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 (SEMPA)

Semaglutide and Empagliflozin Combination Therapy Added to Automated Insulin Delivery in Adults with Type 1 Diabetes (SEMPA)

The goal of this clinical trial is to learn if Empagliflozin and Semaglutide, individually and combined, added to Automated Insulin Delivery (AID) works to improve time-in-range in adults living with Type 1 Diabetes. It will also evaluate the safety of Empagliflozin and Semaglutide in this context.

The primary hypothesis of this study is :

- The combination therapy of semaglutide and empagliflozin will increase time-in-range compared to placebo when added to AID therapy.

The secondary hypotheses are :

• The combination therapy of semaglutide and empagliflozin will increase time-in-range compared to semaglutide alone when added to AID therapy.
• The combination of semaglutide and empagliflozin will increase time-in-range compared to empagliflozin alone when added to AID therapy.

In this study, the research team will compare Empagliflozin and Semaglutide to a placebo (a look-alike substance that contains no drug) to see if they improve time-in-range.

This study has four groups:

Group 1: semaglutide injection + empagliflozin tablet. Group 2: semaglutide injection + placebo tablet. Group 3: placebo injection + empagliflozin tablet. Group 4: placebo injection + placebo tablet.

This is a 2x2 factorial crossover study. This means that all participants will undergo both injection intervention (placebo and semaglutide) arms. Within each injection arm, participants will take both tablets (placebo and empagliflozin). By the end of the study, every participant will have taken part in each study group.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Type 1
• Intervention / Treatment: Drug: Intervention Period 1: Semaglutide + Empagliflozin; Drug: Intervention Period 2: Semaglutide + Empagliflozin Placebo; Drug: Intervention Period 3: Semaglutide Placebo + Empagliflozin; Drug: Intervention Period 4: Semaglutide Placebo + Empagliflozin Placebo

Detailed Description

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.

1. 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.

2. 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.

3. 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.

4. 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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Keddy Moise, BScHS; Phone Number: 438-531-6896; Email: keddy.moise@affiliate.mcgill.ca
• Study Contact Backup: Name: Dr. Ahmad Haidar; Phone Number: 514-398-4491; Email: ahmad.haidar@mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • Recruiting
      • Research Institute of the McGill University Health Centre
      • Contact: Keddy Moise, BScHS; Phone Number: 438-531-6896; Email: keddy.moise@affiliate.mcgill.ca
      • Contact: Dr. Ahmad Haidar, PhD; Phone Number: 514-398-4491; Email: ahmad.haidar@mcgill.ca
      • Contact: Dr. Michael Tsoukas, MD, FRCPC
      • Contact: Dr. Ahmad Haidar, PhD
      • Contact: Dr. Melissa-Rosina Pasqua, MD, FRCPC
      • Contact: Dr. Vanessa Tardio, MD, FRCPC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide, Ozempic® (at maximum tolerated dose) + Automated Insulin Delivery system; Semaglutide is a Glucagon-Like Peptide 1 Receptor Agonist. It stimulates GLP1 in the body, which allows for increased satiety, reduced glucagon levels, delayed gastric emptying, and in some, increased insulin secretion. It is a once per week subcutaneous injection. Participants will self-administer the colourless solution subcutaneously in the abdomen, thighs, or upper arms once weekly per the dosing schedule below. Weeks 1-4 : 0.25 mg (0.19 mL) Weeks 5-8 : 0.50 mg (0.38 mL) Weeks 9-12 : 1.0 mg (0.74 mL) Weeks 13-22 : 1.0 mg (0.74 mL) To match the recommendation from the product monograph and to ensure a steady state is reached before initiating the evaluation period, study drugs will be titrated for 12 weeks.	Drug: Intervention Period 1: Semaglutide + Empagliflozin; Semaglutide Injection: Subcutaneous injection, titrated over 12 weeks to a stable dose (1 mg), administered weekly. Empagliflozin Tablet: Oral tablet (2.5 mg), administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.; Drug: Intervention Period 2: Semaglutide + Empagliflozin Placebo; Semaglutide Injection: Subcutaneous injection, titrated over 12 weeks to a stable dose (1 mg), administered weekly. Empagliflozin Placebo Tablet: Oral placebo tablet, matched in appearance to empagliflozin (2.5 mg), administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.; Drug: Intervention Period 3: Semaglutide Placebo + Empagliflozin; Semaglutide Placebo Injection: Subcutaneous placebo injection (titrated over 12 weeks to a stable 1 mg dose), matched in appearance to semaglutide, administered weekly. Empagliflozin Tablet: Oral tablet (2.5 mg), administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.; Drug: Intervention Period 4: Semaglutide Placebo + Empagliflozin Placebo; Semaglutide Placebo Injection: Subcutaneous placebo injection (titrated over 12 weeks to a stable 1 mg dose), matched in appearance to semaglutide, administered weekly. Empagliflozin Placebo Tablet: Oral placebo tablet (2.5 mg), matched in appearance to empagliflozin, administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.
Active Comparator: Placebo + Automated Insulin Delivery system; Participants will self-administer the colourless solution subcutaneously in the abdomen, thighs, or upper arms once weekly per the dosing schedule below. Weeks 1-4 : 0.19 mL Weeks 5-8 : 0.38 mL Weeks 9-12 : 0.74 mL Weeks 13-22 : 0.74 mL To match the recommendation from the product monograph and to ensure a steady state is reached before initiating the evaluation period, study drugs will be titrated for 12 weeks.	Drug: Intervention Period 1: Semaglutide + Empagliflozin; Semaglutide Injection: Subcutaneous injection, titrated over 12 weeks to a stable dose (1 mg), administered weekly. Empagliflozin Tablet: Oral tablet (2.5 mg), administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.; Drug: Intervention Period 2: Semaglutide + Empagliflozin Placebo; Semaglutide Injection: Subcutaneous injection, titrated over 12 weeks to a stable dose (1 mg), administered weekly. Empagliflozin Placebo Tablet: Oral placebo tablet, matched in appearance to empagliflozin (2.5 mg), administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.; Drug: Intervention Period 3: Semaglutide Placebo + Empagliflozin; Semaglutide Placebo Injection: Subcutaneous placebo injection (titrated over 12 weeks to a stable 1 mg dose), matched in appearance to semaglutide, administered weekly. Empagliflozin Tablet: Oral tablet (2.5 mg), administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.; Drug: Intervention Period 4: Semaglutide Placebo + Empagliflozin Placebo; Semaglutide Placebo Injection: Subcutaneous placebo injection (titrated over 12 weeks to a stable 1 mg dose), matched in appearance to semaglutide, administered weekly. Empagliflozin Placebo Tablet: Oral placebo tablet (2.5 mg), matched in appearance to empagliflozin, administered daily. Automated Insulin Delivery (AID) System: Continuous use of the participant's personal commercial AID system.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-in-Range	The percentage of time spent in target glucose range (3.9-10.0 mmol/L), between Semaglutide and Empagliflozin versus placebo, added to AID therapy.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Time In Range	Percentage of time (%) spent in ranges of glucose levels : between 3.9 to 10 mmol/L Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Optimal Time In Range	Percentage of time (%) spent in ranges of glucose levels : between 3.9 to 7.8 mmol/L Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Time In Hypoglycemia	Percentage of time (%) spent in ranges of glucose levels : below 3.9 and 3.0 mmol/L Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Time In Mild Hyperglycemia	Percentage of time (%) spent in ranges of glucose levels : above 7.8 mmol/L Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Time Above Range	Percentage of time (%) spent in ranges of glucose levels : above 10 mmol/L Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Time In Severe Hyperglycemia	Percentage of time (%) spent in ranges of glucose levels : above 13.9 mmol/L Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Total Insulin dose	Total daily insulin dose (U/l) Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Basal insulin dose	Total daily basal dose (U/l) Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Bolus insulin dose	Total daily bolus dose (U/l) Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Carbohydrate intake	Average daily meal carbohydrate intake (grams/day) Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At days 7, 35, 63 of the titration period and days 3 and 7 of each intervention.
Patient-reported outcomes	Average scores (unit) of the questionnaire : - Diabetes Distress Scale Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At the end of each intervention at weeks 16, 21, 29, 34
Patient-reported outcomes	Average scores (unit) of the questionnaire: - Diabetes Treatment Satisfaction Questionnaire Nota Bene: Secondary endpoints will be computed for (i) semaglutide and empagliflozin versus placebo, (ii) semaglutide and empagliflozin versus empagliflozin alone, (iii) semaglutide and empagliflozin versus semaglutide alone.	At the end of each intervention at weeks 16, 21, 29, 34

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Diabetes Canada
• Investigators: Principal Investigator: Dr. Michael Tsoukas, Division of Endocrinology and Metabolism - McGill University Health Center; Study Director: Dr. Melissa-Rosina Pasqua, Division of Endocrinology and Metabolism - McGill University Health Center; Study Director: Dr. Vanessa Tardio, Division of Endocrinology and Metabolism - McGill University Health Center; Study Director: Dr. Ahmad Haidar, Department of Biomedical Engineering - McGill University

Publications and helpful links

General Publications

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Helpful Links

• Sizar O, Podder V, Talati R. Empagliflozin. In: StatPearls. StatPearls Publishing; 2024. Accessed April 15, 2024
• Ozempic® Side Effects | Ozempic® (semaglutide) injection. Accessed April 15, 2024

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: March 7, 2025
• First Submitted That Met QC Criteria: March 19, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Insulin; T1D; Combination Therapy; Artificial Pancreas; Diabetes Mellitus, Type 1; GLP-1 receptor agonist; Automated Insulin Delivery; GLP1-RA; SGLT2-i
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Sodium-Glucose Transporter 2 Inhibitors; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Semaglutide; Empagliflozin
• Other Study ID Numbers: 2025-10723

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Protocol will be included upon finalization onto the website, as well as upon request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes