Efficacy and Safety of Unfractionated Heparin on Severe Sepsis With Suspected Disseminated Intravascular Coagulation

Phase 3 Study of the Efficacy and Safety of Unfractionated Heparin in Patients With Severe Sepsis/Septic Shock With Suspected DIC

The primary objective of this study is to estimate the efficacy of unfractionated heparin(UFH) on ICU mortality in severe sepsis with suspected DIC.The Second objective is to estimate the effect of UFH on 28-day mortality,and the change of the Japanese Association for Acute Medicine(JAAM) score and SOFA score. The third one is to evaluate the safety of UFH in severe sepsis patients with suspected DIC.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Disseminated Intravascular Coagulation
• Intervention / Treatment: Drug: Saline; Drug: Heparin Sodium

Detailed Description

During the study, the whole process of data validation and registry procedures will be implemented by the Principal Investigator of the study, and monitored by the Ethics Committee of the First Affiliated Hospital of China Medical University.There are 2 research supervisors(2 ICU doctors) to assess the accuracy, completeness and representativeness of registry data, and to report the study process and research results to Principal Investigator.Investigators have also edited a data dictionary including each variable used by the registry and normal ranges of all detection indexes. The standard operating procedures have been formulated to address the registry and data analysis. The feasibility and significance have been assessed carefully and funded by the Health and Family Planning Commission of Liaoning Province(No.LNCC-B01-2014).The sample size is 600 participants through statistic calculation. The plan for missing data and statistical analysis will be implemented by specialized statisticians of China Medical University.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Xiaochun Ma, M.D.; Phone Number: 0086-13840192939; Email: maxc_cmu@sina.com
• Study Contact Backup: Name: Yini Sun, Ph.D; Phone Number: 0086-13700017130; Email: sunyini_1006@163.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • People's Hospital of Peking University
    • Contact: youzhong an, doctor
    • Principal Investigator: jie lv, doctor
  • Beijing, China
    • Recruiting
    • Beijing Friendship Hospital , Capital Medical University
    • Contact: meili duan
    • Principal Investigator: yu qiu, doctor
  • Beijing, China
    • Recruiting
    • Changgeng Hospital of Tsinghua University
    • Contact: yuan xu
  • Jilin, China
    • Recruiting
    • First Affiliated Hospital of Jilin Medical University
    • Contact: dong zhang
    • Principal Investigator: lina gu
  • Qinhuangdao, China
    • Recruiting
    • Qinhuangdao First Hospital
    • Contact: xiujuan liu
  • Shenyang, China
    • Recruiting
    • Liaoning Provincial People's Hospital
    • Contact: xinghuo feng
    • Principal Investigator: chengshu dong, master
  • Heilongjiang
    • Haerbin, Heilongjiang, China
      • Recruiting
      • The fist Affiliated Hospital Harbin Medical University
      • Contact: wei yang, master
      • Principal Investigator: mingyan zhao, doctor
  • Hunan
    • Changsha, Hunan, China
      • Recruiting
      • Xiangya Third Hospital of Central South University
      • Contact: min gao
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Recruiting
      • Zhongda Hospital
      • Contact: chun pan, MD
      • Principal Investigator: chun pan, doctor
      • Contact: Haibo Qiu, MD
  • Liaoning
    • Dalian, Liaoning, China
      • Recruiting
      • First Affiliated Hospital of Dalian Medical University
      • Contact: xianyao wan
      • Principal Investigator: chen chen, master
    • Dalian, Liaoning, China
      • Recruiting
      • Second Affiliated Hospital of Dalian Medical University
      • Contact: jian yu
      • Principal Investigator: dandan zhu
    • Shenyang, Liaoning, China
      • Recruiting
      • second Affiliated Hospital of china Medical University
      • Contact: bin zang, doctor
      • Principal Investigator: di chang, master
    • Shenyang, Liaoning, China
      • Recruiting
      • Shenyang Fourth People's Hospital
      • Contact: Wei Feng
      • Principal Investigator: yinan guo, master
  • Shandong
    • Qingdao, Shandong, China
      • Recruiting
      • Qilu Hospital of Shandong University(Qingdao)
      • Contact: dawei wu
      • Principal Investigator: chanyuan bu, master
  • Sichuan
    • Chengdu, Sichuan, China
      • Recruiting
      • West China Hospital of Sichuan University
      • Contact: yan kang
      • Principal Investigator: qin sun, doctor
  • Yunnan
    • Kunming, Yunnan, China
      • Recruiting
      • First Affiliated Hospital of Kunming Medical University
      • Principal Investigator: Li Wang
      • Contact: chuanyun qian
    • Kunming, Yunnan, China
      • Recruiting
      • the Second Affiliated Hospital of Kunming University
      • Contact: qingqing huang, doctor
      • Contact: yuanyuan wang, doctor
      • Principal Investigator: yuangyuan wang, doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical diagnosis of severe sepsis or/and septic shock
• suspected DIC:the score of Platelets plus International Normalized Ratio in the JAAM criteria is equal or more than 3 scores

Exclusion Criteria:

• consent declined
• pregnant or breastfeeding
• the length during ICU is less than 24 hours
• with other types of shock
• have bleeding or high risk for bleeding
• have an indication for therapeutic anticoagulation
• have a known or suspected adverse reaction to UFH including HIT
• are currently enrolled in another trial
• known or suspected cirrhosis or other severe hepatic diseases
• terminal illness with a life expectancy of less than 28 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Saline	Drug: Saline; For all the severe sepsis or septic shock patients, normal saline will be administered for fluid resuscitation according to the Guideline of Survival Sepsis Campaign.; Other Names: Normal saline
Experimental: Heparin; If severe sepsis with suspected DIC is diagnosed, the Heparin sodium(2ml:12500 units) will be administered intravenously continuously for 24 hours. The course of treatment will last 7 days or until the death or discharge.	Drug: Saline; For all the severe sepsis or septic shock patients, normal saline will be administered for fluid resuscitation according to the Guideline of Survival Sepsis Campaign.; Other Names: Normal saline; Drug: Heparin Sodium; A bottle solution of Heparin Sodium(2ml:12500IU) is added to 50ml saline and administered i.v. continuously for 24 hours, which last 7 days or until the death or discharge. The same amount of 0.9% saline as the heparin group will be administered in the placebo group.; Other Names: Unfractionated heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU mortality	The mortality during ICU stay	during ICU stay (up to day 28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day all-cause mortality	The all-cause mortality at day 28 after enrollment	after 28 days of enrollment of all the cases
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	during ICU stay (up to day 28)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in SOFA scores	The difference of SOFA scores between day 7 and day 1 upon enrollment	during the intervention period (up to day 7 after enrollment)
Change in JAAM and ISTH scores	The difference of JAAM and ISTH scores between day7 and day1 upon enrollment	during the intervention period (up to day 7 upon enrollment)

Collaborators and Investigators

• Sponsor: China Medical University, China
• Collaborators: The First Affiliated Hospital of Nanchang University; Peking University People's Hospital; Beijing Friendship Hospital; West China Hospital; Qilu Hospital of Shandong University; Shengjing Hospital; The Affiliated Hospital of Qingdao University; The People's Hospital of Liaoning Province; The First Hospital of Jilin University; Zhongda Hospital; General Hospital of Ningxia Medical University; The First Affiliated Hospital of Dalian Medical University; First Affiliated Hospital of Harbin Medical University; The First Hospital of Qinhuangdao; The Second Affiliated Hospital of Dalian Medical University; The Second Affiliated Hospital of Kunming Medical University; Beijing Tsinghua Changgeng Hospital; Fourth People's Hospital of Shenyang; First Affiliated Hospital of Kunming Medical University

Publications and helpful links

General Publications

• Jaimes F, De La Rosa G, Morales C, Fortich F, Arango C, Aguirre D, Munoz A. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med. 2009 Apr;37(4):1185-96. doi: 10.1097/CCM.0b013e31819c06bc.
• Zhang XJ, Ma XC. [Therapeutic effects of early administration of low-dose heparin in patients with severe sepsis]. Zhonghua Wai Ke Za Zhi. 2006 Sep 1;44(17):1209-11. Chinese.
• Zhao C, Zhang ZD, Zhang XJ, Li X, Zhu R, Ma XC. [Evaluation of clinical effects on low-dose heparin therapy for sepsis]. Zhonghua Nei Ke Za Zhi. 2009 Jul;48(7):566-9. Chinese.
• Liu XL, Wang XZ, Liu XX, Hao D, Jaladat Y, Lu F, Sun T, Lv CJ. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study. Exp Ther Med. 2014 Mar;7(3):604-608. doi: 10.3892/etm.2013.1466. Epub 2013 Dec 31.
• Barkun J, Christou NV; CAGS Evidence Based Reviews in Surgery Group. Canadian Association of General Surgeons Evidence Based Reviews in Surgery. 8. Efficacy and safety of recombinant human activated protein C for severe sepsis. Can J Surg. 2003 Dec;46(6):468-70. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2018
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: August 25, 2015
• First Submitted That Met QC Criteria: January 12, 2016
• First Posted (Estimated): January 13, 2016

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Severe sepsis; Unfractionated heparin; Disseminated intravascular coagulation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Hematologic Diseases; Hemorrhagic Disorders; Blood Coagulation Disorders; Thrombophilia; Sepsis; Toxemia; Disseminated Intravascular Coagulation; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: LNCCC-B01-2014

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No