Clinical trial NCT06013865: Empagliflozin Treatment in Kidney Transplant Recipients
Official title: An Exploratory Investigation of the Safety of Empagliflozin in Kidney Transplant Recipients (SEKTR)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Kidney Transplant
Chronic Kidney Disease
Keywords: Transplant
Diabetes
Kidney Failure
Rejection
Proteinuria
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Iowa City VA Health Care System
name: VA Pittsburgh Healthcare System
name: VA Tennessee Valley Health Care System
name: VA Hines Health Care
First posted: 2023-08-28
Enrollment: 264
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective Observational Cohort Study
Primary purpose: TREATMENT

Brief summary: 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.

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 with and without T2DM. The hypothesis is treatment with SGLT2i will lead to improvements in graft and cardiovascular outcomes in patients with chronic kidney disease, with acceptable side effect profile.

Methods: To test this hypothesis, the investigators will execute a multicenter clinical trial at 5 VA medical centers, including 4 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 with and without 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.

Eligibility 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. For subjects with T2DM or post-transplant diabetes (PTDM), measured kidney function by CKD epi eGFR must be 30mL/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).
5. For subjects without T2DM or PTDM: measured kidney function by CKD epi eGFR must be 20mL/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:

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 for those with T2DM or \< 20 mL/min/1.73m2 for those without T2DM or anyone with 5mL/min/1.73m2 fall in eGFR 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 2 years of screening
17. Known of 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. Recent (within 6 months) Positive Hep B PCR or active disease
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
22. A condition, in the eyes of the investigator, that precludes inclusion into the study.

Primary outcomes:
measure: Discontinuation of Empagliflozin
timeFrame: about 2 years
Secondary outcomes:
measure: Infection
timeFrame: about 2 years
measure: Hypoglycemia
timeFrame: about 2 years
measure: Major cardiorenal events
timeFrame: about 2 years
measure: Acute Graft Dysfunction
timeFrame: about 2 years
measure: Volume Depletion
timeFrame: about 2 years
measure: Acute Cellular Rejection
timeFrame: about 2 years
measure: Amputation and foot ulceration
timeFrame: About 2 years
measure: Proteinuria
timeFrame: 12 and 24 months
measure: Allograft Biopsy
timeFrame: about 2 years
measure: MACER
timeFrame: about 2 years
measure: Death
timeFrame: about 2 years
measure: Acute graft dysfunction
timeFrame: About 2 years
measure: Slope of kidney function
timeFrame: over 2 years
measure: Glycemic Control
timeFrame: over 2 years
measure: Body Weight
timeFrame: over 2 years
measure: Blood Pressure
timeFrame: over 2 years
Other outcomes:
Locations:
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Iowa City
country: United States
facility: Iowa City VA Health Care System, Iowa City, IA
state: Iowa
city: Omaha
country: United States
facility: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
state: Nebraska
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
state: Tennessee
Study officials:
affiliation: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
name: Roslyn B Mannon, MD
role: PRINCIPAL_INVESTIGATOR
References: