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

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.

Study Overview

• Status: Recruiting
• Conditions: Hemodialysis; Kidney Disease, Chronic; Kidney Failure; Dialysis; Diabetic; End-stage Kidney Disease; Kidney Dysfunction; Non-diabetic
• Intervention / Treatment: Other: Placebo; Drug: Empagliflozin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 75
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Monique E Cho, MD; Phone Number: 801-581-8090; Email: monique.cho@hsc.utah.edu
• Study Contact Backup: Name: Jonathan Gutierrez; Phone Number: 801-587-1911; Email: jonathan.gutierrez@utah.edu

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah
      • Contact: Jonathan Gutierrez; Phone Number: 801-587-1911; Email: jonathan.gutierrez@utah.edu
      • Contact: Mary Jane Tinnes; Phone Number: 801-585-2254; Email: maryjane.tinnes@hsc.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin 10mg; 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; is a sodium-glucose co-transporter 2 (SGLT2) inhibitor.; Other Names: Jardiance®; CL-JAR-100113 02.28.2022
Experimental: Empagliflozin 25mg; 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; is a sodium-glucose co-transporter 2 (SGLT2) inhibitor.; Other Names: Jardiance®; CL-JAR-100113 02.28.2022
Placebo Comparator: Placebo; 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; Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2023
• Primary Completion (Anticipated): March 31, 2025
• Study Completion (Anticipated): March 31, 2025

Study Registration Dates

• First Submitted: October 26, 2022
• First Submitted That Met QC Criteria: November 4, 2022
• First Posted (Actual): November 14, 2022

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Renal Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: IRB_00155825; 1R01DK131265 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No