlled, inpatient setting:  
1a. The time course of ketosis and ketoacidosis during insulin withdrawal 
(mimicking insulin pump failure or missed insulin injections) in patients with 
T1D on insulin therapy to that on insulin + adjunctive therapy with an SGLT-2 
inhibitor and 
1b. Insulin and carbohydrate requirements to reverse ketosis during these  
conditions.  
 
Hypothesis: We hypothesize that, compared to insulin alone, adjunctive SGLT-2 
inhibitor use will increase the rate of increase and maximal levels of ketones and 
ketoacidosis during insulin withdrawal in participants with T1D. This will 
necessitate adapting CKM ketone thresholds for DKA risk mitigation in participants 
with T1D on adjunctive SGLT-2 inhibitor. It may also suggest a more aggressive 
recovery protocol is required for those who develop ketosis on SGLT-2 inhibitors 
as opposed to those not on drug.  
Secondary Objective/Aim/Goal/Hypothesis 
Aim 2 of this clinical study is to test the effectiveness of a CKM-enabled personalized 
DKA risk mitigation strategy that accounts for the increased risk for ketosis and 
ketoacidosis with SGLT-2 inhibitors compared to a generalized DKA risk mitigation plan, 
for reducing ketone events.  
Hypothesis: We hypothesize that a personalized strategy (including ketone 
thresholds, carbohydrate intake, insulin dose, and other physiological factors) 
accounting for the effects of SGLT-2 inhibitors on the development and resolution 
of ketosis will be more effective at reducing ketosis events than a generalized 
one-size-fits-all approach. 
 

 
 
 
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Study Design 
Research Design 
Aim 1 will be a repeated measures design used to compare changes in ketones during 
two different settings, which include: 1) outpatient free-living conditions in the presence 
and absence of an SGLT-2 inhibitor and 2) during a highly controlled inpatient insulin 
withdrawal test that is expected to increase ketones (and therefore increase DKA risk) 
in the presence and absence of an SGLT-2 inhibitor. Secondarily, the recovery 
protocols that reverse elevated ketones during the insulin withdrawal test will be refined. 
This will be tested during Period 1 and Period 2 of the clinical trial.  
 
 
 
Aim 2 will use a sequential, 2-phase study design to compare the number of ketone 
events during a generalized risk mitigation strategy vs. a personalized risk mitigation 
strategy. In Phase I/ Period 3 (6 months in duration), we will implement a generalized 
DKA risk mitigation strategy. In Phase 2/ Period 4 (6 months in duration), we will 
implement a personalized DKA risk mitigation strategy. We expect that ketone events 
will be reduced on the personalized risk mitigation plan (Phase 2, Period 4), compared 
to a generalized risk mitigation plan (Phase 2, Period 3). We will actively update 
‘decision tree algorithms’ for broad risk mitigation advice to incorporate new learnings 
(including ketone thresholds, carbohydrate intake, insulin dose, and other physiological 
factors) during the duration of the award period (hence ‘adaptive’) to better inform 
clinical advice that is provided for risk mitigation. Factors that may be considered when 
designing the personalized risk mitigation strategy could include the number, frequency 
and magnitude of ketone events during SGLT-2 inhibitor use, the rate of development of 
ketosis during insulin withdrawal, insulin and carbohydrate doses to resolve ketosis 
during the insulin withdrawal test, demographic factors including age, sex, and BMI and 
T1D related factors including duration of disease, HbA1c and insulin dose.   
 
 

 
 
 
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The participant cohort that is recruited for Aim 1 is the same cohort that will complete 
Aim 2. Therefore, the recruitment and retention plan and eligibility criteria for Aim 1 
applies to Aim 2. 
 
Research Intervention Description  
Aim 1 will use the following interventions: continuous ketone monitor/ continuous 
glucose monitor (device), sotagliflozin, an SGLT-1 and 2 inhibitors(drug) and 
generalized DKA risk mitigation strategy. Descriptions of these interventions are below. 
  
Device Description: 
The Abbott Sensor Based Dual Glucose / Ketone Monitoring System is intended to 
monitor interstitial fluid glucose levels and β-hydroxybutyrate (β-ketone) levels in persons 
aged 2 and older. The System is manufactured by Abbott Diabetes Care and consists of 
two primary components. 
• 
A disposable sensor application device (Sensor Applicator), that is used to adhere the 
disposable sensor assembly (Sensor) to the skin. The sensor assembly contains on-
body electronics that connect to a subcutaneously implanted electrochemical dual 
glucose and β-ketone sensor that is inserted just below the surface of the skin. The 
sensor adheres to the skin of the user. 
• 
A smartphone with a mobile app which activates the sensor and continuously logs 
glucose and ketone readings via Bluetooth and/or other electronic communication with 
the sensor. The device's dynamic range for glucose is between 40 and 400 mg/dL. 
The device’s dynamic range for β-ketone is between 0.0 and 3.0 mmol/L. 
Smartphones, sensors, and sensor applicators are uniquely identifiable through individual 
serial numbers. The Abbott Sensor Based Dual Glucose / Ketone Monitoring (DGK) 
System is a dual glucose and ketone sensor. To measure two analytes, the investigational 
device will contain two working electrodes such that one electrode measures glucose and 
the other measures ketones. These measurements will not be used for treatment 
adjustment decisions but would rather prompt a confirmatory test of capillary glucose or 
ketones.  
The DGK device is currently under review by the FDA. 
  
Study drug (Sotagliflozin): 
Sotagliflozin is an oral antihyperglycemic drug that works as a dual inhibitor of the sodium 
glucose co-transporters 1 and 2, referred to as SGLT-1 and SGLT-2, to lower blood 
glucose through mechanisms that are insulin-independent. Sotagliflozin is approved for 
the treatment of heart failure based on the results of two pivotal phase 3 cardiovascular 
outcomes studies in over 12,000 participants with T2D that demonstrated statistically 
significant and clinically meaningful efficacy of sotagliflozin in reducing the composite 
outcome of CV death, hospitalization for heart failure, and urgent visits for heart failure. 
  

 
 
 
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Sotagliflozin has also been studied in three randomized controlled phase 3 studies in 
almost 3000 participants with T1D. Each of these studies showed statistically significant 
reductions in HbA1C as well as effects on clinically relevant secondary endpoints. 
However, an increased risk of DKA was noted in these studies and as a result, 
sotagliflozin has not received FDA approval for glycemic control in T1D.  
  
Rationale for dose selection: 
Sotagliflozin has been studied at doses of 200 mg and 400 mg p.o. once daily in phase 3 
trials in participants with T2D and T1D. In the SOLOIST and SCORED trials, which 
demonstrated a significant CV benefit in participants with T2D, participants were to start 
on 200 mg p.o. once daily then advance the dose to 400 mg p.o. once daily if tolerated. 
In 2 of the 3 Phase 3 trials in participants with T1D, both the 200 mg and 400 mg once 
daily doses were tested. In the 3rd trial, only the 400 mg daily dose was tested. While the 
risk of diabetic ketoacidosis was increased in participants with T1D relative to placebo, it 
was still uncommon (5% of subjects) and did not appear to be dose-dependent.  
In the present study, sotagliflozin will be dosed at 200 mg p.o. once daily for the first two 
weeks, then the dose will be increased to 400 mg p.o. once daily as tolerated following 
the strategy for T2D as well that used in the majority of T1D participants in phase 3 
studies. The rationale for this strategy is that the 400 mg daily dose was the most 
efficacious dose for glycemic control and weight reduction in participants with T1D and is 
aligned with the dose demonstrated to have CV benefits in T2D. Moreover, this dose does 
not seem to be associated with an increased risk of DKA or other adverse events, relative 
to the 200 mg daily dose.  
Sotagliflozin will be stored between the temperature of +15°C and +30°C (59°F and 86°F). 
Drug will be dispensed by our study pharmacist for the duration of outpatient assessment 
period. The participants will take the drug for ~ 13 months. 
As sotagliflozin is not currently approved by the FDA as adjunctive to insulin therapy in 
people with T1D, an investigator-initiated  Investigational New Drug (IND) application 
will be filed for sotagliflozin for the purposes of this study. The principal investigator will 
ensure that 21 CFR 11, 21 CFR 54, 21 CFR 210, 21 CFR 211, 21 CFR 312, 21 CFR 
812, and 21 CFR 820 regulations are understood and met. This includes but is not 
limited to adhering to consenting requirements, protocol adherence, record keeping, 
coordinating reports to be submitted directly to the FDA such as serious, unexpected 
adverse reactions reports, annual reports, amendment submissions, study/project 
closures. 
Aim 2 will use the following interventions: continuous ketone monitor/ continuous 
glucose monitor (device) and sotagliflozin (drug), which are described above. Aim 2 will 
additionally use a generalized and a personalized DKA risk mitigation strategy that is 
described below. 
 

 
 
 
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Generalized DKA Risk Mitigation Strategy: We will implement a generalized risk 
mitigation strategy based upon published protocols in clinical use. This strategy includes 
two components, which are 1) the clinical integration of CKM devices that provide 
participants with real time monitoring of interstitial ketones and glucose values potentially 
alerting participants to an upcoming ketone event and 2) patient education on DKA risks 
of with SGLT-2 inhibitors as well as resolution protocols. We will use protocols that were 
previously developed in the STOP DKA Protocol {Goldenberg, 2019 #1324}. This 
protocol includes educating patients on DKA risk mitigation steps: Symptoms, Testing 
ketones and glucose every 2-4 h, Oral ingestion of fluid (250-500 mL) and carbohydrates 
(30-60 carbohydrates) every 2-4 h and follow Protocol instructions for supplemental 
insulin and carbohydrates. This protocol includes general guidelines for DKA resolution, 
and various ketone ranges are associated with recommendations for insulin, 
carbohydrates, and fluid intake instructions.  
• Patient Education: Participants will be given educational materials covering 
relevant medication and safety information including an introduction to SGLT-2 
inhibitors, diabetic ketoacidosis including euglycemic ketoacidosis, continuous 
ketone monitoring, and instructions for who to contact if high (>1.0 mmol/L) ketone 
levels are detected. Patient education materials will be provided via multiple media 
to respond to individual learning styles and preferences, including web-based blog 
posts, audio podcasts, and videos.  
• Weekly Telephone Follow-ups:  Participants will communicate with the study 
team on a weekly basis through electronic means (e.g., phone calls, telehealth, 
or a secure TEAMS or via EPIC communication) to review any symptoms of DKA 
or perceived issues with the CKM device and/or the SGLT-2 inhibitor. During 
these visits, we will also assess whether there are any safety issues related to 
glycemic control that might warrant adjustment of the insulin dose. 
Personalized risk mitigation strategy: The personalized DKA risk mitigation strategy 
maintains the two components of the generalized risk mitigation strategy described 
above. We will revise the previously developed STOP DKA Protocol {Goldenberg, 2019 
#1324} to include personalized ketone ranges based on findings from the outpatient and 
inpatient testing. Thus, the central feature of the personalized risk mitigation strategy is 
the addition of personalized ketone thresholds and ketosis recovery protocols. While it is 
difficult to predict with precision, we expect that there will be between-subject 
heterogeneity in ketone events that is sufficient to warrant participant-specific ketone 
thresholds associated with risk mitigation strategies, and we aim to account for these 
differences using personalized advice. We will also take into account external factors 
including diet and exercise when formulating personalized risk mitigation advice.  
• Adaptive Patient Advice through Education Materials: Participants will 
continue to receive education materials on relevant medication and safety 
information. We will adapt and disseminate these materials to reflect new 
learnings from the outpatient and inpatient testing on a semi-annual basis. 
Education materials will be re-distributed via multiple mediums including web-

 
 
 
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based blog posts, audio podcasts, and videos. We expect that findings related to 
the heterogeneity of ketone responses and DKA symptoms will be used to develop 
and disseminate risk mitigation strategies. We will additionally assess patient 
education materials for effectiveness at 1 month and 6 months after study 
enrollment using the Patient Education Materials Assessment Tool (PEMAT) 
Shoemaker, 2014 #1325}. The PEMAT is a validated instrument used to 
systematically assess the understandability and actionability of both print and 
audiovisual patient education materials. 
 
Study Site(s)/Location(s) and Number of Subjects 
 
AdventHealth sites (hospital(s), campus, physician offices, etc.): AdventHealth 
Translational Research Institute, AdventHealth Orlando.  
 
Estimated number of subjects at AdventHealth sites: ~150 screened, 75 enrolled  
 
Name of external site(s) outside of AdventHealth: N/A 
 
Estimated number of subjects at external sites: N/A 
 
Total number of all sites: 1 
Estimated number of subjects at all sites combined: 150 
 
Multi-Site Research Logistics/Communication Plan 
N/A 
Research Conducted in a Foreign Country 
 
N/A 
 
Community-Based Participatory Research 
We will leverage our relationships with the T1D stakeholders, associations of patients 
with T1D, advisory board, and theT1D community for this research. The engagement of 
stakeholders and the incorporation of multiple, diverse perspectives beyond the 
traditional research team in the execution of the proposed study will improve research 
quality and acceptability, as well as the generalizability and translation of the results into 
clinical practice. In particular, people with T1D will provide a unique perspective into the 
burden of diabetes and DKA, as well as insight into the feasibility and acceptability of 
interventions to address these issues.  

 
 
 
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Subject Selection 
Vulnerable Populations (if applicable) 
AdventHealth Employees: Recruitment efforts will follow AdventHealth recruitment 
Standard Operating Procedures (SOPs) for research. AdventHealth employees will not 
be individually targeted nor excluded from study participation based on employment. 
AdventHealth employees who engage the AdventHealth Translational Research Institute 
asking to participate in the study will be processed per standard consent procedures for 
participants. In addition, during the consent process, the study staff will review standard 
consent language stating that an employee’s participation or lack of participation in the 
study will not affect their employment status or relationship with AdventHealth. 
 
Students: Students will not be individually targeted nor excluded from study participation 
based on employment.  
Inclusion Criteria 
1. Men and nonpregnant women ≥18 years and older 
2. Diagnosis of T1D according to American Diabetes Association (ADA) criteria  
3. HbA1c < 9 %  
4. Participants treated with multiple daily injections of insulin, insulin pump, or 
advanced insulin delivery systems 
5. Has provided written informed consent to participate in the study. 
6. Must be willing to wear the investigational device  
7. Use of adequate contraception for the duration of the study by women of 
childbearing potential 
 
Exclusion Criteria 
1. Pregnancy, lactation or planning to become pregnant 
2. Any form of diabetes other than T1D 
3. People with T1D using weekly insulin (when approved) 
4. Use of sodium-glucose cotransporter 2 inhibitors within 4  weeks prior to 
screening 
5. Chronic systematic corticosteroids (>4 consecutive weeks) within 6 months 
before screening 
6. History of diabetic ketoacidosis within 6  months of screening 
7. History of multiple (≥ 3 infections) genital mycotic infections within 6 months 
of screening 
8. Hypotension at screening is defined as systolic blood pressure < 90 and 
diastolic blood pressure < 60 with symptoms of low blood pressure 
(confusion, dizziness, lightheadedness, fainting, heart palpitations) 
9. History of a level 3 hypoglycemic event (as defined by ADA criteria) within 3 
months of screening 

 
 
 
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10. Recent myocardial infarction, stroke, hospitalization for unstable angina or 
heart failure within 3 months prior to screening 
11. New York Heart Association Class IV heart failure 
12. CKD-EPI estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m²  
13. Impairment of systems and organs that may increase their risk of participating 
in the intervention study or compromise the results (for example: end stage 
kidney disease, active liver dysfunction, gastroparesis, anemia, ), organ 
transplant. 
14. Cancer treatment (excluding non-melanoma skin cancer treated by excision, 
carcinoma in situ of the cervix or uterus, ductal breast cancer in situ, resected 
non-metastatic breast or prostate cancer) within one year of screening 
15. Active Hepatitis B or C, acquired immunodeficiency syndrome (HIV infection 
controlled with suppressive medications is allowed) or tuberculosis 
16. Abnormal liver function at screening defined as any of the following: aspartate 
aminotransferase (AST) >2X upper limit of the normal reference range (ULN), 
ALT >2X ULN, serum total bilirubin (TB) >1.5X ULN 
17. Current or past history of decompensated cirrhosis (defined as variceal 
bleeding, ascites, or hepatic encephalopathy), and/or known diagnosis of 
cirrhosis 
18. Heavy alcohol use (for men, ≥5 drinks on any day or ≥15 drinks per week; for 
women, ≥4 drinks on any day or ≥8 drinks per week) at screening, history of 
alcohol use disorder or binge drinking 
19. Any condition or factor that would compromise the participant’s safety or the 
scientific integrity of the study (cognitive impairment, bipolar disorder, or 
history of eating disorder)  
20. Inability to perform the study follow up/ unwilling to wear the investigational 
device 
21. People who are unwilling to consume at least 20% of calories from 
carbohydrates 
Female contraception: Females of childbearing potential, must use clinically 
acceptable and highly effective methods of contraception/birth control during the entire 
study. Examples of these include an IUD, hormonal implant, or surgical sterilization 
(tubal ligation or hysterectomy). If they use other methods of birth control, like not 
having sex, hormonal birth control (pills, patch, or injections), vaginal ring, a condom or 
barrier methods, they must use TWO of these methods together throughout the course 
of the study. 
Resources Available 
We attest that all AdventHealth Translational Research Institute faculty and staff 
will be trained, and this training will be documented as described in AdventHealth 
Translational Research Institute Work Instruction 031.100.015 Documentation of 
Protocol Training. 
 

 
 
 
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We will implement regular, ongoing discussions between the PI, the study team 
and coordinator as per the AdventHealth Translational Research Institute SOP 
030.000.002 Oversight of Research Studies at the Translational Research 
Institute. The coordinator will review source and communicate with all applicable 
study team members involved in the study on a regular basis regarding 
reportable new information, implementing amendments, study progress, and 
quality assurance/control.  
 
The AdventHealth Translational Research Institute facilities are state-of-the-art, 
and we have within our building all the required resources and staff to execute 
the study. We have a medical oversight team, Medical Oversight Committee, and 
a Quality Committee to appropriately monitor and address adverse events. 
 
Study Procedures 
 
Subject Recruitment and Screening 
Recruitment methods utilized may include, but will not be limited to, the following: 
recruitment from within the AdventHealth TRI patient population, electronic 
medical records and database searches (including third party recruitment 
vendors); advertising in multiple media such as print ads, flyers, brochures, 
posters; radio ads; television spots; and internet/social media advertising.  All 
advertising materials will be submitted to the AdventHealth IRB for review prior to 
using or publishing them. Recruitment efforts will follow AdventHealth recruitment 
SOPs for research. 
 
Consent Process  
We attest that all study staff delegated the authority to obtain informed consent 
will follow CW AHC 216, “Informed Consent Process and Written Documentation 
of Informed Consent”. Upon consent, a research team member will provide the 
participant with a copy of the signed consent and the original consent form 
placed in the participant’s chart 
Subjects who are not yet adults (infants, children, teenagers) 
N/A 
Cognitively Impaired Adults 
N/A 
Adults Unable to Consent 
N/A 

 
 
 
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Documentation of Informed Consent Process 
Documentation of the informed consent process is required to establish that the subject 
was accurately and adequately informed and that no study-related procedures were 
initiated prior to obtaining informed consent. A research team member will note in the 
source documentation the consent process, date consent was obtained, and that 
consent was obtained prior to initiating any research procedures. 
Waiver of Written Documentation of Consent or Waiver of Consent  
Waiver of Written documentation of Consent (consent will be obtained but 
signatures will not be required)   
N/A 
Waiver or Alteration of the Consent Process (consent will not be obtained, 
required information will not be disclosed, or the research involves deception) 
N/A 
 
Waiver or Alteration of HIPAA Authorization 
A partial waiver of HIPAA authorization will be requested. 
 
Non-English-Speaking Subjects 
Spanish speaking participants will be enrolled to ensure that the study cohort 
accurately reflects the racial and ethnic composition of the local population., The 
consent form along with all the study educational materials will be translated in 
Spanish by the qualified bilingual team. Additionally, the bilingual qualified staff 
will conduct weekly telehealth consultation follow-ups in the study. Potential 
participants who do not speak English or Spanish will not be enrolled at the 
present time.  
Randomization 
N/A 
Study Visits  
The study will enroll 75 participants with T1D. The study will have the following periods: 
1. Period 1: Baseline without SGLT-2 inhibitor (~32 days) 
2. Period 2: Baseline with SGLT-2 inhibitor (~32 days) 

 
 
 
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3. Period 3: Risk mitigation strategy- Generalized Risk Mitigation Strategy (~ 6 
months: this will include 1 month of Period 2 as participants will be on the SGLT-2 
inhibitor during Period 2 and will follow the generalized risk mitigation strategy) 
4. Period 4: Personalized Risk Mitigation Strategy (~ 6 months) 
The following table summarizes the duration of each period.  
 
Study Periods 
Description 
Duration 
Location 
Screening 
Screening visit 
1 day 
AdventHealth Orlando 
Translational 
Research Institute 
(TRI)  
Outpatient clinic 
Period 1 
Baseline phase 
without SGLT-2 
inhibitor use 
30 consecutive 
days 
Outpatient 
2 consecutive days 
TRI Clinical Research 
Unit – inpatient 
Period 2 
Baseline phase with 
SGLT-2 inhibitor use 
30 consecutive 
days 
Outpatient 
2 consecutive days 
TRI Clinical Research 
Unit – inpatient 
Period 3 
Risk mitigation 
strategy – 
generalized care 
6 months (including 
1 month of Period 
2) 
Outpatient 
Period 4 
Risk mitigation 
strategy – 
personalized 
6 months 
Outpatient 
 
SCREENING 
 
Screening visit (SV) / (Day –28 – Day –7): Outpatient; ~ 2 – 3 hours 
 
This study visit will take place in AdventHealth Orlando Translational Research Institute 
(TRI) Outpatient clinic. Participants will arrive for this visit after an 8 hour overnight fast. 
After obtaining the informed consent, the potential participant will undergo a screening 
visit to confirm eligibility as per the eligibility criteria. The screening visit will include: 
• Consent Process Checklist assessing the potential participants’ understanding of 
and willingness to perform all study activities. 

 
 
 
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• Demographics and complete medical history (including, but not limited to, alcohol 
use, concomitant medications, health conditions, allergies, and exercise habits)   
• Standard physical examination is performed by a study physician, physician 
assistant, or nurse practitioner. Standard physical examination includes general 
status, skin, HEENT, neck, cardiovascular, lungs, abdomen, upper and lower 
extremities, neurological, musculoskeletal, and psychiatric systems. 
• Vital signs measure: Heart rate, blood pressure, respiratory rate, and body 
temperature will be measured. 
• Anthropometrics: Body weight (calibrated scale) and height will be obtained while 
the participant is gowned, without shoes. BMI will be calculated. Waist and hip 
circumference will be measured and waist- hip ratio will be calculated  
Screening blood draw to measure the following: (~25 ml)  
a. Complete blood count (CBC) white blood count, red blood count, hemoglobin, 
hematocrit, MCV, MCH, MCHC, RDW, Platelet Count, MPV, Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils, Abs Neutrophil Count, Abs 
Lymphocyte Count, Abs Monocyte Count, Abs Eosinophil Count, Abs Basophil 
Count 
b. Comprehensive metabolic panel (CMP) (Anion Gap, Albumin, Globulin, A/G 
Ratio, Alkaline Phosphatase, ALT, AST, Bilirubin Total, BUN, Creatinine, eGFR 
by CKD-EPI, Calcium, Chloride, CO2, Creatinine, Glucose, Potassium, Sodium, 
Total Protein) 
c. Lipid panel (Total Cholesterol, HDL, LDL, Chol/HDL ratio, LDL/HDL Ratio, Non-
HDL Cholesterol, Triglycerides, VLDL, CHD Risk Assessment) 
d. HbA1c 
e. Hepatitis B and Hepatitis C antibody tests [Hepatitis B Surface Antigen 
(HBsAg), Hepatitis B Surface Antibody (HBsAb), Hepatitis C Surface Antibody 
(HCsAB)] 
f. HIV 1 &2 Ag/Ab Screening 
g. Blood will also be archived for the biorepository. 
• Urine collection for: 
a. Urinalysis  
b. Urine albumin/creatinine ratio (UACR) 
c. Urine toxicology screening test (Amphetamine, Barbiturate, Benzodiazepine, 
Cocaine, Methadone, Opiate, THC, Tricyclics, Oxycodone) 
d. Urine pregnancy test in women of childbearing potential 
e. Urine collection for the biorepository 
• Electrocardiogram (ECG)  
• Questionnaires: MOCA, KIMS, Gold score (see details in the Questionnaires 
section) 

 
 
 
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Upon review of all clinical and laboratory-based screening endpoints, eligible 
participants will then be scheduled for Visit 1. Laboratories can be repeated, and 
participants may be rescreened for the study at the PI or provider’s discretion. 
PERIOD 1: BASELINE WITHOUT SGLT-2 INHIBITORS 
OUTPATIENT PHASE (DAY 1 – DAY 30) 
 
Visit 1 / Day 1:  Outpatient visit, ~ 3 ─ 4 hours 
Eligible participants will come to TRI for an outpatient visit (Visit 1) and start the 
baseline phase of the study. During this period (Day 1 – Day 30) participants will not 
use any SGLT-2 inhibitor. The following procedures will be performed in non-fasting 
condition during this visit:  
• Vital signs measurement 
• Non-fasting blood draw of ~6.5 mL for C-peptide and glucose (which correlates 
better with the mixed meal test stimulated C-peptide)  
• Continuous Dual Glucose Ketone (DGK) Monitoring device placement: All the 
patients will wear a DGK (Abbott) for the duration of the study. A member of the 
study team will place the DGK initially, and participants will be instructed on the use, 
removal and reinsertion of the device as needed every 15 days. The study 
participants may continue using their personal glucose monitoring devices (CGM) 
during the study. When using both devices (personal CGM and DGK), the devices 
will be inserted at an appropriate distance from each other (typically 2 – 3 inches 
apart or as specified in the DGK manual of procedures). During DGK wear, 
participants will be instructed to perform standard fingerstick glucose measurements 
to confirm abnormal glucose values. Additionally, the participants will not use the 
DGK device for making glucose-based treatment decisions during the first 12 hours 
of sensor wear. The  participants will be instructed to perform fingerstick blood 
ketone measurements if DGK monitor shows ketones >1.0 mmol/L or if they have 
symptoms of diabetic ketoacidosis (DKA). (see ketone action plan) 
• 24-hour dietary recall collected by The Automated Self-Administered 24-hour 
(ASA24®) Dietary Assessment Tool: This is a free, extensively validated web-based 
tool developed by the National Cancer Institute. It enables multiple, automatically 
coded, self-administered 24-hour diet recalls. The most recent version (2024) will be 
used. On average, it takes 24 minutes to complete this assessment. Three days of 
dietary intake will be reported during each of the four measurement periods to 
enable estimation of means and standard deviations for energy and nutrient intake 
with sufficient rigor to enable correlations with physiological data. Participants will 
receive phone and text reminders to complete two of these assessments remotely, 
with the third recall completed on the first day of each in-person clinic visit. Thus, two 
of the three recalls will be unscheduled. Study team members will call/ text/ email 
participants the day of the unscheduled recalls to ask them to fill out the 
questionnaires for the previous day. The dietary recalls should ideally include two 

 
 
 
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weekdays and one weekend day, with no consecutive days of reporting. Dietary 
intake variables will include, but are not limited to, absolute and relative 
macronutrient intake, total energy intake, and daily fasting duration.  
• International Physical Activity Questionnaire (IPAQ): This 27-item questionnaire 
captures physical activity performed for at least 10 minutes over the past week in 4 
different domains: 1) job-related; 2) transportation-related; 3) housework, house 
maintenance, family caregiving; 4) recreation, sport and leisure time. Computation of 
the total scores for the long for requires summation of the duration (in minutes) and 
frequency (days) for all the types of activities in all domains. Domain specific scores 
or activity specific sub scores may be calculated. Domain specific scores require 
summation of the scores for walking, moderate-intensity and vigorous-intensity 
activities within the specific domain, whereas activity-specific scores require 
summation of the scores for the specific type of activity across domains. The 
questionnaire also assesses time spent sitting as a proxy for sedentary behavior. 
• If available, participants will continue to wear personal devices (smart watches) to 
collect wearable activity data. Data will be downloaded to the study site via the 
respective applications (e.g., Apple Health) and incorporated into the trial database 
for assessment of activity/sleep etc.  
• Participants will be instructed to maintain their usual diet and levels of physical 
activity throughout the duration of the study 
Participants will wear the DGK monitor for 30 days during this outpatient period and will 
return to AdventHealth TRI for Visit 2. Data from the insulin pump, watches/ phones will 
be collected throughout this study period. 
 
PERIOD 1: BASELINE WITHOUT SGLT-2 INHIBITORS  
INPATIENT PHASE  
 
Visit 2 / Day 31- Day 32 ± 5 days: Inpatient in CRU for 2 days 
At the end of 30 days of DGK use, participants will return to AdventHealth TRI for an in-
patient stay of 2 days. Participants will be admitted to the clinical research unit (CRU) for 
an overnight in-patient stay. During this visit: 
1. The study team will download the data from all the wearable monitors (DGK device, 
insulin pumps, activity from phones/ watches) and  
2. Pregnancy test will be performed for the women of childbearing potential before the 
DEXA scan is performed. 
3. Vital signs and anthropometrics will be measured,  
4. Adverse events and concomitant meds will be assessed.  
5. For participants on multiple daily dose insulin (MDI), the last dose of long-acting insulin 
will be withheld, depending on the timing and type of insulin. Participants will be 
advised to adjust insulin dosing with rapid acting insulin to maintain glycemic control. 
6. An IV insulin infusion will be started for glycemic management at 20:00.  

 
 
 
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7. 24-hour dietary recall, IPAQ, System Usability Scale, and  Assessments of adverse 
device effects on day 31 
8. Stool sample collection (see details below) 
9. DEXA scan on Day 31 (see details below) 
10. Participants will be informed about the risk of diabetic ketoacidosis (DKA) with the use 
of sotagliflozin and they will be given generalized guidance regarding the mitigation 
strategies of DKA. 
11. On day 2 of this in-patient visit (Day 32), participants will undergo an insulin withdrawal 
test (IWT) after an overnight fast of at least 8 hours. See details of overnight in-patient 
stay and IWT below 
12. Questionnaires: MOCA, KIMS will be done on day 32 of V2 during the insulin 
withdrawal test when the blood sugar is between 250 –350 mg/dL x 2.  
13. At the end of the visit, the SGLT-2 inhibitor (sotagliflozin) will be dispensed to the 
participants for the outpatient assessment period. 
 
Dual Energy X-Ray Absorptiometry (DEXA): DEXA Scans will be performed to 
measure body fat and estimate muscle mass using a GE Lunar iDXA whole-body 
scanner. The participant will remove all metal accessories and may be asked to change 
into a hospital gown. The participant will lie on the DEXA table while the scanner arm 
emits low energy X-rays as it passes along the body. The scan takes up to 15 minutes, 
and the radiation dose is less than 1 mrem, less than half the average daily radiation dose 
in America. A urine pregnancy test will be completed on all women of childbearing 
potential (all women except those with prior hysterectomy, tubal ligation, or absence of 
menses for >2 years) prior to the DEXA scan for safety.  
Stool sample collection: Participants will be asked to produce a stool sample using a 
standard kit. A commode hat and container will be provided to collect the sample after 
receiving instructions from a member of the study team. The container will be sealed 
immediately after sample is produced. Samples will be processed within 60 minutes of 
collection with our existing protocols. Briefly, 1-2 g of the fecal specimen will be aliquoted 
into two empty 2 mL cryovials. Aliquots will be snap frozen and archived at -80° C for 
future use, including whole shotgun metagenomic sequencing for measurement of 
microbiome composition, and function, and fecal metabolomics. 
 
Overnight in-patient stay: Participants will be admitted to the clinical research unit at ~ 
6:00 p.m. the evening before the insulin withdrawal test. They will be fed a standard, 
weight-maintaining meal and allowed to cover the meal with insulin according to their carb 
ratio/correction factor. At ~8:00 pm, their insulin pump (if worn) will be disconnected and 
an IV placed. Regular human insulin will be administered by intravenous infusion to 
maintain glucose levels at a target of 100-120 mg/dL using a computerized program 
(Glucomander). For participants on MDI, they will be instructed to discontinue long-acting 
insulins at least 2 half-lives before admission but will be allowed to manage glucose 
excursions with short acting insulins up until dinner as above. People with T1D using 

 
 
 
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weekly insulin administration (when approved) will not be included in the study. At ~8:00 
p.m. an insulin infusion will be initiated to manage glucose as above.  
 
Insulin withdrawal test (IWT) 
On day 2 of the in-patient stay, participants will undergo IWT after an overnight fast of at 
least 8 hours. A peripheral intravenous cannula will be inserted into an antecubital vein 
for blood sampling for a total of approximately 221.0 mL of blood drawn. To induce 
insulinopenia and ketogenesis, the insulin infusion will be suspended at ~6:00 am. 
Participants in Period 1 will not take any sotagliflozin during IWT. Participants in Period 2 
will take sotagliflozin 400 mg orally at the time of insulin suspension. During the IWT, 
glucose, BOHB, lactate, bicarbonate and venous pH will be measured in real time at 30 
min intervals. Glucose and BOHB will be measured using a bedside Glucose/Ketone 
meter (StatStrip glucose/ketone monitor, Nova Biomedical) and pH, lactate and 
bicarbonate will be measured by iSTAT analyzer (i-STAT CG4+ Abbott). Participants will 
consume 200 mL water hourly. Fluid intake and urine output will be monitored. The IWT 
will conclude after 6 hours or sooner if participants meet the early termination criteria 
(bedside ketone ≥3.0 mmol/L, bedside glucose >399 mg/dL or persistent bothersome 
symptoms including but not limited to nausea, vomiting). From 6 a.m. to 2 p.m. blood 
samples will be collected every 30 minutes for biorepository. Furthermore, urine voids 
occurring between 6:00 AM and 2:00 PM will be individually collected for volume 
assessment and will be stored in biorepository. After the test, participants will receive 
intravenous and oral fluids, a subcutaneous insulin bolus, and a meal. Basal insulin via 
insulin pump or subcutaneous injectable insulin will resume. Participants will be 
discharged from clinical research unit (CRU) when symptoms are improved, BOHB <1.0 
mmol/L, and glucose trends downwards. 
 
PERIOD 2: BASELINE WITH SGLT-2 INHIBITORS  
OUTPATIENT PHASE (DAY 33 – DAY 63) 
 
Participants will start Period 2 of the study from Day 33 (±5 days) in which they will take 
SGLT-2 inhibitors for approximately 30 days. During the first 2 weeks, participants will 
take 200 mg of sotagliflozin, orally, once daily before the first meal of the day. If tolerated, 
they will increase to 400 mg of sotagliflozin, orally, once daily for the duration of their 
participation in the study. Participants will wear the DGK monitor for ~30 days during this 
outpatient period and will return to AdventHealth TRI for Visit 3. 
Female participants will be instructed to use appropriate contraception methods.  
Participants will be instructed to maintain their usual diet and levels of physical activity 
throughout the duration of the study 

 
 
 
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Weekly Telephone Follow-ups 
Week 1 – 4 (Day 40 – Day 61 ±2 days): remote, ~30minutes  
A study team member will have weekly telephone or telehealth follow-up visits to assess 
adverse events and to answer their questions during this study period. 
 
PERIOD 2: WITH SGLT-2 INHIBITORS 
INPATIENT PHASE 
 
Visit 3 / Day 64 – Day 65 (± 5 day): Inpatient in CRU for 2 days, 
 
At the end of 30 consecutive days of sotagliflozin and DGK use, participants will return to 
AdventHealth TRI for an in-patient stay of 2 days. 
1. Participants will be admitted to the clinical research unit (CRU) for an overnight stay. 
2. The study team will download the data from all the wearable monitors  
(DGK device, insulin pumps, activity from phones/ watches) 
3. Pregnancy test will be performed for the childbearing females  
4. Vital signs and anthropometrics will be measured 
5. Adverse events and conmeds will be assessed.  
6. 24-hour dietary recall and IPAQ 
7. Stool sample collection  
For those participants on MDI, long-acting insulin will be stopped a day before the IWT.  
8. An IV insulin infusion will be started for glycemic management at 20:00 hr.  
9. On day 2 of this in-patient visit, participants will take the study drug before the start of 
IWT.  
10. Participants will undergo an IWT after an overnight fast of at least 8 hours. See details 
of IWT above. 
11. At the end of the visit, the SGLT-2 inhibitor (Sotagliflozin) will be dispensed to the 
participants. 
12. Questionnaires: MOCA, KIMS will be done on day 65 of V3 during the insulin 
withdrawal test when the blood sugar is between 250 –350 mg/dL x 2. 
13. Blood draw of approximately 3.0 mL and urine collection for the biorepository. 
 
PERIOD 3: GENERALIZED RISK MITIGATION STRATEGY (DAY 33 – DAY 216) 
 
Participants will continue to take sotagliflozin during Period 3 of the study. 
Simultaneously, they will have a DGK monitor during this period of the study.  
 
Weekly Telephone Follow-up  
Week 5 – 12 (Day 71 – Day 120 ±2 days): remote, ~30minutes  

 
 
 
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A study team member will have weekly telephone follow-ups to assess adverse events 
and to answer their questions during this study period. Any change in the insulin dose will 
be made with consultation of the medical team. 
 
Visit 4 / Day 124 ± 5 days: Outpatient at TRI for ~2 – 3 hours 
• CGM/CKM device distribution/ insertion 
• Study drug distribution 
• Data download from all the available wearable monitors (DGK device, insulin pumps, 
activity from phones/ watches) 
• Adverse events and conmeds will be assessed.  
• Vital signs and anthropometrics will be measured 
• HbA1c blood draw of approximately 3.0 mL 
• Urine pregnancy test will be performed for the childbearing females  
• Blood collection of approximately 10.0 mL and urine collection for biorepository 
 
Weekly Telephone Follow-up 
Week 13 – 25 (Day 127 – Day 211 ±2 days): remote, ~30minutes  
A study team member will have weekly telephone follow-ups to assess adverse events 
and to answer their questions during this study period. 
 
Period 3 of the study will continue until V5. Therefore, participants will follow the general 
risk mitigation strategy for 6 months. 
 
Visit 5 / Day 216 ± 5 days: Outpatient at TRI for ~2 – 3 hours 
• Participants will transition from the generalized DKA risk mitigation strategy to a 
personalized DKA risk mitigation strategy at this visit. 
• DGK  device distribution/ insertion 
• Study drug distribution 
• Data download from all the available wearable monitors (DGK device, insulin pumps, 
activity from phones/ watches) 
• Adverse events and concomitant meds will be assessed.  
• Vital signs and anthropometrics will be measured 
• Blood collection of approximately 17.5 mL for labs (CMP, CBC, HbA1c, biorepository)  
• Urine collection for urine analysis, UACR, and biorepository 
• Pregnancy test will be performed for women of childbearing potential 
• 24-hour dietary recall and IPAQ 
• Participants will be educated about the personalized risk mitigation strategies of DKA. 
These personalized strategies will be inferred from their in-patient and outpatient 
experience including data from the DKA during the study.  
• Questionnaires: MOCA, KIMS, IPAQ, System Usability Scale, Assessments of 
adverse device effects will be done  

 
 
 
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PERIOD 4: PERSONALIZED RISK MITIGATION STRATEGY (DAY 217 – DAY 400) 
The personalized risk mitigation strategy will continue for 6 months following the 
generalized risk mitigation strategy. Participants will continue to take SGLT-2 inhibitor 
during this period 4. Simultaneously, they will have a DGK monitor. Participants will be 
informed about the risks of DKA with the use of SGLT-2 inhibitors. 
 
Visit 6 / Day 308 ± 5 days: Outpatient at TRI for ~2 – 3 hours 
• DGK device distribution/ insertion 
• Study drug distribution 
• Data download from all the available wearable monitors (DGK device, insulin pumps, 
activity from phones/ watches) 
• Adverse events and conmeds will be assessed.  
• Vital signs and anthropometrics will be measured 
• HbA1c blood draw of approximately 3.0 mL 
• Urine pregnancy test will be performed for the childbearing females  
• Blood collection of approximately 10.0 mL and urine collection for biorepository 
• Pregnancy test will be performed for the childbearing females 
 
Weekly Telephone Follow-up 
Week 40 – 53 (Day 316 – Day 393 ±2 days): remote, ~30minutes  
A study team member will have weekly telephone follow-ups to assess adverse events 
and to answer their questions during this study period. 
Visit 7/Day 400 ± 5 days: Outpatient at TRI for ~2 – 3 hours 
• DGK device distribution/ insertion 
• Data download from all the available wearable monitors (DGK device, insulin pumps, 
activity from phones/ watches) 
• Adverse events and conmeds will be assessed.  
• Vital signs and anthropometrics will be measured 
• Blood collection of approximately 17.5 mL for labs like CMP, CBC, HbA1c, 
biorepository  
• Urine collection for urine analysis and UACR, biorepository 
• Pregnancy test will be performed for the childbearing females before the DEXA scan 
is performed 
• 24-hour dietary recall and IPAQ 
• Stool sample collection 
• DEXA scan 
• Removal of DGK device.  
• Questionnaires: MOCA, KIMS, Gold score, IPAQ, System Usability Scale, 
Assessments of adverse device effects, device issues will be done 

 
 
 
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The personalized risk mitigation strategy for DKA will end at V7. 
Weekly Telephone Follow-ups 
Week 53 – 57 (Day 407 – Day 421 ±2 days): remote, ~30minutes  
A study team member will have weekly telephone follow-ups to assess adverse events 
and to answer their questions during this study period. 
Visit 8: End of study safety follow up / Day 430 ± 5 days: Outpatient at TRI for ~2 – 3 
hours 
Approximately one month after visit 7, participants will have an end of study safety 
follow up visit. The participants will undergo the following procedures during this visit:  
• Medical history, physical exam,  
• Vital signs measurement,  
• Anthropometrics measurement,  
• Blood draw of approximately 7.5 mL for safety labs (CBC, CMP, HbA1c),  
• Urine analysis, UACR 
• Assessment of adverse events and conmeds. 
Questionnaires: 
KIMS: The Kentucky Inventory of Mindfulness Skills (KIMS) is a 39-item self-report 
questionnaire designed to assess four core mindfulness skills: Observing, Describing, 
Acting with Awareness, and Accepting without Judgment. Each skill is measured 
through a dedicated subscale, and responses are scored on a Likert scale, with some 
items reverse-scored. The KIMS is widely used in both clinical and research settings to 
evaluate mindfulness as a teachable and measurable trait. (6) 
MOCA: The Montreal Cognitive Assessment; Performance-based assessment of 
general mental status consisting of several short tasks (executive function, visual spatial 
skills, naming, attention, language, verbal, memory and orientation). Total score = 30. 
(7) 
Gold Score: The Gold score is a questionnaire used to assess hypoglycemia 
awareness. It consists of a single question. Responses are scored from 1 to 7. (8) 
System Usability Scale: A 10-item questionnaire that measures the overall usability of a 
system. It is a valid and reliable measure of the perceived usability of a system and is 
technology-agnostic. (9) 
 
 

 
 
 
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Schedule of Activities for Period 1 and Period 2 
Study Period 
Screening 
Period 1/Baseline 
(No SGLT-2 
inhibitor) 
Period 2 (Daily 
SGLT-2 inhibitor) 
Visit number 
SV 
V1 
V2 
V3  
Day number 
1 
31 
32 
33 
64 
65 
Informed Consent, review of eligibility 
criteria, history, and medical exam 
x 
 
 
 
 
 
 
Vital signs, anthropometrics (height, 
weight, BMI, waist-hip ratio) 
x 
 
x 
 
 
x 
 
Stool sample collection* 
 
 
x 
 
 
x 
 
Screening labs (CMP, CBC, lipid 
profile, TSH, Hep B and Hep C, HIV 
screening, urine analysis, UACR, 
ECG, toxicology screen) 
x 
 
 
 
 
 
 
HbA1c 
x 
 
 
 
 
x 
 
Pregnancy test 
x 
 
x 
 
 
x 
 
Assess adverse events, conmeds 
x 
x 
x 
 
 
x 
 
Non-fasting C-peptide and glucose 
 
x 
 
 
 
 
 
DGK Wear 
 
x 
x 
x 
 
x 
x 
Activity Monitor Wear, if available 
x 
x 
x 
x 
 
x 
x 
24-hour dietary recall (ASA-24) ▲ 
 
x (3) 
x (3) 
 
 
x (3) 
 
International Physical Activity 
Questionnaire (IPAQ) 
 
x 
x 
 
 
x 
 
Questionnaires (KIMS, MOCA) 
x 
 
 
x 
 
 
x 
Questionnaires (Gold score) 
x 
 
 
 
 
 
 
Questionnaires (System Usability 
Scale, Assessments of adverse 
device effects, device issues) 
 
 
 
x 
 
 
 
Blood and urine collection for 
Biorepository 
x 
 
 
 
 
 
 
Drug distribution 
 
 
 
x 
 
 
 
Data Download (DGK/ insulin/ activity 
monitor) 
 
 
 
x 
 
 
x 

 
 
 
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Patient Education for Generalized 
Risk Mitigation  
 
 
x 
 
 
 
 
Telehealth consults/text messages to 
assess AEs and con-meds 
(Frequency: Weekly) 
 
 
x(4) 
 
 
x(4) 
 
Inpatient Testing in CRU 
Admit in CRU  
 
 
x 
 
 
x 
 
DEXA scan 
 
 
x 
 
 
 
 
Test: Insulin Withdrawal Test (IWT) 
 
 
 
x 
 
 
x 
Standard Meal 
 
 
x 
x 
 
x 
x 
For 10h time series: Assess ketones, 
glucose, lactate, bicarbonate, and 
venous pH 
 
 
 
x 
 
 
x 
6 AM to 2PM blood samples collected 
every 30 minutes for biorepository 
 
 
 
x 
 
 
x 
6 AM to 2PM urine voids collected for 
biorepository samples, assess 
volume 
 
 
 
x 
 
 
x 
*Stool sample can be collected on either day of V2 (day 31 or 32) and V3 (day 64 or day 65).  
DGK: continuous ketone/glucose monitor, ▲Two unscheduled dietary recalls will be collected by 
the study team before this visit. 
 
Schedule of Activities for Period 3 and Period 4 
Study Period 
Period 3:ǂ 
Generalized Risk 
Mitigation 
Strategy 
Period 4: 
Personalized Risk 
Mitigation Strategy 
EOS 
Safety 
Follow 
Up 
Visit number 
V4  
V5¶ 
V6  
V7  
V8 
Month number/ (Day number) 
3 (124) 
6 
(216) 
9 (308) 
12 
(400) 
13 (430) 
 
 
 
 
 
DGK Wear 
x 
x 
x 
x 
x 
Activity Monitor Wear (optional) 
x 
x 
x 
x 
x 
Assess adverse events, conmeds 
x 
x 
x 
x 
x 

 
 
 
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Vital signs and anthropometric 
measurement 
x 
x 
x 
x 
x 
HbA1c 
x 
x 
x 
x 
x 
Safety labs (CMP/CBC, urine 
analysis, UACR) 
 
x 
 
x 
x 
Questionnaires (KIMS, MOCA) 
 
x 
 
x 
 
Questionnaires (Gold score) 
 
 
 
x 
 
Questionnaires (System Usability 
Scale, Assessments of adverse 
device effects, device issues) 
 
x 
 
x 
 
Stool sample collection 
 
 
 
x 
 
DEXA scan 
 
 
 
x 
 
24-hour dietary recall (ASA-24) 
 
x (3) 
 
x (3) 
 
International Physical Activity 
Questionnaire (IPAQ) 
 
x 
 
x 
 
Blood and Urine Collection for 
Biorepository 
x 
x 
x 
x 
 
Pregnancy test (urine) 
x 
x 
x 
x 
 
Data Download (DGK/insulin/activity 
monitor) 
x 
x 
x 
x 
 
Drug distribution 
x 
x 
x 
 
 
Patient Education for Generalized 
Risk Mitigation  
 
 
 
 
 
Patient Education for Personalized 
Risk Mitigation 
 
x 
 
 
 
Tele-consults/ text messages to 
assess AEs and con-meds 
(Frequency: Weekly) 
x (13) 
x 
(13) 
x(13) 
x(13) 
x (4) 
ǂPeriod 3 will start from Day 33 and will overlap with Period 2 for the first month. ¶V5 is the 
transition visit between Period 3 and Period 4. Period 3 will end at V5, and Period 4 will start 
from V5 
 
Study Duration 
Projected start date of study: December 2025   

 
 
 
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Estimated duration to enroll all study subjects: 15 months  
Total length of time participants will remain in the study: approximately 15 months which 
includes 14 months of intervention and 1 month of follow-up  
Estimated date for investigators to complete the study (including analysis): December 
2028 (3 years)  
 
Materials of Human Origin:  Collection, Preparation, Handling and Shipping 
Materials of human origin will be collected as described in the specific study visits 
section of this protocol.  
 
Biospecimen samples will be stored in ultra-low temperature freezers and liquid nitrogen 
drawers, or other storage units located at each facility. The TRI facility is secured via 
key card and equipped with a back-up generator system. Laboratory personnel in the 
facility have 24/7 key-controlled access to the laboratory. Chain of custody of 
biospecimen samples is maintained through requisition forms and in the StarLIMS 
database. All biospecimen tubes are coded and labeled appropriately, and biospecimen 
requests and distribution are documented. 
 
The TRI facility will be the main repository for biospecimen samples 
    
Study Outcome Measures (Endpoints) 
 
Outcomes 
Description 
Primary Outcomes 
Ketone events with Beta-
hydroxybutyrate (BOHB) >1.5 
mmol/L  
Number of ketone events with BOHB > 1.5 mmol/L 
for 15 consecutive minutes, as measured by the 
DGK. The event will end when BOHB is < 1.5 for 15 
consecutive minutes. These events will be 
measured during the risk mitigation phase (Period 3 
and Period 4) of the study. 
Ketone events with Beta-
hydroxybutyrate (BOHB) 
>1.0mmol/L 
Number of ketone events with BOHB >1.0mmol/L 
for 15 consecutive minutes, as measured by the 
DGK. The event will end when BOHB is <1.0 
mmol/L respectively for 15 consecutive minutes. 
These events will be measured during the risk 
mitigation phase (Period 3 and Period 4) of the 
study. 
% time spent in ketosis of > 1.5 
mmol/L 
Average percentage of time spent in ketosis (>1.5 
mmol/L) in 24 hours, measured by the DGK, during 
the risk mitigation Period 3 and Period 4 of the 
study. 

 
 
 
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% time spent in ketosis of >1.0 
mmol/L 
Average percentage of time spent in ketosis (> 1.0 
mmol/L) in 24 hours, measured by the DGK, during 
Period 3 and Period 4 of the study. 
Mean BOHB levels 
Mean BOHB levels (mmol/L) across period 3 and 
period 4, as measured by the DGK. 
%CV of BOHB 
Mean percentage of coefficient of variation of 
ketones across period 3 and period 4, as measured 
by the DGK. 
Symptomatic ketone events 
Number of symptomatic ketone events; defined as 
BOHB >1.0 mmol/L along with symptoms (including 
weakness, nausea, vomiting, confusion, fruity-
breath, polyuria, and/or polydipsia) across Period 3 
and Period 4 of the study 
Severe ketone events 
Number of severe ketone events requiring hospital 
admissions/ emergency room visits/ or third-party 
intervention across Period 3 and Period 4 of the 
study 
BOHB responses during Insulin 
withdrawal test (IWT) 
Measured by Ketogenesis index; calculated by 
dividing the max BOHB level by the termination time 
of the IWC (max BOHB/Time min); maximum BOHB 
during IWC; time to BOHB max during IWC; 
difference in BOHB (max-min) during IWC 
Secondary Outcomes 
Venous pH responses during 
IWT 
Measured by change in pH over time during IWT,  
minimum level of pH, time to minimum pH, pH delta 
(max-min). 
Lactate and glucose responses 
during IWT 
Measured by change in lactate and glucose over 
time during IWT,  
• 
maximum lactate and glucose,  
• 
time to maximum lactate and glucose, 
• 
lactate and glucose delta (max-min) 
Glycemic outcomes measured 
by continuous glucose 
monitoring (CGM) 
Glycemic outcomes will be measured by mean 
glucose and standard deviation, % time below 
range < 70 mg/dL, % time below range < 54 mg/dL, 
% time in range 70-180 mg/dL, %time above range 
>180 mg/dL, % time above range >250 mg/dL, 
coefficient of variation across period 3 and period 4 
Insulin requirements 
Average units of insulin delivered daily as basal 
insulin, bolus insulin, total daily dose of insulin 
(TDD), TDD/kg body weight across period 3 and 
period 4 
Body weight, blood pressure, 
HbA1c, kidney functions 
Body weight in kg, mean systolic and diastolic blood 
pressure (mmHg), HbA1c, eGFR will be measured 
across period 3 and period 4. 

 
 
 
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Bicarbonate response during 
IWT 
Measured by change in bicarbonate over time 
during IWT, minimum bicarbonate, time to minimum 
bicarbonate, bicarbonate delta (max-min) 
Other Outcomes 
BOHB response to changes in 
glucose during IWT 
Measured during IWT as change over time (slopes) 
in BOHB and glucose; differences in BOHB and 
glucose across time points. 
BOHB response to changes in 
lactate during IWT 
Measured during IWT as change over time (slopes) 
in BOHB and lactate; differences in BOHB and 
lactate across time points. 
BOHB response to changes in 
pH during IWT 
Measured during IWT as change over time (slopes) 
in BOHB and pH; differences in BOHB and pH 
across time points. 
Data Management and Quality Plan 
Clinical trial monitoring will be conducted by AdventHealth Office of Research Integrity 
and Compliance (ORIC) monitoring team to ensure compliance with all applicable 
federal and state regulations, ICH GCP E6 (R2) standards and approved protocol. This 
study will be monitored using a risk-based approach. A monitoring plan will be created 
to ensure patient safety; data quality and integrity is ongoing throughout the life of the 
study. The frequency and elements of monitoring will be outlined in the monitoring plan. 
The monitor will ensure the study is conducted, recorded, and reported as required by 
federal regulations and IRB of record. Monitoring will be conducted on-site and/or 
remotely. After completion of the site monitoring, a report will be provided to PI and 
study team. The PI and study team are required to review the report and work on 
significant findings or discrepancies to resolution. If any findings are required to be 
reported to the IRB, the PI will be made aware and prompted to self-report. All serious 
and continuing non-compliance is shared with the Research Oversight Committee who 
may require appropriate actions. 
Data De-identification 
Participants will be enrolled and assigned a participant identification number (PID) at 
TRI. This PID is a code consisting of a combination of numerals and letters, which 
serves as the identifier for this participant for this research study and links them back to 
their hospital medical record and/or their protected health information (PHI). Access to 
the “link” between the PIDs, the PHI, and to the clinical data are only granted to the 
clinical research team as assigned on the Delegation of Authority Log. All the clinical 
research and survey data is recorded in a de-identified fashion onto our paper source 
documents and/or electronic case report forms (CRF). Data will be entered into 
REDCap, a HIPAA-compliant, web-based forms and survey platform approved for use 
by AdventHealth. REDCap will be used for storage and to facilitate analysis. All data not 
entered into REDCap (e.g., data collected from individual activity monitors, insulin 

 
 
 
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pumps, wearables) will be stored on a shared OneDrive folder only accessible to the 
assigned study-specific research team at AH TRI. 
Clinical data generated by research devices also uses the PID, and once the data has 
been transformed into interpretable results it is stored into the clinical research 
database (either REDCap or OneDrive). Both storage locations are password-protected, 
secured and only assessable to the assigned clinical research team from AH TRI. The 
“link” will not be used to re-identify participants except in the event of a serious adverse 
event (SAE) requiring “unblinding” to treat the participant. The “link” will be stored in the 
Patient Protocol Manager and in the OneDrive folder, where only the research team has 
access.  
Data Confidentiality, Storage, and Retention 
The identity and personal health information of study participants will be kept 
confidential to the extent permitted by the applicable laws and/or regulations and will not 
be made publicly available. If the results of this study are published or presented, the 
identities will not be revealed. Confidentiality will be maintained during and after the 
study. This information is also included in the informed consent, which is discussed with 
participants prior to enrollment.  
Study documentation and paperwork will be stored in our locked medical records room 
at AH TRI. The data records will also be stored as electronic records in REDCap and 
OneDrive. This data will be safeguarded so that only those on the research team have 
access to any of the clinical data (both source documentation and data warehouse 
storage). The electronic data is maintained by Adventist Information Technology (AIT) 
security controls.  
AdventHealth Translational Research Institute retention policy is maintained in the 
Records Management Policy. Electronic de-identified data will be kept indefinitely in our 
data warehouse. Per the institutional policy, investigator records must be kept for a 
minimum of 7 years after completion of discontinuation of the study, or for longer if 
required by applicable local regulations, or what is applicable per the Sponsor. 
Data Quality  
Data quality control will occur according to our SOPs on Data Entry, Quality Control 
Procedures and Query Management. All data will be entered into an electronic data 
capture (EDC) system (REDCap) and checked against the paper source for accuracy 
by a second party (Data Entry SOP) and errors resolved through the Query 
Management SOP.  Ten percent of the data points will be routinely checked at the 
beginning, middle, and close of a study for quality control (Quality Control SOP).  
Finally, all critical endpoints (as determined by the PI or Sub-I) will be assessed using 
quality control analyses.  The data will be loaded into the clinical research database.  
Data in the warehouse will also be routinely monitored over time. 

 
 
 
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Data Sharing  
Some of the endpoint testing might be conducted at outside institutions. To perform 
these analyses/testing/etc. and to interpret results, certain data elements will need to be 
shared along with the biospecimen samples. Data Use Agreements will be obtained, 
which will identify the specific data elements to be shared and will govern the sharing of 
data related to this study. Data will be de-identified, but a link/code is managed within 
an electronic research management system and maintained by a study coordinator 
  
Sample Size Determination 
The primary endpoint to address the overarching aim is the number of ketone events 
with BOHB >1.5 mmol/L during generalized vs. personalized risk mitigation strategies. 
We therefore estimated a standardized effect size of 0.29 calculated from the mean and 
standard deviation of fasting BOHB in a randomized crossover placebo-controlled study 
testing the effects of SGLT-2 inhibitor therapy with or without concomitant glucagon 
receptor antagonist therapy in 12 adults with type 1 diabetes. A sample size of 75 
participants provides 80% power to detect an effect size of 0.29 using a one-sided 
paired t-test at an alpha level <0.05. We assume an equivalent or larger effect size in 
our study given the longer follow-up duration. 
 
Statistical Analysis Plan 
Primary Objective Analysis 
The primary objective is to compare the ketosis and ketoacidosis (beta-hydroxybutyrate, 
pH, lactate, bicarbonate, glucose) response during the insulin withdrawal challenge in 
participants with T1D with and without SGLT-2 inhibitor. To analyze this, within-subjects 
repeated measures linear mixed model will be used to compare these outcomes 
assessed during IWT with and without SGLT-2 inhibitor.  
Secondary Objective Analysis 
The secondary objective is to compare the number of ketone events (DGK assessed 
BOHB levels) with 6-months personalized DKA risk mitigation strategy compared to 6-
months generalized DKA risk mitigation plan in participants with T1D on SGLT-2 
inhibitors use. A stratified Cox proportional hazards model using the intervention 
assignment (generalized vs. personalized risk mitigation strategy) as fixed factors will 
be used. Subgroup analyses will be performed by adding the interaction term between 
subgroup at intervention assignment 
 

 
 
 
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Potential Risks and Benefits 
Potential Benefits 
Potential benefit for the participants could be: 
• Access to SGLT-2 inhibitors may improve their glycemic control and 
body weight. 
• SGLT-2 inhibitors have been shown to reduce progression of chronic 
kidney disease and cardiovascular disease including heart failure in 
other populations. It is unknown whether these benefits will be evident 
in persons with T1D 
• Access to advanced education and support provided by highly qualified 
personnel. 
• Participants could benefit from a better understanding of diabetic 
ketoacidosis and its management. 
• Results from clinical blood work will be shared with the participants. 
Potential Risks 
 
Described below are all the known risks of being in this study 
• Intravenous lines/blood draws (lab samples, e.g.): there is a risk of pain, vasovagal 
syncope, hematomas, and/or infection at IV insertion/blood draw site (low risk of 
SAEs). The total amount of blood collected is about 542.5 mL over 430 days.  
• Surveys: There are no risks involved beyond what would reasonably be encountered 
in everyday life. It is possible that participants may experience the following during 
completion of surveys: 
1. 
Loss of privacy as a result of a breach of confidentiality  
2. 
Undue stress related to content on the survey instruments 
• Dual Glucose and Ketone monitoring: There is a low risk of developing a local skin 
infection at the site of the sensor needle placement. Itchiness, redness, bleeding, 
and bruising at the insertion site, and local tape allergies may occur. Individuals who 
develop severe reactions may be withdrawn from the study. 
• Insulin delivery methods: Participants will continue to use their preferred insulin 
delivery methods for the duration of the study. They could use hybrid closed loop 
systems (HCL), continuous subcutaneous insulin infusion, or multiple daily injections 
of insulin. Hypoglycemia is a potential risk of insulin use. All insulin delivery methods 
are standard of care for persons with T1D. 
• Insulin withdrawal test: During this test, participants might have symptoms of 
weakness, fatigue, nausea, vomiting, excessive thirst, frequent urination, abdominal 
pain, confusion. 
SGLT-2 inhibitor (sotagliflozin) use: Use of sotagliflozin in people with T1D lowers blood 
glucose in a manner not dependent upon insulin. There is a risk of developing atypical 

 
 
 
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or euglycemic DKA. Additionally, sotagliflozin use may increase the risk of genital and 
urinary tract infections, necrotizing fasciitis, dehydration, and death. SGLT-2 inhibitors 
are associated with osmotic diuresis and volume depletion, which may lead to dizziness 
or hypotension, especially in the elderly. The risk of hypoglycemia was not increased 
with sotagliflozin in clinical trials. However, insulin is known to cause hypoglycemia. The 
dose of insulin may need to be adjusted to minimize the risk of hypoglycemia when 
these agents are used in combination with sotagliflozin in patients with T1D. Overall, the 
risks associated with sotagliflozin use are mild to moderate, and the risk of serious DKA 
mitigated by continuous monitoring with the DKG device.  
• DEXA scan – there is a very small risk of cancer with excessive exposure to any 
radiation. There are also risks for unborn children associated with radiation 
exposure. The radiation dose from the scan is less than a chest x-ray, or less than 
half the average amount a person would receive in a day in America 
Mitigation of Risks  
The following risk minimization procedures will be in place. 
Privacy and Confidentiality 
The information gathered during this study will be kept confidential to the extent permitted 
by law. To ensure the privacy of interests of participants, conversations or other 
communications about individual information will be conducted privately and the 
information held in confidence. All study data will be collected by the research team, 
reviewed by the PI, and stored in secure, locked files and/or password-protected 
electronic databases to protect from inadvertent loss or improper access. All laboratory 
specimens, evaluation forms, reports, and other records that are processed in 
laboratories, used in analyses, or shared with laboratory staff will be identified only by 
coded number to maintain subject confidentiality. Blood samples will be stored in alarmed 
-80ºC freezers in the TRI’s locked laboratory. All specimen containers will be labeled by 
subject code and date. There will be no direct link to participant identifying information 
without access to protected files containing the identifying information linking the 
specimens to a given subject. Access to linked identifiers will be limited to research 
personnel directly involved with the project. Information gained from this study that can 
be linked to the subject's identity will generally not be released to anyone other than the 
PI, Research Coordinator, other key personnel, the participant, or the subject's physician. 
However, representatives of the coordinating center (monitors), sponsor (National 
Institutes of Health), the Data Safety Monitoring Board, the U.S. Food and Drug 
Administration (FDA), and AdventHealth’s Institutional Review Board (IRB) - will be able 
to inspect data records and have access to confidential information that identifies the 
subject by name. The results of these studies will be the subject of scientific presentations 
or published in scientific journals without identifying individual subjects. 
Laboratory tests  
Qualified staff will conduct all venipuncture and infusion procedures using aseptic 
techniques to avoid extravasation or excessive discomfort.  

 
 
 
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DEXA Scan: A urine pregnancy test will be done prior to scans of all women of 
childbearing potential (all women except those with prior hysterectomy, tubal ligation, or 
absence of menses for >2 years). 
Insulin withdrawal test (IWT) 
The following will be done to protect against the risk of DKA: 
• In-house supervision by a qualified physician or mid-level provider at all times during 
the procedure 
• Frequent monitoring of blood glucose, ketones, lactate, bicarbonate, and pH during 
the procedure (every 30 minutes)  
• Establishing early termination criteria for the IWT: bedside ketone ≥3.0 mmol/L, 
bedside glucose >399 mg/dL or persistent bothersome symptoms including but not 
limited to nausea and vomiting. 
• Immediate availability of corrective measures (insulin, glucose, hydration) 
Dual glucose and ketone monitoring 
The site of sensor insertion will be periodically monitored, and strategies to prevent local 
skin reactions will be suggested, such as site rotation, liquid adhesive, or changing the 
type of tape in contact with the skin. Individuals who develop severe skin reactions to the 
device may need to be discontinued from the study. 
Insulin use with sotagliflozin: 
In people with T1D, concomitant use of sotagliflozin with insulin may lead to 
hypoglycemia, hyperglycemia, and/or DKA. The DGK will be used to trigger capillary 
blood ketone measurements to assess and treat DKA. The DGK device provided by 
Abbott provides alarms when ketone levels are above a certain threshold. For ketones, 
there will be two available alarms – an optional alarm at 0.6 mmol/dL and a mandatory 
alarm at 1.5 mmol/dL. For ketones, there will be 3 trend arrows indicating rapidly rising, 
rapidly falling, and steady ketone levels. 
Similarly, the device provides alarms when glucose is above or below a certain threshold 
and will trigger capillary blood testing. For glucose, there will be 5 trend arrows indicating 
rapidly rising, rising, falling, rapidly falling, and steady glucose levels. To prevent 
medically relevant hyperglycemia during the intervention, cut-offs have been set up to 
modify insulin treatment. Participants will be expected to cover meals with prandial insulin 
and correct for hyperglycemia. If the blood glucose is persistently > 250 mg/dl, the study 
team will notify the TRI provider immediately to review glucose values and initiate 
treatment. To prevent severe hypoglycemia, participants will be instructed to consume 
carbohydrate according to the “rule of 15” for glucose values ≤70 mg/dl as prescribed in 
clinical practice i.e., consume 15 grams of carbohydrate, wait about 15 minutes, then 
recheck blood glucose levels.  
The CGM glucose level should be checked anytime a patient has symptoms of 
hypoglycemia or hyperglycemia and verified with a fingerstick glucose meter. 

 
 
 
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Participants will be monitored weekly by telephone/video/ text messages consultation by 
the study team. Periodic DGK profile downloads, insulin pump downloads, study 
smartphone app downloads, adverse events, and concomitant medication collection will 
take place throughout the study. 
Risk of DKA with sotagliflozin in T1D 
There is an increased risk of diabetic ketoacidosis with the use of sotagliflozin in people 
with T1D. Proposed mitigation strategies of DKA are attached. Please refer to the 
generalized DKA risk mitigation strategies which will leverage on the evidence from 
previous studies of sotagliflozin and other SGLT-2 inhibitors in people with T1D.(4, 5) 
The risk of DKA increases if the reduction of total daily dose of insulin is approximately 
20% or more from baseline. Participants will be instructed to closely monitor their ketone 
levels when taking the SGLT-2 inhibitor. The importance of monitoring ketone levels, 
irrespective of glucose levels will be emphasized as DKA can occur with low, normal, or 
high blood sugars in patients with T1D taking SGLT-2 inhibitors. Ketones should also be 
monitored regardless of blood glucose levels when a patient is not eating, is more 
physically active, drinking alcohol, or experiencing symptoms like general malaise and 
abdominal pain.  
Temporary stopping criteria for SGLT-2 inhibitors: 
• If participants have symptoms of DKA (as outlined in patient education handout), 
they will stop the drug as per the STOPDKA protocol. 
• Participants will be advised to stop sotagliflozin 3-4 days before an elective surgery 
or procedure associated with prolonged fasting and resume post-operatively when 
tolerating oral intake. 
• If the DGK monitor shows blood ketone ≥ 1.0 mmol/L without any symptoms of 
DKA, confirm the ketone levels with fingerstick blood ketone monitor, and withhold 
the next sotagliflozin dose if ketones of ≥ 1.0 mmol/L are confirmed on the blood 
ketone monitor. Participants will be instructed to reach out to the clinical site in 
case the blood ketone is ≥ 1.0 mmol/L 
If blood ketones ≥ 1.0 mmol/L, participants will be instructed to  
• 
Hold the SGLT-2 inhibitor 
• 
Continue insulin, consider increasing basal insulin. 
• 
Consume 15 – 30 grams of carbs each hour (glucose containing sports drinks/ oral 
rehydration fluid) 
• 
Give bolus insulin for the carbs even if blood glucose is normal 
• 
Take anti-emetics if necessary 
• 
Sotagliflozin will be restarted if ketones remain <0.6mmol/L for 48 hours 
Participants may experience an episode of DKA while participating in the study. If this 
occurs, the study team will investigate the circumstances of the episode. In the event that 
there was a clear precipitating factor (pump failure, occlusion, intercurrent illness, etc.), 
participants will be given the choice of restarting the SGLT-2 inhibitor. If they elect not to, 

 
 
 
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they will be able to remain in the study and continue to participate in DGK monitoring and 
scheduled visits.  
Mandatory discontinuation of drug 
The reasons for permanent discontinuation of the study drug are as follows:  
1. A serious adverse event (SAE) related to the study drug or an intolerable AE such as 
a persistent allergy or rash  
2. Diabetic Ketoacidosis (DKA) 
a. One episode of DKA requiring hospitalization, an Emergency Room visit, 
and/or intensive therapy (e.g., intravenous fluids)  
2. Severe (Grade 3) hypoglycemia as per the definition of ADA 
Two episodes of severe hypoglycemia associated with significant impairment of 
mental function such that the person requires assistance from another person to 
recover 
4. Unexplained clinically significant persistent changes from baseline based on 
laboratory safety assessment which do not respond to temporary 2-week 
discontinuation of study drug and/or recurs upon re-institution of drug  
5. Non-compliance 
6. Pregnancy 
7. Possible evidence of drug-induced liver injury that meets one (or more) of the following 
criteria: 
a. Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x 
upper limit of normal (ULN) with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain/tenderness, fever, rash, and/or eosinophilia (>5%); 
b. ALT or AST > 3x ULN and total bilirubin > 2x ULN or INR > 1.5; 
c. ALT or AST > 5x ULN for more than 2 weeks; 
d. ALT or AST > 8x ULN  
Volume depletion with Sotagliflozin:  
SGLT-2 inhibitors are associated with osmotic diuresis and volume depletion, which may 
lead to dizziness or hypotension, especially in the elderly. All patients will be advised to 
maintain proper fluid intake (200 mL/hour) and to consider increasing it if they sense 
greater thirst, increased urination, or if they feel dizzy or faint. 
In cases of clinically significant volume depletion, study drug may be temporarily 
discontinued until the event has resolved.  
Note: If serum creatinine increases by ≥30% above the baseline value during the study, 
the following assessments will be considered: volume status, diuretic dosage, 
discontinuing nonsteroidal anti-inflammatory drugs (NSAIDs), and other relevant testing 
including renal imaging techniques, as appropriate.  

 
 
 
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Patient Education: Participants will be given educational materials covering relevant 
medication and safety information including an introduction to SGLT-2 inhibitors, diabetic 
ketoacidosis, continuous ketone monitoring, and instructions for who to contact if high 
(>1.0 mmol/L) ketone levels are detected. Patient education materials will be provided via 
multiple mediums to respond to individual learning styles and preferences, including web-
based blog posts, audio podcasts, and videos. 
Emergency Card: Participants will be provided an emergency card stating that they are 
participating in a clinical trial and taking the drug sotagliflozin. The card will state that 
sotagliflozin may cause euglycemic ketoacidosis and provide the lead coordinator’s 
mobile phone number and email address. Participants will be instructed to show during 
an event and other interactions with health providers. 
 
Provisions to Protect the Privacy Interest of Subjects 
Participants will be assigned unique identifiers for study-related records. All precautions 
will be taken to ensure only authorized individuals access participant research records. 
The collection of sensitive information about participants will be limited to the minimum 
necessary to achieve the aims of the research, so that no unneeded sensitive 
information will be collected 
 
Early Withdrawal of Subjects 
Investigator Withdrawal of Subjects 
Participation in this study may be stopped at any time by the study PI without the 
participant’s consent because:  
• The study medical investigator thinks it is necessary for the subject’s health or 
safety. 
• Participants have not followed study instructions (non-compliance).  
• The AdventHealth Translational Research Institute has stopped the study.  
• Administrative reasons require the participants’ withdrawal.  
• After one  event of Diabetic Ketoacidosis (DKA). 
• ADA defined Level 3 Hypoglycemic Event. A severe hypoglycemic event 
characterized by altered mental or physical status requiring the assistance for 
treatment of hypoglycemia, irrespective of glucose level.  
• Possible evidence of drug-induced liver injury that meets one (or more) of the 
following criteria: 
o Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x 
upper limit of normal (ULN) with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain/tenderness, fever, rash, and/or 
eosinophilia (>5%) 
o ALT or AST > 3x ULN and total bilirubin > 2x ULN or INR > 1.5 
o ALT or AST > 5x ULN for more than 2 weeks 

 
 
 
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o ALT or AST > 8x ULN 
• Pregnancy. 
 
Subject Request for Withdrawal from Study 
Participation in this study is voluntary. Participants may decide not to participate in this 
study or may withdraw from this study at any time without penalty or loss of benefits. If a 
participant leaves the study before the final regularly scheduled visit, she/he may be 
asked by the study doctor to make a final visit for some ‘end-of–study’ procedures. This 
is to make sure that there are no safety concerns. 
Data Collection and Follow-up for Withdrawn Subjects 
Participants who request withdrawal or who are withdrawn by the PI from the study will 
have their data maintained in the research database up to the point of withdrawal. The 
available data will be included in subsequent analysis because keeping these 
participants in the analysis is essential for study validity. 
 
Adverse Events - Recording and Reporting 
Each participant will be evaluated for adverse events at every study visit and weekly via 
phone calls and/or text message consultations. Any event that is reported to the study 
staff will be documented as such and graded as to its attribution (unrelated to protocol, 
or, probably, or definitely related to protocol) and severity (mild, moderate, or severe). 
Any severe and/or unanticipated adverse event will be immediately reported to the IRB 
according to AdventHealth IRB guidelines.  
At each contact with the subject, the study team will seek information on adverse events 
by specific questioning and, as appropriate, by the Provider through examination. 
Information on all adverse events will be recorded immediately in the source document, 
also in the appropriate adverse event module of the case report form CRF. All clearly 
related signs, symptoms, and abnormal diagnostic procedures results will be recorded 
in the source document. All adverse and unexpected events will be reported according 
to AdventHealth IRB guidelines. 
Safety Monitoring Plan   
Safety Monitoring 
Adverse events (AEs) will be documented periodically during the study. AEs will be 
collected during study visits. Additionally, participants will be contacted weekly to inquire 
about AEs. AEs will be reported by the study coordinator, medical investigator, or other 
TRI staff. Research and safety data will be reviewed by the PI. This review will take 
place at regular meetings with the research coordinator and principal investigator. Other 

 
 
 
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items discussed will include progress or adverse events occurring in the following: 
participant confidentiality, participant recruitment, and consent process. TRI has a 
standing committee that meets monthly to review all adverse events in the clinical trials 
and will additionally be charged with review of the study. 
All adverse events (AEs) will have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention (de-
challenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory re-challenge procedure if 
necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and follows a clinically reasonable response on withdrawal (de-
challenge). Re-challenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to another 

 
 
 
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etiology. There must be an alternative, definitive etiology documented by the 
clinician. 
 
The study may be stopped for any of the following: 
• Grade 5 (death) in a subject likely related to the study intervention 
• At the discretion of the Medical Monitor/ Safety Committee after review of SAEs 
The Study may be paused (will be placed on enrollment hold; we will continue to f/u 
with enrolled patients) for any of the following:  
• Any death irrespective of attribution 
• A grade 4 SAE that is not unrelated to the study procedures 
• A grade 3 or above SAE in the first 3 subjects that is not unrelated to the study 
procedures 
• 3 grade 3 SAEs that are for the same SAE that are not unrelated to the study 
procedures 
• 2 grade 3 SAEs that are related or likely related to the procedure 
 
The DSMB will re-evaluate the study design to determine potential explanations for 
SAEs. Further decisions related to the trial will depend on the outcome of such 
investigations. 
If for any of the above reasons the study is paused or stopped (terminated), the IRB will 
be notified of these actions, and if the study resumes, they will be alerted prior. 
No interim statistical analysis is planned to assess the safety data during the study. 
However, regular monitoring of the study will be performed as mentioned in the ‘Study 
monitoring’ section below. 
Study monitoring: 
Study monitor(s) will be appointed to provide routine monitoring of study beginning of 
the review of the first subject enrolled and then periodically (for example approximately 
every 6 to 10 weeks during the recruitment period), schedule will be adjusted based on 
recruitment volume. The monitoring schedule after the end of recruitment period will be 
extended to 8 to 12 weeks for review of data elements until close out, if applicable. 
Some elements are monitored at 100% and others at a lower percentage based on 
criteria, such as total number of subjects enrolled, or screen failed. During the course of 
the study, if Serious and Non-Compliance is observed, the monitoring frequency will be 
adjusted to ensure compliance with approved protocol and applicable requirements. 
The monitor will meet with principal investigator and/or delegate at each of the 
monitoring visits to discuss study progress and any issues that might be observed. The 
Biostatistics Research Center will be in charge of monitoring the study. 
Monitoring will focus on evaluating the following processes to ensure patient safety, 
data quality and integrity are occurring throughout the life of the study until study close 
out. The first 1-2 subjects enrolled will be reviewed shortly after their first in-patient visit. 

 
 
 
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Access to EMR (electronic medical record), source documents (paper), EDC (Electronic 
Data Capture) system and regulatory documents are required to perform the following 
monitoring activities:  
➢ Informed consent process  
➢ Study Eligibility Criteria is met. . 
➢ Accurate abstraction of data from paper source information to EDC system  
o Source will be reviewed against data entered into the EDC system  
➢ Reporting of serious adverse events and protocol violations according to IRB policies and 
procedures 
➢ Procedures Assessment Review  
o  Insulin withdrawal challenge, imaging study, device usage and other protocol 
required procedures will be reviewed to ensure they were conducted as required 
per protocol and AE reported promptly if applicable.  
➢ Training Process  
o Documentation of protocol training documents  
o Research personnel and Delegation of Responsibility log review.  
➢ Regulatory Documentation  
o Review and verification of completed preparatory to research forms for all 
members which are involved in screening subjects.  
o IRB approvals are obtained, renewed and on file  
o IRB correspondence is filed  
o Deviations reported to the IRB and filed  
o All other applicable regulatory documentation will be reviewed as detailed in the 
table above  
➢  PI Oversight  
o Confirm PI/Sub-I and designee are reviewing Inclusion/Exclusion Criteria, SAEs 
and present and/or signing PI oversight study status meetings.  
 Each time on site or remote monitoring is conducted, the monitor will sign the 
monitoring site visit log, and a report will be generated by the monitor within 
approximately 10 days of site visit.  
➢ Monitoring Report  
• 
The monitoring report will consist of a summary of study observations along with 
significant findings, action items, subsequent requirements, and recommendations that 
are needed to ensure study is compliant with all rules and regulations as described in this 
report.  
➢ Monitor Responsibility  
• 
The monitor is tasked to ensure study is conducted, recorded, and reported as required 
by protocol, institutional policies and procedures and applicable regulatory bodies. 
Monitor is to communicate any concerns or issues at the time of the visit that might arise 
to the attention of the PI and/or designee, IRB, and any applicable regulatory bodies.  
• 
In the event a high error rate is noted, the monitor will escalate the incidence to the 
monitor’s leadership for consideration of monitoring additional subjects over what is 
outlined in this monitoring plan.  
• 
Any Serious and Continuing non-compliance will be reported to the Research Oversight 
Committee/DSMB and additional requirements may be required by PI and/or study team.  

 
 
 
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• 
Report will be completed within approximately 10 business Days of the visit. If it’s 
determined there would be a delay in the report completion the monitor will communicate 
any pressing issues via phone or email until the report is delivered.  
➢ Dissemination of report  
• 
The monitoring report will be sent via email to the following parties:  
o Principal Investigators  
o Sub-Investigators  
o Study Coordinator 
o Regulatory Manager  
o Team Manager/Director  
➢ Site Responsibilities  
• 
The site is expected to promptly review monitoring reports, work on significant findings 
or discrepancies till resolution.  
• 
 Action items must be completed by the specified due date on the monitoring report.  
• 
If any findings require IRB reporting, it’s expected that site will report these findings in an 
“Promptly Reportable Information” form to the IRB promptly as required by the IRB of 
record and any applicable regulatory bodies.  
• 
Promptly notify Regulatory team and the monitor of any reportable new information, 
deviations, enrollment activities and all inspections.  
• 
Submit all monitoring reports to the IRB. 
 
 
Data and Safety Monitoring Board (DSMB) or Equivalent 
Since the project has more than minimal risk and plans to enroll participants with a wide 
age range including the elderly, the NIDDK Program Official(s) will appoint an 
independent Data and Safety Monitoring Board (DSMB) according to NIDDK 
requirements. The board will review compiled safety data, study progress, and interim 
results at periodic intervals. The DSMB will be comprised of conflict-free independent 
experts. The NIDDK Program Official will serve as the Executive Secretary and/or 
NIDDK program representative on the DSMB. 
The DSMB will consist of members with the following range of qualifications: 
1.  A physician with particular expertise in type 1 diabetes 
2.  A physician who can lead the effort in monitoring the overall event rate of  
     various adverse events (AE) and serious adverse events (SAE), as well as 
     balance between intervention groups 
3.  A physician who can lead the effort in monitoring the safety of insulin 
     withdrawal test 
4.  A person with T1D with a medical background (nurse, nutritionist, diabetes  
     educator, etc.) 
5.  An external statistician who can monitor data collection, critique analysis 
plans, request additional data analysis, and provide an interpretation of results     
the DSMB 

 
 
 
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This DSMB will meet quarterly, unless enrollment numbers do not warrant a meeting. 
The study team will provide semiannual data and safety monitoring reports to the NIH 
for electronic review. 
 
Ethical Considerations 
Participation in this study is voluntary. Subjects may decide not to participate in this 
study or may withdraw from this study at any time without penalty or loss of benefits. No 
vulnerable populations will be studied in this protocol. 
Sharing of Results with Subjects:  
Participants will be offered the opportunity to meet with the Principal Investigator or 
designated medical staff to review the results of their lab assessments or other standard 
clinical data. Copies of their testing results will be made available to the participants 
upon request. In addition, the Principal Investigator or designated study staff will provide 
an overview of the study's outcome to the participant if he or she requests the 
information. 
Funding Source 
This study is supported by the National Institutes of Health, National Institute of 
Diabetes and Digestive and Kidney Diseases 1U01DK143384 - 01.  
 
Subject Stipends or Payments 
Participants may receive up to $1850.00 for completion of all procedures.  
 
Participant compensation will occur as follows: 
• A reloadable Payment Card will be provided to receive payments for the study. 
The terms and Conditions for this card will be provided to the participant for 
review. 
• Payment will be requested within 3 business days from completion of the 
following study visit(s) or task completion; Screening visit, Period 1 (Visit 1 & Visit 
2), Period 2 (Visit 3), Education (Visits 4 – Visit 7), and completing all ASA 24 
forms. 
• If participant is unable to complete all study visits or it is determined by the study 
doctor or sponsor that you should stop the study early, the stipends will be 
prorated to the following:    
   
Visit   
Prorated amount   
Screening visit  
$ 50.00 
Period 1 (Visit 1 & Visit 2) 
$ 250.00 
Period 2 (Visit 3) 
$ 250.00 
Visit 4 – Visit 7 (Education) 
$1200.00 
Completing all ASA 24 forms 
$ 100.00 

 
 
 
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Total for all completed visits   
$1850.00 
   
Publication Plan 
We attest that the AH-TRI faculty and staff will adhere to POLICY-TRI-ADM-005 
(Access to Clinical Trial Data for Publication Purposes). Assignment of authorship and 
the contributions of each author will be determined by the International Committee of 
Medical Journal Editors (ICMJE) policy to guide authorship.  
 
References 
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2. Taylor SI, Yazdi ZS, Beitelshees AL. Pharmacological treatment of hyperglycemia in type 
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PMCID: PMC7810496. 
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