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Lack of recruitment of patients into the trial
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Tocilizumab is an effective treatment for severe coronavirus disease 2019 (Covid-19) pneumonia and related inflammation. Given limited global supplies, clarification of the optimal tocilizumab dose is critical. We conducted an open-label, randomized, controlled trial evaluating two different dose levels of tocilizumab in Covid-19 (40mg and 120mg). Randomization was stratified on remdesivir and corticosteroid at enrollment. The primary outcome was the time to recovery. The key secondary outcome was 28-day mortality.
COVID-19's high mortality may be driven by hyperinflammation. Interleukin-6 (IL-6) axis therapies may reduce COVID-19 mortality. Retrospective analyses of tocilizumab in severe to critical COVID-19 patients have demonstrated survival advantage and lower likelihood of requiring invasive ventilation following tocilizumab administration. The majority of patients have 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.
The investigators hypothesized that a dose of tocilizumab significantly lower than the EMA- and FDA-labeled dose (8mg/kg) as well as the emerging standard of care dose (400mg) may be effective in patients with COVID-19 pneumonitis and hyperinflammation. Advantages to the lower dose of tocilizumab may include lower likelihood of secondary bacterial infections as well as extension of this drug's limited supply. The investigators conducted an adaptive single-arm phase 2 trial (NCT04331795) evaluating clinical and biochemical response to low-dose tocilizumab in patients with COVID-19 pneumonitis and hyperinflammation.
This multi-center, prospective, randomized controlled phase 2 trial -- designed as two sub-studies to allow for the possible emergence of data demonstrating the clinical efficacy of tocilizumab 8mg/kg or 400mg -- formally tests the clinical efficacy of low-dose tocilizumab in COVID-19 pneumonia.
Sub-Study A Primary Objective A: To establish whether low-dose tocilizumab reduces the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation, when compared to a tocilizumab-free standard of care.
Hypothesis A: The investigators hypothesize that low-dose tocilizumab, when compared to a tocilizumab-free standard of care, decreases the time to recovery in hospitalized, non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation by three days or more.
Sub-Study B Primary Objective B: To establish whether low-dose tocilizumab is near-equivalent to high-dose tocilizumab (400mg or 8 mg/kg) in reducing the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation.
Hypothesis B: The investigators hypothesize that low-dose tocilizumab is near-equivalent to high-dose tocilizumab in reducing the time to clinical recovery in hospitalized, non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sub-study A, Tocilizumab-Free Standard of Care | Active Comparator | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab. |
|
| Sub-study A, Tocilizumab 40mg | Experimental | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg. |
|
| Sub-study A, Tocilizumab 120mg | Experimental | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg. |
|
| Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care | Active Comparator | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg). |
|
| Sub-study B, Tocilizumab 40mg | Experimental | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tocilizumab | Drug | Tocilizumab 40mg |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Recovery | Day of recovery is defined as the first day on which the patient achieves one of the following two categories from a seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented. | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| Achievement of Recovery | This will be defined as the percentage of patients achieving one of the following two categories by day 7: hospitalized but not requiring supplemental oxygen or ongoing medical care or not hospitalized. | 7 days |
| Overall Survival |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pankti D Reid, MD, MPH | University of Chicago | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Chicago Medicine | Chicago | Illinois | 60637 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32488861 | Background | Strohbehn GW, Reid PD, Ratain MJ. Applied Clinical Pharmacology in a Crisis: Interleukin-6 Axis Blockade and COVID-19. Clin Pharmacol Ther. 2020 Sep;108(3):425-427. doi: 10.1002/cpt.1931. Epub 2020 Jul 4. |
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Individual participant data that underlie the results of this article, after de-identification. Sharing period will be 1 month after data are published and available indefinitely thereafter. Researchers who provide methodologically sound proposals for the purposes of achieving stated aims in their proposal will be eligible for data-sharing.
From 1 month following publication of data. Available indefinitely thereafter.
Proposals will need to be sent to study principal investigators. Requestors will need to sign a data access request form. Link to be determined.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sub-study A, Tocilizumab-Free Standard of Care | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab. Standard of Care: Tocilizumab-Free Standard of Care |
| FG001 | Sub-study A, Tocilizumab 40mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg |
| FG002 | Sub-study A, Tocilizumab 120mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg |
| FG003 | Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg). Standard of Care: Tocilizumab 400mg or 8mg/kg |
| FG004 | Sub-study B, Tocilizumab 40mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg |
| FG005 | Sub-study B, Tocilizumab 120mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sub-study A, Tocilizumab-Free Standard of Care | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab. Standard of Care: Tocilizumab-Free Standard of Care |
| BG001 | Sub-study A, Tocilizumab 40mg |
| 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 | Time to Recovery | Day of recovery is defined as the first day on which the patient achieves one of the following two categories from a seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented. | Note: for confidence intervals below, -9999 and 9999 = Upper or lower limit cannot be estimated due to insufficient number of participants with events. | Posted | Median | 95% Confidence Interval | days | 28 days |
|
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 | Sub-study A, Tocilizumab-Free Standard of Care | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab. Standard of Care: Tocilizumab-Free Standard of Care |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pankti Reid, MD | University of Chicago | 7737021220 | pankti.reid@bsd.uchicago.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 | Feb 24, 2021 | Feb 19, 2025 | Prot_SAP_000.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 |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
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Two sub-studies in parallel, each of three arms (maximum).
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|
| Sub-study B, Tocilizumab 120mg | Experimental | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg. |
|
| Tocilizumab | Drug | Tocilizumab 120mg |
|
|
| Standard of Care | Other | Tocilizumab-Free Standard of Care |
|
| Standard of Care | Other | Tocilizumab 400mg or 8mg/kg |
|
This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition. |
| 30 days |
| Hospital Length of Stay | This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital. | Up to 1 year |
| Clinical Response: Maximum Temperature (Tmax) Response | Maximum temperature (Tmax) in the 24-hour period immediately following randomization minus the measured Tmax in the 24-hour period immediately preceding randomization. | 24-hour period immediately preceding randomization and 24-hour period immediately following randomization |
| Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation | This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection. | Up to 28 days |
| Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation. | Up to 28 days |
| Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. | Up to 28 days |
| Clinical Response: Rate of Vasopressor/Inotrope Utilization | This will be a binary outcome defined as utilization of any vasopressor or inotropic medication. | Up to 28 days |
| Clinical Response: 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 medications. | Up to 28 days |
| Clinical Response: Time to Vasopressor/Inotrope Utilization | This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. | Up to 28 days |
| Clinical Response: Duration of Increased Supplemental Oxygen From Baseline | This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over 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. | 28 days |
| Biochemical Response: C-reactive Protein Response Rate | Decline in CRP of ≥ 25% in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline. | Pre-treatment baseline and 27 +/- 3 hours after tocilizumab administration |
| Safety: Rate of Secondary Infection | This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival. | 28 days |
Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg |
| BG002 | Sub-study A, Tocilizumab 120mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg |
| BG003 | Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg). Standard of Care: Tocilizumab 400mg or 8mg/kg |
| BG004 | Sub-study B, Tocilizumab 40mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg |
| BG005 | Sub-study B, Tocilizumab 120mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg |
| BG006 | 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 |
|
| OG001 | Sub-study A, Tocilizumab 40mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg |
| OG002 | Sub-study A, Tocilizumab 120mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg |
| OG003 | Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg). Standard of Care: Tocilizumab 400mg or 8mg/kg |
| OG004 | Sub-study B, Tocilizumab 40mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg |
| OG005 | Sub-study B, Tocilizumab 120mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg |
|
|
| Secondary | Achievement of Recovery | This will be defined as the percentage of patients achieving one of the following two categories by day 7: hospitalized but not requiring supplemental oxygen or ongoing medical care or not hospitalized. | Posted | Count of Participants | Participants | 7 days |
|
|
|
| Secondary | Overall Survival | This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition. | Posted | Count of Participants | Participants | 30 days |
|
|
|
| Secondary | Hospital Length of Stay | This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital. | Posted | Median | Full Range | days | Up to 1 year |
|
|
|
| Secondary | Clinical Response: Maximum Temperature (Tmax) Response | Maximum temperature (Tmax) in the 24-hour period immediately following randomization minus the measured Tmax in the 24-hour period immediately preceding randomization. | Sub-study A, SOC: 16 patients had missing data; Sub-study A, 40 mg: 11 patients had missing data; Sub-study A, 120 mg: 15 patients had missing data; Sub-study B, 400 mg: 3 patients had missing data; Sub-study B, 40 mg: 3 patients had missing data; Sub-Study B, 120 mg: 1 patient had missing data. | Posted | Median | Full Range | Degrees celcius | 24-hour period immediately preceding randomization and 24-hour period immediately following randomization |
|
|
|
| Secondary | Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation | This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection. | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| Secondary | Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation. | Patients who required non-elective mechanical ventilation | Posted | Median | Full Range | days | Up to 28 days |
|
|
|
| Secondary | Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation | This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. | Patients who required non-elective invasive mechanical ventilation | Posted | Median | Full Range | days | Up to 28 days |
|
|
|
| Secondary | Clinical Response: Rate of Vasopressor/Inotrope Utilization | This will be a binary outcome defined as utilization of any vasopressor or inotropic medication. | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| Secondary | Clinical Response: 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 medications. | Analysis population are patients who required vasopressor or inotrope medication. | Posted | Median | Inter-Quartile Range | days | Up to 28 days |
|
|
|
| Secondary | Clinical Response: Time to Vasopressor/Inotrope Utilization | This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. | Analysis population are patients who required vasopressor or inotropic medication | Posted | Median | Full Range | days | Up to 28 days |
|
|
|
| Secondary | Clinical Response: Duration of Increased Supplemental Oxygen From Baseline | This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over 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. | Posted | Mean | Full Range | days | 28 days |
|
|
|
| Secondary | Biochemical Response: C-reactive Protein Response Rate | Decline in CRP of ≥ 25% in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline. | 7 patients in study A, SOC had missing data; 8 patients in Study A, 40mg had missing data; 2 patients in Study A, 120 mg had missing data; 1 patient in Study B, SOC had missing data; 1 patient in Study B, 40 mg had missing data; 1 patient in Study B, 120 mg had missing data. | Posted | Count of Participants | Participants | Pre-treatment baseline and 27 +/- 3 hours after tocilizumab administration |
|
|
|
| Secondary | Safety: Rate of Secondary Infection | This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival. | 5 patients on Study A, SOC had missing data; 1 patient on Study A, 40 mg had missing data; 5 patients on Study !, 120 mg had missing data. | Posted | Count of Participants | Participants | 28 days |
|
|
|
| 1 |
| 26 |
| 0 |
| 26 |
| 23 |
| 26 |
| EG001 | Sub-study A, Tocilizumab 40mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg | 3 | 25 | 0 | 25 | 22 | 25 |
| EG002 | Sub-study A, Tocilizumab 120mg | Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg | 0 | 25 | 0 | 25 | 21 | 25 |
| EG003 | Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg). Standard of Care: Tocilizumab 400mg or 8mg/kg | 0 | 3 | 0 | 3 | 3 | 3 |
| EG004 | Sub-study B, Tocilizumab 40mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg. Tocilizumab: Tocilizumab 40mg | 0 | 3 | 0 | 3 | 3 | 3 |
| EG005 | Sub-study B, Tocilizumab 120mg | Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg. Tocilizumab: Tocilizumab 120mg | 0 | 1 | 0 | 1 | 1 | 1 |
| Leukocytosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Ventricular tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| Cardiac disorders - other | Cardiac disorders | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
| General disorders and administration site conditions | Gastrointestinal disorders | Non-systematic Assessment |
|
| Infections and infestations | Infections and infestations | Non-systematic Assessment |
|
| Alanine aminotransferase | Investigations | Non-systematic Assessment |
|
| Aspartate aminotransferase | Investigations | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | Non-systematic Assessment |
|
| White blood cell decreased | Investigations | Non-systematic Assessment |
|
| Investigations - other | Investigations | Non-systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Renal and urinary disorders - other | Renal and urinary disorders | Non-systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders - other | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | Non-systematic Assessment |
|
| Thromboembolic event | Vascular disorders | Non-systematic Assessment |
|
| Sinus bradycardia | Cardiac disorders | Non-systematic Assessment |
|
| Hypernatremia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | Non-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 |