Droxidopa to Increase Mean Arterial Pressure in Decompensated Cirrhosis Patients With Acute Kidney Injury (DROP-AKI)

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.

Study Overview

• Status: Recruiting
• Conditions: Cirrhosis; Acute Kidney Injury; Decompensated Cirrhosis of Liver
• Intervention / Treatment: Drug: Droxidopa capsules; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Giuseppe Cullaro, MD, MAS; Phone Number: 2123050914; Email: gc2576@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Giuseppe Cullaro, MD, MAS; Phone Number: 212-305-0914; Email: gc2576@cumc.columbia.edu
      • Principal Investigator: Giuseppe Cullaro, MD, MAS
      • Contact: Theresa Lukose Research Director, PharmD; Phone Number: 212-305-3839; Email: tt2103@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to provide informed consent by subject or legally authorized representative
• Consent to blood and urine collection for biomarker analysis
• Ability to take oral medications
• At least 18 years of age
• Hospitalized at Columbia University Irving Medical Center
• Child-Pugh Score ≥ B7 cirrhosis (documented by imaging, biopsy, or clinical evidence)
• KDIGO Stage 1 AKI or greater, defined as:
• ≥0.3 mg/dL increase in serum creatinine within 48 hours OR
• ≥50% increase in serum creatinine from outpatient baseline
• Mean arterial pressure ≤85 mmHg averaged over 24 hours prior to randomization
• For women of childbearing potential: negative pregnancy test and agreement to use effective contraception

Exclusion Criteria:

• Serum creatinine >4.0 mg/dL or current renal replacement therapy
• Age >70 years
• Severe cardiovascular disease, including:
• Unstable angina
• Congestive heart failure requiring escalating medical therapy
• Symptomatic peripheral vascular disease
• Any cardiovascular condition deemed severe by investigator
• Active gastrointestinal bleeding, defined as requiring ≥ 2 units of packed red blood cells during the screening period
• Acute respiratory failure requiring more than 6L of Nasal Canula
• Use of medications that could interact with droxidopa including:
• MAOI inhibitors
• Norepinephrine reuptake inhibitors
• Other investigational drugs
• Pregnancy or breastfeeding
• Any episode of a SBP ≥ 180 mmHg or a DBP ≥ 120 mmHg on two measurements, 1 minute apart
• Prior liver transplantation

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Droxidopa; Participants in this arm will receive oral droxidopa capsules at an initial dose of 100 mg three times daily, titrated in 100 mg increments every 24 hours based on blood pressure response and tolerability, up to a maximum dose of 300 mg three times daily. Doses will be given approximately 4 hours apart during daytime hours for a total treatment duration of 28 days.	Drug: Droxidopa capsules; Droxidopa is an oral synthetic amino acid that is directly metabolized to norepinephrine by dopa-decarboxylase. It will be administered at an initial dose of 100 mg three times daily, titrated in 100 mg increments every 24 hours based on blood pressure response, up to a maximum of 300 mg three times daily. Doses will be given approximately 4 hours apart during daytime hours, at least 3 hours apart, with a maximum total daily dose of 900 mg. The treatment duration is 28 days. The drug will be over-encapsulated using opaque capsules to maintain the double-blind design.; Other Names: L-threo-3,4-dihydroxyphenylserine
Placebo Comparator: Placebo; Participants in this arm will receive matched placebo capsules following the same dosing schedule and titration protocol as the experimental arm. Placebo capsules will be identical in appearance to droxidopa capsules with the same over-encapsulation process to maintain blinding. Doses will be given three times daily for a total treatment duration of 28 days.	Other: Placebo; Matching placebo capsules containing microcrystalline cellulose (from Millipore Sigma) will be over-encapsulated using identical opaque capsules to maintain blinding. Placebo will be administered following the same schedule as the active treatment: three times daily with the same titration protocol based on blood pressure response, for a treatment duration of 28 days. The Columbia University Research Pharmacy will perform over-encapsulation of both active drug and placebo to ensure they are identical in appearance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean arterial pressure (MAP)	The difference in mean arterial pressure between treatment groups over the 28-day treatment period, assessed using a linear mixed-effects model with fixed effects for treatment group and time, plus their interaction, while accounting for between-subject variability through random intercepts.	Baseline to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	The proportion of participants who die from any cause during the study period.	58 days
Liver transplantation	The proportion of participants who undergo liver transplantation during the study period.	58 days
Change in serum creatinine	The difference in serum creatinine between treatment groups over the 28-day treatment period, assessed using a linear mixed-effects model with fixed effects for treatment group and time, plus their interaction, while accounting for between-subject variability through random intercepts.	28 days

Collaborators and Investigators

• Sponsor: Giuseppe Cullaro, MD
• Investigators: Principal Investigator: Giuseppe Cullaro, MD, MAS, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: April 15, 2025
• First Submitted That Met QC Criteria: April 15, 2025
• First Posted (Actual): April 22, 2025

Study Record Updates

• Last Update Posted (Actual): June 4, 2025
• Last Update Submitted That Met QC Criteria: June 3, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Cirrhosis; Acute Kidney Injury; Decompensated Cirrhosis
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Digestive System Diseases; Liver Diseases; Renal Insufficiency; Acute Kidney Injury; Wounds and Injuries; Fibrosis; Liver Cirrhosis; Antiparkinson Agents; Anti-Dyskinesia Agents; Droxidopa
• Other Study ID Numbers: AAAV7484

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data sharing decisions remain under institutional review. Key considerations include: (1) protecting sensitive health information for vulnerable cirrhosis patients, (2) aligning with Columbia University's data governance frameworks, (3) determining appropriate de-identification methodologies, and (4) developing suitable data dictionaries and transfer protocols. Upon study completion, a comprehensive data sharing determination will be made, with potential for de-identified datasets to be shared through secure repositories following primary publication.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No