Weekly Subcutaneous Semaglutide as Adjunct to Closed-loop Therapy in Type 1 Diabetes Care (SEMA-AP)

• ClinicalTrials.gov Identifier: NCT05205928
• Recruitment Status: Active, not recruiting
• First Posted: January 25, 2022
• Last Update Posted: April 3, 2024
• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Information provided by (Responsible Party): Michael Tsoukas, McGill University Health Centre/Research Institute of the McGill University Health Centre

Tracking Information

• First Submitted Date: December 13, 2021
• First Posted Date: January 25, 2022
• Last Update Posted Date: April 3, 2024
• Actual Study Start Date: October 2, 2022
• Estimated Primary Completion Date: April 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2022)

Percentage of time of plasma glucose levels spent in target range (semaglutide vs placebo) [ Time Frame: 4 weeks ]

Target range is defined to be between 3.9 and 10.0 mmol/L of placebo on closed-loop system vs semaglutide (at maximal tolerated dose) on closed-loop insulin system.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 23, 2023)

• Percentage of time spent in the following ranges of glucose levels between 3.9 and 7.8 mmol/L [ Time Frame: 4 weeks ]
  % as per CGM data
• Percentage of time spent in the following ranges of glucose levels: below 3.9 and 3.0 mmol/L [ Time Frame: 4 weeks ]
  % as per CGM data
• Percentage of time spent in the following ranges of glucose levels: above 7.8, 10, and 13.9 mmol/L [ Time Frame: 4 weeks ]
  % as per CGM data
• Mean glucose level [ Time Frame: 4 weeks ]
  Defined as per CGM data, in mmol/L
• Standard deviation of glucose levels as a measure of glucose variability [ Time Frame: 4 weeks ]
  Defined as per CGM data, in mmol/L
• Percentage coefficient of variation of glucose levels [ Time Frame: 4 weeks ]
  % as per CGM data
• Proportion of participants with TIR between 3.9 - 10.0 mol/L ≥ 70% [ Time Frame: 4 weeks ]
  As per CGM data
• Glycated hemoglobin [ Time Frame: 15 weeks ]
  Blood test to assess control within last 3-4 months
• Average scores between interventions based on quality of life questionnaires [ Time Frame: 15 weeks ]
  These include: Type 1 Diabetes Distress Scale, Hypoglycemic Fear Survey - II, INSPIRE questionnaire for adults, Diabetes Bowel Syndrome Questionnaire, Diabetes Treatment Satisfaction Questionnaire
• Blood pressure and heart rate [ Time Frame: 15 weeks ]
  Body measurements as described (mmHg and beats per minutes)
• Measured of body mass: weight, body mass index, waist circumference, hip circumference, waist-to-hip ratio [ Time Frame: 15 weeks ]
  Measurements done at visit - weight in kilograms, body mass index as per kg/m^2, circumferences in cm
• Lipid profile, specifically: LDL-cholesterol, HDL-cholesterol, triglycerides [ Time Frame: 15 weeks ]
  Blood tests, in mmol/L
• Biochemical analyses (exploratory) [ Time Frame: 15 weeks ]
  CRP, ferritin, IL-6, Brain natriuretic peptide, TXNIP
• Urine albumin-creatinine ratio [ Time Frame: 15 weeks ]
  Urine test
• Glucagon, C-peptide, Paracetamol absorption after mixed meal tolerance test (in first 15 participants) [ Time Frame: 15 weeks ]
  Test done where beverage given and subsequent blood tests done after.

Original Secondary Outcome Measures (submitted: January 12, 2022)

• Percentage of time spent in the following ranges of glucose levels between 3.9 and 7.8 mmol/L [ Time Frame: 4 weeks ]
  % as per CGM data
• Percentage of time spent in the following ranges of glucose levels: below 3.9 and 3.0 mmol/L [ Time Frame: 4 weeks ]
  % as per CGM data
• Percentage of time spent in the following ranges of glucose levels: above 7.8, 10, and 13.9 mmol/L [ Time Frame: 4 weeks ]
  % as per CGM data
• Mean glucose level [ Time Frame: 4 weeks ]
  Defined as per CGM data, in mmol/L
• Standard deviation of glucose levels as a measure of glucose variability [ Time Frame: 4 weeks ]
  Defined as per CGM data, in mmol/L
• Percentage coefficient of variation of glucose levels [ Time Frame: 4 weeks ]
  % as per CGM data
• Proportion of participants with TIR between 3.9 - 10.0 mol/L ≥ 70% [ Time Frame: 4 weeks ]
  As per CGM data
• Glycated hemoglobin [ Time Frame: 13 weeks ]
  Blood test to assess control within last 3-4 months
• Average scores between interventions based on quality of life questionnaires [ Time Frame: 13 weeks ]
  These include: Type 1 Diabetes Distress Scale, Hypoglycemic Fear Survey - II, INSPIRE questionnaire for adults, Diabetes Bowel Syndrome Questionnaire, Diabetes Treatment Satisfaction Questionnaire
• Blood pressure and heart rate [ Time Frame: 13 weeks ]
  Body measurements as described (mmHg and beats per minutes)
• Measured of body mass: weight, body mass index, waist circumference, hip circumference, waist-to-hip ratio [ Time Frame: 13 weeks ]
  Measurements done at visit - weight in kilograms, body mass index as per kg/m^2, circumferences in cm
• Lipid profile, specifically: LDL-cholesterol, HDL-cholesterol, triglycerides [ Time Frame: 13 weeks ]
  Blood tests, in mmol/L
• Biochemical analyses (exploratory) [ Time Frame: 13 weeks ]
  hs-CRP, ferritin, IL-6, TNFα, Brain natriuretic peptide, TXNIP
• Urine albumin-creatinine ratio [ Time Frame: 13 weeks ]
  Urine test
• Glucagon, C-peptide, Paracetamol absorption after mixed meal tolerance test (in first 15 participants) [ Time Frame: 13 weeks ]
  Test done where beverage given and subsequent blood tests done after.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Weekly Subcutaneous Semaglutide as Adjunct to Closed-loop Therapy in Type 1 Diabetes Care
• Official Title: Weekly Subcutaneous Semaglutide as Adjunct to Closed-loop Therapy in Type 1 Diabetes Care: a Double-blind, Cross-over, Randomized Controlled Trial

Brief Summary

A closed-loop insulin system, also referred to as the "artificial pancreas" (AP), is made up of an insulin pump, a continuous glucose monitor, and an application communicating between the two to adjust insulin administration based on glucose control. This is meant for the treatment of type 1 diabetes. The McGill Artificial Pancreas (MAP) has been used previously in type 1 diabetes with significant benefits. Though prior studies have shown significant benefit with this system, some challenges still exist.

Semaglutide is used in type 2 diabetes and obesity; it is a once-weekly injectable medication that increases levels of a gut hormone called Glucagon-Like Peptide-1, which modifies gastric emptying, suppresses glucagon, and suppresses appetite. Though its use is not approved in type 1 diabetes in North America, it (along with similar drugs) has been used in studies as adjunctive therapy with insulin with benefits on blood sugar control. Similar medications have been used in type 1 diabetes (such as liraglutide and exenatide), but are not as strong in glucose effect even in type 2 diabetes as compared with semaglutide.

The purpose of our study is to see if semaglutide administered weekly at the maximum tolerated dose in those with type 1 diabetes will have improved glucose control (as per time in target range from continuous glucose monitoring data) compared to placebo, while using a closed-loop insulin system.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Type 1 Diabetes
• Diabetes Mellitus, Type 1

Intervention

Drug: Outpatient therapy: 11 weeks of drug therapy with usual treatment + 4 weeks of closed-loop therapy

The blinded drug will be used with participant's routine therapy (+ continuous glucose monitoring if not already in use) for 11 weeks with follow-up from qualified research personnel concerning pump settings, side effects, and incremental dose increase. While continuing to use the medication, there are 4 weeks of closed-loop pump therapy and drug use; glycemic outcomes will be taken from the last 4 weeks. This will be followed by laboratory and anthropometric testing, followed by 2 weeks of wash-out.

Study Arms

• Active Comparator: Placebo + closed-loop insulin system
  Intervention: Drug: Outpatient therapy: 11 weeks of drug therapy with usual treatment + 4 weeks of closed-loop therapy
• Experimental: Semaglutide, Ozempic® (at maximum tolerated dose) + closed-loop insulin 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.
  Intervention: Drug: Outpatient therapy: 11 weeks of drug therapy with usual treatment + 4 weeks of closed-loop therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 12, 2022): 28
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2024
• Estimated Primary Completion Date: April 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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)
• Glycated hemoglobin (HbA1c) up to 11% (inclusive), performed within the last 6 months prior to study inclusion
• Insulin pump use (of any modality) for minimum 3 months
• Agreement to the use of highly effective method of birth control in persons of child-bearing age (if sexually active) and active avoidance of pregnancy during the trial. Child-bearing potential refers to participants of the female sex post-menarche and have not reached menopause or have a disclosed 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. Current or < 2 week use of another GLP1-receptor agonist
2. Less than 2 weeks use of any anti-hyperglycemic agent other than insulin
3. Planned or ongoing pregnancy
4. Breastfeeding individuals
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 <15 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. History of bariatric surgery within 6 months of screening
12. Any serious medical or psychiatric illness likely to interfere with study participation as per the judgment of the investigator (e.g. cirrhosis, active cancer, decompensated schizophrenia)
13. Prior adverse reaction to GLP1-RAs
14. Body mass index ≤ 21 kg/m2
15. Regular use of hydroxyurea during the expected time of Dexcom G6 use, as this medication is known to cause inaccurate measurements (43)
16. Failure to comply to the study protocol and/or research group's recommendations (e.g. change in pump parameters, ketone measurement)
17. 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)
18. Any demonstrate of difficulty in using the iMAP system following training, as per investigator's judgment
19. Concern for safety of the participant, as per the clinical judgment of the primary investigator

**Note that for reasons of medicolegal protection for medical supervision, participants must be Canadian residents.**

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT05205928
• Other Study ID Numbers: 2022-8097
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Protocol will be included upon finalization onto the website, as well as upon request.
• Supporting Materials: Study Protocol

• Current Responsible Party: Michael Tsoukas, McGill University Health Centre/Research Institute of the McGill University Health Centre
• Original Responsible Party: Same as current
• Current Study Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Verification Date: April 2024