Effect of Subcutaneous Semaglutide on Kidney Transplant Candidacy

Phase 3

Terminated

• Conditions: Obesity; Severe Obesity; Type 2 Diabetes Mellitus in Obese; CKD; Diabetic Kidney Disease
• Interventions: Drug: Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution; Drug: Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection solution

• Registration Number: NCT04741074
• Lead Sponsor: Geisinger Clinic

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2021-02-02
• Study First Submitted QC: 2021-02-02
• Study First Posted: 2021-02-05
• Study Start: 2021-07-23
• Primary Completion: 2023-01-31
• Study Completion: 2023-01-31
• Results First Submitted: 2024-01-12
• Status Verified: 2024-02
• Results First Submitted QC: 2024-02-06
• Last Update Submitted: 2024-02-06
• Results First Posted: 2024-02-09
• Last Update Posted: 2024-02-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

1. • Age ≥ 18 years
2. • BMI 25-45 kg/m2
3. • T2DM
4. • 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).
5. • 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].
6. • Ability to provide informed consent before any trial-related activities

7. • 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)

1. • Active malignancy
2. • History of pancreatitis
3. • Active substance abuse
4. • Severe COPD
5. • Pulmonary fibrosis
6. • Symptomatic angina or recent myocardial infarction within 6 months
7. • Severe peripheral vascular disease
8. • Cirrhosis
9. • New York Health Association (NYHA) Class III-IV congestive heart failure
10. • Severe cognitive impairment
11. • Drug addiction
12. • History of non-adherence to therapy
13. • Active infection
14. • Expected life expectancy < 5 years

    Additional exclusion criteria

15. • Type 1 diabetes mellitus
16. • History of diabetic ketoacidosis within the last 12 months
17. • Planning on undergoing bariatric surgery in next 9 months.
18. • Pregnant, breast-feeding, or planned pregnancy prior to the end of participation or not using adequate contraceptive measures
19. • Self-reported average consumption of > 21 alcoholic beverages per week or binge drinking
20. • Psychiatric hospitalization in past year
21. • Principal investigator discretion (i.e. concerns about safety, compliance)
22. • Known or suspected allergy to trial medication
23. • Previous participation (i.e. randomized) in this trial
24. • Use of GLP1-RA or pramlintide within 90 days prior to screening
25. • Use of metformin (contraindicated with eGFR < 30 ml/min/1.73m2)
26. • Use of DPP-4 inhibitors within 30 days prior to screening
27. • Personal or family history of medullary thyroid cancer, multiple endocrine neoplasia types 2A and 2B syndrome
28. • Last hemoglobin A1c ≥ 12% or A1c <6% (to avoid risk of hypoglycemia) prior to screening

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution	This arm will receive placebo.
Semaglutide	Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection solution	This arm will receive semaglutide.

Primary Outcome Measures

Name	Time	Method
Kidney Transplant Eligibility	Ascertained at the end of 9 months	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)

Secondary Outcome Measures

Name	Time	Method
Change in Hemoglobin A1c (HgbA1c)	From baseline to 9 months	HgbA1c will be collected using routine procedures and measured on the same day at the central Geisinger laboratory by Turbidimetric inhibition immunoassay.
Change in BMI	From baseline to 9 months	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.
Change in Waist Circumference	From baseline to 9 months	Waist circumference will be measured at each study visit to the nearest 0.1 cm using a Gulick II tape measure.
Change in Waist-to-hip Ratio	From baseline to 9 months	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.
Change in Body Fat Percentage	From baseline to 9 months	Measured using bioelectrical impedance analysis
New Activation on the Transplant List	Assessed at end of 9 months	Proportion of participants who were newly added to a transplant list during study period. Assessed by Geisinger kidney transplant committee (blinded to randomization assignment, independent of investigators)
Receipt of Kidney Transplant	Assessed at end of 9 months	Confirmed by review of electronic health record (EHR)

Trial Locations

Locations (2)

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

Geisinger Wyoming Valley; 🇺🇸 Wilkes-Barre, Pennsylvania, United States