Clinical trial NCT02647554: Ulinastatin Treatment in Adult Patients With Sepsis and Septic Shock in China
Official title: A Prospective, Multi-Centre, Double-Blind, Randomized, Placebo-Controlled, Trial of Ulinastatin Treatment in Adult Patients With Sepsis and Septic Shock in China
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Sepsis
Septic Shock
Keywords: sepsis
septic shock
Ulinastatin
adult
China
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: Techpool Bio-Pharma Co., Ltd.
First posted: 2016-01-06
Enrollment: 347
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A Prospective, Multi-Centre, Double-Blind, Randomized, Placebo-Controlled, Trial of Ulinastatin Treatment in Adult Patients with Sepsis and Septic Shock in China

Detailed description: Investigational drug：Ulinastain for Injection

Study title： A Prospective, Multi-Centre, Double-Blind, Randomized, Placebo-Controlled, Trial of Ulinastatin Treatment in Adult Patients with Sepsis and Septic Shock in China

Principal Investigator：Professor Bin Du, Medical Intensive Care Unit, Peking Union Medical College Hospital; Professor Xiangyou Yu, Critical Care Medicine, First Affiliated Hospital, Xinjiang Medical University

Study subjects： Adult patients with sepsis and septic shock will be eligible for inclusion if all of the inclusion criteria are met within 48 hours of meeting criteria of sepsis-3 definition

Study phase： Investigator Initiated Trial(IIT)

Study objectives： The primary objective of the study is to determine whether ulinastatin, compared to placebo, reduces 28-day all-cause mortality in patients with sepsis and septic shock

Study design： Prospective, Multi-Centre, Double-Blind, Randomized, Placebo-Controlled, Clinical Trial

Medication method：

* Ulinastain treatment group： 400,000 IU ulinastatin or matching placebo will be reconstituted in 10 mL of 0.9% normal saline, and then dissolved in 100 mL of 0.9% normal saline every 8 hours for 10 days in a double-blind fashion. Intravenous infusion, The study drug will be infused intravenously over 1 hour.
* Placebo control group：Matching with medication

Course：10 days

Sample size： 348(174 patients of treatment group, 174 patients of control group)

Sites： 15

Primary endpoint：The primary outcome measure for the study is death from all causes at 28-days.

Secondary endpoints:

* Mortality rate at 90-days
* Mortality rate in ICU
* Mortality rate at hospital discharge
* ICU-free days in 28 days
* Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score at 1, 3, 6, 10,14, and 28 days after randomization
* Incidence and duration of supportive care for organ dysfunction including vasoactive agents, invasive or noninvasive mechanical ventilation, continuous renal replacement therapy(CRRT)
* Blood lactate concentration at 1, 3, 6 and 10 days after randomization
* Condition of fluid balance within 10 days after randomization
* High-sensitivity C-reactive protein (hs-CRP), IL-6, IL-10, TNF-α at 1, 3,6 and 10 days after randomization
* ADL level at hospital discharge

Safety endpoints

* adverse events
* serious adverse events
* vital signs, complete blood counts, chemistry, electrocardiograms

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)

1. Suspected or confirmed infection AND
2. Evidence of acute organ dysfunction • in patients not known to have preexisting organ dysfunction (The baseline SOFA score can be assumed to be zero): total SOFA score ≥2 points from 48 hours before infection to 24 hours after infection.

   • in patients known to have preexisting organ dysfunction (The baseline SOFA score can be assumed according to baseline conditions): changes of total SOFA score ≥2 points from 48 hours before infection to 24 hours after infection.

   2）48 hours within diagnosis of sepsis 3）Signed and dated informed consent should be obtained prior to any screening procedures from subjects (or legal representatives). If the subject is unable to provide consent, it could be obtained from legal representatives according to local regulation. Consent from subject should be obtained afterwards when available.

   4） Fertile men or women should agree to use efficient birth control methods during the treatment period and at least 28 days after last dose. Fertile is defined as biologically fertile and sexually active from investigator's view.

   5） Non-childbearing women (meet at least one of following criteria):

   • Past hysterectomy or bilateral oothectomy；

   • Medically confirmed ovarian failure, or menopause (amenorrhea for 12 month or more and with no other pathological or physiological reason)

   Exclusion Criteria:

   1) Age \< 18 years, or age\>80 years 2) Pregnancy or lactating 3) New York Heart Association Class IV congestive heart failure, nonseptic cardiogenic shock, or uncontrolled acute blood loss 4) Severe, preexisting, parenchymal liver disease with clinically significant portal hypertension, Child-Pugh C stage cirrhosis or acute liver failure 5) Receipt of a solid-organ or bone marrow transplant 6) Advanced pulmonary fibrosis or non invasive ventilation before study entry 7) Myocardial infarction within the previous 3 months 8) Cardiopulmonary resuscitation within 72 hours before study entry 9） Invasive fungal infection or active pulmonary tuberculosis 10) Full-thickness thermal or chemical burn involving 30% or more of body surface area 11) Evidence of significant drug- or disease-induced immunosuppression

   · Evidence of moderate or severe neutropenia, i.e. absolute neutrophil count (ANC) \< 1.0 x 10\^9/L
   * Administration of high doses of corticosteroids, i.e. doses of \> 20 mg/day of prednisone or equivalent, for ≥ 2 weeks immediately prior to evaluation for enrollment. Hydrocortisone at dose ≤ 300 mg/d for treatment of septic shock is acceptable.
   * Immunomodulatory medication (e.g. cyclosporine, azathioprine, OKT3), chemotherapy, or radiation therapy within 2 months before study entry
   * Known HIV seropositivity
   * Any disease sufficiently advanced to suppress resistance to infection
   * Non-remission stage of hematological/lymphoid tumor 12) Previous Xuebijing, thymosin or IVIG Within 2 months before study entry 12) Inability to obtain informed consent or assent 13) Participation in an investigational clinical trial within 6 months of screening 14) Expected survival \< 2 months or chronic vegetative state 15) Lack of commitment to full, aggressive, life support 16) History of hypersensitivity to ulinastatin or any excipients or preservatives

Primary outcomes:
measure: all cause mortality
timeFrame: 28 days
Secondary outcomes:
measure: mortality
timeFrame: 90 days
measure: mortality in ICU
timeFrame: through ICU discharge, an average of 14 days
measure: mortality rate at hospital discharge
timeFrame: through hospital discharge, an average of 21 days
measure: ICU-free days
timeFrame: 28 days
measure: SOFA score
timeFrame: Day 1,3,6,10,14,28 after randomization
measure: incidence of supportive care
timeFrame: through ICU discharge, an average of 14 days
measure: duration of supportive care
timeFrame: through ICU discharge, an average of 14 days
measure: blood lactate concentration
timeFrame: Day 1,3,6,10 after randomization
measure: fluid balance
timeFrame: through ICU discharge, an average of 10 days
measure: serum hsCRP
timeFrame: Day 1,3,6,10 after randomization
measure: serum IL-6
timeFrame: Day 1,3,6,10 after randomization
measure: serum IL-10
timeFrame: Day 1,3,6,10 after randomization
measure: serum TNF-α
timeFrame: Day 1,3,6,10 after randomization
measure: complete blood counts
timeFrame: Day 1-10, 14, 28 after randomization
measure: liver function (alanine aminotransferase, ALT)
timeFrame: Day 1-10, 14, 28 after randomization
measure: liver function (Aspartate transaminase, AST)
timeFrame: Day 1-10, 14, 28 after randomization
measure: liver function (bilirubin)
timeFrame: Day 1-10, 14, 28 after randomization
measure: respiratory function
timeFrame: Day 1-10, 14, 28 after randomization
measure: renal function
timeFrame: Day 1-10, 14, 28 after randomization
measure: Activities of daily living (ADL) at hospital discharge
timeFrame: through hospital discharge, an average of 21 days
measure: adverse events
timeFrame: till 28 days after randomization
measure: serious adverse events
timeFrame: till 28 days after randomization
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
Study officials:
affiliation: Peking Union Medical College Hospital, Beijing, China
name: Bin Du, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chalfin DB, Holbein ME, Fein AM, Carlon GC. Cost-effectiveness of monoclonal antibodies to gram-negative endotoxin in the treatment of gram-negative sepsis in ICU patients. JAMA. 1993 Jan 13;269(2):249-54.
citation: Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002.
citation: Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004 Apr;30(4):589-96. doi: 10.1007/s00134-004-2157-0. Epub 2004 Feb 12.
citation: Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003 Sep;31(9):2332-8. doi: 10.1097/01.CCM.0000085141.75513.2B.
citation: Brun-Buisson C, Meshaka P, Pinton P, Vallet B; EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004 Apr;30(4):580-8. doi: 10.1007/s00134-003-2121-4. Epub 2004 Mar 2.
citation: Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, Fang Q, Xu Q, Wang D, Jin Y, Yuan S, Wang J, Du Z, Sun Y, Fang X. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med. 2007 Nov;35(11):2538-46. doi: 10.1097/01.CCM.0000284492.30800.00.
citation: Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Nov 21;369(21):2063. doi: 10.1056/NEJMc1312359. No abstract available.
citation: Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.
citation: Christaki E, Anyfanti P, Opal SM. Immunomodulatory therapy for sepsis: an update. Expert Rev Anti Infect Ther. 2011 Nov;9(11):1013-33. doi: 10.1586/eri.11.122.
citation: Sharony R, Yu PJ, Park J, Galloway AC, Mignatti P, Pintucci G. Protein targets of inflammatory serine proteases and cardiovascular disease. J Inflamm (Lond). 2010 Aug 30;7:45. doi: 10.1186/1476-9255-7-45.
citation: Inoue K, Takano H, Yanagisawa R, Yoshikawa T. Protective effects of urinary trypsin inhibitor on systemic inflammatory response induced by lipopolysaccharide. J Clin Biochem Nutr. 2008 Nov;43(3):139-42. doi: 10.3164/jcbn.2008059. Epub 2008 Oct 31.
citation: Huang N, Wang F, Wang Y, Hou J, Li J, Deng X. Ulinastatin improves survival of septic mice by suppressing inflammatory response and lymphocyte apoptosis. J Surg Res. 2013 Jun 15;182(2):296-302. doi: 10.1016/j.jss.2012.10.043. Epub 2012 Nov 9.
citation: Shao YM, Zhang LQ, Deng LH, Yao HG. [Clinical study on effects of ulinastatin on patients with systemic inflammatory response syndrome]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2005 Apr;17(4):228-30. Chinese.
citation: Karnad DR, Bhadade R, Verma PK, Moulick ND, Daga MK, Chafekar ND, Iyer S. Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study. Intensive Care Med. 2014 Jun;40(6):830-8. doi: 10.1007/s00134-014-3278-8. Epub 2014 Apr 16.
citation: Yuhara H, Ogawa M, Kawaguchi Y, Igarashi M, Shimosegawa T, Mine T. Pharmacologic prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis: protease inhibitors and NSAIDs in a meta-analysis. J Gastroenterol. 2014 Mar;49(3):388-99. doi: 10.1007/s00535-013-0834-x. Epub 2013 May 30.
citation: Jiang W, Yu X, Sun T, Chai Y, Chang P, Chen Z, Pan J, Peng Z, Wang R, Wang X, Xu Y, Yu L, Zheng Q, Du B; China Critical Care Clinical Trials Group (CCCCTG). ADJunctive Ulinastatin in Sepsis Treatment in China (ADJUST study): study protocol for a randomized controlled trial. Trials. 2018 Feb 21;19(1):133. doi: 10.1186/s13063-018-2513-y.