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Coronavirus disease-2019 (COVID-19) has a quoted inpatient mortality as high as 25%. This high mortality may be driven by hyperinflammation resembling cytokine release syndrome (CRS), offering the hope that therapies targeting the interleukin-6 (IL-6) axis therapies commonly used to treat CRS can be used to reduce COVID-19 mortality. Retrospective analysis of severe to critical COVID-19 patients receiving tocilizumab demonstrated that the majority of patients had rapid resolution (i.e., within 24-72 hours following administration) of both clinical and biochemical signs (fever and CRP, respectively) of hyperinflammation with only a single tocilizumab dose.
Hypotheses:
Objectives:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A | Experimental | Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation |
|
| Group B | Experimental | Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tocilizumab | Drug | Group A: Tocilizumab (beginning dose 200mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Clinical Response in Maximum Temperature (Tmax) | Number of Participants with Clinical Response in Maximum Temperature (Tmax) | Assessed for the 24 hour period after tocilizumab administration |
| Number of Participants With Biochemical Response as Determined by CRP Response | Number of Participants with Biochemical Response as determined by CRP Response. Defined as at least 25% decrease in CRP from baseline at least 16 hours after administration of drug. | Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival | 28-Day Overall Survival is defined as the status of the patient at the end of 28 days, beginning from the time of the first dose of tocilizumab. | 28 days |
| Survival to Hospital Discharge |
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Inclusion Criteria:
Exclusion Criteria:
Patients will be assigned to Group A if:
● C-reactive protein (CRP) ≥ 75 ug/mL
AND
Any one of the following criteria are met:
All other eligible patients assigned to Group B
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| Name | Affiliation | Role |
|---|---|---|
| Pankti Reid, MD, MPH | University of Chicago, Department of Medicine, Section of Rheumatology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Chicago Medicine | Chicago | Illinois | 60637 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33210302 | Result | Strohbehn GW, Heiss BL, Rouhani SJ, Trujillo JA, Yu J, Kacew AJ, Higgs EF, Bloodworth JC, Cabanov A, Wright RC, Koziol AK, Weiss A, Danahey K, Karrison TG, Edens CC, Bauer Ventura I, Pettit NN, Patel BK, Pisano J, Strek ME, Gajewski TF, Ratain MJ, Reid PD. COVIDOSE: A Phase II Clinical Trial of Low-Dose Tocilizumab in the Treatment of Noncritical COVID-19 Pneumonia. Clin Pharmacol Ther. 2021 Mar;109(3):688-696. doi: 10.1002/cpt.2117. Epub 2020 Dec 10. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Group A | Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation Tocilizumab: Group A: Tocilizumab (beginning dose 200mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
| FG001 | Group B | Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation Tocilizumab: Group B: Low-dose tocilizumab (beginning dose 80mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group A | Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation Tocilizumab: Group A: Tocilizumab (beginning dose 200mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Number of Participants With Clinical Response in Maximum Temperature (Tmax) | Number of Participants with Clinical Response in Maximum Temperature (Tmax) | Posted | Count of Participants | Participants | Assessed for the 24 hour period after tocilizumab administration |
|
28 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 | Group A | Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation Tocilizumab: Group A: Tocilizumab (beginning dose 200mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Pankti Reid | University of Chicago, Department of Medicine Section of Rheumatology | 773-702-6119 | pankti.reid@uchospitals.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 | Apr 20, 2020 | Apr 29, 2021 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C502936 | tocilizumab |
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|
| Tocilizumab | Drug | Group B: Low-dose tocilizumab (beginning dose 80mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
|
This will be defined as the percentage of patients who are discharged in stable condition compared to the percentage of patients who die in the hospital. Patients who are discharged to hospice will be excluded from this calculation.
| Hospitalization, up to 4 weeks after tocilizumab administration |
| Progression of COVID-19 Pneumonitis | This will be a binary outcome defined by worsening COVID-19 pneumonitis resulting in transition from clinical Group A or Group B COVID-19 pneumonitis to critical COVID-19 pneumonitis during the course of the patient's COVID-19 infection. This diagnosis will be determined by treating physicians on the basis of worsening pulmonary infiltrates on chest imaging as well as clinical deterioration marked by persistent fever, rising supplemental oxygen requirement, declining PaO2/FiO2 ratio, and the need for intensive care such as mechanical ventilation or vasopressor/inotrope medication(s). | Hospitalization, up to 4 weeks after tocilizumab administration |
| Rate of Non-elective Mechanical Ventilation | This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of non-invasive (BiPap, heated high-flow nasal cannula) or invasive positive pressure ventilation during the course of the patient's COVID-19 infection. For patients admitted to the hospital using non-invasive mechanical ventilation, the utilization of mechanical ventilation will count toward this metric, as well. Calculated as the ratio of the number of patients who require non-invasive or invasive positive pressure ventilation during hospitalization and total number of patients who receive tocilizumab. | Hospitalization, up to 4 weeks after tocilizumab administration |
| Duration of Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between initiation and cessation of mechanical ventilation (invasive and non-invasive). | Hospitalization, up to 4 weeks after tocilizumab administration |
| Time to Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between tocilizumab dose administration and the initiation of mechanical ventilation. This will be treated as a time-to-event with possible censoring. | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |
| Rate of Vasopressor/Inotrope Utilization | This will be a binary outcome defined as utilization of any vasopressor or inotropic medication during the course of the patient's COVID-19 infection. Calculated as the ratio of the number of patients who require vasopressor or inotrope medication during hospitalization and total number of patients who receive tocilizumab. | Hospitalization, up to 4 weeks after tocilizumab administration |
| Duration of Vasopressor/Inotrope Utilization | This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor or inotrope medication(s). | Hospitalization, up to 4 weeks after tocilizumab administration |
| Time to Vasopressor or Inotropic Utilization | This will be a continuous outcome defined by the amount of time between first tocilizumab dose administration and the initiation of vasopressor or inotropic medication(s). This will be treated as a time-to-event with possible censoring. | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |
| Number of ICU Days | Number of ICU days is defined as the time period when a patient is admitted to the ICU (defined as the timestamp on the first vital signs collected in an ICU) until they are transferred from the ICU to a non-ICU setting such as a general acute care bed (defined as the timestamp on the first vital signs collected outside an ICU, excepting any "off the floor" vital signs charted from operating rooms or procedure or imaging suites). Death in the ICU will be a competing risk. | Hospitalization, up to 4 weeks after tocilizumab administration |
| Duration of Increased Supplemental Oxygen Requirement From Baseline | Duration of increased supplemental oxygen requirement from baseline is defined as the time period (number of days) during which the participant requires supplemental oxygen in excess of his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization. | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |
| BG001 | Group B | Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation Tocilizumab: Group B: Low-dose tocilizumab (beginning dose 80mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| C-Reactive protein | Mean | Standard Deviation | mg/L |
|
| OG001 |
| Group B |
Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation Tocilizumab: Group B: Low-dose tocilizumab (beginning dose 80mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
|
|
|
| Primary | Number of Participants With Biochemical Response as Determined by CRP Response | Number of Participants with Biochemical Response as determined by CRP Response. Defined as at least 25% decrease in CRP from baseline at least 16 hours after administration of drug. | One patient in Group A and 2 patients in Group B were deceased before measure of CRP. | Posted | Count of Participants | Participants | Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration |
|
|
|
| Secondary | Overall Survival | 28-Day Overall Survival is defined as the status of the patient at the end of 28 days, beginning from the time of the first dose of tocilizumab. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| Secondary | Survival to Hospital Discharge | This will be defined as the percentage of patients who are discharged in stable condition compared to the percentage of patients who die in the hospital. Patients who are discharged to hospice will be excluded from this calculation. | Posted | Count of Participants | Participants | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
|
| Secondary | Progression of COVID-19 Pneumonitis | This will be a binary outcome defined by worsening COVID-19 pneumonitis resulting in transition from clinical Group A or Group B COVID-19 pneumonitis to critical COVID-19 pneumonitis during the course of the patient's COVID-19 infection. This diagnosis will be determined by treating physicians on the basis of worsening pulmonary infiltrates on chest imaging as well as clinical deterioration marked by persistent fever, rising supplemental oxygen requirement, declining PaO2/FiO2 ratio, and the need for intensive care such as mechanical ventilation or vasopressor/inotrope medication(s). | No data were collected on this outcome. Given the volumes of patients being cared for and demand for radiology services, it proved impractical during the conduct of the trial to re-examine radiographs of every enrolled patient in the absence of a clinical reason. | Posted | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
| Secondary | Rate of Non-elective Mechanical Ventilation | This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of non-invasive (BiPap, heated high-flow nasal cannula) or invasive positive pressure ventilation during the course of the patient's COVID-19 infection. For patients admitted to the hospital using non-invasive mechanical ventilation, the utilization of mechanical ventilation will count toward this metric, as well. Calculated as the ratio of the number of patients who require non-invasive or invasive positive pressure ventilation during hospitalization and total number of patients who receive tocilizumab. | Posted | Count of Participants | Participants | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
|
| Secondary | Duration of Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between initiation and cessation of mechanical ventilation (invasive and non-invasive). | Posted | Median | Full Range | days | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
|
| Secondary | Time to Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between tocilizumab dose administration and the initiation of mechanical ventilation. This will be treated as a time-to-event with possible censoring. | Posted | Median | Full Range | days | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |
|
|
|
| Secondary | Rate of Vasopressor/Inotrope Utilization | This will be a binary outcome defined as utilization of any vasopressor or inotropic medication during the course of the patient's COVID-19 infection. Calculated as the ratio of the number of patients who require vasopressor or inotrope medication during hospitalization and total number of patients who receive tocilizumab. | In reviewing inotropic medication utilization, there was a disconnect between orders being placed and medication administration, precluding high-throughput data extraction from electronic health record. | Posted | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
| Secondary | Duration of Vasopressor/Inotrope Utilization | This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor or inotrope medication(s). | In reviewing inotropic medication utilization, there was a disconnect between orders being placed and medication administration, precluding high-throughput data extraction from electronic health record. | Posted | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
| Secondary | Time to Vasopressor or Inotropic Utilization | This will be a continuous outcome defined by the amount of time between first tocilizumab dose administration and the initiation of vasopressor or inotropic medication(s). This will be treated as a time-to-event with possible censoring. | In reviewing inotropic medication utilization, there was a disconnect between orders being placed and medication administration, precluding high-throughput data extraction from electronic health record. | Posted | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |
|
|
| Secondary | Number of ICU Days | Number of ICU days is defined as the time period when a patient is admitted to the ICU (defined as the timestamp on the first vital signs collected in an ICU) until they are transferred from the ICU to a non-ICU setting such as a general acute care bed (defined as the timestamp on the first vital signs collected outside an ICU, excepting any "off the floor" vital signs charted from operating rooms or procedure or imaging suites). Death in the ICU will be a competing risk. | Median number of ICU days could not be calculated from our records due to lag in timing of ICU admission order placement, ICU arrival, ICU transfer order, and general ward admission order placement. Therefore, no data was collected for this outcome. | Posted | Hospitalization, up to 4 weeks after tocilizumab administration |
|
|
| Secondary | Duration of Increased Supplemental Oxygen Requirement From Baseline | Duration of increased supplemental oxygen requirement from baseline is defined as the time period (number of days) during which the participant requires supplemental oxygen in excess of his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization. | 0 patients analyzed due to heterogeneity in the recording of supplemental oxygen requirement in the electronic health record, complicating data extraction and analysis. There were no patient data collected for this outcome. | Posted | Assessed over hospitalization, up to 4 weeks after tocilizumab administration |
|
|
| 2 |
| 12 |
| 0 |
| 12 |
| 9 |
| 12 |
| EG001 | Group B | Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation Tocilizumab: Group B: Low-dose tocilizumab (beginning dose 80mg) Single dose is provisioned, patient is eligible to receive up to two doses, with re-evaluation of clinical and biochemical responses performed every 24 hours. Second dose is provisioned if:
| 3 | 20 | 0 | 20 | 17 | 20 |
| QTC prolangulation | Cardiac disorders | Systematic Assessment |
|
| Type II NSTEMO | Cardiac disorders | Systematic Assessment |
|
| Atrial Flutter | Cardiac disorders | Systematic Assessment |
|
| Chest pain | Cardiac disorders | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Blurred vision | Ear and labyrinth disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | Systematic Assessment |
|
| Emisis | Gastrointestinal disorders | Systematic Assessment |
|
| Hematoschezia | Gastrointestinal disorders | Systematic Assessment |
|
| Thick secretions | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Poor appetite | General disorders | Systematic Assessment |
|
| H. Pylori infection | Infections and infestations | Systematic Assessment |
|
| Acinetobacter PNA | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| ALT elevation | Investigations | Systematic Assessment |
|
| AST elevation | Investigations | Systematic Assessment |
|
| Creatinine elevation | Investigations | Systematic Assessment |
|
| BUN elevation | Infections and infestations | Systematic Assessment |
|
| Bilirubin elevation | Infections and infestations | Systematic Assessment |
|
| Hypokalemia | Endocrine disorders | Systematic Assessment |
|
| Starvation ketosis | Endocrine disorders | Systematic Assessment |
|
| Hyperglycemia | Endocrine disorders | Systematic Assessment |
|
| Hyperkalemia | Endocrine disorders | Systematic Assessment |
|
| Hypernatremia | Endocrine disorders | Systematic Assessment |
|
| Hypocalcemia | Endocrine disorders | Systematic Assessment |
|
| Hypoglycemia | Endocrine disorders | Systematic Assessment |
|
| Hypophosphatemia | Endocrine disorders | Systematic Assessment |
|
| Transaminitis | Endocrine disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Right arm contracture | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Bone mineral disease | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Multifocal subacute stroke | Nervous system disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Delirium | Psychiatric disorders | Systematic Assessment |
|
| Worsening altered mental status | Psychiatric disorders | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| Chronic kidney disease | Renal and urinary disorders | Systematic Assessment |
|
| Hematuria | Renal and urinary disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| healthcare-associated pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Aspiration event pneumonitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Right soleal deep vein thrombosis | Vascular disorders | Systematic Assessment |
|
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| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |