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

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

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