Nafamostat Mesylate Versus Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy in Sepsis-Associated Acute Kidney Injury (NICE-AKI)

This multicenter, randomized, open-label, active-controlled, parallel-group trial will evaluate the efficacy and safety of nafamostat mesylate anticoagulation compared with regional citrate anticoagulation in adult patients with sepsis-associated acute kidney injury requiring continuous renal replacement therapy. Eligible participants will be randomized in a 1:1 ratio to receive either nafamostat mesylate or regional citrate anticoagulation during CRRT. The primary outcome is MAKE30, a composite of all-cause mortality, new or ongoing renal replacement therapy, or persistent renal dysfunction within 30 days after randomization. Secondary outcomes include filter lifespan, CRRT-free days, 30-day all-cause mortality, renal replacement therapy status, persistent renal dysfunction, ICU and hospital mortality, length of stay, CRRT duration, major bleeding, new bloodstream infection during ICU stay, SOFA score, number of filters used, and protocol-defined safety outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis; Acute Kidney Injury; Continuous Renal Replacement Therapy (CRRT)
• Intervention / Treatment: Drug: Citrate anticoagulation; Drug: Nafamostat Mesylate

Detailed Description

Sepsis-associated acute kidney injury is common among critically ill patients and is associated with increased mortality, delayed renal recovery, and adverse long-term kidney outcomes. Continuous renal replacement therapy is frequently used in hemodynamically unstable patients with severe AKI, and its effective delivery depends on extracorporeal circuit patency and appropriate anticoagulation. Regional citrate anticoagulation is recommended as a first-line CRRT anticoagulation strategy in patients without contraindications, but citrate accumulation, electrolyte disturbances, and acid-base disorders may occur in patients with severe shock, liver dysfunction, or complex metabolic derangements. Nafamostat mesylate is a short-acting serine protease inhibitor with anticoagulant effects that are relatively confined to the extracorporeal circuit and may be associated with a lower systemic bleeding risk.

This study will compare nafamostat mesylate with regional citrate anticoagulation in patients with sepsis-associated acute kidney injury undergoing CRRT. The trial is designed as a multicenter, randomized, open-label, active-controlled, parallel-group non-inferiority study. Participants will be randomized centrally using the IWRS, stratified by study center and SOFA cardiovascular subscore. The primary objective is to determine whether nafamostat mesylate is non-inferior to regional citrate anticoagulation with respect to MAKE30, defined as death, new or ongoing renal replacement therapy, or persistent renal dysfunction within 30 days after randomization.

• Study Type: Interventional
• Enrollment (Estimated): 1162
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Xiwen Zhang; Phone Number: +86 025-83262750; Email: xiwen_zhang@126.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18 to 90 years, inclusive, regardless of sex.
• Meets Sepsis 3.0 diagnostic criteria and develops acute kidney injury within 7 days after the diagnosis of sepsis.
• After adequate resuscitation, meets KDIGO 2012 stage 2 or stage 3 acute kidney injury criteria, including any of the following:

Serum creatinine increased to more than 3 times baseline; or Serum creatinine ≥4.0 mg/dL [353.6 μmol/L]; or Urine output <0.3 mL/kg/h for ≥24 hours; or Anuria, defined as extremely low or absent urine output, lasting ≥12 hours.

Or has an indication for CRRT, including any of the following:

Blood urea nitrogen >150 mg/dL; or Serum potassium >6 mmol/L; or pH <7.15; or Organ edema and/or fluid overload in the setting of AKI that is refractory to diuretic therapy.

• Expected duration of CRRT treatment >48 hours.
• Written informed consent obtained.

Exclusion Criteria:

• Requirement for therapeutic anticoagulation, such as pulmonary embolism or deep vein thrombosis.
• Contraindication to systemic anticoagulation.
• Hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
• Acute liver failure and/or shock with persistent severe lactic acidosis, defined as two consecutive measurements of pH <7.2 lasting for more than 2 hours, with lactate >72.1 mg/dL [8 mmol/L].
• Chronic kidney disease requiring long-term regular dialysis.
• Acute kidney injury caused by permanent bilateral renal artery occlusion or surgical injury.
• Acute kidney injury caused by glomerulonephritis, interstitial nephritis, or vasculitis.
• Known allergy to study drugs, including nafamostat mesylate, sodium citrate, or their excipients.
• Kidney transplantation within 1 year.
• Planning pregnancy in the near term, pregnancy, or lactation.
• HIV infection.
• Only adsorptive filters such as oXiris are available at study enrollment.
• Participation in another clinical trial within the previous 3 months.
• Judged by the investigator to be in a moribund state or unlikely to complete the study intervention and primary outcome assessment, including but not limited to expected death within 24 hours after enrollment, decision for do-not-resuscitate order or limitation/withdrawal of life-sustaining treatment, or planned abandonment of active treatment and self-discharge within 24 hours due to terminal disease or patient/family preference.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NM group; Nafamostat mesylate is administered as a continuous pre-filter infusion at an initial dose of 50 mg/h, adjusted to maintain activated partial thromboplastin time (aPTT) or other regional anticoagulation parameters as specified in the protocol. Dose modifications are made based on filter lifespan and bleeding risk.	Drug: Nafamostat Mesylate; Nafamostat mesylate is a synthetic serine protease inhibitor with a very short half-life (approximately 8 minutes). It acts locally as an anticoagulant by inhibiting thrombin, factor Xa, and other coagulation proteases. The investigational product is supplied as a lyophilized powder for injection. It must be protected from light and stored below 25 °C. For use during continuous renal replacement therapy (CRRT), the powder is reconstituted and administered as a continuous pre-filter infusion.
Active Comparator: Citrate group; Participants in this arm receive regional citrate anticoagulation during continuous renal replacement therapy (CRRT) according to standard institutional protocols. Citrate is infused pre-filter to maintain post-filter ionized calcium concentration between 0.2-0.4 mmol/L, with a maximum not exceeding 0.6 mmol/L. Calcium is replaced post-filter or systemically to maintain normal systemic ionized calcium (1.0-1.2 mmol/L). Anticoagulation targets and dose adjustments follow predefined operational guidelines. Citrate accumulation is monitored by total-to-ionized calcium ratio, and protocol modifications are applied for patients with liver dysfunction or metabolic complications.	Drug: Citrate anticoagulation; Citrate (3% or 4% trisodium citrate solution) is a regional anticoagulant that chelates ionized calcium in the extracorporeal circuit, thereby inhibiting the coagulation cascade. The control product is supplied as an injection solution. It should be stored in a tightly closed container. During CRRT, citrate is infused pre-filter (before the blood pump) and requires separate systemic calcium replacement to maintain normal ionized calcium levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Adverse Kidney Events at Day 30 (MAKE30)	MAKE30 is a composite endpoint defined as the occurrence of any of the following within 30 days after randomization: All-cause death: the participant dies within 30 days after enrollment. If death has not occurred, proceed to the next criterion.; New initiation of or persistent need for renal replacement therapy: on Day 30 after enrollment, the participant still requires any form of renal replacement therapy, including CRRT, intermittent hemodialysis, sustained low-efficiency daily dialysis/continuous intermittent renal replacement therapy, peritoneal dialysis, and related modalities. Even if the participant had been temporarily weaned from therapy during the interval, the event is considered to have occurred if renal replacement therapy is still required on Day 30. If this criterion is not met, proceed to the next criterion.; Persistent renal dysfunction: on Day 30, the participant's serum creatinine level reaches or exceeds twice the baseline value.	From randomization to day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean filter lifespan	Defined as the time from CRRT initiation to technical filter failure or nontechnical termination. Nontechnical termination events will be censored in the primary analysis.; Technical filter failure (meeting any of the following):a. transmembrane pressure (TMP) persistently > 250 mmHg and not reversible after flushing or adjusting blood flow rate; b. visible circuit clotting at grade 2-3 (grade 0: no visible clotting; grade 1: mild fibrin deposition; grade 2: obvious clotting but the circuit remains functional; grade 3: severe clotting requiring immediate filter replacement); c. complete occlusion of the filter or circuit such that blood flow > 100 mL/min cannot be maintained; or d. unplanned treatment interruption caused by circuit clotting.; Nontechnical termination (not counted as filter failure)	From first CRRT initiation to last CRRT discontinuation within 30 days after randomization
CRRT-free days through Day 30		From randomization to day 30
All-cause mortality by Day 30		From randomization to day 30
ICU mortality		To be evaluated up to 30 days post randomization
In-hospital mortality		To be evaluated up to 30 days post randomization
ICU length of stay		To be evaluated up to 30 days post randomization
Hospital length of stay		To be evaluated up to 30 days post randomization
Duration of CRRT		From first CRRT initiation to last CRRT discontinuation within 30 days after randomization
SOFA scores on Days 1, 3, 7, 14, and 30		From randomization to day 30
Total number of filters used during CRRT		From randomization to day 30
New or Ongoing Renal Replacement Therapy	Requirement for any form of renal replacement therapy at days 27-33 after enrollment, including CRRT, intermittent hemodialysis, slow low-efficiency daily dialysis, sustained low-efficiency dialysis, peritoneal dialysis, or any other form of renal replacement therapy.	Days 27-33 after randomization
Persistent Renal Dysfunction at Day 30	Serum creatinine at day 30 reaching or exceeding 2 times baseline. If the day 30 value is unavailable, the last available pre-discharge serum creatinine value will be used. Baseline serum creatinine will be defined or estimated according to the protocol-specified hierarchy.	Day 30 after randomization
Major Bleeding Events	Major bleeding is defined as any of the following: life-threatening bleeding associated with hypovolemic shock, such as bleeding caused by ruptured abdominal aortic aneurysm or upper or lower gastrointestinal bleeding; life-threatening bleeding at a critical site, such as intracranial, retroperitoneal, or pericardial bleeding; overt clinically important bleeding associated within 24 hours with hemoglobin decrease >20 g/L or transfusion of ≥2 units of packed red blood cells; or bleeding requiring invasive intervention, such as re-operation.	From randomization to day 30
New Bloodstream Infection During ICU Stay	New bloodstream infection is defined as a bloodstream infection event that occurs during the study observation period and is not present at baseline. The event must meet the following criteria: during the same suspected infection assessment, blood culture specimens are independently collected and submitted from at least two different peripheral venipuncture sites on the same day or consecutive days, and the same pathogenic microorganism is detected in the separately reported cultures. For participants with baseline bloodstream infection, a new bloodstream infection will be identified only when the newly detected pathogen differs from the baseline pathogen or when the clinical endpoint adjudication committee determines that the event represents a new bloodstream infection.	During ICU stay within 30 days after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolic acidosis		From randomization to day 30
Citrate toxicity	Defined as total calcium/ionized calcium ratio > 2.5 or worsening metabolic acidosis	From randomization to day 30
Metabolic alkalosis		From randomization to day 30
Hypercalcemia	Defined as serum total calcium > 2.75 mmol/L	From randomization to day 30
Hypocalcemia	Defined as serum total calcium < 2.25 mmol/L	From randomization to day 30
Hypophosphatemia	Defined as serum inorganic phosphorus < 0.8 mmol/L	From randomization to day 30
Hyperkalemia	Defined as serum potassium > 5.5 mmol/L	From randomization to day 30
Hypernatremia	Defined as serum sodium > 150 mmol/L	From randomization to day 30

Collaborators and Investigators

• Sponsor: Jianfeng Xie
• Collaborators: Southeast University, China
• Investigators: Principal Investigator: Yingzi Huang, Zhongda Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 10, 2026
• Primary Completion (Estimated): June 10, 2028
• Study Completion (Estimated): December 10, 2028

Study Registration Dates

• First Submitted: March 29, 2026
• First Submitted That Met QC Criteria: April 4, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Sepsis; Continuous Renal Replacement Therapy (CRRT); Acute Kidney Injury (AKI); Randomized Clinical Trial (RCT); Nafamostat Mesylate
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Acute Kidney Injury; Sepsis; nafamostat
• Other Study ID Numbers: 2026ZDSYLL076-P01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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