Alleviating Carbohydrate Counting for Patients with Type-1 Diabetes Using a Closed Loop System with Weekly Subcutaneous Semaglutide (SEMA SMA)

Alleviating Carbohydrate Counting Using Weekly Subcutaneous Semaglutide Injections in People with Type 1 Diabetes on Closed-Loop Insulin Therapy: a 2x4 Factorial Randomized Placebo-Controlled Trial

A closed-loop insulin system, often labelled the "artificial pancreas" (AP), consists of an insulin pump, a continuous glucose monitor, and an interface coordinating between them to regulate insulin dosage based on glucose levels. Primarily designed for managing type 1 diabetes, this system has demonstrated significant benefits in previous studies. Yet, despite these advantages, certain challenges persist.

Semaglutide, utilized in treating type 2 diabetes and obesity, is a once-weekly injectable medication that elevates levels of a gastrointestinal hormone known as Glucagon-Like Peptide-1 (GLP-1). This hormone alters gastric emptying, inhibits glucagon release, and reduces appetite. While not officially sanctioned for type 1 diabetes treatment in North America, studies have explored its efficacy as an adjunctive therapy alongside insulin, yielding favorable outcomes in blood glucose regulation. Comparable drugs like liraglutide and exenatide have been employed in type 1 diabetes treatment as well, albeit with less pronounced glucose-regulating effects compared to semaglutide, even in type 2 diabetes.

The goal of this 50-week randomized placebo-controlled crossover 2x4 factorial designed trial is to assess whether commercial automated insulin delivery (AID) systems using rapid-acting insulin with adjunct weekly injections of semaglutide (at the maximally tolerated dose) can replace carbohydrate counting with simple meal announcements (SMA) without degrading glucose control.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus; Type 1 Diabetes
• Intervention / Treatment: Drug: Placebo with 4 meal strategies; Drug: Semaglutide with 4 meal strategies

Detailed Description

The main questions this study aims to answer are:

• Can weekly injections of semaglutide at the maximum tolerated dose in individuals with T1D on closed-loop therapy with SMA and rapid-acting insulin result in a non-inferior time spent in target range (3.9-10 mmol/L) compared to weekly placebo injections on closed-loop system with full carbohydrate counting.

• Can weekly injections of semaglutide at the maximum tolerated dose, in combination with ultra-rapid actin insulin (Lyumjev);

  1. Eliminate carbohydrate counting and any meal announcement (i.e fully closed-loop) in people with T1D on closed-loop therapy without degrading glucose control.
  2. Be more effective in substituting carbohydrate counting with SMA in people with T1D on closed-loop therapy compared with traditional rapid-acting insulin.

Participants will be asked to undergo two subsequent blinded drug interventions; one with semaglutide and the other with placebo. Both interventions include 4 meal strategies each with a 3-week duration; full carbohydrate counting with rapid-acting insulin, SMA with rapid-acting insulin, SMA with Lyumjev and fully closed-loop system with Lyumjev.

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Gabrielle Kemp, Registered Nurse; Phone Number: (438) 886-2171; Email: gabrielle.kemp@rimuhc.ca
• Study Contact Backup: Name: Nicholas Sabelli, B.Sc. (Hons); Phone Number: (514) 377-9455; Email: nicholas.sabelli@mail.mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • Research Institute of the McGill University Health Centre
      • Contact: Gabrielle Kemp, DEC Nursing; Phone Number: (438) 886-2171; Email: gabrielle.kemp@rimuhc.ca
      • Contact: Michael Tsoukas, MD
      • Contact: Ahmad Haidar, Ph.D
      • Contact: Vanessa Tardio, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. At least 18 years of age
2. A clinical diagnosis of T1D for at least one year, as per their treating diabetes physician in agreement with the primary investigator's clinical judgment (confirmatory C-peptide and antibodies will not be required)
3. Minimum 3-month use of a commercial advanced automated insulin delivery system. 4.4. Agreement to use an effective method of birth control for individuals with child-bearing potential. Child-bearing potential refers to participants of the female sex post-menarche who have not reached menopause and who do not have a medical condition causing sterility (e.g., hysterectomy). Post-menopausal state refers to the absence of menses for 12 months without any alternative cause.

Exclusion Criteria:

1. Use of GLP1-RAs within the last 4 weeks.
2. Use of any anti-hyperglycemic agent other than insulin within the last 2 weeks.
3. Planned or ongoing pregnancy
4. Breastfeeding
5. Severe hypoglycemic episode within the last 3 months, defined as an event where glucose was < 4 mmol/L resulting in seizure, loss of consciousness, or need to present to the emergency department
6. Severe diabetic ketoacidosis (DKA) within the last 6 months ("severe" referring to need to present to medical attention and requirement of intravenous insulin)
7. Prior history of acute pancreatitis, chronic pancreatitis, or gallbladder disease
8. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2
9. Severe impairment of renal function with eGFR <30 mL/min/1.73 m2 (using CKD-EPI formula), measured within the last 12 months
10. Clinically significant diabetic retinopathy or gastroparesis, as per the clinical judgment of the investigator
11. Bariatric surgery within the last 6 months.
12. A serious medical or psychiatric illness that is likely to interfere with study participation as per the judgment of the investigator (e.g. cirrhosis, active cancer, decompensated schizophrenia).
13. Body mass index ≤ 21 kg/m2
14. Inability or unwillingness to comply to safe diabetes management in the view of the study group (e.g. inappropriate treatment of hypoglycemia or lack thereof)
15. Concern for safety of the participant, as per the clinical judgment of the primary investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Weekly placebo injections on regular closed-loop insulin pump therapy	Drug: Placebo with 4 meal strategies; The blinded drug will be used in addition to the participants routine closed-loop insulin pump therapy. It will be administered through subcutaneous injection on a weekly basis. The first 12 weeks will include progressively increasing doses of the drug whereby, the dose increases every 4 weeks. Once the maximum tolerated dose is achieved after 12 weeks, participants will undergo 4 meal strategies in a randomized order. These include (in no particular order); full carbohydrate counting with rapid-acting insulin, SMA with rapid-acting insulin, SMA with Lyumjev and fully closed-loop system with Lyumjev. Each meal strategy will be 3 weeks in duration and will occur sequentially in the designated order.
Experimental: Weekly semaglutide (Ozempic®) injections on regular closed-loop insulin pump therapy; Semaglutide is a Glucagon-like peptide 1 (GLP-1) receptor agonist. It up regulates GLP-1, which reduces glucagon levels, increases satiety and - in some particular cases - increases insulin production. It will be subcutaneously injected weekly by participants at progressively increasing doses. Once the maximum tolerated dose is achieved, participants will begin the meal strategies.	Drug: Semaglutide with 4 meal strategies; The blinded drug will be used in addition to the participants routine closed-loop insulin pump therapy. It will be administered through subcutaneous injection on a weekly basis. The first 12 weeks will include progressively increasing doses of the drug whereby, the dose increases every 4 weeks. Once the maximum tolerated dose is achieved after 12 weeks, participants will undergo 4 meal strategies in a randomized order. These include (in no particular order); full carbohydrate counting with rapid-acting insulin, SMA with rapid-acting insulin, SMA with Lyumjev and fully closed-loop system with Lyumjev. Each meal strategy will be 3 weeks in duration and will occur sequentially in the designated order.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of daytime plasma glucose levels spent in target range (semaglutide vs. placebo)	Target range is defined to be between 3.9 and 10.0 mmol/L of plasma glucose for placebo vs semaglutide (at maximal tolerated dose) on closed-loop insulin therapy	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of time spent in the range of glucose levels between 3.9 and 7.8 mmol/L	% as per CGM data	24 weeks
Percentage of time spent in glucose levels below 3.9 and 3.0 mmol/L	% as per CGM data	24 weeks
Percentage of time spent in glucose levels above 7.8, 10 and 13.9 mmol/L	% as per CGM data	24 weeks
Mean glucose level	Defined as per CGM data, in mmol/L	24 weeks
Standard deviation of glucose levels as a measure of glucose variability	Defined as per CGM data, in mmol/L	24 weeks
Percentage coefficient of variation of glucose levels	% as per CGM data	24 weeks
Proportions of participants with time in range between 3.9 - 10.0 mmol/L≥ 70%	As per CGM data	24 weeks
Glycated hemoglobin (HbA1c)	Blood test to assess glucose control within 3-4 months	24 weeks
Area under the curve 0-2h post meal, 0-3h post peal	As per CGM data	24 weeks
Average scores between interventions on the Type 1 Diabetes Distress Scale questionnaire	17-item questionnaire with a 6-point Likert scale from 1 (no stress) to 6 (high stress) for each item. Total score obtained from summing the scores of all items	24 weeks
Average scores between interventions on the Diabetes Treatment Satisfaction questionnaire	8-item questionnaire with a 7-point Likert scale ranging from 0 (low satisfaction) to 6 (high satisfaction). Total score obtained from summing the scores of all items.	24 weeks
Average scores between interventions based on the Hypoglycemic Fear Survey - II	33-item questionnaire with a 5-point Likert scale ranging from 1 (never) to 5 (almost always). Total score obtained from summing the scores of all items.	24 weeks
Heart rate	Beats per minute	24 weeks
Blood pressure	mmHg	24 weeks
Measure of body weight	Measurements done at visit - weight in kilograms	24 weeks
Measure of body mass index	Measurements done at visit - body mass index as per kg/m^2	24 weeks
Measure of waist circumference and hip circumference	Measurements done at visit - circumference in cm	24 weeks
Measure of waist-to-hip ratio	Measurements done at visit	24 weeks
Lipid profile, specifically: LDL-cholesterol, HDL-cholesterol, triglycerides	Blood tests, in mmol/L	24 weeks
Urine albumin-creatinine ratio	Urine test	24 weeks

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: April 18, 2024
• First Submitted That Met QC Criteria: April 23, 2024
• First Posted (Actual): April 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 13, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Semaglutide; insulin; Diabetes mellitus, type 1; GLP-1 receptor agonist; Closed-loop system; ozempic
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Hypoglycemic Agents; Semaglutide
• Other Study ID Numbers: 2024-10227

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The raw data (that is, insulin delivery, glucose levels and individual participant data) and informed consent form will be shared by the corresponding author, for academic purposes, subject to a material transfer agreement and approval of the McGill University Health Center's Research Ethics Board. All data shared will be de-identified. Raw data will be shared for non-commercial use upon reasonable request and a material transfer agreement.
• IPD Sharing Supporting Information Type: ICF

Drug and device information, study documents

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