Safety, Tolerability, and Feasibility of Empagliflozin Therapy in Dialysis-dependent ESKD

Study Overview
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Brief Summary
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The purpose of this study is to find out if empagliflozin, a new diabetic medication that has been shown to be very effective in lowering the risk of heart failure, is safe and tolerated in dialysis patients. In the recent years, empagliflozin has become a major tool to prevent heart failure hospitalization and to reduce the risk for cardiovascular death in diabetic and non-diabetic patients. Although patients with severe chronic kidney disease and ESKD have very high risk of heart failure and cardiovascular death, they have been excluded from all of the previous studies. If this medication is found to be well tolerated and safe in dialysis patients through this study, future clinical studies can evaluate if this medication can also reduce the risk of heart failure and cardiovascular death in dialysis patients.

Detailed Description
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Patients on dialysis have a very high risk of heart failure and heart-related death compared to people who do not require dialysis. While treatment options for heart failure have improved over the years for those without kidney disease, there has been very limited discoveries to improve survival for dialysis patients. Empagliflozin, a new diabetic medication that works by making the kidney put out more sugar in the urine, has recently shown to have significant efficacy to protect the kidney and to reduce heart failure hospitalization and cardiovascular death in both diabetic and non-diabetic patients. Studies suggest that this medication may have benefits on the heart, fat cells, blood vessels, and possibly other organ systems. The benefit remains consistent whether you have diabetes or not. Empagliflozin is now approved by the U.S. Food and Drug Administration (FDA) to treat not only diabetes but also chronic kidney disease and to reduce the risk of cardiovascular death and hospitalization for heart failure in adults regardless of the diabetes status. The clinical studies, however, have excluded those with severe kidney disease and those requiring dialysis. The safety of empagliflozin in the dialysis patients has not been established, and thus it is not available for people with end-stage kidney disease. If empagliflozin is safe in dialysis patients, it may potentially become a very powerful tool to lower the risk of heart-related complications and prolong survival. Although empagliflozin is approved by the FDA to treat patients with chronic kidney disease, heart failure, and/or diabetes, our study will evaluate empagliflozin as an investigational drug to assess if it is safe in patients receiving chronic dialysis. If we can establish safety, the next step would be to conduct a larger clinical study to evaluate its ability to lower heart failure and death risk in dialysis patients.

Official Title
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Safety, Tolerability, and Feasibility of Empagliflozin Therapy in Dialysis-dependent ESKD

Conditions
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End-stage Kidney Disease, Kidney Disease, Chronic, Dialysis, Diabetic, Non-diabetic, Kidney Dysfunction, Kidney Failure, Hemodialysis

Intervention / Treatment
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* Drug: Empagliflozin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: include diabetic and non-diabetic adults dialysis treatment history of ≥3 months Exclusion Criteria: type 1 diabetes ongoing intravenous antibiotic therapy for infectious disease active treatment for malignancy unhealed lower extremity skin ulceration history of Fournier's gangrene diabetic ketoacidosis severe hypoglycemia (requiring external assistance within the past one year) allergy to empagliflozin pregnancy

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: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will be conducted in two phases, a dose-escalation phase (week 0-4) and a treatment phase (week 5-12).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin 10mg<br>Empagliflozin10mg oral: Those randomized to 10 mg daily dose will be treated with 10 mg QD throughout the dose escalation and the treatment phase for a total of 12 weeks. | Drug: Empagliflozin<br>* is a sodium-glucose co-transporter 2 (SGLT2) inhibitor.<br>* Other names: CL-JAR-100113 02.28.2022;|
| Experimental: Empagliflozin 25mg<br>Empagliflozin 25 mg oral: Those randomized to 25 mg daily dose will be treated with 10 mg QD for the first 2 weeks before escalating the dose to 25 mg QD in week 3, based on tolerability. At the end of the dose-escalation phase (weeks 3-4), participants will continue the randomized assignment for additional 8 weeks (weeks 5-12, treatment phase), for a total of 12 weeks. | Drug: Empagliflozin<br>* is a sodium-glucose co-transporter 2 (SGLT2) inhibitor.<br>* Other names: CL-JAR-100113 02.28.2022;|
| Placebo Comparator: Placebo<br>Encapsulated placebo with an identical appearance to empagliflozin: Those randomized to placebo will be treated with an oral placebo QD throughout the dose escalation and the treatment phase for a total of 12 weeks. | Other: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants in each intervention group who remain in follow-up and adhere to the full randomized dose of empagliflozin at the end of the 12-week intervention period. |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of participants in each group who reduce and/or discontinue treatment for safety | Safety outcomes (to be assessed in each treatment group): Proportions of participants with any of the following prespecified adverse events of interest: (i) Severe hypoglycemia1; (ii) Ketoacidosis; (iii) Hypotension; (iv) Genital infection; (v) Hepatic injury Composite of the individual components of the prespecified adverse events of interest (i) through (v) Occurrence of any hospitalization and/or visit to Emergency Department | 12-weeks | 
| Proportions of participants in each group who reduce and/or discontinue treatment because of intolerance (i.e., allergy, nausea) or other reasons unrelated to safety (i.e., pill burden, study withdrawal due to transplant) |  | 12-weeks | 
| Proportions of participants in each group who have ≥ 80% pill count compliance. |  | 12-weeks | 
| Dialytic clearance of empagliflozin |  | 4 hours post-dose during hemodialysis | 
| Long-term accumulation of empagliflozin |  | 10 weeks |