Empagliflozin Treatment in Kidney Transplant Recipients (SEKTR)

An Exploratory Investigation of the Safety of Empagliflozin in Kidney Transplant Recipients (SEKTR)

Kidney transplantation improves the health and quality of life for those Veterans with end stage kidney disease (ESKD). While early patient and graft survival are excellent, long-term outcomes continue to be challenging. Patient death with existing kidney graft function occurs in about half of all recipients over time. This is primarily due to the development of cardiovascular disease in a patient population with multiple preexisting cardiac disease risk factors. There has been little progress in improving outcomes in this area for over two decades. Recent studies in chronic kidney disease (CKD) patients using SGLT2 inhibitors (SGLT2i), regardless of the presence of type 2 diabetes mellitus (T2DM), results in both kidney protective and cardiac protective impacts and improved patient outcomes. However, kidney transplant recipients (KTRs) were excluded from these clinical trials due to concerns that these agents promote infection, diminish graft function, and may alter immunosuppressive drug levels that are the mainstay of patient's transplant therapy. There are limited published data of SGLT2i treatment of selected KTRs.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 2 Diabetes; Kidney Transplant
• Intervention / Treatment: Drug: Empagliflozin

Detailed Description

Background: Kidney transplantation improves the health and quality of life for those veterans with end stage kidney disease (ESKD). While early patient and graft survival are excellent, long-term outcomes continue to be challenging. Patient death with existing kidney graft function occurs in about half of all recipients over time. This is primarily due to the development of cardiovascular disease in a patient population with multiple preexisting cardiac disease risk factors. There has been little progress in improving outcomes in this area for over two decades. Recent studies in chronic kidney disease (CKD) patients using SGLT2 inhibitors (SGLT2i), regardless of the presence of type 2 diabetes mellitus (T2DM), results in both kidney protective and cardiac protective impacts and improved patient outcomes. However, kidney transplant recipients (KTRs) were excluded from these clinical trials due to concerns that these agents promote infection, diminish graft function, and may alter immunosuppressive drug levels that are the mainstay of patient's transplant therapy. There are limited published data of SGLT2i treatment of selected KTRs.

Objective: The goal of this submission is to examine the safety and efficacy of SGLT2i therapy in Veterans with KTRs and T2DM. The hypothesis is treatment with SGLT2i will lead to improvements in graft and cardiovascular outcomes in patients with T2DM, with acceptable side effect profile.

Methods: To test this hypothesis, the investigators will execute a multicenter clinical trial at 4 VA medical centers, including 3 that serve as primary kidney transplant programs. The multidisciplinary research team includes transplant medical and surgical expertise, diabetology, and informatics and statistical support familiar with VA data systems. In open label fashion, the investigators will treat eligible KTRs and comprehensively assess adverse and serious adverse event data, as well as assess any untoward impacts on graft function and diabetes management. Secondly, the investigators will utilize VA data from the VINCI corporate data warehouse to develop a control cohort of Veterans with KTRs and T2DM, not treated with SGLT2i. The investigators will utilize propensity score matching to reduce bias that may occur in observational studies. With this strategy, the investigators will further address the potential beneficial impact of SGLT2i treatment on cardiovascular outcomes, as well as kidney disease progression in the transplanted kidney. The investigators will also analyze the cost impact of using this agent in this patient population, in terms of hospitalizations, unanticipated procedures, and CKD management.

Findings: These studies will provide new information to the transplant community for both Veteran and non-Veteran alike, with a detailed assessment of safety and feasibility of this agent class using a pragmatic approach to transplant care. These results will translate into an opportunity to mitigate late graft loss in this patient population, and a potential breakthrough in clinical care that to date has been unrecognized.

• Study Type: Interventional
• Enrollment (Estimated): 264
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Roslyn B Mannon, MD; Phone Number: (205) 999-7362; Email: roslyn.mannon@va.gov
• Study Contact Backup: Name: Ramesh K Ramalingam; Phone Number: (402) 995-4873; Email: Ramesh.Ramalingam@va.gov

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52246-2292
      • Iowa City VA Health Care System, Iowa City, IA
      • Contact: Marion L Sanders, MD; Phone Number: x635200 319-338-0581; Email: marion.sanders2@va.gov
  • Nebraska
    • Omaha, Nebraska, United States, 68105-1850
      • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
      • Contact: Ramesh K Ramalingam; Phone Number: (402) 995-4873; Email: Ramesh.Ramalingam@va.gov
      • Contact: Roslyn B Mannon, MD; Phone Number: 205-999-7362; Email: roslyn.mannon@va.gov
      • Principal Investigator: Roslyn B Mannon, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
      • Contact: Mohan Ramkumar, MBBS; Phone Number: 412-360-3910; Email: mohan.ramkumar@va.gov
      • Contact: Samantha Gray, MS; Phone Number: 4123603788; Email: Samantha.Gray6@va.gov
  • Tennessee
    • Nashville, Tennessee, United States, 37212-2637
      • Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
      • Contact: Kelly Birdwell, MD; Phone Number: 615-873-6974; Email: kelly.birdwell@va.gov
      • Contact: Cindy A Mambungu, LPN; Phone Number: 6153435828; Email: cindy.mambungu@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

INCLUSION CRITERIA

1. Adult (>18 years of age) male and female recipients (all races and ethnicities)
2. Subject must be able to understand and provide consent
3. Recipient of a primary or secondary kidney transplant at least 3 months or longer since transplant
4. Subject must have a diagnosis of Type 2 Diabetes Mellitus or post-transplant diabetes mellitus (PTDM) 2DM or PTDM
5. Subject must be able to travel to and from VAMC for care and monitoring
6. Subject must have kidney function measured by CKD epi eGFR 30 mL/min/1.73m2 to < 45ml/min/1.73m2 or CKD epi eGFR 45 mL/min/1.73m2 to 90ml/min/1.73m2 with urinary albumin:creatinine ratio 200 mg/g (or protein:creatinine 300 mg/g).

Exclusion Criteria:

EXCLUSION CRITERIA

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol
2. History of prior pancreas transplant
3. CKD epi eGFR< 30 mL/min/1.73m2 with 5mL/min/1.73m2 fall per year
4. Uncontrolled type 2 diabetes mellitus with most recent A1C>12%
5. History of >2 urinary tract infections per year or UTIs requiring admission in the last year, or urosepsis in the last year.
6. Use of SGLT2i within 90 days
7. Documented allergy to SGLT2i
8. History of Type I diabetes mellitus
9. History of diabetic ketoacidosis
10. Indwelling foley catheter or urinary diversion
11. Acute rejection in the prior 3 months
12. Acute MACE event within 3 months of the study
13. Severe congestive heart failure (NYHA functional class III or higher)
14. Active mucocutaneous mycotic infection of the groin or external genitalia.
15. History of amputation due to peripheral vascular disease and/or diabetic foot ulcers within prior year
16. History of malignancy except non-melanoma skin cancer within 5 years of screening
17. Known active current viral, fungal, mycobacterial, or other infections (including, but not limited to tuberculosis and atypical mycobacterial disease)
18. HIV infected subjects, including those who are well controlled on anti-retrovirals
19. Positive Hep B PCR
20. Hepatitis C virus antibody positive (HCVAb+) subjects who have failed to demonstrate sustained viral remission for more than 12 weeks (after anti-viral treatment)
21. Active pregnancy in a female transplant recipient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Empagliflozin; Open Label, Empagliflozin 12.5 mg QD	Drug: Empagliflozin; SGLT2 Inhibitor; Other Names: jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discontinuation of Empagliflozin	The incidence of therapeutic discontinuation of empagliflozin in the kidney transplant recipient from time of initiation.	about 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infection	Defined as the cumulative incidence of study defined Grade 3 or higher infection of the urinary tract or perineum after initiation of treatment.	about 2 years
Hypoglycemia	The cumulative incidence of grade 3 hypoglycemia	about 2 years
Major cardiorenal events	Time to first occurrence of the composite of major adverse cardiorenal events (MACER) as defined as all-cause mortality, stroke, non-fatal myocardial infarction, heart failure events including hospitalization for CHF or urgent CHF treatment, sustained (for at least 3 months) 40% decline in eGFR, or allograft failure as defined by chronic dialysis, re-transplantation, or persistent eGFR <15mL/min/1.73m2)	about 2 years
Acute Graft Dysfunction	The cumulative incidence of >15% elevation in serum creatinine for more than 4 weeks from the baseline defined prior to treatment.	about 2 years
Volume Depletion	The cumulative incidence of grade 3 volume depletion.	about 2 years
Acute Cellular Rejection	The cumulative incidence of acute rejection biopsy proven using 2017 criteria: Type IA Moderate tubulitis and at least moderate interstitial inflammation t2i2 or t2i3 Type IB Severe tubulitis and at least moderate interstitial inflammation t3i2 or t3i3 Type IIA Mild to moderate intimal arteritis v1 Type IIB Severe intimal arteritis (> 25% of the luminal area) v2 Type III Transmural' arteritis and/or fibrinoid necrosis v3 Borderline: no intimal arteritis is present, t>0 and i1 or i2/i3 and t1	about 2 years
Amputation and foot ulceration	The cumulative incidence of Grade 3 foot ulceration and/or need for amputation.	About 2 years
Proteinuria	Spot Urine Protein/creatinine ratio	12 and 24 months
Allograft Biopsy	Time to incidence of a decline in eGFR sufficient to trigger a clinical decision for an allograft biopsy	about 2 years
MACER	Time to first occurrence of individual component of the MACER secondary outcome	about 2 years
Death	Time to the occurrence of cardiovascular death	about 2 years
Acute graft dysfunction	Time to acute kidney injury as defined as a >15% change in eGFR from baseline	About 2 years
Slope of kidney function	Serum creatinine measured in mg/dL for all participants prior to treatment, at month 6, month 12 and month 24 of treatment.	over 2 years
Glycemic Control	Changes in Hemoglobin A1C over time of treatment	over 2 years
Body Weight	Change in body weight over time of treatment	over 2 years
Blood Pressure	Change in blood pressure measured in mmHg over the course of the study	over 2 years

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: VA Pittsburgh Healthcare System; Nashville VA Medical Center; Iowa City VA Health Care System
• Investigators: Principal Investigator: Roslyn B Mannon, MD, Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 31, 2030
• Study Completion (Estimated): March 31, 2030

Study Registration Dates

• First Submitted: August 22, 2023
• First Submitted That Met QC Criteria: August 22, 2023
• First Posted (Actual): August 28, 2023

Study Record Updates

• Last Update Posted (Estimated): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Diabetes; Rejection; Transplant; Kidney Failure
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: NEPH-008-22F; CSR&D (Other Grant/Funding Number: VAMC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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