Empagliflozin in ESKD - A Feasibility Study

Heart Failure Clinical Trial

Official title:

Empagliflozin in ESKD - A Feasibility Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05687058
• Other study ID #: UMMC-Neph-EMPESKD-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 1, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: March 2024
• Source: University of Mississippi Medical Center
• Contact: Yoshitsugu Obi, MD, PhD
• Phone: 601-984-5670
• Email: yobi[@]umc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 31, 2024
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Heart Failure
• Kidney Failure, Chronic
• Renal Insufficiency

Intervention

Drug:
• Empagliflozin 25 mg thrice-weekly post-hemodialysis dosing
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.
• Empagliflozin 10 mg daily dosing
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.

Locations

Country	Name	City	State
United States	Jackson Medicall Mall Dialysis Clinic	Jackson	Mississippi
United States	University of Mississippi Medical Center	Jackson	Mississippi

Sponsors (1)

Lead Sponsor	Collaborator
University of Mississippi Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Semi-structured interview	The results would be qualitative and provide data that are needed to improve the enrollment efficiency and protocol adherence. This will be done by tracking eligible screened patients who then go on to participate in the study as well as overall participant compliance with study procedures.	3 months
Primary	Proportion of eligible patients out of screened patients		During the screening process
Primary	Success rate of obtaining consent from those eligible patients		During the enrollment process
Primary	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
Primary	Proportion of empagliflozin discontinuation	Proportion of participants who discontinue empagliflozin for any reason	3 months
Primary	Dropout rate	Proportion of participants who dropped out from the study for any reason	3 months
Primary	Length of time on continuous glucose monitoring	Continuous glucose monitoring will be done for up to 14 days.	3 months
Primary	Completion rate of timed urine collection		3 months
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Random blood empagliflozin level	Time since the last dose will be recorded.	At Month 1
Primary	Random blood empagliflozin level	Time since the last dose will be recorded.	At Month 2
Primary	Random blood empagliflozin level	Time since the last dose will be recorded.	At Month 3
Primary	Peritoneal dialysis clearance of empagliflozin	Peritoneal dialysis fluid will be collected for 24 hours.	At Month 3
Secondary	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
Secondary	Number of Participants with Ketoacidosis	defined by elevated serum beta hydroxybutyrate =3.0 mmol/L	3 months
Secondary	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
Secondary	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
Secondary	Number of Participants with genital infection	per patient report	3 months
Secondary	Number of Participants with Tinea cruris	per patient report	3 months
Secondary	Number of Participants with Nausea	per patient report	3 months
Secondary	Number of Participants with Vomiting	per patient report	3 months
Secondary	Number of Participants with Skin and soft tissue infection	per patient report	3 months
Secondary	Days on continuous glucose monitoring (CGM)	Per CGM report	Run in (within one month prior to the study start)
Secondary	Days on continuous glucose monitoring (CGM)	Per CGM report	At Month 0
Secondary	Days on continuous glucose monitoring (CGM)	Per CGM report	At Month 2
Secondary	% Time of active CGM	Per CGM report	Run in (within one month prior to the study start)
Secondary	% Time of active CGM	Per CGM report	At Month 0
Secondary	% Time of active CGM	Per CGM report	At Month 2
Secondary	Average glucose	Per CGM report	Run in (within one month prior to the study start)
Secondary	Average glucose	Per CGM report	At Month 0
Secondary	Average glucose	Per CGM report	At Month 2
Secondary	Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)	Per CGM report	Run in (within one month prior to the study start)
Secondary	Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)	Per CGM report	At Month 0
Secondary	Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)	Per CGM report	At Month 2
Secondary	Glucose variability	Per CGM report	Run in (within one month prior to the study start)
Secondary	Glucose variability	Per CGM report	At Month 0
Secondary	Glucose variability	Per CGM report	At Month 2
Secondary	Time in very high range (%)	Percent time for plasma glucose >250 mg/dL	Run in (within one month prior to the study start)
Secondary	Time in very high range (%)	Percent time for plasma glucose >250 mg/dL	At Month 0
Secondary	Time in very high range (%)	Percent time for plasma glucose >250 mg/dL	At Month 2
Secondary	Time in high range (%)	Percent time for plasma glucose >180 to 250 mg/dL	Run in (within one month prior to the study start)
Secondary	Time in high range (%)	Percent time for plasma glucose >180 to 250 mg/dL	At Month 0
Secondary	Time in high range (%)	Percent time for plasma glucose >180 to 250 mg/dL	At Month 2
Secondary	Time in target range (%)	Percent time for plasma glucose >70 to 180 mg/dL	Run in (within one month prior to the study start)
Secondary	Time in target range (%)	Percent time for plasma glucose >70 to 180 mg/dL	At Month 0
Secondary	Time in target range (%)	Percent time for plasma glucose >70 to 180 mg/dL	At Month 2
Secondary	Time in low range (%)	Percent time for plasma glucose >54 to 70 mg/dL	Run in (within one month prior to the study start)
Secondary	Time in low range (%)	Percent time for plasma glucose >54 to 70 mg/dL	At Month 0
Secondary	Time in low range (%)	Percent time for plasma glucose >54 to 70 mg/dL	At Month 2
Secondary	Time in very low range (%)	Percent time for plasma glucose 54 mg/dL or lower	Run in (within one month prior to the study start)
Secondary	Time in very low range (%)	Percent time for plasma glucose 54 mg/dL or lower	At Month 0
Secondary	Time in very low range (%)	Percent time for plasma glucose 54 mg/dL or lower	At Month 2
Secondary	Number of Participants with Hypoglycemia levels 1	Plasma glucose <70 mg/dL for =15 minutes	Run in (within one month prior to the study start)
Secondary	Number of Participants with Hypoglycemia levels 1	Plasma glucose <70 mg/dL for =15 minutes	At Month 0
Secondary	Number of Participants with Hypoglycemia levels 1	Plasma glucose <70 mg/dL for =15 minutes	At Month 2
Secondary	Number of Participants with Hypoglycemia levels 2	Plasma glucose <54 mg/dL for =15 minutes	Run in (within one month prior to the study start)
Secondary	Number of Participants with Hypoglycemia levels 2	Plasma glucose <54 mg/dL for =15 minutes	At Month 0
Secondary	Number of Participants with Hypoglycemia levels 2	Plasma glucose <54 mg/dL for =15 minutes	At Month 2
Secondary	Number of Participants with Prolonged hypoglycemia	Plasma glucose <54 mg/dL for =2.0 hours	Run in (within one month prior to the study start)
Secondary	Number of Participants with Prolonged hypoglycemia	Plasma glucose <54 mg/dL for =2.0 hours	At Month 0
Secondary	Number of Participants with Prolonged hypoglycemia	Plasma glucose <54 mg/dL for =2.0 hours	At Month 2
Secondary	Changes from baseline to Month 3 in left ventricular end-diastolic volume	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in left ventricular end-systolic volume	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in left ventricular mass index	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in left ventricular ejection fraction	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in left ventricular diastolic function	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in longitudinal global strain	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in radial global strain	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in circumferential global strain	To be evaluated by transthoracic echocardiogram (optional)	3 months
Secondary	Changes from baseline to Month 3 in home systolic blood pressure		3 months
Secondary	Changes from baseline to Month 3 in home diastolic blood pressure		3 months
Secondary	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
Secondary	Changes from baseline to Month 3 in residual kidney function	Renal urea clearance	3 months
Secondary	Changes from baseline to Month 3 in hemoglobin		3 months
Secondary	Changes from baseline to Month 3 in erythropoiesis stimulating drug dose		3 months
Secondary	Hospitalization/Emergency room visit rate for heart failure		3 months
Secondary	Cardiovascular mortality		3 months
Secondary	All-cause mortality		3 months
Secondary	Changes Estimated glomerular filtration rate (GFR) from baseline to Month 3	Estimated by Cystatin C and beta-2 macroglobulin	3 months