Empagliflozin in ESKD - A Feasibility Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Empagliflozin in ESKD - A Feasibility Study

Conditions
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Kidney Failure, Chronic, Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin 25 mg thrice-weekly post-hemodialysis dosing
* Drug: Empagliflozin 10 mg daily dosing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥18 years; diagnosis of end-stage kidney disease requiring dialysis, and ability to provide informed consent. Exclusion Criteria: systolic blood pressure <100 mm Hg (pre-dialysis for HD patients) two or more episodes of urinary tract infection within the last 12 months history of urinary retention or urinary tract obstruction liver cirrhosis advanced heart failure requiring heart assist device or inotropic support heart or liver transplant recipient major surgery performed within the last 3 months (major per the investigator's assessment) major surgery scheduled within 3 months after screening (major per the investigator's assessment) active cancer pregnant or lactating women known allergy or hypersensitivity to any SGLT2 inhibitors history of ketoacidosis during the last 12 months any other medical condition considered unappropriated by their nephrologists or a study physician (i.e., cachexia, short life expectancy, or uncontrolled personality/phycological disorder).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A single-center, non-randomized, two-arm intervention study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin 25 mg thrice-weekly post-hemodialysis dosing<br>All participants undergoing thrice-weekly hemodialysis (HD) on the Monday-Wednesday-Friday (MWF) schedule will be assigned to the empagliflozin 25 mg thrice-weekly post-hemodialysis dosing arm (Group I). | Drug: Empagliflozin 25 mg thrice-weekly post-hemodialysis dosing<br>* Participants in Group I will be asked to take empagliflozin 25 mg after each hemodialysis session under direct observation by a trained health care worker.<br>* Other names: Jardiance 25 mg thrice-weekly post-hemodialysis dosing;|
| Experimental: Empagliflozin 10 mg daily dosing<br>Patients undergoing thrice-weekly hemodialysis (HD) on the Tuesday-Thursday-Saturday (TTS) schedule, patients on twice-weekly HD, or patients on peritoneal dialysis will receive empagliflozin 10 mg daily (Group II). | Drug: Empagliflozin 10 mg daily dosing<br>* Participants assigned to Group II will be asked to take empagliflozin 10 mg each morning between 8:30 and 9:30 a.m. at home.<br>* Other names: Jardiance 10 mg daily dosing;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of eligible patients out of screened patients |  | During the screening process | 
| Success rate of obtaining consent from those eligible patients |  | During the enrollment process | 
| Proportion of missing doses | The investigators will do pill count using medication bottles and calculate the proportion of missing doses from each patient. | 3 months | 
| Proportion of empagliflozin discontinuation | Proportion of participants who discontinue empagliflozin for any reason | 3 months | 
| Dropout rate | Proportion of participants who dropped out from the study for any reason | 3 months | 
| Length of time on continuous glucose monitoring | Continuous glucose monitoring will be done for up to 14 days. | 3 months | 
| Completion rate of timed urine collection |  | 3 months | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 1st blood draw for the pharmacokinetic study among patients on peritoneal dialysis | Immediately before the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 2nd blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 30 minutes of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 3rd blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 1 hour of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 4th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 1.5 hours of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 5th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 2 hours of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 6th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 3 hours of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 7th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 4 hours of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 8th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 8 hours of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 9th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 12 hours of the first dose | 
| Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis | The 10th blood draw for the pharmacokinetic study among patients on peritoneal dialysis | At 24 hours of the first dose | 
| Random blood empagliflozin level | Time since the last dose will be recorded. | At Month 1 | 
| Random blood empagliflozin level | Time since the last dose will be recorded. | At Month 2 | 
| Random blood empagliflozin level | Time since the last dose will be recorded. | At Month 3 | 
| Peritoneal dialysis clearance of empagliflozin | Peritoneal dialysis fluid will be collected for 24 hours. | At Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Hepatic injury | defined by an elevation of AST and/or ALT >3-fold upper limit of normal (ULN) combined with an elevation of total bilirubin >2-fold ULN measured, and/or marked peak aminotransferase (ALT and/or AST) elevations ≥5-fold ULN | 3 months | 
| Number of Participants with Ketoacidosis | defined by elevated serum beta hydroxybutyrate ≥3.0 mmol/L | 3 months | 
| Number of Participants with Lower limb amputation | defined by any non-trauma-related event leading to a lower limb procedure of amputation, auto-amputation or disarticulation | 3 months | 
| Number of Participants with Symptomatic urinary tract infection | defined by symptoms consistent with urinary tract infection plus pyuria and bacteriuria - urine culture sample has to be taken and sent to central lab for confirmation of the diagnosis | 3 months | 
| Number of Participants with genital infection | per patient report | 3 months | 
| Number of Participants with Tinea cruris | per patient report | 3 months | 
| Number of Participants with Nausea | per patient report | 3 months | 
| Number of Participants with Vomiting | per patient report | 3 months | 
| Number of Participants with Skin and soft tissue infection | per patient report | 3 months | 
| Number of Participants with Hypoglycemia levels 1 | Plasma glucose <70 mg/dL for ≥15 minutes | 3 months | 
| Number of Participants with Hypoglycemia levels 2 | Plasma glucose <54 mg/dL for ≥15 minutes | 3 months | 
| Number of Participants with Prolonged hypoglycemia | Plasma glucose <54 mg/dL for ≥2.0 hours | 3 months | 
| Changes from baseline to Month 3 in left ventricular end-diastolic volume | To be evaluated by transthoracic echocardiogram (optional) | 3 months | 
| Changes from baseline to Month 3 in left ventricular end-systolic volume | To be evaluated by transthoracic echocardiogram (optional) | 3 months | 
| Changes from baseline to Month 3 in left ventricular mass | To be evaluated by transthoracic echocardiogram (optional) | 3 months | 
| Changes from baseline to Month 3 in left ventricular ejection fraction | To be evaluated by transthoracic echocardiogram (optional) | 3 months | 
| Changes from baseline to Month 3 in left ventricular diastolic function | To be evaluated by transthoracic echocardiogram (optional) | 3 months | 
| Changes from baseline to Month 3 in home systolic blood pressure |  | 3 months | 
| Changes from baseline to Month 3 in home diastolic blood pressure |  | 3 months | 
| Changes from baseline to Month 3 in Kidney Disease Quality of Life (KDQOL)-36 questionnaire | Details are available at the URL below. https://www.rand.org/content/dam/rand/www/external/health/surveys_tools/kdqol/kdqol36.pdf | 3 months | 
| Changes from baseline to Month 3 in residual kidney function | Renal urea clearance | 3 months | 
| Changes from baseline to Month 3 in hemoglobin |  | 3 months | 
| Changes from baseline to Month 3 in erythropoiesis stimulating drug dose |  | 3 months | 
| Hospitalization/Emergency room visit rate for heart failure |  | 3 months | 
| Cardiovascular mortality |  | 3 months | 
| All-cause mortality |  | 3 months | 
| Changes Estimated glomerular filtration rate (GFR) from baseline to Month 3 | Estimated by Cystatin C and beta-2 macroglobulin | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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residual kidney function, Sodium-glucose transporter type 2 inhibitor, empagliflozin, end-stage kidney disease, pharmacokinetics, pharmacodynamics, feasibility trial, heart failure