Acute Kidney Injury, Continuous Renal Replacement Therapy (CRRT), Sepsis
Conditions
Keywords
Nafamostat Mesylate, Continuous Renal Replacement Therapy (CRRT), Sepsis, Acute Kidney Injury (AKI), Randomized Clinical Trial (RCT)
Brief summary
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.
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.
Interventions
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.
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.
Sponsors
Jianfeng Xie
Southeast University, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Kidney Events at Day 30 (MAKE30) | From randomization to day 30 | MAKE30 is a composite endpoint defined as the occurrence of any of the following within 30 days after randomization: 1. All-cause death: the participant dies within 30 days after enrollment. If death has not occurred, proceed to the next criterion. 2. 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. 3. Persistent renal dysfunction: on Day 30, the participant's serum creatinine level reaches or exceeds twice the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean filter lifespan | From first CRRT initiation to last CRRT discontinuation within 30 days after randomization | Defined as the time from CRRT initiation to technical filter failure or nontechnical termination. Nontechnical termination events will be censored in the primary analysis. 1. 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. 2. Nontechnical termination (not counted as filter failure) |
| CRRT-free days through Day 30 | From randomization to day 30 | — |
| All-cause mortality by Day 30 | From randomization to day 30 | — |
| New or Ongoing Renal Replacement Therapy | Days 27-33 after randomization | 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. |
| Persistent Renal Dysfunction at Day 30 | Day 30 after randomization | 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. |
| 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 | — |
| Major Bleeding Events | From randomization to day 30 | 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. |
| New Bloodstream Infection During ICU Stay | During ICU stay within 30 days after randomization | 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. |
| 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 | — |
Contacts
CONTACTXiwen Zhang
PRINCIPAL_INVESTIGATORYingzi Huang
Zhongda Hospital
Outcome results
None listed