Empagliflozin Treatment in Kidney Transplant Recipients
- Registration Number
- NCT06013865
- Lead Sponsor
- VA Office of Research and Development
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 264
- Adult (>18 years of age) male and female recipients (all races and ethnicities)
- Subject must be able to understand and provide consent
- Recipient of a primary or secondary kidney transplant at least 3 months or longer since transplant
- 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).
- 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).
- Inability or unwillingness of a participant to give written informed consent or comply with study protocol
- History of prior pancreas transplant
- 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
- Uncontrolled type 2 diabetes mellitus with most recent A1C>12%
- History of >2 urinary tract infections per year or UTIs requiring admission in the last year, or urosepsis in the last year.
- Use of SGLT2i within 90 days
- Documented allergy to SGLT2i
- History of Type I diabetes mellitus
- History of diabetic ketoacidosis
- Indwelling foley catheter or urinary diversion
- Acute rejection in the prior 3 months
- Acute MACE event within 3 months of the study
- Severe congestive heart failure (NYHA functional class III or higher)
- Active mucocutaneous mycotic infection of the groin or external genitalia.
- History of amputation due to peripheral vascular disease and/or diabetic foot ulcers within prior year
- History of malignancy except non-melanoma skin cancer within 2 years of screening
- Known of active current viral, fungal, mycobacterial, or other infections (including, but not limited to tuberculosis and atypical mycobacterial disease)
- HIV infected subjects, including those who are well controlled on anti-retrovirals
- Recent (within 6 months) Positive Hep B PCR or active disease
- Hepatitis C virus antibody positive (HCVAb+) subjects who have failed to demonstrate sustained viral remission for more than 12 weeks (after anti-viral treatment)
- Active pregnancy in a female transplant recipient
- A condition, in the eyes of the investigator, that precludes inclusion into the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Empagliflozin Empagliflozin Open Label, Empagliflozin 12.5 mg QD
- Primary Outcome Measures
Name Time Method Discontinuation of Empagliflozin about 2 years The incidence of therapeutic discontinuation of empagliflozin in the kidney transplant recipient from time of initiation.
- Secondary Outcome Measures
Name Time Method Death about 2 years Time to the occurrence of cardiovascular death
Hypoglycemia about 2 years The cumulative incidence of grade 3 hypoglycemia
Volume Depletion about 2 years The cumulative incidence of grade 3 volume depletion.
Acute Graft Dysfunction about 2 years The cumulative incidence of \>15% elevation in serum creatinine for more than 4 weeks from the baseline defined prior to treatment.
Amputation and foot ulceration About 2 years The cumulative incidence of Grade 3 foot ulceration and/or need for amputation.
Allograft Biopsy about 2 years Time to incidence of a decline in eGFR sufficient to trigger a clinical decision for an allograft biopsy
Infection about 2 years Defined as the cumulative incidence of study defined Grade 3 or higher infection of the urinary tract or perineum after initiation of treatment.
Major cardiorenal events about 2 years 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)
MACER about 2 years Time to first occurrence of individual component of the MACER secondary outcome
Acute graft dysfunction About 2 years Time to acute kidney injury as defined as a \>15% change in eGFR from baseline
Slope of kidney function over 2 years Serum creatinine measured in mg/dL for all participants prior to treatment, at month 6, month 12 and month 24 of treatment.
Acute Cellular Rejection about 2 years 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 t1Proteinuria 12 and 24 months Spot Urine Protein/creatinine ratio
Body Weight over 2 years Change in body weight over time of treatment
Glycemic Control over 2 years Changes in Hemoglobin A1C over time of treatment
Blood Pressure over 2 years Change in blood pressure measured in mmHg over the course of the study
Trial Locations
- Locations (5)
Edward Hines Jr. VA Hospital, Hines, IL
🇺🇸Hines, Illinois, United States
Iowa City VA Health Care System, Iowa City, IA
🇺🇸Iowa City, Iowa, United States
Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
🇺🇸Omaha, Nebraska, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
🇺🇸Pittsburgh, Pennsylvania, United States
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
🇺🇸Nashville, Tennessee, United States