Ulinastatin on Systemic Immune-Inflammation in Patients With Complicated Intra-Abdominal Infection

Официальное название

A Single-Center Randomized Controlled Pilot Study on the Effect of Ulinastatin on Systemic Immune and Inflammatory Response in Patients With Complicated Intra-Abdominal Infection

Обзор

Complicated intra-abdominal infection (cIAI) triggers dysregulated systemic inflammation and immune paralysis leading to high organ failure and death risk. Ulinastatin is a protease inhibitor with anti-inflammatory properties, but its dose-related effects on immune-inflammation of cIAI patients remain unclear. This single-center single-blinded three-arm randomized controlled pilot study enrolls adult cIAI patients (≥18 years, SOFA≥2) at Fujian Medical University Union Hospital. Eligible patients are randomized into low-dose ulinastatin, high-dose ulinastatin and normal saline placebo groups (1:1:1, 5 days intravenous treatment plus standard care), total planned enrollment 165 participants after 10% dropout adjustment. Primary endpoint is Day5 change of Systemic Immune-Inflammation Index (SII); secondary outcomes include serial inflammatory biomarkers, SOFA variation, organ dysfunction, hospitalization duration, 28-day mortality and safety profiles. This pilot aims to clarify ulinastatin's immune-modulating effect and inform future large RCT design.

Подробное описание

This is a single-center, randomized, single-blind, three-arm parallel-group superiority pilot clinical trial performed at Fujian Medical University Union Hospital. Randomization sequence is generated with SAS 9.3 software, and random grouping is implemented by sealed envelope method at a 1:1:1 allocation ratio (low-dose ulinastatin : high-dose ulinastatin : normal saline control =1:1:1). A total of 165 participants are planned, with 55 subjects in each group after accounting for an anticipated 10% dropout rate.

All enrolled patients are adults aged ≥18 years diagnosed with complicated intra-abdominal infection (cIAI) within 48 hours, confirmed by clinical manifestation, laboratory tests and abdominal imaging, accompanied by SOFA score ≥2. Subjects with severe immunodeficiency, end-stage liver or renal disease, malignancy, pregnancy, hypersensitivity to ulinastatin and other severe comorbidities are excluded. Written informed consent is obtained prior to any study-related procedures.

All participants receive standardized routine management including surgical source control, antibacterial therapy and organ function supportive treatment. Intervention regimens last for consecutive 5 days via intravenous drip: low-dose group receives ulinastatin 100,000 IU three times daily diluted in 100 mL normal saline; high-dose group receives ulinastatin 300,000 IU three times daily diluted in 100 mL normal saline; control group receives equal volume of sterile normal saline three times daily as placebo. For patients with progressive organ dysfunction after 24-48 hours without improvement, rescue high-dose ulinastatin is allowed per investigator's clinical judgment.

Primary endpoint is the absolute change of Systemic Immune-Inflammation Index (SII) from baseline to treatment Day 5. Secondary endpoints include dynamic changes of CRP, PCT, IL-6, NLR, PLR, LMR, CLR, CD4⁺/CD8⁺ T cell counts at Days 1,3,5 and 7; sequential SOFA score changes; cumulative incidence of new organ failure within 7 and 14 days; ICU and total hospital stay duration; reoperation rate, secondary infection rate, in-hospital and 28-day all-cause mortality. Subgroup analyses are preset stratified by operation type, pathogenic bacteria (multidrug-resistant pathogen or candidiasis) and baseline disease severity (MPI/SOFA score).

All adverse events (AEs) from informed consent to 4 weeks after final study medication are documented following CTCAE Version 5.0. All serious adverse events (SAEs) must be reported to the sponsor (Techpool Bio-Pharma Co., Ltd.) within 24 hours. Study will be prematurely terminated if excessive unexpected severe adverse events occur or interim analysis demonstrates no meaningful intergroup difference in primary inflammatory markers. Study monitoring, source document verification and data management are conducted in accordance with GCP and Declaration of Helsinki principles.

Вмешательства

• Препарат ulinastatin
  Low dose:100000 IU iv tid×5d; High dose:300000 IU iv tid×5d, diluted in 100mL normal saline
• Препарат Normal Saline (0.9% NaCl)
  Equal-volume 0.9% normal saline iv tid×5d as placebo

Первичные конечные точки

• Mean change from baseline in Systemic Immune-Inflammation Index (SII) at Day 5 [Срок оценки: Baseline (before treatment), Day 5]

Вторичные конечные точки (10)

• Mean change from baseline in Systemic Immune-Inflammation Index (SII) at 48 Hours [Срок оценки: Baseline, 48 hours]
• Mean change from baseline in C-reactive protein (CRP) at Day 1, Day 3, Day 5 [Срок оценки: Baseline, Day 1, Day 3, Day 5]
• Mean change from baseline in Interleukin-6 (IL-6) at Day 1, Day 3, Day 5 [Срок оценки: Baseline, Day 1, Day 3, Day 5]
• Mean change from baseline in CD4+ T cell count at Day 1, Day 3, Day 5 [Срок оценки: Baseline, Day 1, Day 3, Day 5]
• Mean change from baseline in CD4+/CD8+ T cell ratio at Day 1, Day 3, Day 5 [Срок оценки: Baseline, Day 1, Day 3, Day 5]
• Mean change from baseline in Sequential Organ Failure Assessment (SOFA) total score at Day 3, Day 5, Day 7 [Срок оценки: Baseline, Day 3, Day 5, Day 7]
• Cumulative incidence of new-onset organ failure at Day 7 [Срок оценки: Up to Day 7]
• Correlation coefficients between serial immune-inflammatory marker changes and 28-day all-cause mortality [Срок оценки: Baseline, Day 1, Day 3, Day 5, up to Day 28]
• Proportion of participants with 28-day all-cause mortality [Срок оценки: Up to Day 28]
• Incidence of adverse events during treatment [Срок оценки: From the start of intervention to 4 weeks after the last study drug administration]

Критерии участия

Критерии включения

• Able to provide written informed consent voluntarily.
• Age ≥ 18 years old, any gender.
• Diagnosed with severe complicated intra-abdominal infection (cIAI) within 48 hours, consistent with the 2025 expert consensus for cIAI diagnosis. Diagnosis is confirmed by clinical symptoms (fever, abdominal pain, distension, etc.), abdominal imaging (CT/ultrasound/MRI), intraoperative findings, or positive pathogen culture of abdominal drainage fluid.
• Baseline Sequential Organ Failure Assessment (SOFA) score ≥ 2 points.

Критерии исключения

• Severe immune deficiency conditions, including AIDS, prior solid organ or bone marrow transplantation, HIV infection with CD4 count < 200 cells/mm³, long-term high-dose glucocorticoid therapy (prednisone > 20 mg/day), ongoing chemotherapy for malignant tumors, or absolute neutrophil count < 1000 cells/mm³.
• Severe irreversible underlying diseases, including chronic renal failure requiring dialysis, Child-Pugh grade C liver disease, liver disease with severe portal hypertension, or acute liver failure.
• Patients with active malignant tumors, pregnancy, or severe psychiatric disorders.
• American Society of Anesthesiologists (ASA) physical status grade IV or above.
• Severe coagulation disorder defined as ISTH-DIC score ≥ 5 points.
• Critically ill patients with expected death within 48 hours after admission.
• Known allergy to ulinastatin or any ingredients of the study preparation.
• Any condition that, in the judgment of the principal investigator, makes the patient inappropriate for trial participation.

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

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Fujian Medical University Union Hospital — Фучжоу

Публикации

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• Huston JM, Barie PS, Dellinger EP, Forrester JD, Duane TM, Tessier JM, Sawyer RG, Cainzos MA, Rasa K, Chipman JG, Kao LS, Pieracci FM, Colling KP, Heffernan DS, Lester J; Therapeutics and Guidelines Committee. The Surgical Infection Society Guidelines on the Management of Intra-Abdominal Infection: 2024 Update. Surg Infect (Larchmt). 2024 Aug;25(6):419-435. doi: 10.1089/sur.2024.137. Epub 2024 Jul PMID 38990709

Идентификаторы

NCT: NCT07672496 · FJXH-2026-0506

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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