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| Name | Class |
|---|---|
| Southeast University, China | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Citrate group | Active Comparator | 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. |
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| NM group | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Citrate anticoagulation | Drug | 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. |
| 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:
| From randomization to day 30 |
| 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.
|
| 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 |
Inclusion Criteria:
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.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xiwen Zhang | Contact | +86 025-83262750 | xiwen_zhang@126.com |
| Name | Affiliation | Role |
|---|---|---|
| Yingzi Huang | Zhongda Hospital | Principal Investigator |
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| Nafamostat Mesylate | Drug | 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. |
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| 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 |
| 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 |
| 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 | 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 |
| 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 |
| 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 |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D058186 | Acute Kidney Injury |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
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| ID | Term |
|---|---|
| C032855 | nafamostat |
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