ADJUnct Semaglutide Treatment in Type 1 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to assess the use of once weekly semaglutide injection in inadequately controlled obese adults with type 1 diabetes (T1D) using FDA-approved hybrid closed-loop therapies.

Detailed Description
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After being informed about the study and potential risks, all patients given written informed consent will undergo a 2-week screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in a double-blind manner using computer generated randomization scheme to receive either semaglutide or placebo (1:1 ratio) for 26 weeks.

Official Title
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Efficacy and Safety of Once Weekly Semaglutide in Adults With Obesity and Inadequately Controlled Type 1 Diabetes Using Hybrid Closed-Loop System.

Conditions
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Type 1 Diabetes, Obesity

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For an eligible subject, all inclusion criteria must be answered yes Age >18 years at screening Patients with clinical diagnosis of T1D diagnosed for at least 12 months Patient is on FDA- approved hybrid closed-loop system for ≥ 3 months Willing to use once weekly semaglutide Willing to share devices (HCL system) data uploads Point-of-care HbA1c >7.0% and <10.0% Body mass index ≥30 kg/m2 Has current glucagon product to treat severe hypoglycemia Has current ketone meters to check ketones Ability to provide informed consent before any trial-related activities Exclusion Criteria: Age ≤18 years and ≥60 years HbA1c ≤7.0 % or ≥ 10.0% at screening Less than 12 months of insulin treatment Use of unapproved insulin for HCL system. E.g. use of Fiasp in the Tandem Control-IQ system Not willing to share the devices (HCL system) data uploads Non compatible devices (e.g. pump, CGM or smart phones) for data transfer Current use of multiple daily injection or inhaled insulin (Afrezza) Patients with T1D using any glucose lowering medications other than insulin at the time of screening Pregnancy, breast feeding, and positive pregnancy test during screening Women of childbearing age wanting to become pregnant Unwilling to use acceptable contraceptive methods (for both men and women) during the trial period Current use (≥ 2 weeks of continuous use) of any steroidal medication, or anticipated long-term steroidal treatment (>4 weeks continuously), during the study period Use of GLP-1RA or weight loss medications in the past 3 month Clinical diagnosis/history of gastroparesis or gastric motility disorders Fasting serum triglycerides >500 mg/dL Planning for bariatric surgery during the study period eGFR below 45 ml/min/1.73 m^2 using CKD-EPI formula History of severe hypoglycemia in the previous 3 months History of diabetic ketoacidosis requiring hospitalization in the past 3 months History of allergy to any form of insulin, GLP-1RA or its excipients History of any form of pancreatitis History of stroke, myocardial infarction in the past 3 months History of congestive heart failure class III or IV History of acute or chronic liver disease History of malignancy requiring chemotherapy, surgery or radiation in previous 5 years Personal or family history of multiple endocrine neoplasia type 2 (MEN-2) or familial thyroid carcinoma or non-familial medullary thyroid carcinoma Have a pacemaker, metal implants, or aneurysm clips (exclusion only if doing MRI and CT scan) Use of investigational drugs within 5 half-lives prior to screening Participation to other intervention trials during the study period Any comorbidities or medical conditions such as severe psychiatric disorder that make a person unfit for the study at the discretion of the investigators

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Semaglutide<br>Participants in this group will receive semaglutide once weekly injection in addition to their standard closed-loop therapy | Drug: Semaglutide<br>* Semaglutide up to 1 mg per week in addition to standard closed-loop therapy<br>|
| Placebo Comparator: Control<br>Participants in this group will receive placebo once weekly injection in addition to their standard closed-loop therapy | Drug: Placebo<br>* Injection placebo up to 1 mg per week in addition to standard closed-loop therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of adults with T1D achieving composite outcome (CGM-measured time in range (TIR)>70% with time below range (TBR) of <4% and reduction in body weight by 5%) at 26 weeks in the semaglutide group compared to placebo group | The primary endpoint (differences in proportion of patients achieving composite outcomes) will be compared, including the proportion of study participants achieving a reduction in body weight of 5% or more between 4 and 26 weeks and achieving TIR >70% and TBR of <4% at 26 weeks. This comparison between the proportion meeting the composite endpoint will be examined while adjusting for pre-specified covariates, baseline A1c and BMI. Baseline A1c is known to affect TIR (better improvement in TIR in those with higher A1c). Similarly, higher BMI may affect weight loss. Therefore, the investigator decided to use these covariates for adjustment. Sustain 7 post hoc analysis suggested that efficacy of semaglutide on glycemic control and weight loss remains the same regardless of baseline age, diabetes duration or sex. Therefore, the investigator did not include those variables in the pre-specified adjustment. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | HbA1c will be measured at a central laboratory and change in Hba1c from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis. | 26 weeks | 
| Change in mean glucose | Mean glucose (mg/dL) will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis.weeks will be compared by randomization group using intention to treat (ITT) analysis. | 26 weeks | 
| Percent time spent in CGM-measured glucose range of 70-140 mg/dL (time in tight target range; TTIR) | Percent of time spent in tight glucose range (70-140 mg/dL) will be obtained by CGM and change in percent time in range from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis. | 26 weeks | 
| Percent time spent in CGM-measured glucose >180 mg/dL and >250 mg/dL | Percent of time spent in glucose range (70-140 mg/dL) will be obtained by CGM and change in mean CGM glucose from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis. | 26 weeks | 
| Change in CGM measured glycemic variability (coefficient of variation) | Glucose coefficient of variation (mg/dL) will be obtained by CGM and change in glucose CV from 4 weeks to 26 weeks will be compared by randomization group using intention to treat (ITT) analysis. | 26 weeks | 
| Differences in CGM metrics (mean glucose, TIR, TAR, TBR and CV) by daytime vs nighttime | CGM metrics (TIR, TBR, TAR) during the day (6am - midnight) compared to at night (>midnight to <6am) will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Percentage of patients achieving HbA1c <7% | The proportion of patients achieving HbA1c <7% at 26 weeks will be compared by randomization group using an ITT analysis | 26 weeks | 
| Percentage of patients achieving TIR >70% | The proportion of patients achieving TIR >70% at 26 weeks will be compared by randomization group using an ITT analysis | 26 weeks | 
| Change in patient reported quality of life | Patient reported quality of life will be measured using a validated instrument (ADDQOL) and the change in score from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in insulin dose (total daily dose, units/kg of body weight) | The change in total daily dose of insulin per kg of body weight from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in weight | The change in kg of body weight from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Severe hypoglycemia and diabetic ketoacidosis episodes | The number of severe hypoglyemia and diabetic ketoacidosis events during the study period will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in blood pressure (systolic, diastolic, mean and pulse pressure) | The change in blood metric metrics (systolic, diastolic, mean arterial pressure and pulse pressure) from 4 weeks to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in brachial arterial distensibility (Brach D), augmentation index by radial artery tonometry [pulse wave analysis [PWA]), pulse wave velocity (PWV)], and carotid atherosclerosis by carotid intima media thickness (cIMT) | Changes in arterial stiffness measures (BrachD, PWV, PWA) and carotid IMT from 4 weeks to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in lipid parameters | Changes in fasting lipids (total cholesterol, triglyceride, LDL-C and HDL-C) from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in albumin to creatinine ratio (ACR) | Changes in renal function as measured by urinary ACR from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in BMI (Kg/m2) | Change in body mass index (BMI) calculated as kg body weight per meter squared of height from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in estimated glomerular filtration rate (eGFR) | Changes in renal function as measured by eGFR from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 
| Change in NAFLD biomarkers | Changes in NAFLD biomarkers, HSI and FIB-4 from 4 to 26 weeks will be compared by randomization group using an ITT analysis. | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Obesity, HbA1c, Time-in-range, Weight loss, Cardiovascular risk