Empagliflozin in Patients With Cirrhosis and Ascites

Study Overview
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Brief Summary
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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.

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

Conditions
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Cirrhosis, Liver Failure

Intervention / Treatment
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* Drug: Empagliflozin 10 MG
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 eGFR >= 30mL/min/1.73 m2 >=18 years old Exclusion Criteria: Hospitalization due to a complication of cirrhosis in the previous 8 weeks (e.g. variceal hemorrhage, encephalopathy, acute kidney injury, spontaneous bacterial peritonitis) Direct bilirubin >=3 mg/dL Systolic blood pressure < 100 mmHg Active malignancy including hepatocellular carcinoma undergoing treatment History of bladder dysfunction, incontinence, pyelonephritis, urosepsis, or frequent urinary tract infections Use of SGLT-2 inhibitors in the last 10 days, or previous use with intolerance Type 1 diabetes History of frequent hypoglycemic episodes Use of a non-loop diuretic aside from aldosterone antagonists 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. Hepatic hydrothorax Hepatic encephalopathy grade II or greater at the time of enrollment Patients who have had TIPS placed Previous liver transplant Participation in another trial with an investigational drug within the 30 days prior to informed consent Pregnancy or breastfeeding Inability to give written informed consent or follow study protocol (e.g. clinically-significant psychiatric, addictive, or neurological disease) Change in diuretic dose in the prior 4 weeks Patients with hospitalization for alcoholic hepatitis in the past 6 months Significant worsening of creatinine (more than 50% increase) in the past 4 weeks MELD-Na <20

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Proof of concept, randomized, cross over, phase II double-blind placebo-controlled study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin<br>Empagliflozin vs placebo for 14 days, followed by 14 day washout period, before crossing over to the alternate drug. | Drug: Empagliflozin 10 MG<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Empagliflozin vs placebo for 14 days, followed by 14 day washout period, before crossing over to the alternate drug. | Drug: Matching Placebo<br>* 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.<br>|

What is the study measuring?
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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 |