Clinical Efficacy of Ulinastatin for Treatment of Sepsis With Systemic Inflammatory Response Syndrome (CURE-SepSIRS)

Clinical Efficacy of Ulinastatin for Treatment of Sepsis With Systemic Inflammatory Response Syndrome: a Multicenter, Randomized, Double-blind, Multi Dose and Placebo-controlled Clinical Trial.

Sepsis is a life-threatening organ dysfunction caused by the maladjusted response of the host to infection. It is a clinical syndrome with high mortality. Studies have confirmed that many cytokines play a vital role in the pathogenesis of sepsis. Ulinastatin (UTI) is a glycoprotein that exists in human blood and can be isolated and purified from human urine. It is a broad-spectrum protease inhibitor. Previous studies have shown that Ulinastatin may have the effect of treating sepsis.

120 septic patients with systemic inflammatory response syndrome would be recruited and randomly assigned to the ordinary dose group, high dose group and placebo control group according to the ratio of 1:1:1.

The trial will be followed up on days 0, 1, 3, 5, 7 and 28. Sofa on day 7 compared with baseline and all-cause mortality on day 28 were investigated to explore the efficacy of ulinastatin in the treatment of adult sepsis patients with systemic inflammatory response syndrome.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis
• Intervention / Treatment: Drug: Ulinastatin; Drug: Placebo

Detailed Description

The study plans to recruit 120 septic patients with systemic inflammatory response syndrome. After signing the informed consent, they will be included as day 0. They will be randomly assigned to the ordinary dose group, high dose group and placebo control group according to the ratio of 1:1:1, and the evaluation of basic clinical information of subjects will be supplemented and improved.The ordinary dose group will receive 400000 units of ulinastatin, which will be injected intravenously every 8 hours, The high-dose group will receive 800000 units of ulinastatin intravenously every 8 hours, and the control group will use equal volume solvent (50ml normal saline) as placebo intravenously every 8 hours. When the patient does not have systemic inflammatory response syndrome, the dose will be halved and then continue to be used for 2 days. The total course of Ulinastatin injection shall be at least 3 days.

Inclusion criteria:

1) Adults ≥ 18 years old and ≤ 80 years old 2) meet the sepsis-3.0 standard specified by the American Society of critical care medicine and the European Society of critical care medicine 3) sepsis diagnosis time < 48h 4) systemic inflammatory response syndrome (SIRS) 5) obtain the informed consent signed by the patient or authorized immediate family members

Exclusion criteria:

1) Congestive heart failure, NYHA grade IV cardiac function, cerebrovascular accident or acute coronary syndrome within 3 months, cardiac arrest in this hospital or within 7 days, non infectious cardiogenic shock, uncontrolled acute bleeding 2) severe chronic liver disease (child Pugh grade C), liver parenchymal disease with significant portal hypertension Acute liver failure 3) chronic renal failure, who had received dialysis treatment before enrollment 4) severe abnormal coagulation function: isth-dic score ≥ 5 points 5) significant immune abnormalities / damage: organ or bone marrow transplantation and moderate and severe leucopenia within 3 months before screening, such as neutrophils < 1.5 × 109 / L, received radiotherapy or chemotherapy within 3 months, HIV seropositive, hematological / lymphatic system tumor active period 6) received Xuebijing, thymosin or gamma globulin treatment within 3 months before study enrollment 7) others: allergic to study drugs, pregnancy, lactation, participated in other clinical trials within 3 months, and other situations that researchers think are not suitable to participate.

The trial will be followed up on days 0, 1, 3, 5, 7 and 28. The changes of sofa on day 7 compared with baseline, all-cause mortality on day 28, ICU hospitalization time, antibiotic use time, SIRS duration, vasoactive drug time, mechanical ventilation time, CRRT time, infection and inflammation indexes, coagulation and fibrinolysis indexes, liver function, renal function, nervous and mental system function and endothelial cell function were compared, To explore the efficacy of ulinastatin in the treatment of adult sepsis patients with systemic inflammatory response syndrome.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sen Wang, Doctor; Phone Number: +86 13636616175; Email: wangsen329@126.com

Study Locations

• China
  • Shanghai
    • Jingan, Shanghai, China
      • HuaShan Hospital Affiliated To Fudan University
      • Contact: Wenhong Zhang, Professor; Phone Number: 021-52887970; Email: zhangwenhong@fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. sepsis-3 specified by SCCM and ESICM 1) suspected or confirmed infection: diagnosed by a clinician 2) evidence of acute organ dysfunction: for patients without chronic organ dysfunction in the past (assuming a baseline SOFA score of 0): sofa ≥ 2 points from 48 hours before diagnosis of infection to 24 hours after diagnosis of infection for patients with chronic organ dysfunction in the past (SOFA score should be based on baseline): the increase of sofa ≥ 2 points from 48 hours before diagnosis of infection to 24 hours after diagnosis of infection
2. diagnosis of sepsis for less than 48 hours
3. Systemic inflammatory response syndrome (SIRS) 1) body temperature > 38 ℃ or < 36 ℃ 2) heart rate > 90 3) respiratory rate> 20 4) WBC count > 12 × 10 ^ 9 / L or < 4 × 10^9/L (>12000/ μ L or < 4000/ μ L or immature granulocytes > 10%)
4. Obtained informed consent signed by the patient or authorized immediate family member

Exclusion Criteria:

1. Congestive heart failure (NYHA heart function level 4), cerebrovascular accident or acute coronary syndrome within 3 months, cardiac arrest within 7 days of this hospitalization, non-infectious cardiogenic shock, uncontrolled acute bleeding
2. Severe chronic liver disease (Child-Pugh grade C), liver parenchymal lesions with obvious portal hypertension, acute liver failure
3. Chronic renal failure, received dialysis treatment before being selected
4. Severe coagulation function: ISTH-DIC score ≥ 5 points
5. Significant immune abnormality/injury: received organ or bone marrow transplantation within 3 months before screening, moderate to severe leukopenia such as neutrophils <1.5×10^9/L, received radiotherapy or chemotherapy within 3 months , HIV seropositivity, active blood/lymphatic system tumor
6. Have received Xuebijing, thymosin or gamma globulin treatment within 3 months before being selected for the study
7. Others: allergies to study drugs, pregnancy, breast-feeding, participating in other clinical trials within 3 months, and other conditions deemed unsuitable by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: normal dose; Patients would be given 400000 units of ulinastatin (specification: 100000 units / vial) dissolved in 50 ml of 0.9% normal saline intravenously for at least 1 hour, once every 8 hours. It is evaluated by the attending doctor every day. When the patient does not have systemic inflammatory response syndrome (SIRS), halve the dose and continue to use it for 2 days, with a total course of treatment of at least 3 days	Drug: Ulinastatin; Patients would be given 400000 or 800000units of ulinastatin (specification: 100000 units / vial) dissolved in 50 ml of 0.9% normal saline intravenously for at least 1 hour, once every 8 hours. It is evaluated by the attending doctor every day. When the patient does not have systemic inflammatory response syndrome (SIRS), halve the dose and continue to use it for 2 days, with a total course of treatment of at least 3 days; Other Names: Treatment
Experimental: high dose; Patients would be given 800000 units of ulinastatin (specification: 100000 units / vial) dissolved in 50 ml of 0.9% normal saline intravenously for at least 1 hour, once every 8 hours. It is evaluated by the attending doctor every day. When the patient does not have systemic inflammatory response syndrome (SIRS), halve the dose and continue to use it for 2 days, with a total course of treatment of at least 3 days	Drug: Ulinastatin; Patients would be given 400000 or 800000units of ulinastatin (specification: 100000 units / vial) dissolved in 50 ml of 0.9% normal saline intravenously for at least 1 hour, once every 8 hours. It is evaluated by the attending doctor every day. When the patient does not have systemic inflammatory response syndrome (SIRS), halve the dose and continue to use it for 2 days, with a total course of treatment of at least 3 days; Other Names: Treatment
Placebo Comparator: placebo; Patients would be given 50 ml of 0.9% normal saline intravenously for at least 1 hour once every 8 hours.It is evaluated by the attending doctor every day. When the patient does not have systemic inflammatory response syndrome (SIRS), continue to use it for 2 days, with a total course of treatment of at least 3 days.	Drug: Placebo; Patients would be given 50 ml of 0.9% normal saline intravenously for at least 1 hour once every 8 hours.It is evaluated by the attending doctor every day. When the patient does not have systemic inflammatory response syndrome (SIRS), continue to use it for 2 days, with a total course of treatment of at least 3 days.; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
delta sofa, ΔSOFA	Sequential organ failure asses(SOFA) of day 5 , compared with the baseline.	Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sofa vs. baseline change in sofa at randomization (delta sofa, Δ SOFA）	Sequential Organ Failure Assessment	Day 1,3,7
28 day all-cause mortality	28 day all-cause mortality	Day 28
ICU hospitalization days	ICU hospitalization days	Day 28
antibiotic use days	antibiotic use days	Day 28
SIRS days	SIRS days	Day 28
vasoactive drugs days	vasoactive drugs days	Day 28
mechanical ventilation days	mechanical ventilation days	Day 28
CRRT days	CRRT days	Day 28
Blood routine	Blood routine	Day 1,3,5,7
coagulation and fibrinolysis indexes: PT, PLT, D-dimer	coagulation and fibrinolysis indexes	Day 1,3,5,7
DIC score	The ISTH group produced a simple scoring system for the diagnosis of DIC depending on the Platelet count, the PT, the fibrinogen level and critically the FDP/D-Dimer results. A person's ISTH DIC score ranges from 0 to 8. <5 is suggestive of non-overt/low grade DIC. ≥5 means laboratory evidence is consistent with overt DIC	Day 1,3,5,7
AST, ALT, bilirubin	Liver function	Day 1,3,5,7
urine volume	urine volume	Day 1,3,5,7
creatinine	creatinine	Day 1,3,5,7
urea nitrogen	urea nitrogen	Day 1,3,5,7
blood lactate	blood lactate	Day 1,3,5,7
oxygenation index	oxygenation index	Day 1,3,5,7
oxygen saturation	oxygen saturation	Day 1,3,5,7
Glasgow Coma Scale	Glasgow Coma Scale. A person's GCS score can range from 3 (completely unresponsive) to 15 (responsive). A lower score means a more serious condition.	Day 1,3,5,7
days of delirium and coma	days of delirium and coma	Day 1,3,5,7
APACHE-II on day 5	Acute Physiology and Chronic Health Evaluation	Day 5
ADL on day 1,3,5,7;	Activities of Daily Living score	Day 1,3,5,7
intercellular adhesion factor	Endothelial cell function	Day 1,3,7
concentration of endothelial cell specific molecules	Endothelial cell function	Day 1,3,7
heparan sulfate	Endothelial cell function	Day 1,3,7
lymphocyte subsets and inflammatory factor levels (IL-6, IL-10, CRP, PCT, TNF- α、 HMGB-1）	Immune and inflammatory indexes	Day 1,3,7

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse event	safety endpoint	Day 28
Serious adverse events	safety endpoint	Day 28
Vital signs	any abnormalities in vital signs	Day 28
Blood biochemistry	safety endpoint	Day 28
physical examination results	any abnormalities in physical examination results	Day 28
electrocardiogram	any abnormalities in electrocardiogram	Day 28

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Investigators: Principal Investigator: Wenhong Wenhong, Professor, Huashan Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2022
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: December 28, 2021
• First Submitted That Met QC Criteria: May 20, 2022
• First Posted (Actual): May 26, 2022

Study Record Updates

• Last Update Posted (Actual): May 26, 2022
• Last Update Submitted That Met QC Criteria: May 20, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Inflammation; Shock; Sepsis; Toxemia; Systemic Inflammatory Response Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Urinastatin
• Other Study ID Numbers: KY2021-924

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No