Effectiveness of Empagliflozin Added to Automated Insulin Delivery (AID) Systems in Adults With Type 1 Diabetes With Sub-optimal Glycemic Outcomes

Study Overview
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Brief Summary
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The goal of this 26-week multicenter, randomized, parallel, placebo-controlled trial is to test the effectiveness of empagliflozin use in conjunction with automated insulin delivery (AID) to improve glucose control in individuals with type 1 diabetes who do not meet target recommendations for time in range (3.9-10.0 mmol/L). The main question it aims to answer is: - Will use of empagliflozin (2.5 mg/day) increase time spent in the target range of 3.9 to 10.0 mmol/L compared to placebo for individuals on an AID system who do not meet glycemic targets? Participants will either take 2.5 mg of empagliflozin or a placebo daily for 26 weeks while remaining on their current AID system.

Official Title
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Effectiveness of Empagliflozin Added to Automated Insulin Delivery (AID) Systems in Adults With Type 1 Diabetes With Sub-optimal Glycemic Outcomes: a Randomized Controlled Parallel Trial

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals ≥ 18 years of age. A clinical diagnosis of type 1 diabetes for at least one year, as per the investigators' clinical judgment (confirmatory C-peptide and antibodies will not be required). Minimum 3-month use of a commercial advanced AID system. Time in range (3.9 to 10.0 mmol/L) < 70% on their personal AID system in the 30 days prior to screening (with minimum 70% time spent in closed-loop mode). Agreement to use a highly effective method of birth control for individuals of child-bearing age and active avoidance of pregnancy during the trial. Child-bearing potential refers to participants of the female sex post-menarche who have not reached menopause and who do not have a disclosed medical condition causing sterility (ex: hysterectomy). Post-menopausal state refers to the absence of menses for 12 months without any alternative cause. Exclusion Criteria: Current or ≤ 2 week use of any anti-hyperglycemic agent other than insulin (such as SGTL2i). Current or ≤ 1 month use of Glucagon-like Peptide 1 (GLP1)-Receptor Agonists. Current or ≤ 1 month use of supraphysiological doses of oral or intravenous glucocorticoids. Planned or ongoing very low carbohydrate diet (< 50g/day). Glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as per CKD-EPI formula with creatinine levels measured within the last 12 months. Use of hydroxyurea. Planned or ongoing pregnancy. Breastfeeding. Ongoing active risk of recurrent genito-urinary infections, as per the clinical judgement of the investigators. Severe hypoglycemic episode within 1 month of screening, defined as an event resulting in seizure, loss of consciousness, or need to present to the emergency department. Diabetic ketoacidosis within 6 months of screening, defined as an event requiring the need to present to medical attention and administration of intravenous insulin. Any serious medical illness likely to interfere with the ability to complete the trial per the judgment of the investigators. Clinically significant retinopathy as judged by the investigator. Recent (< 3 months) acute macrovascular event (ex: acute coronary syndrome or cardiac surgery). Prior serious reaction to SGLT2i. Use of the Medtronic 670G or 770G system in the last 30 days. In the opinion of the investigator, inability to observe the contraindications of the study drugs, or failure to comply to the study protocol or research team's recommendations (e.g., changing pump parameters, ketone measurements).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin 2.5 mg daily<br>Empagliflozin is a sodium/glucose cotransporter 2 inhibitor (SGLT2i) that inhibits glucose reabsorption in the kidney. In this study, a capsule of empagliflozin 2.5 mg will be taken daily in conjunction with the participant's personal automated insulin delivery system for 26 weeks. | Drug: Empagliflozin<br>* 26-week use of automated insulin delivery system with empagliflozin (2.5 mg daily) in individuals with suboptimal time in range.<br>|
| Active Comparator: Placebo<br>As a control, a placebo capsule will be taken daily in conjunction with the participant's personal automated insulin delivery system for 26 weeks. | Drug: Placebo<br>* 26-week use of automated insulin delivery system with placebo (daily) in individuals with suboptimal time in range.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time of glucose levels spent in the target range (empagliflozin vs placebo) | Target range is defined to be between 3.9 and 10.0 mmol/L of placebo on an automated insulin delivery system vs empagliflozin (2.5 mg) on an automated insulin delivery system. Percent measured as per continuous glucose monitor (CGM) data. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time spent in the glucose range between 3.9 and 7.8 mmol/L | Percent as per CGM data | 4 weeks | 
| Percentage of time spent in the glucose range below 3.9 mmol/L and 3.0 mmol/L | Percent as per CGM data | 4 weeks | 
| Percentage of time spent in the glucose range above 10.0 mmol/L and 13.9 mmol/L | Percent as per CGM data | 4 weeks | 
| Mean glucose levels | Defined as per CGM data, in mmol/L | 4 weeks | 
| Standard deviation of glucose levels | Defined as per CGM data, in mmol/L | 4 weeks | 
| Coefficient of variance of glucose levels | Percent as per CGM data | 4 weeks | 
| Total insulin delivery (overall, basal, and bolus) | Defined as per participant's pump data | 4 weeks | 
| Mean daily carbohydrate intake | Defined as per participant's pump data | 4 weeks | 
| HbA1c | Percent as per blood test | 26 weeks | 
| Estimated glomerular filtration rate (eGFR) | mL/min/1.73 m^2 as per blood test | 26 weeks | 
| Lipid profile | Includes measurements in mmol/L as per blood test: total cholesterol, triglycerides, HDL-C, LDL-C, nonHDL-C | 26 weeks | 
| Brain Natriuretic Peptide (NT-pro-BNP) | ng/L as per blood test | 26 weeks | 
| Liver profile - bilirubin | umol/L as per blood test | 26 weeks | 
| Liver profile - alanine transaminase (ALT) and alkaline phosphatase (ALP) | U/L as per blood test | 26 weeks | 
| Measurement of body mass: weight and height | Body measurement as described (weight in kilograms and height in meters). Weight and height will be combined to report body mass index in kg/m^2. | 26 weeks | 
| Waist and hip circumference, and waist-to-hip ratio | Body measurements as described (waist and hip circumference in centimeters). Waist and hip cirumference will be combined to report waist-to-hip ratio. | 26 weeks | 
| Heart rate | Body measurement as described (beats per minutes) | 26 weeks | 
| Blood pressure | Body measurement as described (diastolic and systolic pressure; mmHg) | 26 weeks | 
| Average scores between interventions based on Type 1 Diabetes Distress Scale Questionnaire | Self-report scale (1 min = not a problem to 6 max = a very serious problem) that assesses a participant's distress surrounding their diabetes with higher scores correlating to higher distress. | 26 weeks | 
| Average scores between interventions based on Hypoglycemic Fear Survey - II | Likert scale (1 min to 5 max) that assesses a participant's worry surrounding hypoglycemia with higher scores indicating increased fear of hypoglycemia. | 26 weeks | 
| Average scores between interventions based on Diabetes Treatment Satisfaction Questionnaire | Self-report scale (0 min = very dissatisfied to 6 max = very satisfied) that assesses a participant's satisfaction surrounding the treatment for their diabetes with higher scores indicating greater satisfaction with treatment. | 26 weeks | 
| Fasting ketone levels | As per ketone test strip and meter; measured by participant | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, empagliflozin, 26-week