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

Jianfeng Xie

Status and phase: Not yet enrolling; Phase 4

Conditions: Acute Kidney Injury; Continuous Renal Replacement Therapy (CRRT); Sepsis

Treatments: Drug: Nafamostat Mesylate; Drug: Citrate anticoagulation

Study type: Interventional

Funder types: Other

Identifiers

NCT07518303

2026ZDSYLL076-P01

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,162 estimated patients

Sex: All

Ages: 18 to 90 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,162 participants in 2 patient groups

Citrate group

Active Comparator group

Description:

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.

Treatment:

Drug: Citrate anticoagulation

NM group

Experimental group

Description:

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.

Treatment:

Drug: Nafamostat Mesylate