Prevention of Ulinastatin on Acute Respiratory Distress Syndrome (ARDS)

Prevention of Ulinastatin on Acute Respiratory Distress Syndrome (ARDS) A Randomized Controlled Trial

Since strategies were applied in intensive care medicine, including low tidal volume ventilation, fluid resuscitation, use of antibiotics, restrictive transfusion strategy and bundle of ventilator therapy, the incidence of Acute Respiratory Distress Syndrome (ARDS) has been decreased recent years. However, the mortality of severe ARDS is still higher to 45%. Few medications did were indicated to be effective in working on development of ARDS. Different with other disease, ARDS were difficult to prevent in its later stage like a domino effect. The medication interventions are all used after ARDS was developed, including ulinastatin. The investigators hypothesized that the key point in failure of medication therapy is the delay timing of medication intervention. If given the preventive strategy, such as ulinastatin, the incidence or the severity of ARDS might be decreased. Therefore this is a randomized controlled trial to test the hypothesis of the preventive effect of ulinastatin in ARDS.

This is a multi-center, randomized, double blinded, placebo controlled study.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Ulinastatin; Other: Usual care

Detailed Description

Since strategies were applied in intensive care medicine, including low tidal volume ventilation, fluid resuscitation, use of antibiotics, restrictive transfusion strategy and bundle of ventilator therapy, the incidence of Acute Respiratory Distress Syndrome (ARDS) has been decreased recent years. However, the mortality of severe ARDS is still higher to 45%. Few medications did were indicated to be effective in working on development of ARDS. Different with other disease, ARDS were difficult to prevent in its later stage like a domino effect. The medication interventions are all used after ARDS was developed, including ulinastatin. The investigators hypothesized that the key point in failure of medication therapy is the delay timing of medication intervention. If given the preventive strategy, such as ulinastatin, the incidence or the severity of ARDS might be decreased.

Ulinastatin is a urinary trypsin inhibitor (UTI) that inhibits various inflammatory proteases has been widely used in China, Japan, and Korea for the treatment of patients with inflammatory disorders, postoperative organs protection, shock, and pancreatitis.

Therefore this is a randomized controlled trial to test the hypothesis of the preventive effect of ulinastatin in ARDS.

This is a multi-center, randomized, double blinded, placebo controlled study.

• Study Type: Interventional
• Enrollment (Actual): 840
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xi Zhu, M.D.; Email: xizhuccm@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100191
      • Peking University Third Hospital
    • Beijing, Beijing, China
      • Chinese PLA General Hospital
    • Beijing, Beijing, China
      • Beijing Anzhen Hospital ,Capital Medical University
    • Beijing, Beijing, China
      • Beijing Shijitan Hospital Affiliated to Capital Medical University
  • Guangdong
    • Shenzhen, Guangdong, China
      • Peking University Shenzhen Hospital
  • Guangxi
    • Nanning, Guangxi, China
      • The First Affiliated Hospital of Guangxi Medical University
  • Hebei
    • Cangzhou, Hebei, China
      • Cangzhou People's Hospital
  • Henan
    • Zhengzhou, Henan, China
      • The First Affiliated Hospital of Zhengzhou University
  • Liaoning
    • Dalian, Liaoning, China
      • The Second Hospital of Dalian Medical University
  • Shandong
    • Zibo, Shandong, China
      • Central Hospital of Zi Bo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients should be more than 18 years old
• Patients are expected to living within 72 hours of ICU admission
• Patients' Lung Injury Prediction Score (LIPS) more than 4 and got at least 1 risk factors as below: bacteremia, sepsis or sepsis shock, pneumonia, multiple fractures, pulmonary contusion, aspiration, multiple blood transfusion, severe acute pancreatitis.

Exclusion Criteria: Patients will be excluded when they are

• diagnosed as ARDS
• without written informed consent
• with HIV infection
• with other immunologic deficiency (leukaemia, immune deficiency syndrome, etc)
• with organ transplantation or bone marrow transplantation
• with chronic pulmonary disease (except for Chronic Obstructive Pulmonary Disease (COPD) or asthma)
• with angitis
• with neutropenia (except for secondary to sepsis)
• using granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor
• using asprin or clopidogrel
• using glucocorticoid
• withdrawing treatment
• treated by Xuebijing, thymosin, or intravenous immunoglobulin 1 month before enrollment
• enrolled in other clinical trials 3 months before enrollment
• being pregnancy
• being lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ulinastatin group; 200,000 IU ulinastatin will be dissolved in 100 mL of 0.9% normal saline by continuous intravenous infusion for 1h, 3 times per day for 5 days.	Drug: Ulinastatin; 200,000 IU ulinastatin will be dissolved in 100 mL of 0.9% normal saline by continuous intravenous infusion for 1h, 3 times per day for 5 days.; Other: Usual care; Usual care in ICU.
Placebo Comparator: Control group; Control group will be in usual care without any intervention.	Other: Usual care; Usual care in ICU.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The incidence of ARDS	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The numbers of ARDS patients who meet the criteria for mild, moderate, and severe using the Berlin Definition, separately.	The severity of ARDS will be assessed by the Berlin Definition in mild, moderate and severe ARDs according to oxygenation.	3 years
The number of patients who need mechanical ventilation		3 years
Lengths of mechanical ventilation		3 years
Lengths of ICU		3 years
Lengths of stay		3 years
The incidence of other organ disorders		3 years
Mortality of 28 days		0-28 days
Mortality of 60 days		0-60 days
Total cost in admission		3 years
Adverse events related to drugs.		3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Including white blood cell decrease, eosinophils increase, nausea, vomiting, diarrhoea, liver enzymes increase, allergy, adverse events in injection sites and etc.	3 years

Collaborators and Investigators

• Sponsor: Peking University Third Hospital
• Collaborators: Chinese PLA General Hospital; The First Affiliated Hospital of Zhengzhou University; Beijing Anzhen Hospital; Peking University Shenzhen Hospital; The Second Affiliated Hospital of Dalian Medical University; First Affiliated Hospital of Guangxi Medical University; Central Hospital of Zi Bo; Beijing Shijitan Hospital Affiliated to Capital Medical University
• Investigators: Principal Investigator: Xi Zhu, M.D., Peking University Third Hospital

Publications and helpful links

General Publications

• Jeong CW, Lee CS, Lee SH, Jeung HJ, Kwak SH. Urinary trypsin inhibitor attenuates liver enzyme elevation after liver resection. Korean J Anesthesiol. 2012 Aug;63(2):120-3. doi: 10.4097/kjae.2012.63.2.120. Epub 2012 Aug 14.
• Levitt JE, Calfee CS, Goldstein BA, Vojnik R, Matthay MA. Early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation*. Crit Care Med. 2013 Aug;41(8):1929-37. doi: 10.1097/CCM.0b013e31828a3d99.
• Wang Z, Beach D, Su L, Zhai R, Christiani DC. A genome-wide expression analysis in blood identifies pre-elafin as a biomarker in ARDS. Am J Respir Cell Mol Biol. 2008 Jun;38(6):724-32. doi: 10.1165/rcmb.2007-0354OC. Epub 2008 Jan 18.
• Wang Z, Tao L, Yan Y, Zhu X. Rationale and design of a prospective, multicentre, randomised, conventional treatment-controlled, parallel-group trial to evaluate the efficacy and safety of ulinastatin in preventing acute respiratory distress syndrome in high-risk patients. BMJ Open. 2019 Mar 7;9(3):e025523. doi: 10.1136/bmjopen-2018-025523.
• ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2017
• Primary Completion (Actual): December 17, 2020
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: March 12, 2017
• First Submitted That Met QC Criteria: March 19, 2017
• First Posted (Actual): March 24, 2017

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Critical Illness; Acute Respiratory Distress Syndrome; Ulinastatin
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease Attributes; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Critical Illness; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Urinastatin
• Other Study ID Numbers: 2016-0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: All data will be shared with other researchers in papers.

Drug and device information, study documents

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