Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection

Sepsis Clinical Trial

Official title:

Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04861922
• Other study ID #: XY3-UFH2021
• Status: Recruiting
• Phase: Phase 3
• Start date: May 11, 2021
• Est. completion date: July 30, 2024

Study information

• Verified date: March 2023
• Source: The Third Xiangya Hospital of Central South University
• Contact: Zhijun Huang, MD
• Phone: 0086-13908472564
• Email: xy3gcp[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: July 30, 2024
• Est. primary completion date: December 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Bacterial Infections
• Communicable Diseases
• Gram-Negative Bacterial Infections
• Heparin
• Infections
• Intraabdominal Infections
• Sepsis
• Toxemia

Intervention

Drug:
• Unfractionated Heparin
10 unit/kgBW/hour continuous infusion for 5 days

Locations

Country	Name	City	State
China	The third Xiangya Hospital, Central South University	Changsha	Hunan

Sponsors (6)

Lead Sponsor	Collaborator
The Third Xiangya Hospital of Central South University	Central South University, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, The Second Hospital of South China University, Wuhan Union Hospital, China, Xiangya Hospital of Central South University

Country where clinical trial is conducted

China, 

References & Publications (5)

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. — View 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. Erratum In: Nat Commun. 2020 Mar 9;11(1):1349. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-Cause Mortality	Death from all causes at 28-days	28 Days after randomization
Secondary	Death in ICU	Death from all causes at ICU discharge	28 Days after randomization
Secondary	SOFA score	Total Sequential Organ Failure Assessment (SOFA) score(0-24) , higher values represent a worse outcome	Day 0,3,6 after randomization
Secondary	APACHE?	Acute Physiology and Chronic Health Evaluation (include Acute physiology score, APS and age and Chronic physiology score, totally 0-71 Points)	Day 0,3,6 after randomization
Secondary	SIC score	Sepsis-induced coagulopathy score (totally 0-6 Points)	Day 0,3,6 after randomization
Secondary	DIC score	Disseminated intravascular coagulation score (totally 0-8 Points)	Day 0,3,6 after randomization
Secondary	Duration of mechanical ventilation and continuous renal replacement therapy	Duration of mechanical ventilation and continuous renal replacement therapy in ICU	28 days after randomization
Secondary	ICU stay	Duration of stay in ICU	28 days after randomization
Secondary	Inflammation	Concentration of inflammation markers such as c-reactive protein, procalcitonin, IL-1ß and IL-1a at 0, 3,6 days after randomization	0,3,6 days after randomization
Secondary	Coagulation	Concentration of coagulation related indexes such as fibrinogen degradation products, d-dimer, thrombin-antithrombin complex, plasminogen activator inhibitor-1, plasmin antiplasmin complex, and thrombomodulin at 0,3,6 days after randomization	0,3,6 days after randomization
Secondary	The incidence of major bleeding	"Major bleeding" is defined as intracranial bleeding, life-threatening bleeding, or need red blood cell suspension more than 3 units every 24 hours, and last for 2 days	28 days after randomization