Reducing Risk of Diabetic Ketoacidosis in Type 1 Diabetes and Kidney Disease Using Continuous Ketone Monitoring

Официальное название

Mitigating Diabetic Ketoacidosis in People With T1D and Chronic Kidney Disease on an SGLT1&2 Inhibitor: Ketosis Risk Factor Determination and Incorporation Into an Enhanced Glucose Ketone Report

Обзор

The goal of this clinical trial is to develop and evaluate a novel diabetes ketoacidosis risk mitigation strategy to support the safe use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) therapy in participants with type 1 diabetes (T1D) and mild to moderate chronic kidney disease (CKD). The main objectives of this study are to: 1. Evaluate how ketone metrics differ between participants with mild to moderate chronic kidney disease and those with normal renal function in three time periods. 2. Identify potentially modifiable ketosis risk factors. 3. Use continuous glucose monitoring (CGM) and continuous ketone monitoring (CKM) data prior to and following treatment to determine ketosis risk factors and gain knowledge to further refine reporting of risk factors. 4. Gather information on how participants and clinicians like and use the CGM/CKM reports. Participants will be asked to: * Meet with study investigators to determine if they are eligible * Sign written informed consent * Take a pregnancy test, if applicable * Have blood taken to assess kidney function and hemoglobin A1c * Take the study medication, following the study team instructions * Wear the study provided sensor throughout participation. * Complete 5 in person visits, and 11 phone check ins over a nine-month period * Provide feedback on the usefulness of CGM/CKM reports

Подробное описание

It is estimated that 1.8 million people in the U.S. have type 1 diabetes (T1D) and of these, at least 20% have chronic kidney disease (CKD). Sodium-glucose cotransporter inhibitors (SGLT2i) and similar medications improve glycemic control and are cardioprotective and kidney protective. However, in trials of SGLT2i as an adjunct to insulin in patients with T1D, potential benefits were not fully realized due to increased incidence of diabetic ketoacidosis (DKA). Future approval of SGLT2i for T1D will depend on a more comprehensive understanding of ketosis risks and feasible strategies for prevention of DKA. Use of continuous ketone monitoring (CKM) may allow for the safe use of SGLT2i in patients with T1D, but patient use of the ketone data in real-time and patient and provider use of a retrospective combined CGM/CKM report will both be critical components of how CKM data may help facilitate the safe use of SGLT2i therapy to improve health outcomes.

The overall goals of this study are to develop and evaluate a novel DKA risk mitigation strategy to support the safe use of SGLT2i therapy in patients with T1D. The investigators propose studying SGLT2i medications with a focus on patients with T1D and mild to moderate CKD; this group is the most likely to benefit from the SGLT2i kidney protective effects and, once approved for use in T1D, patients at risk for kidney disease may be prioritized for treatment with SGLT2i therapy. The DKA risk mitigation strategy will leverage early detection of risk for DKA through CKM technology and our team's expertise in developing and implementing standardized, comprehensive, and clinically relevant reports for CGM data. The combined CGM/CKM report, in addition to continuous glucose and ketone data, will incorporate patient data on potentially modifiable ketosis risk factors. The CGM/CKM report will be refined taking into account the preferences of patients and providers, ensuring an accessible and interpretable user interface and supporting sustained behavior changes to prevent episodes of ketosis and to ensure that when episodes of ketosis do occur, they do not progress to DKA. This study builds on our extensive clinical and research expertise in diabetes care, qualitative and quantitative analyses, and leadership in optimization of CGM reports to improve glycemic control and long-term clinical outcomes while preventing DKA in patients with T1D and CKD progression.

The medication to be used in this study is sotagliflozin, a combination SGLT 1 and 2 inhibitor manufactured by Lexicon Pharmaceuticals (The Woodlands, TX). The medication is approved by FDA in the United States as treatment for heart failure, including for those with T2D. Sotagliflozin is administered orally in the outpatient setting. It has also been approved in Europe by the European Medicines Agency as an adjunct to insulin therapy to improve glycemic control in adults with T1D with a BMI \>27 kg/m2, who have not achieved adequate glycemic control despite optimal insulin therapy. The drug is sold in the United States as Zynquista and is currently available for prescription use through regular pharmacy channels. The decision to increase sotagliflozin dose will be a shared decision between the study subject and the study investigators.

The study device used is the combined continuous glucose and ketone monitor (CGKM) manufactured by Abbott Diabetes (Chicago, IL). The device uses a sensor placed subcutaneously to measure interstitial fluid levels of glucose and BHB every 1 minute and via the attached transmitter on the skin surface, transmit the data to a receiver (or smartphone application). The device is currently pending FDA approval; investigators will ensure the device is FDA approved prior to beginning any study-related activities.

Patients will receive real-time alerts from the device at the manufacturer's programed ketone thresholds (to be determined per the commercially available CKM device). Patients will also be educated on proper identification and management of acute ketonemia, including how to use the data from the CKM in real-time to recognize and treat ketone levels as soon as they arise. This will be based on our own internal standing orders for "Adult Diabetes Management: Hyperglycemia and Ketoacidosis" which is based upon the ADA guidance for hyperglycemia management as well as informed by the STOP protocol to guide CHO intake along with appropriate insulin dosing. This standing order will provide guidance for fluids, insulin, and CHO intake based on the glucose and ketone levels, and factor into account presence and severity of symptoms in when to recommend seeking care in an emergency department. The CKM will have novel trend arrows about ketosis which will also be incorporated into the real-time ketone management guidance (e.g. increase insulin bolus 10% if trend arrows are pointing up). Patients will be provided with detailed instructions as well as a paper wallet card to always carry with them.

Вмешательства

• Препарат Sotagliflozin initiation
  All patients will be started on sotagliflozin at a dose of 200mg/d. After 3 months of sotagliflozin 200 mg/d, patients who do not achieve good glycemic control (TIR \>60%) and who have moderate or no CKD (eGFR \>60) will be offered the option to increase sotagliflozin to 400mg/d. The decision to increase sotagliflozin dose will be a shared decision between the study subject and the study investigators. All other participants will continue taking 200 mg sotagliflozin daily. After completing all s

Первичные конечные точки

• Change in % time in ketone range >1.5/mmol/L [Срок оценки: Baseline 3 months to 3 months following sotagliflozin initiation]
• Number of episodes of diabetic ketoacidosis [Срок оценки: 3 months following sotagliflozin initiation]

Вторичные конечные точки (10)

• Change in mean ketone level [Срок оценки: Baseline 3 months to 3 months following sotagliflozin initiation]
• Highest ketone level observed [Срок оценки: 3 months following sotagliflozin initiation]
• Number of episodes of ketosis with >=15 minutes at >1.5 mmol/L [Срок оценки: 3 months following sotagliflozin initiation]
• Number of prolonged episodes of ketosis with >=120 minutes at >1.5 mmol/L [Срок оценки: 3 months following sotagliflozin initiation]
• Change in % time in ketone range >=3.0/mmol/L [Срок оценки: Baseline 3 months to 3 months following sotagliflozin initiation]
• Change in mean ketone level [Срок оценки: Baseline 3 months to 3 months following sotagliflozin titration]
• Highest ketone level observed [Срок оценки: 3 months following sotagliflozin titration]
• Number of episodes of ketosis with >=15 minutes at >1.5 mmol/L [Срок оценки: 3 months following sotagliflozin titration]
• Number of prolonged episodes of ketosis with >=120 minutes at >1.5 mmol/L [Срок оценки: 3 months following sotagliflozin titration]
• Change in % time in ketone range >=3.0/mmol/L [Срок оценки: Baseline 3 months to 3 months following sotagliflozin titration]

Критерии участия

Критерии включения

• Provision of signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Males and females; Ages 18-75.
• Diagnosis of type 1 diabetes, based on a clinical diagnosis with onset at least 3 months prior to screening.
• Using an automated insulin delivery system (AID) or multiple daily injections (MDI), (defined by use of rapid analogue with meals and approved long-acting analogue (e.g. detemir or glargine)).
• Most recent eGFR ≥30 (and within prior 12 months).
• HbA1c <10%. 8) Have had ≥1 primary or specialty ambulatory visit(s) in the past year in the HealthPartners care system.
• Have never been prescribed SGLT2i medications.
• Must be willing and able to wear a CGM/CKM device and willing to follow the study protocol.
• Must be able to read and speak English.
• Use of adequate contraception for the duration of the study be the women of childbearing potential.
• Access to necessary resources for participating in a technology-based intervention (i.e., computer, smartphone, internet access).

Критерии исключения

• Pregnancy, lactation, planning to become pregnant or unwillingness to be on contraception during the trial.
• Any form of diabetes other than T1D.
• Any history of use of sodium-glucose cotransporter inhibitors and use of other non-insulin glucose lowering medication within the last 6 months.
• Chronic systemic corticosteroids (>4 consecutive weeks) within 6 months before screening or planned use during the study period.
• History of diabetic ketoacidosis within 3 months of screening or 2 or more episodes of DKA within the last year.
• History of multiple (≥ 3 infections) genital mycotic infections within 6 months of screening.
• Hypotension at screening as defined as, systolic blood pressure < 90 and diastolic blood pressure < 60 with symptoms of low blood pressure (confusion, dizziness, lightheadedness, fainting, heart palpitations).
• History of a level 3 hypoglycemic event (as defined by ADA criteria) within 3 months of screening.
• Recent myocardial infarction, stroke, hospitalization for unstable angina or heart failure within 3 months prior to screening.
• New York Heart Association Class IV heart failure.
• CKD-EPI estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2.
• 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).
• Active Hepatitis B or C, or tuberculosis.
• 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.
• History of severe acquired immune deficiency syndrome or human immunodeficiency virus (HIV) infection or severely immunocompromised status, in the opinion of the investigator, including, but not limited to patients who have undergone organ or bone marrow transplantation. HIV positive patients who are on stable immunosuppressive therapy and have undetectable viral load may be eligible for inclusion in the study, subject to the investigator's discretion.
• Current or past history of decompensated cirrhosis (defined as variceal bleeding, ascites or hepatic encephalopathy), and/or known diagnosis of cirrhosis.
• 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.
• History of kidney transplant.
• CKD from a known cause other than T1D.
• A diagnosed eating disorder.
• BMI <22.
• Adherence to a very low CHO or ketogenic diet.
• A foot amputation.
• Non-healing wounds of extremities.
• Inability to perform the study follow up/ unwilling to wear the investigational device.
• 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.
• Participation in another treatment or intervention study within the past six weeks.
• Any condition or factor that would compromise the participant's safety or conduct of the study (for example: cognitive impairment, bipolar disorder, or eating disorder) or any other reason the PI deems that the patient should not be included.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Поддерживающая терапия

Центры проведения

США · 1 центр

• International Diabetes Center — Minneapolis

Публикации

• Bergenstal RM. Continuous glucose monitoring: transforming diabetes management step by step. Lancet. 2018 Apr 7;391(10128):1334-1336. doi: 10.1016/S0140-6736(18)30290-3. Epub 2018 Feb 16. No abstract available. PMID 29459022
• Maines E, Pertile R, Cauvin V, Soffiati M, Franceschi R. Glucose metrics improvement in youths with type 1 diabetes using the Ambulatory Glucose Profile report: A real-world study. Diabetes Res Clin Pract. 2024 Jun;212:111720. doi: 10.1016/j.diabres.2024.111720. Epub 2024 May 24. PMID 38797262
• Huang J, Yeung AM, Bergenstal RM, Castorino K, Cengiz E, Dhatariya K, Niu I, Sherr JL, Umpierrez GE, Klonoff DC. Update on Measuring Ketones. J Diabetes Sci Technol. 2024 May;18(3):714-726. doi: 10.1177/19322968231152236. Epub 2023 Feb 16. PMID 36794812
• Goldenberg RM, Gilbert JD, Hramiak IM, Woo VC, Zinman B. Sodium-glucose co-transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol. Diabetes Obes Metab. 2019 Oct;21(10):2192-2202. doi: 10.1111/dom.13811. Epub 2019 Jun 30. PMID 31183975
• 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. PMID 30129772
• Chow E, Clement S, Garg R. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Res Care. 2023 Oct;11(5):e003666. doi: 10.1136/bmjdrc-2023-003666. PMID 37797963
• Wolfsdorf JI, Ratner RE. SGLT Inhibitors for Type 1 Diabetes: Proceed With Extreme Caution. Diabetes Care. 2019 Jun;42(6):991-993. doi: 10.2337/dci19-0008. No abstract available. PMID 31110116
• Ramphul K, Joynauth J. An Update on the Incidence and Burden of Diabetic Ketoacidosis in the U.S. Diabetes Care. 2020 Dec;43(12):e196-e197. doi: 10.2337/dc20-1258. Epub 2020 Oct 13. No abstract available. PMID 33051332

Идентификаторы

NCT: NCT07325201 · 24-153 · 1U01DK143379

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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