Clinical trial NCT05687058: Empagliflozin in ESKD - A Feasibility Study
Official title: Empagliflozin in ESKD - A Feasibility Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Kidney Failure, Chronic
Heart Failure
Keywords: empagliflozin
end-stage kidney disease
pharmacokinetics
pharmacodynamics
feasibility trial
heart failure
residual kidney function
Sodium-glucose transporter type 2 inhibitor
Lead sponsor: University of Mississippi Medical Center
Sponsor class: OTHER
First posted: 2023-01-17
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A single-center, non-randomized, two-arm intervention study
Primary purpose: TREATMENT

Brief summary: The aim of this study is to learn about the safety of empagliflozin in dialysis patients as a preparation for a future large clinical trial. Empagliflozin has been approved by the Food and Drug Administration for the treatment of either type 2 diabetes, heart failure, or chronic kidney disease among patients not on dialysis. The use of empagliflozin has not been studied or approved among patients on dialysis for kidney failure because empagliflozin acts on the kidneys. However, recent experimental studies have indicated that empagliflozin may provide direct heart benefits. Some dialysis patients have substantial residual kidney function, which may be protected by empagliflozin.

Participants will be given empagliflozin for three (3) months on top of the standard of care (usual medical care for participants' condition) and will be followed up until one (1) month after the last dose. The investigators will collect information about participants' general health, obtain blood, urine, and imaging studies, check home blood pressure, monitor home blood sugar levels, and ask health-related questions to assess the safety and potential benefits of empagliflozin over four (4) months, including one month before the three (3)-month empagliflozin treatment.

Detailed description: The incidence of end-stage kidney disease (ESKD) in the US ranks among the highest in the world. ESKD is the last phase of chronic kidney disease when the kidneys are functioning below 10-15% of normal capacity, and the patient is on dialysis. According to the US Renal Data System (USRDS), 120,834 individuals started dialysis and nearly 524,000 people were living on dialysis in 2017.1 Although advancement in technology and general medical care has led to a modest decrease in mortality among dialysis patients, their mortality rate remains extremely high at approximately 16.5 per 100 patient-years. The leading cause of death among dialysis patients is cardiovascular disease (CVD), accounting for almost 45% of deaths. Unfortunately, established therapies to prevent incident CVD in the general population, such as renin-angiotensin system inhibitors or statins, have not been shown to be effective in the dialysis population.

Sodium-glucose transporter type 2 (SGLT2) inhibitors are originally approved by FDA for the treatment for type 2 diabetes. SGLT2 is localized to the brush border of the early proximal tubule, and hence, SGLT2inhibitors induce osmotic diuresis and natriuresis but do not activate the systemic renin-angiotensin-aldosterone system.2 Recent clinical trials have consistently shown their potent renal and cardiovascular benefits in both diabetic and non-diabetic patients, which cannot be explained only by their glucose-lowering and diuretic properties. In fact, diuretics have not been shown to reduce cardiovascular mortality and such benefits of SGLT2 inhibitors are clear even among non-diabetic populations.3-5 Their renoprotective effect potentially extends to the dialysis population where residual kidney function (RKF) still plays a major role in solute clearance and volume control and has a strong association with patient outcomes.6 Patients who retain greater RKF can consume a more liberal diet and have better nutritional status, less pill burden, better blood pressure, and less interdialytic fluid gain with less frequent intradialytic hypotension, as well as greater quality of life and better survival.6 The pathophysiology underlying the cardiovascular benefits of SGLT2 inhibitors are yet to be fully elucidated, but a recent in-vitro studies indicate its direct effects on cardiomyocytes. Therefore, the investigators hypothesize that dialysis patients also benefit from SGLT2 inhibitors even if they do not have any RKF.

Efficacy and safety studies with SGLT2 inhibitors did not enroll end-stage kidney disease (ESKD) patients on dialysis. Empagliflozin, canagliflozin, and dapagliflozin can be started if the glomerular filtration rate is more than 20-25 mL/min per 1.73 m2 and can be continued until dialysis initiation or kidney transplant. From a pharmacokinetics standpoint, those SGLT2 inhibitors are extensively metabolized by glucuronidation into inactive metabolites, and are not likely to cause dose-dependent toxicity even in ESKD. Nevertheless, extra caution is necessary for their use in the setting of ESKD because SGLT2 inhibitors are not well dialyzable due to large distribution volumes and high protein binding rates.

Our overall goal is to conduct a non-randomized feasibility clinical trial of empagliflozin in the dialysis population to obtain data that will help plan future larger, sufficiently powered efficacy clinical trials. The investigators plan to enroll a total of 24 dialysis patients (18 patients on hemodialysis and 6 patients on peritoneal dialysis). After one month of the run-in period, participants will take oral empagliflozin for 3 months.

\*Hemodialysis is a form of renal replacement therapy that utilizes an external filter (dialyzer) to remove wastes from the bloodstream. Peritoneal dialysis utilizes the peritoneum as a filter to remove wastes.

Eligibility criteria: Inclusion Criteria:

1. age ≥18 years;
2. diagnosis of end-stage kidney disease requiring dialysis, and
3. ability to provide informed consent.

Exclusion Criteria:

1. systolic blood pressure \<100 mm Hg (pre-dialysis for HD patients)
2. two or more episodes of urinary tract infection within the last 12 months
3. history of urinary retention or urinary tract obstruction
4. liver cirrhosis
5. advanced heart failure requiring heart assist device or inotropic support
6. heart or liver transplant recipient
7. major surgery performed within the last 3 months ("major" per the investigator's assessment)
8. major surgery scheduled within 3 months after screening ("major" per the investigator's assessment)
9. active cancer
10. pregnant or lactating women
11. known allergy or hypersensitivity to any SGLT2 inhibitors
12. history of ketoacidosis during the last 12 months
13. any other medical condition considered unappropriated by their nephrologists or a study physician (i.e., cachexia, short life expectancy, or uncontrolled personality/phycological disorder).

Primary outcomes:
measure: Proportion of eligible patients out of screened patients
timeFrame: During the screening process
measure: Success rate of obtaining consent from those eligible patients
timeFrame: During the enrollment process
measure: Proportion of missing doses
timeFrame: 3 months
measure: Proportion of empagliflozin discontinuation
timeFrame: 3 months
measure: Dropout rate
timeFrame: 3 months
measure: Length of time on continuous glucose monitoring
timeFrame: 3 months
measure: Completion rate of timed urine collection
timeFrame: 3 months
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: Immediately before the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 30 minutes of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 1 hour of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 1.5 hours of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 2 hours of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 3 hours of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 4 hours of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 8 hours of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 12 hours of the first dose
measure: Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
timeFrame: At 24 hours of the first dose
measure: Random blood empagliflozin level
timeFrame: At Month 1
measure: Random blood empagliflozin level
timeFrame: At Month 2
measure: Random blood empagliflozin level
timeFrame: At Month 3
measure: Peritoneal dialysis clearance of empagliflozin
timeFrame: At Month 3
Secondary outcomes:
measure: Number of Participants with Hepatic injury
timeFrame: 3 months
measure: Number of Participants with Ketoacidosis
timeFrame: 3 months
measure: Number of Participants with Lower limb amputation
timeFrame: 3 months
measure: Number of Participants with Symptomatic urinary tract infection
timeFrame: 3 months
measure: Number of Participants with genital infection
timeFrame: 3 months
measure: Number of Participants with Tinea cruris
timeFrame: 3 months
measure: Number of Participants with Nausea
timeFrame: 3 months
measure: Number of Participants with Vomiting
timeFrame: 3 months
measure: Number of Participants with Skin and soft tissue infection
timeFrame: 3 months
measure: Days on continuous glucose monitoring (CGM)
timeFrame: Run in (within one month prior to the study start)
measure: Days on continuous glucose monitoring (CGM)
timeFrame: At Month 0
measure: Days on continuous glucose monitoring (CGM)
timeFrame: At Month 2
measure: % Time of active CGM
timeFrame: Run in (within one month prior to the study start)
measure: % Time of active CGM
timeFrame: At Month 0
measure: % Time of active CGM
timeFrame: At Month 2
measure: Average glucose
timeFrame: Run in (within one month prior to the study start)
measure: Average glucose
timeFrame: At Month 0
measure: Average glucose
timeFrame: At Month 2
measure: Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)
timeFrame: Run in (within one month prior to the study start)
measure: Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)
timeFrame: At Month 0
measure: Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)
timeFrame: At Month 2
measure: Glucose variability
timeFrame: Run in (within one month prior to the study start)
measure: Glucose variability
timeFrame: At Month 0
measure: Glucose variability
timeFrame: At Month 2
measure: Time in very high range (%)
timeFrame: Run in (within one month prior to the study start)
measure: Time in very high range (%)
timeFrame: At Month 0
measure: Time in very high range (%)
timeFrame: At Month 2
measure: Time in high range (%)
timeFrame: Run in (within one month prior to the study start)
measure: Time in high range (%)
timeFrame: At Month 0
measure: Time in high range (%)
timeFrame: At Month 2
measure: Time in target range (%)
timeFrame: Run in (within one month prior to the study start)
measure: Time in target range (%)
timeFrame: At Month 0
measure: Time in target range (%)
timeFrame: At Month 2
measure: Time in low range (%)
timeFrame: Run in (within one month prior to the study start)
measure: Time in low range (%)
timeFrame: At Month 0
measure: Time in low range (%)
timeFrame: At Month 2
measure: Time in very low range (%)
timeFrame: Run in (within one month prior to the study start)
measure: Time in very low range (%)
timeFrame: At Month 0
measure: Time in very low range (%)
timeFrame: At Month 2
measure: Number of Participants with Hypoglycemia levels 1
timeFrame: Run in (within one month prior to the study start)
measure: Number of Participants with Hypoglycemia levels 1
timeFrame: At Month 0
measure: Number of Participants with Hypoglycemia levels 1
timeFrame: At Month 2
measure: Number of Participants with Hypoglycemia levels 2
timeFrame: Run in (within one month prior to the study start)
measure: Number of Participants with Hypoglycemia levels 2
timeFrame: At Month 0
measure: Number of Participants with Hypoglycemia levels 2
timeFrame: At Month 2
measure: Number of Participants with Prolonged hypoglycemia
timeFrame: Run in (within one month prior to the study start)
measure: Number of Participants with Prolonged hypoglycemia
timeFrame: At Month 0
measure: Number of Participants with Prolonged hypoglycemia
timeFrame: At Month 2
measure: Changes from baseline to Month 3 in left ventricular end-diastolic volume
timeFrame: 3 months
measure: Changes from baseline to Month 3 in left ventricular end-systolic volume
timeFrame: 3 months
measure: Changes from baseline to Month 3 in left ventricular mass index
timeFrame: 3 months
measure: Changes from baseline to Month 3 in left ventricular ejection fraction
timeFrame: 3 months
measure: Changes from baseline to Month 3 in left ventricular diastolic function
timeFrame: 3 months
measure: Changes from baseline to Month 3 in longitudinal global strain
timeFrame: 3 months
measure: Changes from baseline to Month 3 in radial global strain
timeFrame: 3 months
measure: Changes from baseline to Month 3 in circumferential global strain
timeFrame: 3 months
measure: Changes from baseline to Month 3 in home systolic blood pressure
timeFrame: 3 months
measure: Changes from baseline to Month 3 in home diastolic blood pressure
timeFrame: 3 months
measure: Changes from baseline to Month 3 in Kidney Disease Quality of Life (KDQOL)-36 questionnaire
timeFrame: 3 months
measure: Changes from baseline to Month 3 in residual kidney function
timeFrame: 3 months
measure: Changes from baseline to Month 3 in hemoglobin
timeFrame: 3 months
measure: Changes from baseline to Month 3 in erythropoiesis stimulating drug dose
timeFrame: 3 months
measure: Hospitalization/Emergency room visit rate for heart failure
timeFrame: 3 months
measure: Cardiovascular mortality
timeFrame: 3 months
measure: All-cause mortality
timeFrame: 3 months
measure: Changes Estimated glomerular filtration rate (GFR) from baseline to Month 3
timeFrame: 3 months
Other outcomes:
measure: Semi-structured interview
timeFrame: 3 months
Locations:
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Jackson
country: United States
facility: Jackson Medicall Mall Dialysis Clinic
state: Mississippi
Study officials:
affiliation: University of Mississippi Medical Center
name: Yoshitsugu Obi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: