UMIN-CTR Clinical Trial

Basic information
Public title	Investigation of the relationship between immune system and coagulation system in patient with cardiac arrest outside the hospital
Acronym	Investigation of the relationship between immune responses and coagulation responses in patient with cardiac arrest outside the hospital
Scientific Title	Investigation of the relationship between innate immune responses and coagulofibrinolytic responses in patients with out-of-hospital cardiac arrest
Scientific Title:Acronym	Investigation of the relationship between innate immune responses and coagulofibrinolytic responses in patients with out-of-hospital cardiac arrest
Region	Japan

Condition
Condition	Out-of-hospital cardiac arrest
Classification by specialty	Emergency medicine
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	Danger-associated molecular patterns (DAMPs) such as histones cause the endothelial cell injury and the activation of neutrophil. DAMPs cause hypercoagulation, dysfunction of anticoagulation system and inhibition of fibrinolysis. DAMPs produce immunothrombosis depending on activated neutrophils and systemic inflammation causes disseminated intravascular coagulation (DIC). Cardiac arrest and resuscitation, namely systemic ischemia an reperfusion cause the release of DAMPs. The development of DIC in patients after cardiac arrest and resuscitation cause organ dysfunction, leading to poor outcome. Based on the above reports, the purpose of this study is to prove the hypothesis that thrombin, which is produced by histones released after cardiac arrest and resuscitation is associated with the development of DIC, leading organ dysfunction and poor outcome.
Basic objectives2	Others
Basic objectives -Others	Investigation of pathomechanism
Trial characteristics_1
Trial characteristics_2
Developmental phase

Assessment
Primary outcomes	Severity of organ dysfunction, assessed by Sequential Organ Failure Assessment (SOFA) score
Key secondary outcomes	The levels of histone H3, interleukin-6, and various markers of coagulation and fibrinolysis Outcome (organ dysfunction, 28-days mortality and hospital death) Impact of DIC on outcome

Base
Study type	Observational

Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms
Purpose of intervention
Type of intervention
Interventions/Control_1
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	Patients who are 20 years of age or older at the time of obtaining consent Patients who died without return of spontaneous circulation after out-of-hospital cardiac arrest Patients who get return of spontaneous circulation Investigators have to get informed consent from the patients or their legal authorized representatives after explaining the participation in this study to them and confirming their understanding.
Key exclusion criteria	Patients with cardiac arrest due to trauma, acute aortic dissection or ruptured aortic aneurysm Patients who take anticoagulants Patients with coagulofibrinolytic disorders as underlying diseases Other patients who are judged inappropriate by the principal investigator
Target sample size	120

Research contact person
Name of lead principal investigator	1st name Takeshi Middle name Last name WADA
Organization	Hokkaido University Hospital
Division name	Department of Emergency Medicine
Zip code	060-8648
Address	Kita-ku, N14W15, Sapporo
TEL	011-706-7377
Email	twada1@med.hokudai.ac.jp

Public contact
Name of contact person	1st name Takeshi Middle name Last name WADA
Organization	Hokkaido University Hospital
Division name	Department of Emergency Medicine
Zip code	060-8648
Address	Kita-ku, N14W15, Sapporo
TEL	011-706-7377
Homepage URL
Email	twada1@med.hokudai.ac.jp

Sponsor
Institute	Hokkaido University Hospital
Institute
Department

Funding Source
Organization	Japan Society for the Promotion of Science
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization	JP

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Division of Clinical Research Administration, Hokkaido University Hospital
Address	Kita-ku, N14W5, Sapporo
Tel	0117067636
Email	crjimu@huhp.hokudai.ac.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2020 Year 01 Month 23 Day

Related information
URL releasing protocol	N/A
Publication of results	Published

Result
URL related to results and publications	https://www.frontiersin.org/articles/10.3389/fcvm.2022.885406/full
Number of participants that the trial has enrolled	62
Results	Patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period.Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation and PIC 3 h after arriving at the hospital. This correlation was prominent in the patient population with MODS.
Results date posted	2022 Year 07 Month 29 Day
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics	There were no significant differences in age, sex, or initial rhythm of the electrocardiogram between patients from the two groups. The frequencies of witnessing the onset of cardiac arrest and bystander CPR were comparable between groups. However, the non-MODS group had a significantly higher percentage of patients with cardiogenic cardiac arrests. The CPR duration was significantly longer in the MODS group than in the non-MODS group. Patients in the MODS group exhibited a higher DIC score on day 1 and a higher APACHE II score than those in the non-MODS group. Furthermore, the hospital survival rate was significantly higher in the non-MODS group than in the MODS group.
Participant flow	Out of the 47 patients, 12 were excluded from the study. Among the excluded patients, 11 did not achieve return of spontaneous circulation. We also excluded one patient because the samples were not treated appropriately. In the present study, we analyzed the final cohort of 35 patients. The patients were divided into multiple organ dysfunction (MODS) (n = 15) and non-MODS (n=20) groups.
Adverse events	N/A
Outcome measures	N/A
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Completed
Date of protocol fixation	2018 Year 06 Month 04 Day
Date of IRB	2018 Year 06 Month 22 Day
Anticipated trial start date	2018 Year 09 Month 03 Day
Last follow-up date	2021 Year 03 Month 31 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other

Other related information

Measurement items Histone H3, IL6, activated protein C, soluble fibrin, plasmin antiplasmin complex, soluble thrombomodulin, tPA activity, PAI1 activity Observation items and its implementation methods Researchers investigate the following items in patient group and use the data for this study. These are all items which are performed in daily clinical practice, and their frequency is equivalent to that in daily clinical practice. Basic information of the objectives in this study. age, gender, weight, height, body temperature, blood pressure, pulse rate, respiratory rate, urine volume, medical past history, underlying disease, surgery, treatment, and 28 days or hospital outcome Hematology. Ht, white blood cell counts, platelet counts Blood biochemical tests. total bilirubin, creatinine, Na, K Coagulation and fibrinolysis test. PT, fibrinogen, FDP, D dimer Blood gas test. pH, PaO2, PaCO2, BE, HCO3 Various scores. APACHEII, SOFA, SIRS, DIC

Management information
Registered date	2020 Year 01 Month 23 Day
Last modified on	2022 Year 07 Month 29 Day

Link to view the page
URL(English)	https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000044738