SepsisOuTCAStNCT04306419
Observational Trial on Cytokine Adsorption in Sepsis
An observational study of Sepsis and Septic Shock, run by RWTH Aachen University at 1 site in Germany.
Trial summary
To determine the specific population of critically ill septic patients who benefit most from cytokine adsorption therapy with the HA-380 cartridge. Benefit of the treatment will be assessed on the basis of: The scope of the effect of cytokine adsorption therapy in this specific population of critically ill patients… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Septic Shock, Multiple Organ Failure
- How many people
- 100 participants
- Where
- 1 siteGermany
- Study dates
- 15 Nov 2020to 31 May 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: We will perform an observational trial in a large cohort of patients with sepsis and septic shock who are treated with cytokine adsorption by hemoperfusion with a HA-380 cartridge. Sepsis will be defined as done in the Sepsis-3 definition. In addition to sepsis or septic shock patients must have a confirmed excess of IL-6, IL-10 or TNF-alpha or a combination of these with IL-6 levels > 1000 pg/l, IL-10 levels >250 pg/l or TNF-alpha levels > 100 ng/l. Patients must be in need of CRRT or ECMO therapy to perform the HA-380 therapy. Stand-alone hemoperfusion will not be performed. Patients must be included within 24 hrs of diagnosing sepsis. The IL-6 measurement for inclusion must be from within 24 hrs, IL-10 or TNF-alpha measurements for inclusion can be from within 36 hrs before inclusion.
Who may be able to join
- >18 years of age
- diagnosis of sepsis or septic shock with at least 2 organ-dysfunctions defined by SOFA score
- baseline serum IL-6 > 1000 pg/ml, IL-10 levels >250 pg/ml or TNF-alpha levels > 100 ng/l. The baseline IL-6 measurement must be on the same calendar day that the cytokine adsorption is started, the baseline IL-10 or TNF-alpha can be taken up to 36h before because of higher turn-around times for these tests.
- need for CRRT or ECMO therapy
Who cannot join
- Solid organ malignancies with or without treatment
- Participation or enrollment in another clinical study within 30 day
- Pregnant and lactating females If women of childbearing potential will be enrolled, a pregnancy test will be performed by assessing the value of ß-HCG in the routinely drawn blood and or urine.
- Patient has been committed to an institution by legal or regulatory order
- Participation in a parallel interventional clinical trial
- The subject received an investigational drug within 30 days prior to inclusion into this project
Trial locations and contacts
1 site in 1 country.
Germany1 site, 1 recruiting
- Recruiting
University Hospital RWTH Aachen
Aachen, North Rhine-Westphalia, 52074
Alexander M Kersten, MD, +49-241-800, akersten@ukaachen.de
About this study
To determine the specific population of critically ill septic patients who benefit most from cytokine adsorption therapy with the HA-380 cartridge. Benefit of the treatment will be assessed on the basis of:
- The scope of the effect of cytokine adsorption therapy in this specific population of critically ill patients expressed by cytokine variability within the patients
- The scope of cytokine changes in passing the adsorption cartridge my measuring cytokine levels in the patient's blood directly before passing through the cartridge and directly after having passed through the cartridge.
- The scope of changes in organ dysfunction expressed by SOFA scores that are repeatedly calculated during the treatment with cytokine adsorption and then daily until day 7 of the ICU treatment.
- The scope of changes on cellular function on immune cells in serum samples taken before and after cytokine adsorption therapy.
- The scope of removal of anti-infective drugs from the blood in passing through the cytokine adsorption cartridge by measuring antibiotic drug levels in the patients blood during the cytokine adsorption therapy
- 30 day and 90 day mortality and location status in survivors
Read the detailed description
- Medical Problem Sepsis, a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection. It is a major public health concern, accounting for more than $20 billion (5.2%) of total US hospital costs in 2011. Sepsis has shown an increase in incidence most likely due to a combination of aging patient populations with more comorbidities and greater recognition. Sepsis is by conservative estimates a leading cause of mortality and morbidity in critical illness with long term sequelae for survivors. Underlying to sepsis is a multifaceted host response to an infecting pathogen that may be significantly amplified by endogenous factors and is defined by a nonhomeostatic, dysregulated host response to the infection with a potential lethality that is considerably in excess of that straightforward infection. In the early phases, an overshoot of pro-inflammatory mediators is often observed, caused by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). High levels of pro- and anti-inflammatory cytokines are both associated with increased mortality. Blocking of overproduction of these cytokines using monoclonal anti- bodies targeting specific cytokines such as tumor necrosis factor-α (anti-TNF-α) have not demonstrated mortality benefits in larger trials. Therefore, an approach to decrease cytokine overproduction by using extracorporeal blood purification has previously been examined. Initial trials using Polymyxin B showed favorable results for markers of critical care treatment with a reduction of vasopressor dosage and higher ratios oxygen partial pressure to inspired oxygen. A larger randomized trial by Payenne however did not show any improvement of organ dysfunction or reduction in mortality by using Polymycin B hemoperfusion. A recent trial on the effect of the CytoSorb adsorption device using Interleucin-6 (IL-6) levels as marker of efficacy did also not find an effect of mortality, improved organ dysfunction or in fact a reduction of circulating IL-6 levels. However, in this trial the baseline cytokine levels were only moderately increased to begin with suggesting use of a device within a suboptimal patient population. As no more approved specific therapies to treat sepsis, exist following the withdrawal of recombinant activated protein C (Xigris; Eli Lilly, USA) from the market in 2011 following the results of the PROWESS-SHOCK trial and the pathophysiologic basis for mechanisms in sepsis due to an excess cytokine release are sound, the extracorporeal removal of cytokines remains a promising therapeutic target given the correct patient population.
- Principal research question and novel aspects Within the trials addressing removal of excess cytokines, the selection of patients and timing of the intervention has been difficult, and results have not been conclusive. Data on the patient population which might benefit most in regard to the aspects of cytokine levels removed and organ failure or progressive organ dysfunction averted are sparse or non-existent. Even the largest randomised trial so far was active for 3 years in recruiting 100 patients out of 580 patients screened. This trial failed to show a positive effect on the primary endpoint of IL-6 removal as well as on secondary endpoints of morbidity or 30 day mortality. However, in this small trial there was a very low median cytokine level measured at baseline and randomisation which might be associated with the consecutive failure to detect a reduction in circulating cytokines. The question remains, whether this trial identified a patient population that was going to benefit from such a therapy to begin with. Post-hoc analyses of another trial, the Euphrates trial showed that there might be positive signal for reduced mortality in patients with an endotoxin activity that was in a mid-range and not at the highest end of the spectrum. We therefore aim to undertake an observational trial to examine the effect of treating sepsis according to the surviving sepsis campaign guidelines and using extracorporeal cytokine removal looking at circulating cytokine levels and development of new or worsening organ dysfunction in patients with sepsis or septic shock who show highly increased IL-6 levels.
- HA 330 and HA 380 Hemoperfusion Cartridge The HA type resin cartridge (Jafron Industries, China) is an extracorporeal hemoperfusion device that uses neutral microporous resin, and it has been proven to specifically absorb different media- tors such as bilirubin and cytokines.
The HA380 HA 330 and HA 380 resin cartridges haves the ability to absorb various medium-sized factors, including most inflammatory cytokines (IL-1, IL-6, IL-8, IL-10 and TNF-a) and haves therefore lately been used in the treatment of patients with sepsis in China with several case reports demonstrating promising results on the clinical course of treated patients. Furthermore, there pooled there is emerging data that this therapeutic concept is efficienct and helpful in adequately selected patient populations.
The HA 380 cartridge is the CE-labeled updated version of the HA-330 cartridge which features a larger surface area of the resin beads increasing the overall capacity and thus potential efficacy of the device.
The HA 380 Hemoperfusion Cartridge works using Van der Waals interaction between resin molecular groups and adsorbed substances. Unlike the CytoSorb device, these are incorporated into the resin molecule by a molecular sieve effect of the 3D network structure and the lipophilic hydrophobicity of the molecular group. Therefore, the pass-through effect in removing cytokines is expected to be larger and more sustained, as previously adsorbed cytokines will not again be released by continued blood flow or movement of the device. The range of adsorption is shown in figure 1. The device described has a CE label and is approved for treatment in a variety of clinically situations including but not limited to intra-operative use in cardiac surgery, intoxication, liver failure and sepsis. Compared to other available devices which could be used in the same settings this cartridge offers superior flow characteristics, less flow resistance and a higher capacity of cytokine removal. The effect of combining a standard treatment course of sepsis according to the Surviving Sepsis Campaign guidelines with extracorporeal cytokine removal however is not well examined overall.
In the investigator center, the investigators have therefore undertaken a retrospective pilot observational trial of 15 patients in which the using the HA 380 330 device was used as a rescue therapy in therapy in 15 patients with septic shock and multi-organ failure refractory to conventional treatment. In this trial of extremely ill patients the investigators found a significant difference between hospital survivors and non-survivors in circulating IL-6, IL-10 and TNF-alpha levels after 8 hours of treatment with the HLA 3380 cartridge. However, the overall variation of cytokine levels at baseline and the variation of changes from baseline during therapy were rather large. The sample size was too small to infer any causality or undertake multi-variate analysis.
- Conditions
- Sepsis, Septic Shock, Multiple Organ Failure
- Keywords
- Septic shock, cytokine adsorption therapy, HA-380 cartridge, Sepsis, hemoperfusion, multiple organ failure
- Medical subject headings
- Sepsis, Shock, Septic, Multiple Organ Failure
What is being measured
The primary outcome is the main question the study is designed to answer.
Cytokine variability of Interleucin (IL) -6 , IL-8- IL-10, and Tumor Necrosis Factor-alpha (TNF-alpha) in the patient's IL-6 serum
as expressed by changes in concentration measured every two hours during a first cytokine adsorption treatment of eight hours and measured every four hours during a second eight hour cytokine adsorption treatment. The measurements will be set in relation to the baseline measurement taken immediately (<1 minute) immediately after the end of 8 hours of treatment with the HA 380 cartridge normalized to the initial baseline IL-6 serum concentration immediately before start of the treatment. The standard of care is a pause of four hours between the two treatments intervals
Measured: 16 hours
Secondary outcomes (5)
Efficacy of relative cytokine removal from the patient's blood
by measuring relative differences for IL-6 , IL-8- IL-10 and TNF-alpha in blood samples taken directly before the blood enters the cartridge (inflow) and directly after passing the cartridge (outflow) during the treatments with the HA-380 cartrdige at the timepoints T2, T4, T6, T8 and T12, T16, T20.
Measured: 20 hours
Vasopressor / lactate dose
Normalized change in vasopressor dose and lactate from baseline to after each 8 hours of treatment with the HA 380 cartridge
Measured: 8 hours
P/F ratio
Normalized change in P/F ratio from baseline to after each 8 hours of treatment with the HA 380 cartridge
Measured: 8 hours
Antibiotic drug levels
Changes in antibiotic drug levels between T0, T8 and T20 taken from the patient's blood samples at these time points.
Measured: 20 hours
Sequential Organ Failure Assessment (SOFA)
Individual SOFA score changes and total SOFA Score changes over the course of each 8 hour treatment and the interval between the two treatments (T0,T2,T4,T6,T8,T12,T16,T20), and afterwards daily for a maximum of 7 days after the HA-380 treatment, until death of the patient or t until the patient leaves the ICU for, whichever occurs first.
breathing activity (minimum <100 mmHg gets 4 Points; maximum <400 gets 1 Points; higher Points means a worse outcome)
Liver function (minimum 1,2 mg/dl of Bilirubin gets 1 Points; maximum >12 mg/dl Bilirubin gets 4 Points; higher Points means a worse outcome)
Blood Coagulation (minimum <20 Thrombocyten x10^3/µl gets 4 Points; maximum >150 Thrombocyten x10^3/µl gets 4 Points; higher Points means a worse outcome)
Renal function (minimum 1,2 mg/dl of Kreatinin gets 1 Points; maximum >5 mg/dl Kreatinin gets 4 Points; higher Points means a worse outcome)
Measured: 3 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2020
- Study start15 Nov 2020
- Primary completion28 Jun 2023 (estimated)
- Study completion31 May 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- RWTH Aachen University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alexander Kersten, RWTH Aachen University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04306419
- Sponsor's protocol ID
- 19-058
- Acronym
- OuTCASt
- Status last verified
- Nov 2022
- First submitted
- 10 Mar 2020
- Last updated
- 4 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Torio CM, Andrews RM. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011. 2013 Aug. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Feb-. Statistical Brief #160. Available from http://www.ncbi.nlm.nih.gov/books/NBK169005/
PubMed 24199255Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013 May;41(5):1167-74. doi: 10.1097/CCM.0b013e31827c09f8.
PubMed 23442987Dellinger 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 SA, 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. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af.
PubMed 23353941Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J, Reinhart K, Antonelli M, Pickkers P, Njimi H, Jimenez E, Sakr Y; ICON investigators. Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med. 2014 May;2(5):380-6. doi: 10.1016/S2213-2600(14)70061-X. Epub 2014 Apr 14.
PubMed 24740011Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27;304(16):1787-94. doi: 10.1001/jama.2010.1553.
PubMed 20978258Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC; GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007 Aug 13-27;167(15):1655-63. doi: 10.1001/archinte.167.15.1655.
PubMed 17698689Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995 Mar 22-29;273(12):934-41.
PubMed 7884952Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, Malcangi V, Petrini F, Volta G, Bobbio Pallavicini FM, Rottoli F, Giunta F, Ronco C. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009 Jun 17;301(23):2445-52. doi: 10.1001/jama.2009.856.
PubMed 19531784Payen DM, Guilhot J, Launey Y, Lukaszewicz AC, Kaaki M, Veber B, Pottecher J, Joannes-Boyau O, Martin-Lefevre L, Jabaudon M, Mimoz O, Coudroy R, Ferrandiere M, Kipnis E, Vela C, Chevallier S, Mallat J, Robert R; ABDOMIX Group. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med. 2015 Jun;41(6):975-84. doi: 10.1007/s00134-015-3751-z. Epub 2015 Apr 11.
PubMed 25862039Schadler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, Marx G, Putensen C, Spies C, Jorres A, Quintel M, Engel C, Kellum JA, Kuhlmann MK. The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial. PLoS One. 2017 Oct 30;12(10):e0187015. doi: 10.1371/journal.pone.0187015. eCollection 2017.
PubMed 29084247Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gardlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64. doi: 10.1056/NEJMoa1202290. Epub 2012 May 22.
PubMed 22616830Dellinger RP, Bagshaw SM, Antonelli M, Foster DM, Klein DJ, Marshall JC, Palevsky PM, Weisberg LS, Schorr CA, Trzeciak S, Walker PM; EUPHRATES Trial Investigators. Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial. JAMA. 2018 Oct 9;320(14):1455-1463. doi: 10.1001/jama.2018.14618.
PubMed 30304428Hu XB, Gao HB, Liao ME, He MR. [The use of HA330-II microporous resin plasma adsorption in the treatment of chronic severe hepatitis]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2007 Dec;19(12):760-1. No abstract available. Chinese.
PubMed 18093442Li G, Yang B, Li C, Chen Y, Guo X, He B, Zhang Y, Dai R. [Studies on adsorption of the organic phosphorus pesticide with the macroporous resin]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2000 Dec;17(4):369-72. Chinese.
PubMed 11211815Gruda MC, Ruggeberg KG, O'Sullivan P, Guliashvili T, Scheirer AR, Golobish TD, Capponi VJ, Chan PP. Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb(R) sorbent porous polymer beads. PLoS One. 2018 Jan 25;13(1):e0191676. doi: 10.1371/journal.pone.0191676. eCollection 2018.
PubMed 29370247
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Observational Trial on Cytokine Adsorption in Sepsis
- ClinicalTrials.gov ID
- NCT04306419
- Acronym / sponsor ID
- OuTCASt / 19-058
- Conditions
- Sepsis, Septic Shock, Multiple Organ Failure
- Keywords
- Septic shock, cytokine adsorption therapy, HA-380 cartridge, Sepsis, hemoperfusion, multiple organ failure
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- RWTH Aachen UniversityUniversity, hospital or other
- Study start
- 15 Nov 2020 (actual)
- Primary completion
- 28 Jun 2023 (estimated)
- Study completion
- 31 May 2024 (estimated)
- First posted
- 12 Mar 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To determine the specific population of critically ill septic patients who benefit most from cytokine adsorption therapy with the HA-380 cartridge. Benefit of the treatment will be assessed on the basis of:
- The scope of the effect of cytokine adsorption therapy in this specific population of critically ill patients expressed by cytokine variability within the patients
- The scope of cytokine changes in passing the adsorption cartridge my measuring cytokine levels in the patient's blood directly before passing through the cartridge and directly after having passed through the cartridge.
- The scope of changes in organ dysfunction expressed by SOFA scores that are repeatedly calculated during the treatment with cytokine adsorption and then daily until day 7 of the ICU treatment.
- The scope of changes on cellular function on immune cells in serum samples taken before and after cytokine adsorption therapy.
- The scope of removal of anti-infective drugs from the blood in passing through the cytokine adsorption cartridge by measuring antibiotic drug levels in the patients blood during the cytokine adsorption therapy
- 30 day and 90 day mortality and location status in survivors
Detailed description
- Medical Problem Sepsis, a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection. It is a major public health concern, accounting for more than $20 billion (5.2%) of total US hospital costs in 2011. Sepsis has shown an increase in incidence most likely due to a combination of aging patient populations with more comorbidities and greater recognition. Sepsis is by conservative estimates a leading cause of mortality and morbidity in critical illness with long term sequelae for survivors. Underlying to sepsis is a multifaceted host response to an infecting pathogen that may be significantly amplified by endogenous factors and is defined by a nonhomeostatic, dysregulated host response to the infection with a potential lethality that is considerably in excess of that straightforward infection. In the early phases, an overshoot of pro-inflammatory mediators is often observed, caused by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). High levels of pro- and anti-inflammatory cytokines are both associated with increased mortality. Blocking of overproduction of these cytokines using monoclonal anti- bodies targeting specific cytokines such as tumor necrosis factor-α (anti-TNF-α) have not demonstrated mortality benefits in larger trials. Therefore, an approach to decrease cytokine overproduction by using extracorporeal blood purification has previously been examined. Initial trials using Polymyxin B showed favorable results for markers of critical care treatment with a reduction of vasopressor dosage and higher ratios oxygen partial pressure to inspired oxygen. A larger randomized trial by Payenne however did not show any improvement of organ dysfunction or reduction in mortality by using Polymycin B hemoperfusion. A recent trial on the effect of the CytoSorb adsorption device using Interleucin-6 (IL-6) levels as marker of efficacy did also not find an effect of mortality, improved organ dysfunction or in fact a reduction of circulating IL-6 levels. However, in this trial the baseline cytokine levels were only moderately increased to begin with suggesting use of a device within a suboptimal patient population. As no more approved specific therapies to treat sepsis, exist following the withdrawal of recombinant activated protein C (Xigris; Eli Lilly, USA) from the market in 2011 following the results of the PROWESS-SHOCK trial and the pathophysiologic basis for mechanisms in sepsis due to an excess cytokine release are sound, the extracorporeal removal of cytokines remains a promising therapeutic target given the correct patient population.
- Principal research question and novel aspects Within the trials addressing removal of excess cytokines, the selection of patients and timing of the intervention has been difficult, and results have not been conclusive. Data on the patient population which might benefit most in regard to the aspects of cytokine levels removed and organ failure or progressive organ dysfunction averted are sparse or non-existent. Even the largest randomised trial so far was active for 3 years in recruiting 100 patients out of 580 patients screened. This trial failed to show a positive effect on the primary endpoint of IL-6 removal as well as on secondary endpoints of morbidity or 30 day mortality. However, in this small trial there was a very low median cytokine level measured at baseline and randomisation which might be associated with the consecutive failure to detect a reduction in circulating cytokines. The question remains, whether this trial identified a patient population that was going to benefit from such a therapy to begin with. Post-hoc analyses of another trial, the Euphrates trial showed that there might be positive signal for reduced mortality in patients with an endotoxin activity that was in a mid-range and not at the highest end of the spectrum. We therefore aim to undertake an observational trial to examine the effect of treating sepsis according to the surviving sepsis campaign guidelines and using extracorporeal cytokine removal looking at circulating cytokine levels and development of new or worsening organ dysfunction in patients with sepsis or septic shock who show highly increased IL-6 levels.
- HA 330 and HA 380 Hemoperfusion Cartridge The HA type resin cartridge (Jafron Industries, China) is an extracorporeal hemoperfusion device that uses neutral microporous resin, and it has been proven to specifically absorb different media- tors such as bilirubin and cytokines.
The HA380 HA 330 and HA 380 resin cartridges haves the ability to absorb various medium-sized factors, including most inflammatory cytokines (IL-1, IL-6, IL-8, IL-10 and TNF-a) and haves therefore lately been used in the treatment of patients with sepsis in China with several case reports demonstrating promising results on the clinical course of treated patients. Furthermore, there pooled there is emerging data that this therapeutic concept is efficienct and helpful in adequately selected patient populations.
The HA 380 cartridge is the CE-labeled updated version of the HA-330 cartridge which features a larger surface area of the resin beads increasing the overall capacity and thus potential efficacy of the device.
The HA 380 Hemoperfusion Cartridge works using Van der Waals interaction between resin molecular groups and adsorbed substances. Unlike the CytoSorb device, these are incorporated into the resin molecule by a molecular sieve effect of the 3D network structure and the lipophilic hydrophobicity of the molecular group. Therefore, the pass-through effect in removing cytokines is expected to be larger and more sustained, as previously adsorbed cytokines will not again be released by continued blood flow or movement of the device. The range of adsorption is shown in figure 1. The device described has a CE label and is approved for treatment in a variety of clinically situations including but not limited to intra-operative use in cardiac surgery, intoxication, liver failure and sepsis. Compared to other available devices which could be used in the same settings this cartridge offers superior flow characteristics, less flow resistance and a higher capacity of cytokine removal. The effect of combining a standard treatment course of sepsis according to the Surviving Sepsis Campaign guidelines with extracorporeal cytokine removal however is not well examined overall.
In the investigator center, the investigators have therefore undertaken a retrospective pilot observational trial of 15 patients in which the using the HA 380 330 device was used as a rescue therapy in therapy in 15 patients with septic shock and multi-organ failure refractory to conventional treatment. In this trial of extremely ill patients the investigators found a significant difference between hospital survivors and non-survivors in circulating IL-6, IL-10 and TNF-alpha levels after 8 hours of treatment with the HLA 3380 cartridge. However, the overall variation of cytokine levels at baseline and the variation of changes from baseline during therapy were rather large. The sample size was too small to infer any causality or undertake multi-variate analysis.
Study design
- Observational model
- Other
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- We will perform an observational trial in a large cohort of patients with sepsis and septic shock who are treated with cytokine adsorption by hemoperfusion with a HA-380 cartridge. Sepsis will be defined as done in the Sepsis-3 definition. In addition to sepsis or septic shock patients must have a confirmed excess of IL-6, IL-10 or TNF-alpha or a combination of these with IL-6 levels > 1000 pg/l, IL-10 levels >250 pg/l or TNF-alpha levels > 100 ng/l. Patients must be in need of CRRT or ECMO therapy to perform the HA-380 therapy. Stand-alone hemoperfusion will not be performed. Patients must be included within 24 hrs of diagnosing sepsis. The IL-6 measurement for inclusion must be from within 24 hrs, IL-10 or TNF-alpha measurements for inclusion can be from within 36 hrs before inclusion.
Key inclusion criteria (4 listed)
- >18 years of age
- diagnosis of sepsis or septic shock with at least 2 organ-dysfunctions defined by SOFA score
- baseline serum IL-6 > 1000 pg/ml, IL-10 levels >250 pg/ml or TNF-alpha levels > 100 ng/l. The baseline IL-6 measurement must be on the same calendar day that the cytokine adsorption is started, the baseline IL-10 or TNF-alpha can be taken up to 36h before because of higher turn-around times for these tests.
- need for CRRT or ECMO therapy
Key exclusion criteria (6 listed)
- Solid organ malignancies with or without treatment
- Participation or enrollment in another clinical study within 30 day
- Pregnant and lactating females If women of childbearing potential will be enrolled, a pregnancy test will be performed by assessing the value of ß-HCG in the routinely drawn blood and or urine.
- Patient has been committed to an institution by legal or regulatory order
- Participation in a parallel interventional clinical trial
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Cytokine variability of Interleucin (IL) -6 , IL-8- IL-10, and Tumor Necrosis Factor-alpha (TNF-alpha) in the patient's IL-6 serum
Time frame: 16 hours
as expressed by changes in concentration measured every two hours during a first cytokine adsorption treatment of eight hours and measured every four hours during a second eight hour cytokine adsorption treatment. The measurements will be set in relation to the baseline measurement taken immediately (<1 minute) immediately after the end of 8 hours of treatment with the HA 380 cartridge normalized to the initial baseline IL-6 serum concentration immediately before start of the treatment. The standard of care is a pause of four hours between the two treatments intervals
5 secondary outcomes
Efficacy of relative cytokine removal from the patient's blood
Time frame: 20 hours
Vasopressor / lactate dose
Time frame: 8 hours
P/F ratio
Time frame: 8 hours
Antibiotic drug levels
Time frame: 20 hours
Sequential Organ Failure Assessment (SOFA)
Time frame: 3 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2022.
- Background: PubMed 24199255Torio CM, Andrews RM. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011. 2013 Aug. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Feb-. Statistical Brief #160. Available from http://www.ncbi.nlm.nih.gov/books/NBK169005/
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- Background: PubMed 23353941Dellinger 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 SA, 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. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Sepsis and Septic Shock, run by RWTH Aachen University at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alexander M Kersten, MD (+49-241-800, akersten@ukaachen.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cytokine variability of Interleucin (IL) -6 , IL-8- IL-10, and Tumor Necrosis Factor-alpha (TNF-alpha) in the patient's IL-6 serum (time frame: 16 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04306419, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2022.