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

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05541484
• Other study ID #: 202206078
• Status: Recruiting
• Phase: Phase 4
• Start date: October 14, 2022
• Est. completion date: August 2024

Study information

• Verified date: December 2023
• Source: Washington University School of Medicine
• Contact: Janet B McGill, MD
• Phone: 314-362-8681
• Email: jmcgill[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: August 2024
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1

Intervention

Drug:
• SGLT2 inhibitor
See above.

Device:
• Biosense Breath Ketone Analyzer
The hand-held device tests ketones in exhaled breath

Locations

Country	Name	City	State
United States	Washington University	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	Juvenile Diabetes Research Foundation

Country where clinical trial is conducted

United States, 

References & Publications (11)

Dandona P, Mathieu C, Phillip M, Hansen L, Griffen SC, Tschope D, Thoren F, Xu J, Langkilde AM; DEPICT-1 Investigators. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):864-876. doi: 10.1016/S2213-8587(17)30308-X. Epub 2017 Sep 14. Erratum In: Lancet Diabetes Endocrinol. 2017 Dec;5(12 ):e8. — View Citation

Garg SK, Peters AL, Buse JB, Danne T. Strategy for Mitigating DKA Risk in Patients with Type 1 Diabetes on Adjunctive Treatment with SGLT Inhibitors: A STICH Protocol. Diabetes Technol Ther. 2018 Sep;20(9):571-575. doi: 10.1089/dia.2018.0246. Epub 2018 Aug 21. No abstract available. — View Citation

Hancock G, Sharma S, Galpin M, Lunn D, Megson C, Peverall R, Richmond G, Ritchie GAD, Owen KR. The correlation between breath acetone and blood betahydroxybutyrate in individuals with type 1 diabetes. J Breath Res. 2020 Oct 29;15(1):017101. doi: 10.1088/1752-7163/abbf37. — View Citation

Herring RA, Shojaee-Moradie F, Garesse R, Stevenage M, Jackson N, Fielding BA, Mendis A, Johnsen S, Umpleby AM, Davies M, Russell-Jones DL. Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes. Diabetes Care. 2020 Sep;43(9):2128-2136. doi: 10.2337/dc19-2579. Epub 2020 Jul 8. — View Citation

Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999 Nov-Dec;15(6):412-26. doi: 10.1002/(sici)1520-7560(199911/12)15:63.0.co;2-8. — View Citation

Mathieu C, Dandona P, Gillard P, Senior P, Hasslacher C, Araki E, Lind M, Bain SC, Jabbour S, Arya N, Hansen L, Thoren F, Langkilde AM; DEPICT-2 Investigators. Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial. Diabetes Care. 2018 Sep;41(9):1938-1946. doi: 10.2337/dc18-0623. Epub 2018 Jul 19. — View Citation

Owen OE, Trapp VE, Skutches CL, Mozzoli MA, Hoeldtke RD, Boden G, Reichard GA Jr. Acetone metabolism during diabetic ketoacidosis. Diabetes. 1982 Mar;31(3):242-8. doi: 10.2337/diab.31.3.242. — View Citation

Patel NS, Van Name MA, Cengiz E, Carria LR, Weinzimer SA, Tamborlane WV, Sherr JL. Altered Patterns of Early Metabolic Decompensation in Type 1 Diabetes During Treatment with a SGLT2 Inhibitor: An Insulin Pump Suspension Study. Diabetes Technol Ther. 2017 Nov;19(11):618-622. doi: 10.1089/dia.2017.0267. Epub 2017 Oct 25. — View Citation

Rydosz A. A Negative Correlation Between Blood Glucose and Acetone Measured in Healthy and Type 1 Diabetes Mellitus Patient Breath. J Diabetes Sci Technol. 2015 Jul;9(4):881-4. doi: 10.1177/1932296815572366. Epub 2015 Feb 17. — View Citation

Spanel P, Dryahina K, Rejskova A, Chippendale TW, Smith D. Breath acetone concentration; biological variability and the influence of diet. Physiol Meas. 2011 Aug;32(8):N23-31. doi: 10.1088/0967-3334/32/8/N01. Epub 2011 Jul 1. — View Citation

Suntrup Iii DJ, Ratto TV, Ratto M, McCarter JP. Characterization of a high-resolution breath acetone meter for ketosis monitoring. PeerJ. 2020 Sep 24;8:e9969. doi: 10.7717/peerj.9969. eCollection 2020. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ketone levels in persons with T1D undergoing insulin withdrawal	Comparison of ketone levels (BOHB and BrAce) during insulin withdrawal after usual care and during insulin withdrawal after usual care plus treatment with an SGLT2i.	2 days
Primary	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	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