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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.
• Препарат 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.

Первичные конечные точки

• Major Adverse Kidney Events at Day 30 (MAKE30) [Срок оценки: From randomization to day 30]

Вторичные конечные точки (12)

• Mean filter lifespan [Срок оценки: From first CRRT initiation to last CRRT discontinuation within 30 days after randomization]
• CRRT-free days through Day 30 [Срок оценки: From randomization to day 30]
• All-cause mortality by Day 30 [Срок оценки: From randomization to day 30]
• New or Ongoing Renal Replacement Therapy [Срок оценки: Days 27-33 after randomization]
• Persistent Renal Dysfunction at Day 30 [Срок оценки: Day 30 after randomization]
• ICU mortality [Срок оценки: To be evaluated up to 30 days post randomization]
• In-hospital mortality [Срок оценки: To be evaluated up to 30 days post randomization]
• ICU length of stay [Срок оценки: To be evaluated up to 30 days post randomization]
• Hospital length of stay [Срок оценки: To be evaluated up to 30 days post randomization]
• Duration of CRRT [Срок оценки: From first CRRT initiation to last CRRT discontinuation within 30 days after randomization]
• Major Bleeding Events [Срок оценки: From randomization to day 30]
• New Bloodstream Infection During ICU Stay [Срок оценки: During ICU stay within 30 days after randomization]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07518303 · 2026ZDSYLL076-P01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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