Effect of Subcutaneous Semaglutide on Kidney Transplant Candidacy (RAISE-KT)

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

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.

Study Overview

• Status: Terminated
• Conditions: Obesity; Diabetic Kidney Disease; Type 2 Diabetes Mellitus in Obese; CKD; Severe Obesity
• Intervention / Treatment: 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

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17821
      • Geisinger Medical Center
    • Wilkes-Barre, Pennsylvania, United States, 18702
      • Geisinger Wyoming Valley

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Semaglutide; This arm will receive semaglutide.	Drug: Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection solution; 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.; Other Names: semaglutide
Placebo Comparator: Placebo; This arm will receive placebo.	Drug: Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution; 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.; Other Names: placebo

What is the study measuring?

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 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 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 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
New Activation on the Transplant List	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)	Assessed at end of 9 months
Receipt of Kidney Transplant	Confirmed by review of electronic health record (EHR)	Assessed at end of 9 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Low-Density Lipoprotein (LDL)	Collected at a Geisinger lab using routine procedures and measured on the same day at the central Geisinger laboratory by spectrophotometry.	Baseline to 9 months
Change in Triglycerides	Collected at a Geisinger lab using routine procedures and measured on the same day at the central Geisinger laboratory by spectrophotometry.	Baseline to 9 months
Change in Systolic Blood Pressure	Automated office blood pressure (AOBP) will be measured (attended) using the OMRON 907-XL machine, with a 5-minute rest period in the seated position, followed by 3 measurements separated by 1-minute time intervals by trained research staff. Mid-arm circumference will be measured, and a cuff of appropriate size will be identified and the same size cuff will used for both visits.	Baseline to 9 months
Change in Diastolic Blood Pressure	Automated office blood pressure (AOBP) will be measured (attended) using the OMRON 907-XL machine, with a 5-minute rest period in the seated position, followed by 3 measurements separated by 1-minute time intervals by trained research staff. Mid-arm circumference will be measured, and a cuff of appropriate size will be identified and the same size cuff will used for both visits.	Baseline to 9 months
Change in Albuminuria Among Subset of Participants Without End-stage Kidney Disease	Testing at the central Geisinger laboratory, using immunoturbidimetry (albumin) and Jaffe/Enzymatic (Urine Creatinine)	Baseline to 9 months
Change in Estimated Glomerular Filtration (eGFR) Rate Among Subset of Participants Without End-stage Kidney Disease	Testing at central Geisinger lab; Creatinine-based CKD-EPI equation	Baseline to 9 months
All-cause Hospitalizations	Collected using Geisinger EHR data	Entire 9-month study period
Cardiovascular Disease (CVD) Events	Collected using Geisinger EHR data using ICD codes for CVD-related hospitalizations	Entire 9-month study period
Proportion Experiencing Doubling of Creatinine or End-stage Kidney Disease	Collected using Geisinger EHR data using ICD codes	Entire 9-month study period
Proportion Experiencing Death	Collected using Geisinger EHR data	Entire 9-month study period
Proportion Experiencing Gastrointestinal Disorders	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Gallbladder Disorders	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Neoplasms	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Hepatic Events	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Allergic Reactions	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Injection-site Reactions	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Hypoglycemia Events	Assessed at each study visit	Entire 9-month study period
Proportion Experiencing Acute Pancreatitis Events	Assessed at each study visit	Entire 9-month study period

Collaborators and Investigators

• Sponsor: Geisinger Clinic
• Investigators: Principal Investigator: Alex R Chang, MD, MS, Geisinger Clinic

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2021
• Primary Completion (Actual): January 31, 2023
• Study Completion (Actual): January 31, 2023

Study Registration Dates

• First Submitted: February 2, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 5, 2021

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: obesity; semaglutide; kidney transplant; diabetic kidney disease; glp-1; ckd; transplant wait list
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus, Type 2; Kidney Diseases; Obesity; Diabetic Nephropathies; Obesity, Morbid; Pharmaceutical Solutions
• Other Study ID Numbers: 2020-1050; Universal Trial Number (Registry Identifier: U1111-1183-4093)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Data will become available at the time of publication of the main trial results and will be publicly available indefinitely.
• IPD Sharing Access Criteria: The deidentified IPD will be publicly available without restrictions.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No