Early Treatment of Cytokine Storm Syndrome in Covid-19

Study Overview
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Brief Summary
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This proposal addresses the problem of preventing the very high mortality and morbidity associated with the development of Cytokine Storm Syndrome (CSS) associated respiratory failure in Covid-19 infection.

Detailed Description
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The first aim of this project is to determine whether rapidly assayed early clinical laboratory markers of CSS (eCSS: leucopenia, lymphopenia, and elevated ferritin, d-dimer, LDH, CRP, and AST/ALT) in patients admitted to the hospital with respiratory compromise in the setting of Covid-19 infection can accurately identify patients with CSS as defined by validated CSS case definitions (H-Score, aHLH-2004). Confirmation of eCSS predictive of evolving CSS will identify patients at risk for rapid deterioration of lung function and inform early initiation of treatment for CSS. Genotyping studies will also be performed on patients with confirmed CSS to determine whether perforin pathway mutations commonly present in CSS associated with other disorders are present. The second aim is to determine whether early treatment with rhIL-1Ra (anakinra) in patients admitted to the hospital with markers of CSS improves or prevents deterioration of respiratory dysfunction and prevents the development of respiratory failure requiring mechanical ventilation.

Official Title
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Early Treatment of Cytokine Storm Syndrome in Covid-19

Conditions
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Cytokine Storm, COVID-19

Intervention / Treatment
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* Drug: Anakinra
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years old or older Molecular (pcRNA) diagnosis of SARS-CoV-2 infection Chest imaging studies consistent with Covid-19 pneumonia Hyperferritinemia (>700 ng/ml) History of fever >38 degrees C Any three of the following: Elevated d-dimer (> 500 ng/ml) thrombocytopenia (< 130,000/mm3) leucopenia (WBC <3500/mm3) or lymphopenia (<1000/mm3) elevated AST or ALT (> 2X ULN) elevated LDH (> 2X ULN) CRP > 100 mg/L Exclusion Criteria: Participation in other investigational treatment protocols for Covid-19 infection Culture confirmed active bacterial infection requiring antibiotic therapy On mechanical ventilation Previous known hypersensitivity reaction to anakinra Previous known hypersensitivity reaction to E Coli derived proteins Pregnant or breast-feeding females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Parallel Assignment
Interventional Model Description: Two parallel treatment arms
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra Group<br>The active treatment group will receive anakinra 100 mg subcutaneously every 6 hours for period of 10 days. For subjects meeting complete response criteria at 5 days, dosing will be decreased to 100 mg twice daily for the remaining 5 days. | Drug: Anakinra<br>* The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days<br>* Other names: recombinant human IL-ra (rhIL-1ra);|
| Placebo Comparator: Control Group<br>The control group will receive normal saline placebo subcutaneously every 6 hours for period of 10 days. For subjects meeting complete response criteria at 5 days, dosing will be decreased to twice daily for the remaining 5 days. | Drug: Normal saline<br>* The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days<br>* Other names: NS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Discharged From the Hospital Alive and Without the Need for Mechanical Ventilation. | Percentage of subjects discharged from hospital alive and who did not require intubation and mechanical ventilation | Variable up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With 25% Change (Decrease) in Cytokine Storm Markers at 48-72 Hours After Dosing With Study Agent | 25% change (decrease) in noted baseline elevations of serum ferritin and CRP measured 48-72 hours after following initial dosing of anakinra/placebo. | 48 hours after taking initial dose of anakinra/placebo | 
| Percentage of Subjects Without Increase in Oxygen Requirement and no Increase in Oxygen Delivery/Respiratory Support Measures After 48 Hours. | Supplemental oxygen requirement to maintain oxygen saturation >90% stable or decreased without escalation of respiratory support measures (addition of CPAP, initiation of mechanical ventilation) | Day 2 (48 hours)-Day 10 (240 hours) | 
| Patients Requiring Minimal Oxygen Support at Day 10 | Percentage of participants requiring no more than 2 L/min nasal canula oxygen to maintain oxygen saturation >93% by Day 10 | 0-10 days | 
| Percentage of Subjects With Resolution of Laboratory Markers of Cytokine Storm Syndrome | Normalization or ≥ 75% improvement by Day 10 (120 hours) in each (all) of the following laboratory CSS attributes elevated beyond the normal range at randomization: ferritin, d-dimer, CRP, and LDH. | Day 10 | 
| Percentage of Subjects Who Develop Bacterial or Fungal or Non-Covid-19 Viral Infection | Occurence of new bacterial or fungal or viral infection through the time of hospital discharge or Day 28. | Day 0-28 | 
| Absence of Supplemental Oxygen Requirement at Day 10 | Percentage of participants able to maintain oxygen saturation >93% on room air by Day 10 | 0-10 Days |