Adjunctive Granisetron Therapy in Patients With Sepsis or Septic Shock

Study Overview
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Brief Summary
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In this prospective, single-center,randomized,controlled,single-blind clinical trial,Patients will be randomly assigned to receive granisetron or placebo for 4 days or until leaving the ICU(death or transfer from ICU to general ward or discharge). The primary outcome is all-cause death rate at 28 days.

Detailed Description
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Investigational drug：Granisetron hydrochloride for injection Study title：Adjunctive Granisetron Therapy in Patients with Sepsis or Septic Shock:A Single-center,Randomized,Controlled,Single-blind Clinical trial. Principal Investigator：Professor Ping Chang ,Professor Zhanguo Liu, professor Peng Chen,Department of Critical Care Unit, Zhujiang Hospital, Southern Medical University Study subjects：Adult septic/septic shock patients with procalcitonin(PCT≥2ng/ml when entering the ICU. Study phase： Investigator Initiated Trial(IIT) Study objectives：The objective of the study is to determine whether granisetron, compared to placebo, improve the prognosis of sepsis or septic shock,including the reduction in mortality, the protection of organ function and reduction of inflammatory response,and to determine the safety of granisetron in patients with sepsis. Study design：A Single-center,Randomized,Controlled,Single-blind Clinical trial. Medication method： Granisetron treatment group： Follow the guidelines for sepsis in 2016 and recommend routine treatment + 3mg granisetron in 22 ml normal saline every 8 h for 4 days or until leaving the ICU(death or transfer from ICU to general ward or discharge), whichever come first. Placebo control group：Follow the guidelines for sepsis in 2016 and recommend routine treatment + 25ml normal saline every 8 h for 4 days or until leaving the ICU(death or transfer from ICU to general ward or discharge), whichever come first. Course：4days Sample size：154. Sites：1 Primary endpoint：all-cause death at 28 days Secondary endpoints: The state of liver function: the serum level of transaminase(AST、ALT)、total bilirubin、direct bilirubin at 1,2,3,4,5 days after randomization The state of lung function:oxygenation index(PaO2/FiO2) at 1,2,3,4,5 days after randomization (the patients treated with extracorporeal membrane oxygenation will not collect this indicator). The state of kidney function:serum level of Creatinine (Cr)、blood urea nitrogen(BUN)、Cystatin(Cys) at 1,2,3,4,5 days after randomization The state of inflammatory response:the serum level of interleukin-6(IL-6) 、C-reactive protein 、Superoxide dismutase(SOD) and erythrocyte sedimentation rate(ESR) at 1,3,5 days after randomization. The state of circulation system: the serum level of lactic acid at 1,2,3,4,5 days after randomization The state of immune function:the serum level of white blood cell(WBC)、lymphocyte at 1, 3, 5 days after randomization,the serum level of cluster of differentiation 4 Tcell(CD4+ Tcell) and cluster of differentiation 8 Tcell(CD8+ Tcell) at 1,5days after randomization. The level of plasma 5-hydroxytryptamine(5-HT) at 1,5 days after randomization. Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score at 1, 3, 5 after randomization Incidence and duration of supportive care for organ dysfunction including vasoactive agents, mechanical ventilation, continuous renal replacement therapy(CRRT)、daily condition of fuid balance The length of stay in ICU Safety endpoints： adverse events Serious adverse events

Official Title
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Adjunctive Granisetron Therapy in Patients With Sepsis or Septic Shock：A Single-center, Randomized, Controlled, Single-blind Clinical Trial

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Granisetron Hydrochloride
* Drug: Placebo（Normal saline）


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria(Only patients who fully meet the following criteria are eligible to participate in the trial): Meets the diagnostic criteria for sepsis-3 developed by the American Society of Critical Care Medicine (SCCM)/European Critical Care Medicine Association (ESICM) Age ≥18 years old and age ≤80years old. Procalcitonin ≥2ng/ml Exclusion Criteria: Age<18 years, or age>80 years. Pregnancy or lactating A solid-organ or bone marrow transplant patients. Patients with myocardial infarction within the past 3 months. Advanced pulmonary fibrosis . Patients with cardiopulmonary resuscitation before enrollment. HIV-positive patients. granulocyte-deficient patients. blood/lymphatic system tumors are not remission. patients with limited care (lack of commitment to full，aggressive life support). patients with long-term use of immunosuppressive drugs or with immunodeficiency. patients with advanced tumors. patients combined with non-infectious factors leading to the death(uncontrollable major bleeding, brain hernia, etc.). surgically unresolved infection sources(such as some intraperitoneal infection etc.) patients allergic to granisetron. patients with intestinal obstruction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The participants in treatment group receive intravenous granisetron. The participants in control group receive normal saline.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: granisetron group<br>3ml granisetron（3mg） will be diluted in 22 mL of 0.9% normal saline,and the granisetron diluted will be intravenously injected for at 10 minutes， every 8 hours for 4 days or until leaving the ICU(death or transfer from ICU to general ward or discharge), whichever come first. | Drug: Granisetron Hydrochloride<br>* Granisetron will be diluted with 0.9% saline to ensure that the therapeutic drug and placebo are identical in appearance, and 50 ml syringes will serve as the containers for all intravenous drugs.<br>* Other names: Selective 5-hydroxytryptamine 3 receptor inhibitor;|
| Placebo Comparator: placebo group<br>Normal saline 25ml every 8h for 4 days or until leaving the ICU(death or transfer from ICU to general ward or discharge), whichever come first. | Drug: Placebo（Normal saline）<br>* therapeutic drug and placebo are identical in appearance, and 50 ml syringes will serve as the containers for all intravenous drugs.<br>* Other names: 0.9% saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| all-cause mortality rate | All-cause mortality rate from the enrollment to the 28th days | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| liver function(1) | the serum level of Alanine transaminase(ALT) | Day at 1,2,3,4,5 after randomization | 
| liver function(2) | the serum level of Aspartate transaminase (AST) | Day at 1,2,3,4,5 after randomization | 
| liver function(3) | the serum level of total bilirubin | Day at 1,2,3,4,5 after randomization | 
| liver function(4) | the serum level of direct bilirubin | Day at 1,2,3,4,5 after randomization | 
| lung function | oxygenation index(PaO2/FiO2)，the patients treated with extracorporeal membrane oxygenation will not collect this indicator | Day at 1,2,3,4,5 after randomization | 
| kidney function(1) | serum level of Creatinine (Cr) | Day at 1,2,3,4,5 after randomization | 
| kidney function(2) | serum level of blood urea nitrogen(BUN) | Day at 1,2,3,4,5 after randomization | 
| kidney function(3) | serum level of Cystatin(Cys) | Day at 1,2,3,4,5 after randomization | 
| inflammatory response(1) | the serum level of interleukin-6(IL-6) | Day at 1,3,5 after randomization. | 
| inflammatory response(2） | the serum level of C-reactive protein(CRP) | Day at 1,3,5 after randomization. | 
| inflammatory response(3） | the serum level of superoxide dismutase(SOD) | Day at 1,3,5 after randomization. | 
| inflammatory response(4） | the serum level of erythrocyte sedimentation rate(ESR) | Day at 1,3,5 after randomization. | 
| The level of lactic acid | the serum level of lactic acid | Day at 1,2,3,4,5 after randomization | 
| immune function(1) | the serum level of white blood cell(WBC) | Day at 1, 3, 5 after randomization for test the the serum level of white blood cell(WBC). | 
| immune function(2) | the serum level of lymphocyte | Day at 1, 3, 5 after randomization for test the the serum level of lymphocyte. | 
| immune function(3) | the serum level of CD4+ Tcell | Day at 1,5 after randomization for test the the serum level of CD4+ Tcell. | 
| immune function(4) | the serum level of CD8+Tcell | Day at 1, 5 after randomization for test the the serum level of CD8+Tcell. | 
| The level of 5-hydroxytryptamine (5-HT) | The level of plasma 5-HT | Day at 1,5 after randomization. | 
| Sequential Organ Failure Assessment (SOFA) score | Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score.SOFA score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems.The highest score for each of the six items is 4 points, and the lowest score is 0 points.Finally, the scores of the six items are summed to get the value of the sofa score.The range of the sofa score is 0-24.Higher values represent a worse outcome. | Day at 1, 3, 5 after randomization | 
| The proportion of patients receiving mechanical ventilation | The proportion of patients receiving mechanical ventilation within 28 days after randomization | 28 days | 
| The proportion of patients receiving vasoactive drugs | The proportion of patients receiving vasoactive drugs within 28 days after randomization | 28 days | 
| The proportion of patients receiving renal replacement therapy(CRRT) | The proportion of patients receiving CRRT within 28 days after randomization | 28 days | 
| The duration of mechanical ventilation | The the duration of mechanical ventilation therapy in hours( This outcome measure is intended only for patients receiving mechanical ventilation) | 28 days | 
| The duration of vasoactive drugs | The the duration of vasoactive drugs therapy in hours( This outcome measure is intended only for patients receiving vasoactive drugs) | 28 days | 
| The duration of CRRT | The the duration of CRRT therapy in hours( This outcome measure is intended only for patients receiving CRRT) | 28 days | 
| ICU length of stay | ICU length of stay | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septic shock, granisetron