Effect of Subcutaneous Semaglutide on Kidney Transplant Candidacy

Study Overview
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Brief Summary
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This randomized study evaluates the effect of subcutaneous semaglutide /in combination with lifestyle counseling in patients with type 2 diabetes mellitus (T2DM), overweight/obesity, and stage 4-5 chronic kidney disease (CKD) or dialysis-dependent end-stage kidney disease (ESKD) on patients' eligibility for kidney transplantation at the end of 9 months.

Detailed Description
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Transplant policies regarding listing consider uncontrolled diabetes and severe obesity to be contraindications though there is great variability for exact BMI (35-45 kg/m2) and A1c (9-10%) thresholds for listing by center. Glucagon-lowering peptide-1 receptor agonists (GLP-1 RAs) offer great promise in this population as they have been shown to reduce weight, central adiposity, A1c, and risk of cardiovascular outcomes with similar effects in patients with and without CKD. In this double-blind, placebo-controlled randomized controlled trial, the investigators will evaluate the effect of subcutaneous semaglutide 1.34 mg/ml (up to 1.0 mg per week) in combination with lifestyle counseling in patients with T2DM, overweight/obesity, and stage 4-5 CKD or dialysis-dependent ESKD on patients' eligibility for kidney transplantation in terms of diabetes control (A1c <9%) and obesity (BMI <35 kg/m2 or 35-40 kg/m2 with waist circumference <120 cm) at the end of 9 months.

Official Title
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A RAndomized trIal Examining the Effect of Subcutaneous Semaglutide on Kidney Transplant Candidacy for Patients With Stage 4-5 CKD or Dialysis-dependent ESKD

Conditions
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CKD, Diabetic Kidney Disease, Type 2 Diabetes Mellitus in Obese, Obesity, Severe Obesity

Intervention / Treatment
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* Drug: Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection solution
* Drug: Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Age ≥ 18 years - BMI 25-45 kg/m2 - T2DM - Advanced CKD* (last eGFR <30 ml/min/1.73m2 in EHR or ESKD on dialysis prior to screening) or stage G3B/A2-3 CKD (eGFR 30 to <45 ml/min/1.73m2 with albumin/creatinine ratio >30 mg/g). - Fulfill kidney transplant listing criteria except for one or more of the following reasons (1: uncontrolled diabetes [A1c ≥9%); 2: severe obesity (BMI ≥ 40 kg/m2 or BMI 35-40 kg/m2 with waist circumference >120 cm). See exclusion criteria for general contraindications used for transplant listing used by majority of U.S. transplant centers]. - Ability to provide informed consent before any trial-related activities - Access to a telephone The cause of the CKD does not need to be due specifically to diabetes Exclusion Criteria (General contraindications used for transplant listing used by majority of U.S. transplant centers) - Active malignancy - History of pancreatitis - Active substance abuse - Severe COPD - Pulmonary fibrosis - Symptomatic angina or recent myocardial infarction within 6 months - Severe peripheral vascular disease - Cirrhosis - New York Health Association (NYHA) Class III-IV congestive heart failure - Severe cognitive impairment - Drug addiction - History of non-adherence to therapy - Active infection - Expected life expectancy < 5 years Additional exclusion criteria - Type 1 diabetes mellitus - History of diabetic ketoacidosis within the last 12 months - Planning on undergoing bariatric surgery in next 9 months. - Pregnant, breast-feeding, or planned pregnancy prior to the end of participation or not using adequate contraceptive measures - Self-reported average consumption of > 21 alcoholic beverages per week or binge drinking - Psychiatric hospitalization in past year - Principal investigator discretion (i.e. concerns about safety, compliance) - Known or suspected allergy to trial medication - Previous participation (i.e. randomized) in this trial - Use of GLP1-RA or pramlintide within 90 days prior to screening - Use of metformin (contraindicated with eGFR < 30 ml/min/1.73m2) - Use of DPP-4 inhibitors within 30 days prior to screening - Personal or family history of medullary thyroid cancer, multiple endocrine neoplasia types 2A and 2B syndrome - Last hemoglobin A1c ≥ 12% or A1c <6% (to avoid risk of hypoglycemia) prior to screening

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Semaglutide<br>This arm will receive semaglutide. | Drug: Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection solution<br>* Dose will be started at 0.25 mg per week. Dose escalation will occur every 4 weeks to mitigate risk of gastrointestinal side effects to a maximum dose of 1.0 mg per week.<br>* Other names: semaglutide;|
| Placebo Comparator: Placebo<br>This arm will receive placebo. | Drug: Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution<br>* Matched placebo solution for injection will be provided by Novo Nordisk in a 1.5 ml pre-filled pen-injector for subcutaneous injection with the same instructions on dose escalation.<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney transplant eligibility | Proportion either listed for kidney transplant at 9 months or meeting the following kidney transplant candidacy criteria for A1c (<9%) and obesity (BMI <35 kg/m2 or BMI 35-40 kg/m2 with waist circumference <120 cm) | Ascertained at the end of 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hemoglobin A1c (HgbA1c) | HgbA1c will be collected using routine procedures and measured on the same day at the central Geisinger laboratory by Turbidimetric inhibition immunoassay. | From baseline to 9 months | 
| Change in BMI | Weight will be measured at each study visit in light clothing without shoes by trained, certified staff using a calibrated, digital scale. Scales will be calibrated annually. Height will be measured at the initial study visit to the nearest 0.1 cm using a calibrated, wall-mounted stadiometer without shoes on a firm, level surface, with head in the horizontal plane. | From baseline to 9 months | 
| Change in waist circumference | Waist circumference will be measured at each study visit to the nearest 0.1 cm using a Gulick II tape measure. | From baseline to 9 months | 
| Change in waist-to-hip ratio | Hip circumference will also be measured to the nearest 0.1 cm using a Gulick II tape measure, and waist-to-hip ratio will be calculated. | From baseline to 9 months | 
| Change in body fat percentage | Measured using bioelectrical impedance analysis | From baseline to 9 months | 
| Activation on the transplant list | Assessed by Geisinger kidney transplant committee (blinded to randomization assignment, independent of investigators) | Assessed at end of 9 months | 
| Receipt of kidney transplant | Confirmed by review of electronic health record (EHR) | Assessed at end of 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ckd, obesity, kidney transplant, transplant wait list, diabetic kidney disease, glp-1, semaglutide