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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Anakinra Group | Experimental | 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. |
|
| Control Group | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anakinra | Drug | The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days |
|
| 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 |
| 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 |
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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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Walter W Chatham, MD | University of Alabama at Birmingham | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35294 | United States |
Contact PI by e-mail for protocol specifics Submission of results for peer reviewed publication
During study enrollment
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Patients who met inclusion/exclusion criteria and who had ongoing or increasing oxygen requirement were consented and enrolled. Once consented and enrolled, all subjects were randomly assigned to the two treatment groups. No participants were excluded after enrollment and randomization. Two subjects withdrew consent within 48 hours of enrollment.
Subjects for enrollment were identified by pre-screening all patients admitted to the University of Alabama Hospital for treatment of Covid-19 pneumonia from August 1, 2020-January 15, 2021. Patients who were admitted with a new requirement for supplemental oxygen to maintain arterial oxygen saturation >93% but not yet requiring mechanical ventilation and who had admission laboratory studies meeting study inclusion criteria for evidence of inflammation were approached for enrollment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Anakinra Group | 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. Anakinra: The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days |
| FG001 | Control Group | 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. Normal saline: The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Anakinra Group | 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. Anakinra: The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Count of Participants | Participants | Variable up to Day 28 |
|
60 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Anakinra Group | 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. Anakinra: The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Adult Respiratory Distress Syndrome | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Systematic Assessment | Development of respiratory failure due to diffuse lung inflammation |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Venous thrombosis | Blood and lymphatic system disorders | SNOMED CT | Systematic Assessment | Deep venous thrombosis, with or without pulmonary embolism |
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Walter Winn Chatham MD | University of Alabama at Birmingham | 205-612-7402 | wchatham@uabmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 28, 2020 | Aug 1, 2023 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 28, 2020 | May 16, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000080424 | Cytokine Release Syndrome |
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D053590 | Interleukin 1 Receptor Antagonist Protein |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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Two parallel treatment arms
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Investigator, care provider, and participant blinded
| Normal saline | Drug | The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days |
|
|
| 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 |
| BG001 | Control Group | The control group will receive normal saline placebo subcutaneously every 6 hours for period of 10 days. For subjects meeting complete repsonse criteria at 5 days, dosing wll be decreased to twice daily for the remaining 5 days. Normal saline: The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Co-morbidities | Count of Participants | Participants |
|
| Number of Participants that Smoke | Count of Participants | Participants |
|
The control group will receive normal saline placebo subcutaneously every 6 hours for period of 10 days. For subjects meeting complete repsonse criteria at 5 days, dosing wll be decreased to twice daily for the remaining 5 days.
Normal saline: The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | 48 hours after taking initial dose of anakinra/placebo |
|
|
|
| Secondary | 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) | Posted | Count of Participants | Participants | Day 2 (48 hours)-Day 10 (240 hours) |
|
|
|
| Secondary | 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 | Posted | Count of Participants | Participants | 0-10 days |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | Day 10 |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | Day 0-28 |
|
|
|
| Secondary | Absence of Supplemental Oxygen Requirement at Day 10 | Percentage of participants able to maintain oxygen saturation >93% on room air by Day 10 | Posted | Count of Participants | Participants | 0-10 Days |
|
|
|
| 4 |
| 15 |
| 9 |
| 15 |
| 14 |
| 15 |
| EG001 | Control Group | 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. Normal saline: The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days | 4 | 15 | 7 | 15 | 13 | 15 |
|
| Arterial ischemia | Vascular disorders | SNOMED CT | Systematic Assessment | Evidence of ischemic injury to an extremity or internal organ or central nervous system |
|
|
| Acute Renal Failure | Renal and urinary disorders | SNOMED CT | Systematic Assessment | Development of acute kidney injury with azotemia and decreased urine output |
|
| Neutropenia | Blood and lymphatic system disorders | SNOMED CT | Systematic Assessment | Total neutrophil count less than 1000/mm3 |
|
| Anemia | Blood and lymphatic system disorders | SNOMED CT | Systematic Assessment | Decrease in hemoglobin to less than 8.0 g/dL |
|
| Thrombocytopenia | Blood and lymphatic system disorders | SNOMED CT | Systematic Assessment | Decrease in platelets to less than 100,000/mm3 |
|
| Gastrointestinal bleeding | Gastrointestinal disorders | SNOMED CT | Systematic Assessment | Evidence of clinically significant GI bleed with documented GI blood loss and associated fall in hemoglobin |
|
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| D012769 | Shock |
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |