Trial of Semaglutide for Diabetic Kidney Disease in Type 1 Diabetes

Study Overview
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Brief Summary
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The primary objective of this study is to determine the effects of semaglutide on kidney oxygenation and function in type 1 diabetes. The secondary objective is to determine the glycemic effects and safety of semaglutide in type 1 diabetes.

Detailed Description
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A parallel-group, double-blind, placebo-controlled, randomized study will rigorously test effects of semaglutide on the kidney. Real-time continuous glucose monitoring will be used to control glycemia during study run-in (prior to randomization) and during active therapy, which investigators anticipate will lead to similar glycemic control according to treatment assignment and ability to assess effects independent of glycemia. The trial duration is 26 weeks, a period of time sufficient to gradually titrate study medications to maximum target dose (over 12 weeks) and then observe the full short-term effect of semaglutide on the kidney. Study Aims and Hypotheses: Aim 1: Determine the effects of semaglutide vs. placebo on kidney oxygenation in type 1 diabetes. Hypothesis 1: Semaglutide will improve kidney oxygen availability in adults with type 1 diabetes. Aim 2: Determine the effects of semaglutide vs. placebo on urine albumin-creatinine ratio and estimated glomerular filtration rate in type 1 diabetes. Hypothesis 2: Semaglutide will lower albuminuria and slow estimated glomerular filtration rate decline in adults with type 1 diabetes. Aim 3: Determine the glycemic effects and safety of semaglutide vs. placebo in type 1 diabetes. Hypothesis 3: Semaglutide will reduce total daily insulin dose and improve glycemic variability without increasing risk of severe hypoglycemia or diabetic ketoacidosis in adults with type 1 diabetes.

Official Title
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Trial of Semaglutide for Diabetic Kidney Disease in Type 1 Diabetes

Conditions
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Diabetic Kidney Disease, Type 1 Diabetes

Intervention / Treatment
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* Drug: Semaglutide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥18 years) with type 1 diabetes Diabetes duration of ≥5 years Persistent urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g, on the most recent two measurements within the prior 3 years Estimated glomerular filtration rate ≥ 45 mL/min/1.73m2 Stable doses of drugs altering blood pressure (e.g., Angiotensin-converting enzyme inhibitor) required for at least 4 weeks prior to randomization, and requested for the duration of the trial Stable doses of lipid-lowering medications required for at least 4 weeks prior to randomization, and requested for the duration of the trial Adequate contraceptive method for females of child-bearing potential Exclusion Criteria: HbA1c >9%, recent diabetic ketoacidosis, hyperosmolar hyperglycemic state or severe illness requiring hospitalization in past 30 days Other causes of diabetes mellitus, including type 2 diabetes and maturity-onset diabetes of the young (MODY) Chronic kidney disease unrelated to diabetes Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) or thyroid nodule palpated by endocrinologist at screening Personal history of pancreatitis Current/planned pregnancy or nursing Uncontrolled thyroid disease or hypertension (Systolic blood pressure [SBP] ≥ 160 mm Hg or diastolic blood pressure [DBP] ≥ 100 mm Hg despite treatment) Proliferative retinopathy with treatment in the past 6 months Uncontrolled or potentially unstable diabetic retinopathy or maculopathy, verified by fundus examination with pupil dilation unless performed using a digital fundus photography camera specified for non-dilated examination More than 2 severe hypoglycemic episodes (requiring glucagon and/or assistance from another person) in the past 6 months Frequent hypoglycemia during the last two weeks of the study run-in phase (time below range [<70 mg/dL] ≥4%) Pramlintide and the use of glycemia treatments not approved for type 1 diabetes by the FDA, e.g., metformin, SGT-2 inhibitor, GLP-1 receptor agonist, closed loop insulin delivery using unapproved algorithms Significant systemic conditions or treatment such as cancer or immunomodulators Known liver disease other than non-alcoholic fatty liver disease (NAFLD) or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 IU/L, history of severe gastrointestinal disease (e.g., gastroparesis) or gallstones Body mass index <20 kg/m2 Inability to cooperate with or clinical contraindication for magnetic resonance imaging including severe claustrophobia, nonremovable devices, implanted metal Known or suspected allergy/sensitivity to semaglutide or its excipients Pregnant, breast feeding, or the intention of becoming pregnant The receipt of any investigational drug within 3 months prior to this trial Previously randomized in this trial

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>Semaglutide group from 0.25mg to 1.0mg | Drug: Semaglutide<br>* 1.0 mg<br>|
| Placebo Comparator: Placebo<br>Placebo group | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in kidney cortical relaxation rates (R2*) | Measurement of oxygenation by magnetic resonance imaging | Baseline to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in urine albumin excretion | Measured as mean of multiple urine albumin-creatinine ratio measurements in spot urine | Baseline to 26 weeks | 
| Change in estimated glomerular filtration rate | Estimated glomerular filtration rate will be calculated from age, sex, and the serum concentrations of creatinine and cystatin C | Baseline to 26 weeks | 
| Change in glucose time in range | Proportion of time with glucose 70-180 mg/dL measured by continuous glucose monitoring | Baseline to 26 weeks | 
| Change in glucose coefficient of variation | Measured by continuous glucose monitoring | Baseline to 26 weeks | 
| Change in total daily insulin dose | Mean total dose of insulin administered per day | Baseline to 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon-like peptide-1 receptor agonist