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

Official title

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

Overview

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.

Detailed description

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.

Interventions

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

Primary outcome measures

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

Secondary outcome measures (10)

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

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Fujian Medical University Union Hospital — Fuzhou

Publications

• Chen L, Jin S, Yang M, Gui C, Yuan Y, Dong G, Zeng W, Zeng J, Hu G, Qiao L, Wang J, Xi Y, Sun J, Wang N, Wang M, Xing L, Yang Y, Teng Y, Hou J, Bi Q, Cai H, Zhang G, Hong Y, Zhang Z. Integrated Single Cell and Bulk RNA-Seq Analysis Revealed Immunomodulatory Effects of Ulinastatin in Sepsis: A Multicenter Cohort Study. Front Immunol. 2022 May 11;13:882774. doi: 10.3389/fimmu.2022.882774. eCollectio PMID 35634310
• Karnad DR, Bhadade R, Verma PK, Moulick ND, Daga MK, Chafekar ND, Iyer S. Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study. Intensive Care Med. 2014 Jun;40(6):830-8. doi: 10.1007/s00134-014-3278-8. Epub 2014 Apr 16. PMID 24737258
• Lim YP, Bendelja K, Opal SM, Siryaporn E, Hixson DC, Palardy JE. Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. J Infect Dis. 2003 Sep 15;188(6):919-26. doi: 10.1086/377642. Epub 2003 Aug 26. PMID 12964125
• Aziz MH, Sideras K, Aziz NA, Mauff K, Haen R, Roos D, Saida L, Suker M, van der Harst E, Mieog JS, Bonsing BA, Klaver Y, Koerkamp BG, van Eijck CH. The Systemic-immune-inflammation Index Independently Predicts Survival and Recurrence in Resectable Pancreatic Cancer and its Prognostic Value Depends on Bilirubin Levels: A Retrospective Multicenter Cohort Study. Ann Surg. 2019 Jul;270(1):139-146. doi PMID 29334554
• Feier CVI, Motoc A, Muntean C, Vonica RC, Gaborean V, Olariu S, Murariu MS. Systemic inflammatory indices and age-dependent severity in acute appendicitis: a retrospective cohort study. Front Immunol. 2025 Jul 15;16:1620459. doi: 10.3389/fimmu.2025.1620459. eCollection 2025. PMID 40735314
• Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, Li L, Cao J, Xu F, Zhou Y, Guan CX, Jin SW, Deng J, Fang XM, Jiang JX, Zeng L. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res. 2022 Oct 9;9(1):56. doi: 10.1186/s40779-022-00422-y. PMID 36209190
• Nebelung H, Wotschel N, Held HC, Kirchberg J, Weitz J, Radosa CG, Laniado M, Hoffmann RT, Plodeck V. ICU patients with infectious complications after abdominopelvic surgery: Is thoracic CT in addition to abdominal CT helpful? Ann Intensive Care. 2023 Feb 10;13(1):6. doi: 10.1186/s13613-023-01104-1. PMID 36763198
• 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

Identifiers

NCT: NCT07672496 · FJXH-2026-0506

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗