Droxidopa to Increase Mean Arterial Pressure in Decompensated Cirrhosis Patients With Acute Kidney Injury

Overview

This study tests whether a medication called droxidopa can help improve blood flow to the kidneys in people with liver cirrhosis who develop kidney problems while in the hospital. When someone with cirrhosis experiences kidney injury, having better blood pressure can help their kidneys recover. Droxidopa is an oral medication that may help raise blood pressure without requiring intensive care or invasive treatments. The study will compare droxidopa to a placebo (inactive pill) in 75 people hospitalized with cirrhosis and kidney injury. Participants will take either droxidopa or placebo pills for 28 days and be monitored for an additional 30 days. Researchers will measure changes in blood pressure and kidney function to determine if droxidopa is effective and safe for these patients. This research could identify a new treatment option for a serious complication of liver disease.

Acute kidney injury (AKI) occurs in up to 50% of hospitalized patients with decompensated cirrhosis and carries mortality rates exceeding 50%. Recent evidence indicates that progression of AKI after initial diagnosis significantly impacts outcomes, with patients whose AKI worsens having up to 8 times higher mortality compared to those without progression. Mean arterial pressure (MAP) appears to be a key mediator of kidney function and recovery in cirrhosis. Multiple studies have established that each 5 mmHg increase in MAP is associated with a 1.07-1.19 times greater likelihood of AKI recovery. However, current therapeutic options to increase MAP in cirrhosis are limited to invasive vasopressors requiring ICU admission, terlipressin with significant risks including respiratory failure, or oral midodrine which lacks proven efficacy in decompensated cirrhosis. Droxidopa is an oral synthetic amino acid that is directly metabolized to norepinephrine by dopa-decarboxylase. FDA-approved since 2014 for neurogenic orthostatic hypotension, droxidopa demonstrates a well-established safety profile and consistent ability to increase systolic blood pressure by 7-11 mmHg. This magnitude of effect is similar to that associated with AKI recovery when using invasive vasopressors. Importantly, droxidopa maintains efficacy over 12 weeks with minimal risk of supine hypertension. This study will evaluate droxidopa in a 2:1 randomized, double-blind, placebo-controlled trial of 75 hospitalized patients with Child-Pugh Score ≥B7 cirrhosis and KDIGO Stage 1 AKI or greater who have MAP ≤85 mmHg. Participants will receive droxidopa or placebo initially at 100 mg three times daily, titrated in 100 mg increments every 24 hours based on blood pressure response and tolerability, up to a maximum of 300 mg three times daily for 28 days. The primary endpoint is change in MAP, measured by a linear mixed-effects model with fixed effects for treatment group and time. Secondary endpoints include change in serum creatinine, completion of study day 28, death, and liver transplantation. Safety will be carefully monitored with primary safety endpoints of hypertensive emergency and development of cardiac arrhythmias. An Internal Data and Safety Monitoring Board consisting of an independent hepatologist with cirrhosis expertise, a biostatistician experienced in clinical trials, and a study medical monitor will review safety data monthly and assess stopping rules criteria. Total study duration will be 58 days (28 days of product administration plus 30 days of follow-up) per participant, with an overall study timeline of 2 years.