Modulation of Hyperinflammation in COVID-19

Study Overview
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Brief Summary
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Current treatment recommendations are based on very limited evidence and reliant on the deployment of pharmacological strategies of doubtful efficacy, high toxicity, and near universal shortages of supply. On a global scale, there is a desperate need for readily available therapeutic options to safely and cost effectively target the hyper-inflammatory state in ICU patients based on management of severe COVID-19 (evidence of acute respiratory distress syndrome). The study team proposes to use slow low-efficiency daily dialysis to provide an extracorporeal circuit to target this cytokine storm using immunomodulation of neutrophils with a novel leucocyte modulatory device (L-MOD) to generate an anti-inflammatory phenotype, but without depletion of circulating factors.

Detailed Description
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The coronavirus disease 2019 (COVID-19) is a novel virus that was first reported in December 2019 from Wuhan, China. So far, over 8,000,000 cases have been reported around the globe with >400,000 reported deaths overwhelming hospitals and constraining resources. Death is mainly due to severe acute respiratory syndrome (SARS), requiring mechanical ventilation; however, many hospitals do not have sufficient equipment (i.e. ventilators) to meet the requirements. It had been suggested that severe SARS-related injury may have be related to an excessive reaction of the host's immune system, and a dysregulation of pro-inflammatory cytokines called cytokine storm syndrome. This is characterized by a hyper-inflammatory state leading to fulminant multi-organ failure and elevated cytokine levels. There is a critical and imminent need to identify effective treatments to reduce mortality. The study team proposes to use slow low-efficiency daily dialysis (SLEDD) to provide an extracorporeal circuit to target this cytokine storm using immunomodulation of neutrophils with a novel leukocyte modulatory device (L-MOD) to generate an anti-inflammatory phenotype, without depletion of circulating factors. This is a single center, prospective, randomized controlled pilot study in the Critical Care Trauma Centre at Victoria Hospital and Critical Care at University Hospital, London, Ontario. Critical Care at University Hospital is comprised of two units, the Medical-Surgical ICU and the Cardiac Surgical Recovery Unit. The study team will randomize patients requiring ICU admission of COVID-19 into one of two groups; either to standard of care for severe COVID-19 infection or in the active treatment group (standard supportive care + treatment with leukocyte modulation (using L-MOD)), on 1:1, basis. They will know what treatment group they are randomized to. The study team will use block randomization to randomize the patients into one of these two groups. A computer algorithm is used to generate the randomization sequence in blocks of four (two for standard of care and two for active treatment). This is used to make sure that equal numbers of people get allocated to each arm of the study and that the allocation is equal throughout the lifespan of the trial. Slow low-efficiency daily dialysis will be performed twice, for approximately 12 hours, 2 days in a row. Due to the nature of the intervention, it is not possible to blind neither the patient nor study team members to the treatment group the patient gets randomized to, with the exception of study team members analyzing the data who will be blinded to the patients' treatment group. Additionally, the study uses robust objective measurements that will be unaffected by the patients' awareness of the group they have been randomized to. Blood work will be collected before each dialysis treatment initiation, at the end of each session, and then on after day 4 and no later than day 7 in the ICU for the patients receiving intervention. Patients receiving standard of care will have blood work done on day 1, day 2, and after day 4 and no later than day 7 of admission. We will also collect a urine sample from all participants before the first dialysis session only and then again at after day 4 and no later than day 7 in the ICU. End of study will be defined as the last patient discharged from the hospital.

Official Title
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Novel Extracorporeal Treatment to Modulate Hyperinflammation in COVID-19 Patients

Conditions
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COVID-19, SARS

Intervention / Treatment
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* Device: Control group
* Device: SLEDD with a L-MOD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 years High clinical suspicion of COVID-19 from the opinion of both infectious disease specialist (s) and the ICU team Evidence of acute respiratory distress syndrome requiring admission to the Critical Care Trauma Centre Medical Surgical ICU, or the Cardiac Surgical Recovery Unit Vasopressor support Exclusion Criteria: Pregnant Unconfirmed COVID-19 Chronic immune depression Contra-indications to regional citrate anticoagulation

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: Single centre, prospective, randomized controlled pilot study with approximately 40 patients to be included: 20 in the control group and 20 patients in the L-MOD-SLEDD group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Control<br>Patients diagnosed with severe COVID-19: Those admitted to the intensive care unit with evidence of severe respiratory distress syndrome will undergo standard of care | Device: Control group<br>* Patients randomized into this group will receive standard of care for COVID-19 infection<br>|
| Active Comparator: SLEDD with a L-MOD<br>Patients diagnosed with severe COVID-19: Those admitted to the intensive care unit with evidence of severe respiratory distress syndrome will undergo slow low efficiency daily dialysis for approximately 12 hours, 2 days in a row with a leukocyte modulatory device. | Device: SLEDD with a L-MOD<br>* Patients randomized to this group will undergo slow low efficiency daily dialysis for approximately 12 hours, 2 days in a row with a leukocyte modulatory device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of a L-MOD against controls receiving supportive care in ICU. | Efficacy will be evaluated by reduction of vasopressor support (converted to norepinephrine dose equivalents) compared to control group. | Through dialysis, on average of 12 hours, two days in a row | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Time to ICU and hospital discharge compared to case-matched controls | From date of randomization until the date of death from any cause, whichever came first, assessed up to 2 months | 
| Hospital Discharge | Time to ICU and hospital discharge compared to case-matched controls | From date of randomization until the date of hospital discharge or death from any cause, whichever came first, assessed up to 2 months | 
| Leukocyte Monitoring | Over the course of the disease white blood cells will be monitored (i.e. neutrophils, macrophages...) | Through dialysis, on average of 12 hours, two days in a row and again on day 5 in the ICU | 
| Sequential Organ Failure Assessment (SOFA) Score | Evolution of the Sequential Organ Failure Assessment (SOFA) score. The SOFA score ranges from 0 to 24. The higher score means the worst outcome. | From date of randomization until the date of ICU discharge or death from any cause, whichever came first, assessed up to 1 months | 
| Intubation length | intubation length will be recorded (in day) | From date of randomization until the date of ICU discharge up to 2 months | 
| Markers of Inflammation | Evolution of hsCRP during dialysis treatment | Through dialysis, on average of 12 hours, two days in a row and again after day 4 and no later than day 7 in the ICU | 
| Leukocytes and Macrophages | Characterization of activated/desactivated leukocyte and macrophage subsets in the blood | Through dialysis, on average of 12 hours, two days in a row and again after day 4 and no later than day 7 in the ICU | 
| Myocardial damage | Myocardial damage will be assessed by troponin measurement (ng/mL) | From date of randomization until the date of ICU discharge up to 2 months | 
| Renal recovery | Renal recovery will be assessed by serum creatinin measurement (micromol/L) | From date of randomization until the date of ICU discharge up to 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cytokine storm, SLEDD