A Clinical Trial to Evaluate The Effects of Semaglutide and Empagliflozin Combined to Automated Insulin Delivery on Diabetes Control in Adults Living With Type 1 Diabetes

This study is designed as a 2x2 factorial, randomized, placebo-controlled, double-blind, crossover trial to investigate the effects of semaglutide and empagliflozin, individually and combined, on time-in-range (TIR) in adults with type 1 diabetes (T1D) using automated insulin delivery (AID) systems.

• Study Design and Randomization:

Factorial Design: The 2x2 factorial design allows for the simultaneous assessment of two interventions (semaglutide and empagliflozin) and their interaction. This design efficiently explores the individual and combined effects of the drugs. Randomization: Participants will be randomized in a 1:1 ratio to determine the order of the semaglutide and placebo injections (Arm A: semaglutide first, Arm B: placebo first). Within each arm, the order of empagliflozin and placebo tablets will also be randomized 1:1. This ensures that any potential carryover effects are minimized. Double-Blind: Both participants and investigators will be blinded to the treatment assignments, minimizing bias in data collection and analysis. Crossover Design: Each participant will receive all four treatment combinations (semaglutide + empagliflozin, semaglutide + placebo, placebo + empagliflozin, placebo + placebo), allowing for within-subject comparisons and reducing inter-individual variability.

• Study Procedures:

Screening and Baseline: Participants will undergo a screening visit to confirm eligibility criteria. Baseline characteristics, including demographic data, medical history, and current diabetes management, will be collected. Titration Period (Semaglutide): A 12-week titration period for semaglutide will be implemented to achieve a stable dose and minimize gastrointestinal side effects. This gradual dose escalation will follow standard clinical practice. Intervention Periods (Four Weeks Each): Each participant will undergo four four-week intervention periods, representing the four treatment combinations. During each intervention period, participants will continue to use their AID system.

Participants will receive daily injections (semaglutide or placebo) and daily tablets (empagliflozin or placebo) according to the randomization schedule. Washout Periods: A two to four-week washout period will be implemented between the semaglutide/placebo arms to eliminate any carryover effects of semaglutide. A one to seven-day washout period will be implemented between the empagliflozin/placebo tablet administrations. This short period is considered sufficient for the elimination of empagliflozin. CGM Data Collection:

Continuous glucose monitoring (CGM) data will be collected throughout the study, with a focus on the four-week intervention periods. CGM data will be used to calculate the primary outcome (TIR) and secondary outcomes. Questionnaires: At the end of each four-week intervention period, participants will complete questionnaires to assess: Diabetes distress and treatment satisfaction. Adverse Event Monitoring: Adverse events will be recorded throughout the study, from informed consent to the end of participation.

• Statistical Analysis:

Intention-to-Treat (ITT) Analysis: Statistical analyses will be performed on an ITT basis, including all participants who were randomized. Factorial Analysis: The factorial design allows for the assessment of the main effects of semaglutide and empagliflozin, as well as their interaction. Mixed-Effects Models: Mixed-effects models will be used to account for repeated measures and within-subject variability. Descriptive Statistics: Descriptive statistics will be used to summarize baseline characteristics and outcome measures. Adverse Event Analysis: Adverse events will be summarized and analyzed for frequency and severity.

• Safety Considerations:

Participants will be closely monitored for adverse events. Rescue medications will be available for hypoglycemic events. Participants will receive education on the safe use of semaglutide, empagliflozin, and the AID system. The investigators will have the right to remove any participant from the study at any time if they feel it is in the best interest of the participant.

The inclusion criteria at the time of enrollment are:

• Males and females aged 18 or older.
• Clinical diagnosis of T1D for at least one year.
• Use of AID system for at least three months.
• Body Mass Index (BMI) ≥ 23 kg/m2.

The exclusion criteria are:

• Use of GLP1-RA within one month of admission.
• Use of SGLT2i within two weeks of admission.
• Planned or ongoing pregnancy.
• Breastfeeding.
• Severe hypoglycemic episode within three months of admission (defined as an event where blood glucose levels were < 4.0 mmol/L, resulting in seizure, loss of consciousness, or the need to present to the emergency department).
• Diabetic ketoacidosis episode within six months of admission.
• History of acute pancreatitis, chronic pancreatitis, or gallbladder disease.
• Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2.
• Severe impairment of renal function with an eGFR < 30 mL/min/1.73 m2 within four months of admission. eGFR will be computed using the CKD-EPI method.
• Clinically significant diabetic retinopathy or gastroparesis, as per the investigator's judgement.
• Bariatric surgery within six months of admission.
• A serious medical or psychiatric illness that would likely interfere with participation in this study, as per the investigator's judgement.
• Inability or unwillingness to comply with safe diabetes management practices, as per the investigator's judgment.