SepsisPhase 3NCT04861922
Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection
A Phase 3 study testing Unfractionated Heparin in people with Sepsis and Gram-Negative Bacterial Infections, run by The Third Xiangya Hospital of Central South University at 1 site in China.
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Sepsis, Gram-Negative Bacterial Infections, Heparin
- What is being tested?
- Unfractionated Heparin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 100 participants
- Where
- 1 siteChina
- Study dates
- 11 May 2021to 30 Jul 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
China1 site, 1 recruiting
- Recruiting
The third Xiangya Hospital, Central South University
Changsha, Hunan, 410013
Min Gao, MD, 0086-13808495303, gaomin1@csu.edu.cn
Ben Lu, MD
About this study
Official title: Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study
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.
Read the 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.
- Conditions
- Sepsis, Gram-Negative Bacterial Infections, Heparin
- Being tested
- Unfractionated Heparin
- Medical subject headings
- Sepsis, Gram-Negative Bacterial Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Unfractionated HeparinDrug
Also called Heparin sodium
10 unit/kgBW/hour continuous infusion for 5 days
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Unfractionated Heparin |
What is being measured
The primary outcome is the main question the study is designed to answer.
All-Cause Mortality
Death from all causes at 28-days
Measured: 28 Days after randomization
Secondary outcomes (10)
Death in ICU
Death from all causes at ICU discharge
Measured: 28 Days after randomization
SOFA score
Total Sequential Organ Failure Assessment (SOFA) score(0-24) , higher values represent a worse outcome
Measured: Day 0,3,6 after randomization
APACHEⅡ
Acute Physiology and Chronic Health Evaluation (include Acute physiology score, APS and age and Chronic physiology score, totally 0-71 Points)
Measured: Day 0,3,6 after randomization
SIC score
Sepsis-induced coagulopathy score (totally 0-6 Points)
Measured: Day 0,3,6 after randomization
DIC score
Disseminated intravascular coagulation score (totally 0-8 Points)
Measured: Day 0,3,6 after randomization
Duration of mechanical ventilation and continuous renal replacement therapy
Duration of mechanical ventilation and continuous renal replacement therapy in ICU
Measured: 28 days after randomization
ICU stay
Duration of stay in ICU
Measured: 28 days after randomization
Inflammation
Concentration of inflammation markers such as c-reactive protein, procalcitonin, IL-1β and IL-1α at 0, 3,6 days after randomization
Measured: 0,3,6 days after randomization
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
Measured: 0,3,6 days after randomization
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
Measured: 28 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Apr 2021
- Study start11 May 2021
- Primary completion30 Dec 2023 (estimated)
- Study completion30 Jul 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by The Third Xiangya Hospital of Central South UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Xiangya Hospital of Central South University, Central South University, The Second Hospital University of South China, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Yantai Yuhuangding Hospital
- Responsible party
- Principal investigator, Ben Lu, The Third Xiangya Hospital of Central South University
- Investigators
- Hong Yuan, MD, Study chair, The third Xiangya Hospital, Central South University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04861922
- Sponsor's protocol ID
- XY3-UFH2021
- Status last verified
- Mar 2023
- First submitted
- 22 Apr 2021
- Last updated
- 21 Mar 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 33561388Deng 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.
PubMed 30314759Yang 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.
PubMed 31836429Yang 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.
PubMed 32016282Lu 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.
PubMed 31492850
Study at a glance
From the registry record, last updated by the sponsor on 21 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study
- ClinicalTrials.gov ID
- NCT04861922
- Acronym / sponsor ID
- XY3-UFH2021
- Conditions
- Sepsis, Gram-Negative Bacterial Infections, Heparin
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- The Third Xiangya Hospital of Central South UniversityUniversity, hospital or other
- Collaborators
- Xiangya Hospital of Central South University, Central South University, The Second Hospital University of South China, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Yantai Yuhuangding Hospital
- Study start
- 11 May 2021 (actual)
- Primary completion
- 30 Dec 2023 (estimated)
- Study completion
- 30 Jul 2024 (estimated)
- First posted
- 27 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Unfractionated Heparin | Experimental | Drug: Unfractionated HeparinA 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. |
| Normal saline | Placebo comparator | Drug: Unfractionated HeparinThe same amount of 0.9% saline as the heparin group (50ml) will be administered in the placebo group. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Unfractionated HeparinAlso: Heparin sodium10 unit/kgBW/hour continuous infusion for 5 days | Drug | Normal saline, Unfractionated Heparin |
Primary outcome
All-Cause Mortality
Time frame: 28 Days after randomization
Death from all causes at 28-days
10 secondary outcomes
Death in ICU
Time frame: 28 Days after randomization
SOFA score
Time frame: Day 0,3,6 after randomization
APACHEⅡ
Time frame: Day 0,3,6 after randomization
SIC score
Time frame: Day 0,3,6 after randomization
DIC score
Time frame: Day 0,3,6 after randomization
Duration of mechanical ventilation and continuous renal replacement therapy
Time frame: 28 days after randomization
ICU stay
Time frame: 28 days after randomization
Inflammation
Time frame: 0,3,6 days after randomization
Coagulation
Time frame: 0,3,6 days after randomization
The incidence of major bleeding
Time frame: 28 days after randomization
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Mar 2023.
- Background: PubMed 33561388Tang 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.
- Background: PubMed 30314759Deng 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.
- Background: PubMed 31836429Yang 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.
- Background: PubMed 32016282Yang 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.
- Background: PubMed 31492850Lu 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hong Yuan, MD study chair
The third Xiangya Hospital, Central South University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Unfractionated Heparin in people with Sepsis and Gram-Negative Bacterial Infections, run by The Third Xiangya Hospital of Central South University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Zhijun Huang, MD (0086-13908472564, xy3gcp@163.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
All-Cause Mortality (time frame: 28 Days after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04861922, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Mar 2023.