Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection

NCT04861922 | Unknown Phase 3

• 1 other identifier: XY3-UFH2021
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Sepsis is the leading cause of death in intensive care units and a major public health concern in the world. Heparin, a widely used anticoagulant medicine to prevent or treat thrombotic disorders, has been demonstrated to prevent organ damage and lethality in experimental sepsis models. However, the efficacy of heparin in the treatment of clinical sepsis is not consistent. Caspase-11, a cytosolic receptor of LPS, triggers lethal immune responses in sepsis. Recently, we have revealed that heparin prevents cytosolic delivery of LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx degradation and the HMGB1- LPS interaction, which is independent of its anticoagulant properties. In our study, it is found that heparin treatment could prevent lethal responses in endotoxemia or Gram-negative sepsis, while caspase-11 deficiency or heparin treatment failed to confer protection against sepsis caused by Staphylococcus aureus, a type of Gram-positive bacterium. It is probably that other pathogens such as Gram-positive bacteria might cause death through mechanisms distinct from that of Gram-negative bacteria. Peptidoglycan, a cell-wall component of Gram-positive bacteria, can cause DIC and impair survival in primates by activating both extrinsic and intrinsic coagulation pathways, which might not be targeted by heparin. We speculate that the discrepancy between the previous clinical trials of heparin might be due to the difference in infected pathogens. Thus, stratification of patients based on the type of invading pathogens might improve the therapeutic efficiency of heparin in sepsis, and this merits future investigations.

Conditions

Sepsis; Gram-Negative Bacterial Infections; Heparin

Outcome Measures

Primary Outcomes (1)

• All-Cause Mortality

  Death from all causes at 28-days

  28 Days after randomization

Secondary Outcomes (10)

• Death in ICU

  28 Days after randomization

• SOFA score

  Day 0,3,6 after randomization

• APACHEⅡ

  Day 0,3,6 after randomization

• SIC score

  Day 0,3,6 after randomization

• DIC score

  Day 0,3,6 after randomization

Study Arms (2)

Unfractionated Heparin

EXPERIMENTAL

A bottle solution of Heparin Sodium (2ml:12500IU) is added to 48 ml saline and administered intravenously continuously for 24 hours (10 unit/kgBW/hour), which last 5 days or until the death or discharge.

Drug: Unfractionated Heparin

Normal saline

PLACEBO COMPARATOR

The same amount of 0.9% saline as the heparin group (50ml) will be administered in the placebo group.

Drug: Unfractionated Heparin

Interventions

Unfractionated Heparin DRUG

10 unit/kgBW/hour continuous infusion for 5 days

Also known as: Heparin sodium

Normal saline; Unfractionated Heparin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sepsis-3 criteria from Society of Critical Care Medicine (SCCM) /European Society of Intensive Care Medicine (ESICM), and the infection site is from abdomen 2.18≤ age ≤75years 3.obtain informed consent

You may not qualify if:

• The primary site of infection is from other parts (such as lungs, intracranial, etc.) except abdomen
• Diagnosis of sepsis for more than 48 hour
• Pregnant and lactating women
• Severe primary disease including unrespectable tumours, blood diseases and Human Immunodeficiency Virus (HIV);
• Have a known or suspected adverse reaction to UFH including HIT
• Have bleeding or high risk for bleeding
• Have an indication for therapeutic anticoagulation or have taken anticoagulants within 7 days
• Use of an immunosuppressant or having an organ transplant within the previous 6 months
• Participating in other clinical trials in the previous 30 days
• Have received cardiopulmonary resuscitation within 7 days
• Have terminal illness with a life expectancy of less than 28 days

Sponsors & Collaborators

• The Third Xiangya Hospital of Central South University: lead
• Xiangya Hospital of Central South University: collaborator
• Central South University: collaborator
• The Second Hospital University of South China: collaborator
• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology: collaborator
• The Affiliated Yantai Yuhuangding Hospital of Qingdao University: collaborator

Study Sites (1)

The third Xiangya Hospital, Central South University

Changsha, Hunan, 410013, China

RECRUITING

Related Publications (5)

• Tang Y, Wang X, Li Z, He Z, Yang X, Cheng X, Peng Y, Xue Q, Bai Y, Zhang R, Zhao K, Liang F, Xiao X, Andersson U, Wang H, Billiar TR, Lu B. Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties. Immunity. 2021 Mar 9;54(3):454-467.e6. doi: 10.1016/j.immuni.2021.01.007. Epub 2021 Feb 8.

  PMID: 33561388 BACKGROUND

• Deng M, Tang Y, Li W, Wang X, Zhang R, Zhang X, Zhao X, Liu J, Tang C, Liu Z, Huang Y, Peng H, Xiao L, Tang D, Scott MJ, Wang Q, Liu J, Xiao X, Watkins S, Li J, Yang H, Wang H, Chen F, Tracey KJ, Billiar TR, Lu B. The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis. Immunity. 2018 Oct 16;49(4):740-753.e7. doi: 10.1016/j.immuni.2018.08.016. Epub 2018 Oct 9.

  PMID: 30314759 BACKGROUND

• Yang X, Cheng X, Tang Y, Qiu X, Wang Y, Kang H, Wu J, Wang Z, Liu Y, Chen F, Xiao X, Mackman N, Billiar TR, Han J, Lu B. Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure. Immunity. 2019 Dec 17;51(6):983-996.e6. doi: 10.1016/j.immuni.2019.11.005. Epub 2019 Dec 10.

  PMID: 31836429 BACKGROUND

• Yang X, Cheng X, Tang Y, Qiu X, Wang Z, Fu G, Wu J, Kang H, Wang J, Wang H, Chen F, Xiao X, Billiar TR, Lu B. The role of type 1 interferons in coagulation induced by gram-negative bacteria. Blood. 2020 Apr 2;135(14):1087-1100. doi: 10.1182/blood.2019002282.

  PMID: 32016282 BACKGROUND

• Lu Y, Meng R, Wang X, Xu Y, Tang Y, Wu J, Xue Q, Yu S, Duan M, Shan D, Wang Q, Wang H, Billiar TR, Xiao X, Chen F, Lu B. Caspase-11 signaling enhances graft-versus-host disease. Nat Commun. 2019 Sep 6;10(1):4044. doi: 10.1038/s41467-019-11895-2.

  PMID: 31492850 BACKGROUND

MeSH Terms

Conditions

Sepsis; Gram-Negative Bacterial Infections

Interventions

Heparin

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bacterial Infections; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Hong Yuan, MD

  The third Xiangya Hospital, Central South University

  STUDY CHAIR

Central Study Contacts

Zhijun Huang, MD

CONTACT

0086-13908472564; xy3gcp@163.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 22, 2021
• First Posted: April 27, 2021
• Study Start: May 11, 2021
• Primary Completion: December 30, 2023
• Study Completion: July 30, 2024
• Last Updated: March 21, 2023

Record last verified: 2023-03

Locations

CN (1)