Clinical trial NCT04861922: Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection
Official title: Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sepsis
Gram-Negative Bacterial Infections
Heparin
Lead sponsor: The Third Xiangya Hospital of Central South University
Sponsor class: OTHER
Collaborators: name: Xiangya Hospital of Central South University
name: Central South University
name: The Second Hospital University of South China
name: Wuhan Union Hospital, China
name: The Affiliated Yantai Yuhuangding Hospital of Qingdao University
First posted: 2021-04-27
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: In clinical patients, the major pathogens of sepsis caused by abdominal infection are mostly Gram-negative bacterium. Therefore, aim of this study is to determine effects of low dose unfractionated heparin for treatment of sepsis caused by abdominal infection.

Eligibility criteria: Inclusion Criteria:

Patients will be eligible for inclusion if all of the inclusion criteria are met:

1.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

Exclusion Criteria:

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

Primary outcomes:
measure: All-Cause Mortality
timeFrame: 28 Days after randomization
Secondary outcomes:
measure: Death in ICU
timeFrame: 28 Days after randomization
measure: SOFA score
timeFrame: Day 0,3,6 after randomization
measure: APACHEⅡ
timeFrame: Day 0,3,6 after randomization
measure: SIC score
timeFrame: Day 0,3,6 after randomization
measure: DIC score
timeFrame: Day 0,3,6 after randomization
measure: Duration of mechanical ventilation and continuous renal replacement therapy
timeFrame: 28 days after randomization
measure: ICU stay
timeFrame: 28 days after randomization
measure: Inflammation
timeFrame: 0,3,6 days after randomization
measure: Coagulation
timeFrame: 0,3,6 days after randomization
measure: The incidence of major bleeding
timeFrame: 28 days after randomization
Other outcomes:
Locations:
city: Changsha
country: China
facility: The third Xiangya Hospital, Central South University
state: Hunan
Study officials:
affiliation: The third Xiangya Hospital, Central South University
name: Hong Yuan, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.