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

Giuseppe Cullaro, MD

Status and phase: Enrolling; Phase 2

Conditions: Decompensated Cirrhosis of Liver; Cirrhosis; Acute Kidney Injury

Treatments: Drug: Droxidopa capsules; Other: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT06937307

AAAV7484

Details and patient eligibility

About

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.

Full 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.

Enrollment: 75 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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75 participants in 2 patient groups, including a placebo group

Droxidopa

Experimental group

Description:

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.

Treatment:

Drug: Droxidopa capsules

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Other: Placebo