Adjunctive Granisetron Therapy in Patients With Sepsis or Septic Shock (GRANTISS)

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Granisetron Hydrochloride; Drug: Placebo（Normal saline）

Detailed Description

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:

1. 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
2. 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).
3. 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
4. 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.
5. The state of circulation system: the serum level of lactic acid at 1,2,3,4,5 days after randomization
6. 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.
7. The level of plasma 5-hydroxytryptamine(5-HT) at 1,5 days after randomization.
8. Organ dysfunction assessed by Sequential Organ Failure Assessment (SOFA) score at 1, 3, 5 after randomization
9. Incidence and duration of supportive care for organ dysfunction including vasoactive agents, mechanical ventilation, continuous renal replacement therapy(CRRT)、daily condition of fuid balance
10. The length of stay in ICU

Safety endpoints：

1. adverse events
2. Serious adverse events

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510282
      • Department of Critical Care Medicine of Zhujiang Hospital,Southern Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: granisetron group; 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; 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.; Other Names: Selective 5-hydroxytryptamine 3 receptor inhibitor
Placebo Comparator: placebo group; 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）; therapeutic drug and placebo are identical in appearance, and 50 ml syringes will serve as the containers for all intravenous drugs.; Other Names: 0.9% saline

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	A adverse event refers to any adverse medical event that occur after the intervention of trial. The adverse events are not necessarily causally related to the trial treatment.	28 days
Incidence of serious adverse events	Any adverse medical event occurs at any dose that meets one or more of the following criteria: 1. causes death 2. life-threatening 3. requires hospitalization or hospitalization for an extended period of time 4. causes permanent or significant disability and functional defects 5. causes deformity	28 days

Collaborators and Investigators

• Sponsor: Zhujiang Hospital
• Investigators: Principal Investigator: ping Chang, M.D.PhD, Department of Critical Care Medicine of Zhujiang Hospital

Publications and helpful links

General Publications

• Gong S, Yan Z, Liu Z, Niu M, Fang H, Li N, Huang C, Li L, Chen G, Luo H, Chen X, Zhou H, Hu J, Yang W, Huang Q, Schnabl B, Chang P, Billiar TR, Jiang Y, Chen P. Intestinal Microbiota Mediates the Susceptibility to Polymicrobial Sepsis-Induced Liver Injury by Granisetron Generation in Mice. Hepatology. 2019 Apr;69(4):1751-1767. doi: 10.1002/hep.30361. Epub 2019 Mar 5.
• Guan J, Guo Y, Chang P, Gan J, Zhou J, Wang H, Cen Z, Tang Y, Liu Z, Chen P. Adjunctive granisetron therapy in patients with sepsis or septic shock (GRANTISS): Study protocol for a randomized controlled trial. Medicine (Baltimore). 2019 Sep;98(39):e17354. doi: 10.1097/MD.0000000000017354.

Helpful Links

• Our previous research

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2019
• Primary Completion (Actual): November 28, 2020
• Study Completion (Actual): December 28, 2020

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 22, 2019
• First Posted (Actual): April 23, 2019

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 5, 2022
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: septic shock; sepsis; granisetron
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Toxemia; Shock, Septic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Serotonin Agents; Serotonin Receptor Agonists; Serotonin Antagonists; Granisetron; Serotonin
• Other Study ID Numbers: 2018-ZZJHZX-009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: since some data may involve patients privacy ，we have no plans to share data so far，and some data may be shared later depending on the patient's wishes.

Drug and device information, study documents

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