Efficacy and Safety Study of CA330 Hemoadsorption Device on IL-6 Removal in Septic Patients

Efficacy and Safety Study of CA330 Hemoadsorption Device on IL-6 Removal in Septic Patients: A Multicenter Randomized Controlled Trial

Sepsis persists to be the leading causes of morbidity and mortality worldwide. Moreover, the magnitude of health care resources utilized when managing septic patients is huge. All these hard facts call for constant efforts to optimize therapy. At present, the definitive therapy is adequate antibiotics and infectious source control. Fortunately, research has led to a better understanding of the pathophysiology of sepsis, in which the activation of multiple pro- and anti-inflammatory mediators plays a key role. This has led to the development of treatment strategies aimed at restoring a balanced immune response by eliminating/deactivating these inflammatory mediators. Whilst animal models of sepsis have provided encouraging results with strategies aiming at immune response modulation, clinical studies in patients using targeted pharmacological approaches have so far proved disappointing.

Besides of acute kidney injury (AKI), renal replacement therapy (RRT) is applied to remove inflammatory mediators extracorporeally. Across the different modalities, the application of adsorption may help deactivate and decrease the peak elevation of these mediators in earlier course of sepsis, when levels of endotoxins and cytokines are extremely high. Recently, attempts to improve the outcome of sepsis patients with such devices, ie CytoSorb cytokine hemoadsorption and polymyxin B (Toraymyxin) endotoxin adsorption, have seen a certain renaissance. However, the clinical evidence to date supporting hemoadsorption for removal of endotoxins and/or proinflammatory mediators in sepsis remains incompetent and controversial.

CA330 (Jafron Biomedical Co , Ltd, Zhuhai, China) is a hemoadsorption device containing hemocompatible, porous polymeric beads capable of removing cytokines and other mid-molecular weight toxins from blood by size exclusion and surface adsorption. Compared with HA330, improved resin synthesis technology makes CA330 a better performance in removing cytokines. This trial is the first to evaluate CA330 efficacy of cytokine reduction using the change in plasma interleukin (IL)-6 concentrations over time as a primary outcome. Although the trial was neither designed nor powered to evaluate outcome, we also evaluated organ function parameters as well as 28-day all-cause mortality.

Study Overview

• Status: Unknown
• Conditions: Sepsis
• Intervention / Treatment: Device: hemoperfusion with cytokine adsorption column (CA330)

Detailed Description

Eligible patients are stratified by site and randomly assigned in a 1:1 ratio to either CA330 hemoperfusion plus conventional medical therapy group or conventional medical therapy group. The randomization is performed by researchers on the central randomization system, provided by the Department of Biostatistics, Southern Medical University. In this study, the center coded random number table is produced by stratified and sectional randomization method. Statistical Analysis System(SAS) 9.4 statistical software is used to generate random coding tables with serial numbers (001-144) according to the number of cases allocated in each center and the proportion of experimental group and control group (1:1). The length of selected sections (block) and random seed number are sealed together as confidential data . The random number table is provided by the statisticians of the Department of Biostatistics, Southern Medical University.

The experimental group receive routine treatment of sepsis combined with cytokine adsorption column (CA330) perfusion, and the control group receive routine treatment of sepsis only.

Hemoperfusion treatments are performed using a perfusion machine via centrally inserted standard dialysis catheters at a prescribed blood flow rate of 100-300ml/min. In the beginning, lower flow rate is recommended, if there is no discomfort, then gradually increases. Each patient received 2 hemoperfusion treatments within 24 hours with a target duration for each treatment of 120-180 minutes (minimum of 120 minutes). The shorter the interval between the two hemoperfusion is, the better. It is suggested that the second hemoperfusion be performed within 0-5 hours after the first one.

Anticoagulation was recommended with low-molecular-weight heparin in arterial line of the circuit at the dose of 60-80 international units (IU)/kg. No additional dose is required. The activity of anticoagulant factor α can be monitored at 60 minutes. It is suggested that the activity of anticoagulant factor α should be maintained at 500-1000units/L in subjects without bleeding tendency and 200-400units/L in subjects with bleeding tendency. If the clinical condition is limited, it is not mandatory to monitor this parameter.

• Study Type: Interventional
• Enrollment (Anticipated): 144
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zimeng Liu, PhD; Phone Number: 18826471751 +8618925002766; Email: sumslzm@163.com
• Study Contact Backup: Name: Yao Nie, PhD; Phone Number: 18826471751 +8618826471751; Email: nieyao850622@126.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Recruiting
      • The First Affiliated Hospital of Sun Yat-sen University
      • Contact: Xiangdong Guan, PhD; Phone Number: +8613802925067; Email: carlg@163.net
      • Principal Investigator: Zhiyong Peng, PhD
      • Principal Investigator: Qiuye Kou, PhD
      • Principal Investigator: Weixing Zhang, PhD
      • Principal Investigator: Rongguo Yu, PhD
      • Principal Investigator: Zhanguo Liu, PhD
      • Principal Investigator: Jun Zeng, PhD
      • Principal Investigator: Wenxiong Li, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hospitalized patients aged 18-75 years, regardless of gender;
2. Meet the clinical criteria of sepsis according to the Third International Consensus Definitions for Sepsis;
3. The diagnosis of sepsis is established within last 48 hours.
4. Written informed consent is signed, and agreement to participate in all visits, examinations and treatments as required by the research program is achieved. If a patient is not able to give consent, the legal representative is asked to consent.

Exclusion Criteria:

1. End-stage renal disease that need maintenance hemodialysis treatment;
2. Congenital or acquired immunodeficiency disorders or those who had received organ transplantation within one year;
3. Prescription of immunosuppressive medications (tripterygium wilfordii, mycophenolate mofetil, cyclophosphamide, FK506, etc.) or prednisolone for more than 10 mg/day (or the same dose of other hormone therapy) within 30 days;
4. Coagulation dysfunction, severe bleeding tendency (prothrombin time, activated partial thromboplastin time prolonged significantly with bleeding, or fibrinogen less than 1.2 g/L with bleeding), active bleeding or uncontrolled acute massive bleeding within 24 hours;
5. Malignant tumors, consumptive diseases, site of infection cannot be cleared (ie surgical patients who cannot be operated on) or body weight less than 35kg;
6. A terminal state of organ failure (end stage of chronic obstructive pulmonary disease, pulmonary heart disease, heart dysfunction stage-IV, brain death or persistent vegetative state, chronic liver disease with hepatic encephalopathy, coagulation dysfunction, fluid retention and hepatocellular jaundice);
7. Following results are detected during screening: platelet count < 50 *10^9/L, neutrophil count < 0.5 *10^9/L, hemoglobin < 70 g/L;
8. Despite of adequate volume resuscitation, vasopressors and hormones, the mean arterial blood cannot maintain above 65 mmHg;
9. Those who have been participating in or participated in another interventional clinical study within 30 days prior to enrollment, such as the clinical study of related drugs or medical devices affecting immunity (ie Xuebijing, ulinastatin, continuous renal replacement therapy, etc.);
10. Anaphylaxis to materials of cardiopulmonary bypass, anticoagulants and hemoperfusion or other serious allergic history;
11. Those who are not suitable for this clinical trial, which is determined by researchers, such as pregnant or lactating women, current drug addicts, patients with severe mental or neurological disorders, and those who have a history of alcohol abuse and cannot be terminated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Group; The control group receive routine treatment of sepsis only. All sites agree, when feasible, to follow the tenets of the Surviving Sepsis Campaign clinical practice guidelines for management of sepsis.
Experimental: Experimental Group; The experimental group receive routine treatment of sepsis combined with hemoperfusion with cytokine adsorption column (CA330).	Device: hemoperfusion with cytokine adsorption column (CA330); Hemoperfusion treatments are performed using a perfusion machine via centrally inserted standard dialysis catheters at a prescribed blood flow rate of 100-300ml/min. In the beginning, lower flow rate is recommended, if there is no discomfort, then gradually increases. Each patient received 2 hemoperfusion treatments within 24 hours with a target duration for each treatment of 120-180 minutes (minimum of 120 minutes). The shorter the interval between the two hemoperfusion is, the better. It is suggested that the second hemoperfusion be performed within 0-5 hours after the first one.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the reduction rate of IL-6 serum concentration at the initiation of first adsorption and at the end of the second adsorption	(1-Concentration IL-6 end of second adsorption/ Concentration IL-6 initiation of first adsorption) ×100%	from the initiation of first adsorption until the end of the second adsorption, assessed up to 24hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the reduction rate of IL-10 serum concentration at the initiation of first adsorption and at the end of the second adsorption	(1-Concentration IL-10 end of second adsorption/ Concentration IL-10 initiation of first adsorption) ×100%	from the initiation of first adsorption until the end of the second adsorption, assessed up to 24hours
the reduction rate of lactic acid serum concentration at the initiation of first adsorption and at the end of the second adsorption	(1-Concentration lactic acid end of second adsorption/ Concentration lactic acid initiation of first adsorption) ×100%	from the initiation of first adsorption until the end of the second adsorption, assessed up to 24hours
the reduction rate of tumor necrosis factor-α (TNF-α) serum concentration at the initiation of first adsorption and at the end of the second adsorption	(1-Concentration TNF-α end of second adsorption/ Concentration TNF-α initiation of first adsorption) ×100%	from the initiation of first adsorption until the end of the second adsorption, assessed up to 24hours
the dynamic change of Acute Physiology and Chronic Health Evaluation (APACHE II) score	The maximum APACHE II score is 71, while the minimum score is 0. The higher values represent a worse outcome.	from Day0 to Day28
ventilation time	scale: hour	from Day0 to Day28
oxygenation index	partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2)	from Day0 to Day28
24hour urinary output	scale: ml/24h	from Day0 to Day28
length of vasopressors	scale: hour	from Day0 to Day28
catecholamine index	(dopamine dose*1)+(dobutamine dose*1)+(adrenaline dose*100)+(noradrenaline dose*100)+(phenylephrine dose*100), wherein all doses are expressed as µg/kg/min.	from Day0 to Day28
RRT incidency	the percentages of patients who receive RRT in two groups	from Day0 to Day28
total length of renal replacement therapy	scale: hour	from Day0 to Day28
ICU and hospital length of stay	scale: day	from Day0 to Day28
28-day all-cause mortality	the 28-day all-cause mortality in two groups	from Day0 to Day28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
body temperature	scale: ℃	from Day0 to Day28
heart rate	scale: beats per minute (bpm)	from Day0 to Day28
respiratory rate	scale: times per minute	from Day0 to Day28
blood pressure	Both systolic and diastolic pressure will be measured. Scale: mmHg	from Day0 to Day28
count of white blood cell	scale: cells/L	from Day0 to Day28
count of neutrophils	scale: cells/L	from Day0 to Day28
concentration of hemoglobin	scale: g/dl	from Day0 to Day28
hematocrit value	hematocrit value	from Day0 to Day28
count of platelet	scale: cells/L	from Day0 to Day28
prothrombin time (PT)	scale: second	from Day0 to Day28
activated partial thromboplastin time (APPT)	scale: second	from Day0 to Day28
level of fibrinogen	scale: g/dl	from Day0 to Day28
thrombin time (TT)	scale: second	from Day0 to Day28
level of serum Alanine transaminase (ALT)	scale: Unit/L (U/L)	from Day0 to Day28
level of serum Aspartate transaminase (AST)	scale: Unit/L (U/L)	from Day0 to Day28
level of total bilirubin	scale: µmol/L	from Day0 to Day28
level of direct bilirubin	scale: µmol/L	from Day0 to Day28
level of total protein	scale: g/L	from Day0 to Day28
level of albumin	scale: g/L	from Day0 to Day28
concentration of serum creatinine	scale: mg/dl	from Day0 to Day28
concentration of blood urea nitrogen	scale: mmol/L	from Day0 to Day28
concentration of serum potassium	scale: mmol/L	from Day0 to Day28
concentration of serum sodium	scale: mmol/L	from Day0 to Day28
concentration of serum calcium	scale: mmol/L	from Day0 to Day28
concentration of serum phosphorus	scale: mmol/L	from Day0 to Day28
concentration of serum magnesium	scale: mmol/L	from Day0 to Day28

Collaborators and Investigators

• Sponsor: First Affiliated Hospital, Sun Yat-Sen University
• Collaborators: Wuhan University; Guangzhou First People's Hospital; Beijing Chao Yang Hospital; Zhujiang Hospital; Sixth Affiliated Hospital, Sun Yat-sen University; Peking University Shenzhen Hospital; Fujian Provincial Hospital
• Investigators: Principal Investigator: Xiangdong Guan, PhD, First Affiliated Hospital, Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2018
• Primary Completion (Anticipated): February 1, 2020
• Study Completion (Anticipated): October 1, 2020

Study Registration Dates

• First Submitted: February 13, 2019
• First Submitted That Met QC Criteria: February 18, 2019
• First Posted (Actual): February 20, 2019

Study Record Updates

• Last Update Posted (Actual): February 22, 2019
• Last Update Submitted That Met QC Criteria: February 20, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: sepsis; IL-6; hemoperfusion
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis
• Other Study ID Numbers: 2018-030-02

Drug and device information, study documents

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