Complicated Intra-abdominal Infection (cIAI), Immune Dysfunction, Sepsis, Systemic Inflammatory Response
Conditions
Keywords
immune dysfunction, Complicated intra-abdominal infection, Ulinastatin, SII, inflammation
Brief summary
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
DRUGulinastatin
Low dose:100000 IU iv tid×5d; High dose:300000 IU iv tid×5d, diluted in 100mL normal saline
DRUGNormal Saline (0.9% NaCl)
Equal-volume 0.9% normal saline iv tid×5d as placebo
Sponsors
Fujian Medical University Union Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Only participants are blinded to study medication assignment. Investigators, treating physicians and follow-up assessors remain unblinded.
Intervention model description
Three-arm parallel assignment design. Subjects are randomly divided into low-dose ulinastatin group, high-dose ulinastatin group and normal saline control group at a 1:1:1 ratio, all receiving standardized basic treatment simultaneously.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able to provide written informed consent voluntarily. 2. Age ≥ 18 years old, any gender. 3. 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. 4. Baseline Sequential Organ Failure Assessment (SOFA) score ≥ 2 points.
Exclusion criteria
1. 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. 2. 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. 3. Patients with active malignant tumors, pregnancy, or severe psychiatric disorders. 4. American Society of Anesthesiologists (ASA) physical status grade IV or above. 5. Severe coagulation disorder defined as ISTH-DIC score ≥ 5 points. 6. Critically ill patients with expected death within 48 hours after admission. 7. Known allergy to ulinastatin or any ingredients of the study preparation. 8. Any condition that, in the judgment of the principal investigator, makes the patient inappropriate for trial participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean change from baseline in Systemic Immune-Inflammation Index (SII) at Day 5 | Baseline (before treatment), Day 5 | The Systemic Immune-Inflammation Index (SII) is calculated from routine blood test results as platelet count multiplied by neutrophil count divided by lymphocyte count. The mean change in SII values from baseline to Day 5 will be compared across the three groups to assess the immunomodulatory effect of ulinastatin on systemic immune-inflammatory status in patients with complicated intra-abdominal infection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean change from baseline in Systemic Immune-Inflammation Index (SII) at 48 Hours | Baseline, 48 hours | The Systemic Immune-Inflammation Index (SII) is calculated from routine blood test results as platelet count multiplied by neutrophil count divided by lymphocyte count. We will calculate the mean change in SII at 48 hours relative to baseline, and compare these changes among the three treatment groups to evaluate the sustained anti-inflammatory and immunomodulatory effects of ulinastatin. |
| Mean change from baseline in C-reactive protein (CRP) at Day 1, Day 3, Day 5 | Baseline, Day 1, Day 3, Day 5 | Serum CRP levels will be measured at scheduled time points. Changes from baseline will be compared among groups to evaluate inflammatory status. |
| Mean change from baseline in Interleukin-6 (IL-6) at Day 1, Day 3, Day 5 | Baseline, Day 1, Day 3, Day 5 | Serum IL-6 levels will be measured at scheduled time points. Changes from baseline will be compared among groups to evaluate inflammatory status. |
| Mean change from baseline in CD4+ T cell count at Day 1, Day 3, Day 5 | Baseline, Day 1, Day 3, Day 5 | Peripheral CD4+ T cell count will be measured at scheduled time points. Changes from baseline will be compared among groups. |
| Mean change from baseline in CD4+/CD8+ T cell ratio at Day 1, Day 3, Day 5 | Baseline, Day 1, Day 3, Day 5 | CD4+/CD8+ ratio will be calculated at scheduled time points. Changes from baseline will be compared among groups. |
| Mean change from baseline in Sequential Organ Failure Assessment (SOFA) total score at Day 3, Day 5, Day 7 | Baseline, Day 3, Day 5, Day 7 | The full name of the scale is Sequential Organ Failure Assessment (SOFA) score. The score ranges from a minimum of 0 to a maximum of 24. Higher SOFA scores indicate worse organ dysfunction and poorer clinical outcomes. SOFA scores will be assessed at baseline and follow-up time points. Score changes will be compared to evaluate organ function improvement. |
| Cumulative incidence of new-onset organ failure at Day 7 | Up to Day 7 | New-onset organ failure is defined as an increase in the Sequential Organ Failure Assessment (SOFA) score of ≥2 points from baseline. The cumulative incidence of new organ failure occurring within 7 days after treatment initiation will be calculated and compared across the three study groups. |
| Correlation coefficients between serial immune-inflammatory marker changes and 28-day all-cause mortality | Baseline, Day 1, Day 3, Day 5, up to Day 28 | Serial dynamic values of systemic immune-inflammatory markers, including Systemic Immune-Inflammation Index (SII), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), and CRP-to-Lymphocyte Ratio (CLR), will be collected from baseline to Day 5. Pearson correlation analysis will be performed to evaluate the correlation coefficients between dynamic changes of these markers and 28-day all-cause mortality. |
| Proportion of participants with 28-day all-cause mortality | Up to Day 28 | Vital status followed up to Day 28 after randomization. The percentage of participants who die from any cause within 28 days will be reported and compared between groups. |
| Incidence of adverse events during treatment | From the start of intervention to 4 weeks after the last study drug administration | All adverse events and serious adverse events occurring during the treatment and follow-up period will be recorded in detail. The incidence, severity and correlation with study drugs will be analyzed to evaluate the safety profile of ulinastatin. |
Countries
China
Outcome results
None listed