Empagliflozin in Patients With Cirrhosis and Ascites (EMPA Liver)

Effects of Empagliflozin on Natriuresis and Volume Overload in Patients With Cirrhosis and Ascites

A proof-of-concept placebo-controlled trial to explore the acute and 14-day effects of empagliflozin on natriuresis and total body water in patients with cirrhosis and ascites. We will additionally investigate its effect on neurohumoral activation, and renal hemodynamics.

Study Overview

• Status: Recruiting
• Conditions: Liver Failure; Cirrhosis
• Intervention / Treatment: Drug: Empagliflozin 10 MG; Drug: Matching Placebo

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Veena Rao, PHD; Phone Number: 2037373571; Email: veena.s.rao@yale.edu
• Study Contact Backup: Name: Kara Otis; Phone Number: 2037373571; Email: kara.otis@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale University
      • Contact: Katherine Keith

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients with cirrhosis and ascites on a stable dose of diuretics (spironolactone +/- loop-diuretics based on AASLD guidelines)10 and who do not require large volume paracenteses
2. eGFR >= 30mL/min/1.73 m2
3. >=18 years old

Exclusion Criteria:

1. Hospitalization due to a complication of cirrhosis in the previous 8 weeks (e.g. variceal hemorrhage, encephalopathy, acute kidney injury, spontaneous bacterial peritonitis)
2. Direct bilirubin >=3 mg/dL
3. Systolic blood pressure < 100 mmHg
4. Active malignancy including hepatocellular carcinoma undergoing treatment
5. History of bladder dysfunction, incontinence, pyelonephritis, urosepsis, or frequent urinary tract infections
6. Use of SGLT-2 inhibitors in the last 10 days, or previous use with intolerance
7. Type 1 diabetes
8. History of frequent hypoglycemic episodes
9. Use of a non-loop diuretic aside from aldosterone antagonists or amiloride as they are not standard of care in patients with cirrhosis and could potentially increase the risk of hypovolemia when combined with the standard treatment for ascites along with SGLT2 inhibitor.
10. Hepatic hydrothorax requiring thoracentesis in the prior 8 weeks
11. Hepatic encephalopathy grade II or greater at the time of enrollment
12. Patients who have had TIPS placed
13. Previous liver transplant
14. Participation in another trial with an investigational drug within the 30 days prior to informed consent
15. Pregnancy or breastfeeding
16. Inability to give written informed consent or follow study protocol (e.g. clinically-significant psychiatric, addictive, or neurological disease)
17. Change in diuretic dose in the prior 2 weeks
18. Patients with hospitalization for alcoholic hepatitis in the past 6 months
19. Significant worsening of creatinine (more than 50% increase) in the past 4 weeks
20. MELD-Na > or equal to 20
21. Hemoglobin <8

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Empagliflozin; Empagliflozin vs placebo for 14 days, followed by 14 day washout period, before crossing over to the alternate drug.	Drug: Empagliflozin 10 MG; Participants will be randomized to Empagliflozin 10 mg or placebo for 14 days. A 14 day washout period follows and then participants is crossed over to the alternate treatment for 14 days.
Placebo Comparator: Placebo; Empagliflozin vs placebo for 14 days, followed by 14 day washout period, before crossing over to the alternate drug.	Drug: Matching Placebo; Participants will be randomized to Empagliflozin 10 mg or placebo for 14 days. A 14 day washout period follows and then participants is crossed over to the alternate treatment for 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FENa with administration of study drug (10 mg empagliflozin vs. identical placebo)	Change in fractional excretion of sodium with administration of study drug (10 mg empagliflozin vs. identical placebo)	14 days
Change in total body water (TBW) before and after a 14-day course of study drug	Change in total body water (TBW) before and after a 14-day course of study drug (10 mg/day empagliflozin vs. identical placebo)	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in renal blood flow before and after administration of study drug	Change in renal blood flow (RBF) as determined by PAH clearance, before and after the acute administration of study drug ((RPF assessed using ancillary protocol on page 31)	Baseline to Hour 6
Change in plasma renin activity,total renin, aldosterone, norepinephrine and copeptin	Change in plasma renin activity (PRA), total renin, aldosterone, norepinephrine and copeptin before and after a 14-day course of study drug	14 days

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Jeffrey Testani, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2023
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: February 2, 2023
• First Submitted That Met QC Criteria: February 2, 2023
• First Posted (Actual): February 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Pathologic Processes; Liver Diseases; Fibrosis; Liver Failure; Liver Cirrhosis; Ascites; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2000034606

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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