RAISE-KT: Effect of Subcutaneous Semaglutide on Kidney Transplant Candidacy

Sponsor

Geisinger Clinic (Other)

Overall Status

Recruiting

CT.gov ID

NCT04741074

Collaborator

(none)

150

Enrollment

Locations

Arms

46.3

Anticipated Duration (Months)

Patients Per Site

1.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
CKD Diabetic Kidney Disease Type 2 Diabetes Mellitus in Obese Obesity Severe Obesity	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	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This is a placebo-controlled double-blind clinical trial. Study investigators and participants will be blinded to treatment allocation.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 23, 2021

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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
Activation on the transplant list [Assessed at end of 9 months]
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)

Other Outcome Measures

Change in Low-Density Lipoprotein (LDL) [Baseline to 9 months]
Collected at a Geisinger lab using routine procedures and measured on the same day at the central Geisinger laboratory by spectrophotometry.
Change in triglycerides [Baseline to 9 months]
Collected at a Geisinger lab using routine procedures and measured on the same day at the central Geisinger laboratory by spectrophotometry.
Change in systolic blood pressure [Baseline to 9 months]
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.
Change in diastolic blood pressure [Baseline to 9 months]
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.
Change in albuminuria among subset of participants without end-stage kidney disease [Baseline to 9 months]
Testing at the central Geisinger laboratory, using immunoturbidimetry (albumin) and Jaffe/Enzymatic (Urine Creatinine)
Change in estimated glomerular filtration (eGFR) rate among subset of participants without end-stage kidney disease [Baseline to 9 months]
Testing at central Geisinger lab; Creatinine-based CKD-EPI equation
All-cause hospitalizations [Entire 9-month study period]
Collected using Geisinger EHR data
Cardiovascular disease (CVD) events [Entire 9-month study period]
Collected using Geisinger EHR data using ICD codes for CVD-related hospitalizations
Proportion experiencing doubling of creatinine or end-stage kidney disease [Entire 9-month study period]
Collected using Geisinger EHR data using ICD codes
Proportion experiencing death [Entire 9-month study period]
Collected using Geisinger EHR data
Proportion experiencing gastrointestinal disorders [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing gallbladder disorders [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing neoplasms [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing hepatic events [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing allergic reactions [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing injection-site reactions [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing hypoglycemia events [Entire 9-month study period]
Assessed at each study visit
Proportion experiencing acute pancreatitis events [Entire 9-month study period]
Assessed at each study visit

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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