CLEANSE: CLinical Efficacy of Hemoperfusion With a Cytokine Adsorber in Norepinephrine-Resistant SEptic Shock

Sponsor

Mahidol University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05136183

Collaborator

Faculty of Medicine Siriraj Hospital (Other)

200

Enrollment

Location

Arms

23.5

Anticipated Duration (Months)

8.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Sepsis and septic shock are major causes of ICU admission worldwide. Despite recent advances in treatment, including targeted resuscitation and timely use of antimicrobial agents, mortality of ICU patients with septic shock remains steadily high. Especially in those requiring high dosage of vasopressors, whose 28-day mortality rate could reach 60%.

The pathophysiology of septic shock emphasizes on the role of dysregulated host immune response towards inciting microbes, producing excessive inflammatory cytokines which lead to tissue damage and subsequent organ failures. Multiple therapies targeting the overwhelming inflammatory response in patients with septic shock have been studied (ref). While some showed promising results in modulating inflammation in observational studies (ref), none other than systemic corticosteroids lead to better clinical outcomes in the randomized controlled studies. The reasons for their failures are the complexity of the inflammation cascades, where treatments specifically targeting parts of the process may not be able to achieve meaningful effects.

Extracorporeal blood purification therapy is an adjunctive treatment option more extensively studied over the last decade. By passing patients' blood or plasma through specifically developed absorber, various inflammatory cytokines are absorbed to resins inside the devices and removed from the circulation. Decreasing levels of inflammatory cytokines may subsequently attenuate systemic inflammation leading to shock reversal and better survival.

HA-330 disposable hemoperfusion cartridge (Jafron®, China) is an absorber targeting hyper-inflammatory states including septic shock. It is designed to nonspecifically absorb molecules with molecular weight 10-60 kilo-Dalton, making it effective for removing various pro-inflammatory cytokines and potentially modulating the inflammatory cascade.

Previous randomized study in patients with sepsis compared between the add-on 3 daily session of hemoperfusion with HA-330 adsorber and the standard therapy . .Circulating interleukin-6 and interleukin-8 levels of patients underwent hemoperfusion significantly reduced after two sessions when compared to baseline. Their values on day 3 were also significantly lower than those of the control group. Adjunctive hemoperfusion were associated with lower ICU mortality, butno significant difference in hospital and 28-day mortality between the two groups(ref). However, approximately 50% of enrolled patients had sepsis without shock. Generalization of the findings to more severe cohorts of septic shock patients are therefore limited.

Patients with septic shock have higher cytokines level than septic patients without shock. Hence, they are theoretically more likely to benefit from therapies aiming to reduce cytokine levels. We hypothesize that adjunctive hemoperfusion with HA-330 adsorber would be associated with better outcomes in a more severe group of patients with septic shock.

Condition or Disease	Intervention/Treatment	Phase
Septic Shock Cytokine Storm	Device: HA-330 Disposable Hemoperfusion Cartridge (Jafron, China)	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

CLinical Efficacy of Hemoperfusion With a Cytokine Adsorber in Norepinephrine-Resistant SEptic Shock

Anticipated Study Start Date :

Dec 15, 2021

Anticipated Primary Completion Date :

Nov 30, 2022

Anticipated Study Completion Date :

Nov 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Standard of care Patients randomized to this arm are treated with standard of care for patients with septic shock, including Fluid resuscitation and vasoactive agents Hemodynamic monitoring in intensive care units Antibiotics and infection source control, when applicable Supportive therapies and devices, including mechanical ventilation and renal replacement therapy Immunoregulatory medications, including systemic corticosteroids All treatment provided are according to treating physicians
Experimental: Standard of care, with hemoperfusion with HA-330 Patients randomized to this arm are treated with standard of care for patients with septic shock as described for 'Standard of care' arm, along with hemoperfusion with HA-330 Disposable Hemoperfusion Cartridge, as detailed under 'Interventions'	Device: HA-330 Disposable Hemoperfusion Cartridge (Jafron, China) If no appropriate vascular access available, a double lumen catheter is placed by treating physicians, under ultrasonographic guidance. Two sessions of hemoperfusion using HA-330 Disposable Hemoperfusion Cartridge are performed 24 hours apart. Hemoperfusion is performed using either hemoperfusion or continuous renal replacement therapy machine. The optimal blood flow rate is 150-200 mL/min. The duration for each session in 2 hours. No systemic anticoagulant is given except for priming of the cartridge according to manufacturer recommendations. The first hemoperfusion session is recommended to be initiated within 12 hours after randomization.

Arm

Intervention/Treatment

No Intervention: Standard of care

Patients randomized to this arm are treated with standard of care for patients with septic shock, including Fluid resuscitation and vasoactive agents Hemodynamic monitoring in intensive care units Antibiotics and infection source control, when applicable Supportive therapies and devices, including mechanical ventilation and renal replacement therapy Immunoregulatory medications, including systemic corticosteroids All treatment provided are according to treating physicians

Experimental: Standard of care, with hemoperfusion with HA-330

Patients randomized to this arm are treated with standard of care for patients with septic shock as described for 'Standard of care' arm, along with hemoperfusion with HA-330 Disposable Hemoperfusion Cartridge, as detailed under 'Interventions'

Device: HA-330 Disposable Hemoperfusion Cartridge (Jafron, China)

If no appropriate vascular access available, a double lumen catheter is placed by treating physicians, under ultrasonographic guidance. Two sessions of hemoperfusion using HA-330 Disposable Hemoperfusion Cartridge are performed 24 hours apart. Hemoperfusion is performed using either hemoperfusion or continuous renal replacement therapy machine. The optimal blood flow rate is 150-200 mL/min. The duration for each session in 2 hours. No systemic anticoagulant is given except for priming of the cartridge according to manufacturer recommendations. The first hemoperfusion session is recommended to be initiated within 12 hours after randomization.

Outcome Measures

Primary Outcome Measures

28-day mortality [28 days]

Secondary Outcome Measures

ICU mortality [up to 24 weeks]
Hospital mortality [up to 24 weeks]
ICU-free day [28 days]
Number of days that patient is alive and not admitted in the ICU in the first 28 days, with the day of randomization defined as Day 0 In case of ICU readmission, the days from the final ICU discharge within 28 days are counted. All 28-day non-survivors are counted 0, irrespective of their place of care at the time of death, and censored observations after 28 days
Vasopressor-free day [28 days]
Number of days that patient is alive after successful discontinuation of vasoactive agents in the first 28 days, with the day of randomization defined as Day 0 Successful discontinuation of vasoactive agents is defined as discontinuation of vasoactive agents without resumption until Day 28 or until hospital discharge, whichever is first. In case of multiple periods of vasoactive agents use, the days from the final discontinuation of vasoactive agents are counted. All 28-day non-survivors are counted 0, irrespective of their use of vasoactive agents at the time of death, and censored observations after 28 days
Ventilator-free day [28 days]
Number of days that patient is alive after successful liberation of mechanical ventilation in the first 28 days, with the day of randomization defined as Day 0 Successful liberation of mechanical ventilation is defined as discontinuation mechanical ventilation (either via orotracheal or tracheostomy tube) for 48 hours or more. Non-invasive positive pressure ventilation is not regarded as mechanical ventilation. In case of multiple periods of mechanical ventilation, the days from the final successful liberation of mechanical ventilation within 28 days are counted. All 28-day non-survivors are counted 0, irrespective of their ventilation status at the time of death, and censored observations after 28 days
Renal replacement therapy (RRT) -free day [28 days]
Number of days that patient is alive after successful discontinuation of renal-replacement therapy in the first 28 days, with the day of randomization defined as Day 0 Successful discontinuation of renal-replacement therapy is defined as discontinuation of all modes of renal-replacement therapy without resumption for at least 7 days and until Day 28 or until hospital discharge, whichever is first. Hemoperfusion according to treatment protocol in 'Standard of care and hemoperfusion with HA-330' arm is not counted as renal-replacement therapy. All 28-day non-survivors are counted 0, irrespective of their use of renal-replacement therapy at the time of death, and censored observations after 28 days
Vasoactive inotropic score at Hour 24, Hour 48 and Day 7 [7 days]
Shock reversal at Hour 6 [6 hours]
Shock reversal is defined as mean arterial pressure at or more than 65 mmHg with one of the following: Reduction of serum lactate level of 20% or more Hourly urine output of 0.5 mL/kg or more
Arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) at Hour 24, Hour 48 and Day 7 [7 days]
Acute Physiology and Chronic Health Evaluation score (APACHE II) at Hour 24, Hour 48 and Day 7 [7 days]
Sequential Organ Failure Assessment score (SOFA) at Hour 24, Hour 48 and Day 7 [7 days]
Serum C-reactive protein level at Hour 24 and Hour 48 [48 hours]
Plasma Interleukin-6 level at Hour 24 and Hour 48 [48 hours]
Adverse events [28 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Septic shock patients, according to The Third International Consensus Definitions for Sepsis and Septic Shock and
Is receiving intravenous norepinephrine 0.2 mcg/kg/min or more, or equivalent dose of other vasoactive agents

Exclusion Criteria:

One who has

acute coronary syndrome
life-threatening arrhythmias
acute ischemic stroke
life-threatening, uncontrolled bleeding
underlying conditions judged to have with limited life expectancy (less than 6 months) by primary physicians

One who is

judged by treating physicians as in moribund state and expected not to survive to 24 hours regardless of treatment given
known to be pregnant at enrollment
not in the competent state to give informed consent and not having relatives to do so
not willing to pursue intensive medical therapy considered standard of care for patients with septic shock