Ketone Monitoring in T1D: Effect of SGLT2i During Usual Care and With Insulin Deficiency

Study Overview
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Brief Summary
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This proposed study will test whether measurement of breath acetone (BrAce) can be used for the purpose of identifying ketosis (elevated ketones) in persons with type 1 diabetes (T1D). This is important for the potential use of sodium glucose co-transport inhibitors (SGLT2i) in persons with T1D.

Detailed Description
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The study will consist of 4 distinct segments that include routine testing of ketones during usual care, during insulin deficiency, and while taking a SGLT2i in addition to usual care, then with insulin deficiency after the SGLT2i has reached steady state and ingested that morning. We will study 20 adults with T1D who are using Dexcom G6 continuous glucose monitor (CGM), plus any form of insulin delivery. Study participants will be randomized to Group A or Group B. Simultaneous ketone monitoring using a the Biosense® breath ketone analyzer (BKA) and capillary blood beta hydroxybutyrate (BOHB) measurement will be done 2-3 times daily for 2 weeks during each of the outpatient segments. This will generate >800 data points comparing breath acetone, measured in units called ACEs, versus capillary blood BOHB measurements for each 2 week period. On days of insulin withdrawal, which will take place on the Washington University Intensive Research Unit (IRU), frequent monitoring with capillary blood measurements of BOHB (Precision Xtra®, Abbott) will be compared with breath BrAce measurements (Biosense®, Readout) and laboratory measurements of BOHB and acetoacetate. Electrolytes and glucose will also be measured.

Official Title
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Ketone Monitoring in T1D: Effect of SGLT2i During Usual Care and With Insulin Deficiency

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: SGLT2 inhibitor
* Device: Biosense Breath Ketone Analyzer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes for >1 year Age 18 - 75, any gender, race or ethnicity HbA1c <10% Stable insulin delivery method for the past 30 days Vision of 20/40 or better, including ability to read all device instructions and insulin pump settings Use of an insulin pump and ability to make adjustments to pump settings Insulin delivery by MDI with basal insulin (glargine U100) given in the morning OR willingness to transition to basal glargine given in the morning for at least 48 hours prior to insulin withdrawal visits Use of personal CGM, only Dexcom G6 will be permitted for data consistency Use of cellular phone (iOS11 and above or Android) with data capability with connectivity to Dexcom Clarity app and Biosense Ketone Monitoring app Willing to share CGM, capillary ketone results and BrACE data with the study group Able to understand the study requirements, risks and benefits and able to provide written informed consent Able to schedule the visits and perform study related tasks Exclusion Criteria: History of DKA in the past 6 months, or more than 1 episode of DKA in the past 2 years Use of insulin degludec, insulin glargine U300 or insulin detemir as basal insulin and unwilling to transition to glargine given in the morning for at least 48 hours before the insulin withdrawal visits Use of an SGLT2i in the past 30 days or intolerance to SGLT2i use in the past for any reason Unstable heart disease, including hospitalization for any cardiac or vascular event in the past 6 months. eGFR <30 ml/min/1.73m2 or hemoglobin <11.0 g/dL measured in the past year Cancer that has been under treatment in the past 6 months, or treatment is likely in the 3 months after signing the consent, not including skin cancer or cancers under long-term hormonal reduction treatment (breast or prostate, no other active treatment) Psychiatric condition that interferes with daily activities or diabetes self-care, including substance abuse Any illness or condition that may interfere with study measurements, or contraindications for use of SGLT2i, based on investigator discretion (hemoglobinopathy, orthostatic hypotension) Unwilling to avoid alcohol during the active study periods, specifically to avoid alcohol for 4 hours prior to any breath ketone measurement Currently following or planning to adopt a diet that is low in carbohydrates (defined as <90 grams of carbohydrate per day) or is expected to be ketogenic Use of oral or injected corticosteroids within the past 30 days or planned during the study period Taking disulfiram (due to interference with breath ketone measurements) History of vomiting episodes for any reason in the past 30 days, or hospitalization for cyclic vomiting in the past year History of urinary tract infection in the past 3 months Pregnancy, breast-feeding or intention of becoming pregnant during the study time period and up to 30 days after study completion Pre-menopausal women not using acceptable birth control defined as abstinence, surgical sterilization, hysterectomy, hormonal contraception, IUD or proven effective barrier methods

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will test the breath ketone analyzer under usual care conditions followed by usual care plus SGLT2i treatment (GROUP A) or with usual care plus SGLT2i treatment followed by usual care (GROUP B). At the end of each segment, participants will undergo a one-day insulin withdrawal period with more intense monitoring.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group A: Usual care followed by usual care plus dapagliflozin<br>10 persons with T1D will check capillary beta hydroxybutyrate (BOHB) and concomitant breath acetone (BrAce) 2 - 3 times daily for 2 weeks during usual care, then undergo an insulin withdrawal visit. Subsequently, the Group A patients will repeat the paired measurements of BOHB and BrAce, 2 - 3 times daily for 2 weeks during usual care plus treatment with the SGLT2i dapagliflozin, 10 mg taken orally daily, followed by an insulin withdrawal visit. | Drug: SGLT2 inhibitor<br>* See above.<br>* Other names: Dapagliflozin 10mg (Farxiga);Device: Biosense Breath Ketone Analyzer<br>* The hand-held device tests ketones in exhaled breath<br>|
| Other: Group B: Usual care plus dapagliflozin followed by usual care<br>10 persons with T1D will check capillary beta hydroxybutyrate (BOHB) and concomitant breath acetone (BrAce) 2 - 3 times daily for 2 weeks during usual care plus treatment with the SGLT2i dapagliflozin, 10 mg taken orally daily, then undergo an insulin withdrawal visit. Subsequently, the Group B patients will repeat the paired measurements of BOHB and BrAce, 2 - 3 times daily during usual care alone followed by an insulin withdrawal visit. | Drug: SGLT2 inhibitor<br>* See above.<br>* Other names: Dapagliflozin 10mg (Farxiga);Device: Biosense Breath Ketone Analyzer<br>* The hand-held device tests ketones in exhaled breath<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ketone levels measured in blood and breath in persons with T1D in persons with T1D | Correlation of capillary beta hydroxybutyrate measurements with breath ketone measurements. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ketone levels in persons with T1D during usual care versus usual care plus SGLT2i treatment | Comparison of ketone levels (BOHB and BrAce) during usual care and usual care plus treatment with an SGLT2i. | 2 weeks each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ketosis, beta hydroxybutyrate, sodium glucose co-transport inhibitor, breath ketone