Conditions: COVID-19
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
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:

1. Tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with clinical risk factors for clinical decompensation, intensive care utilization, and death.
2. Low-dose tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with and without clinical risk factors for clinical decompensation, intensive care utilization, and death.

Objectives:

1. To establish proof of concept that tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with clinical risk factors for clinical decompensation, intensive care utilization, and death, as determined by the clinical outcome of resolution of fever and the biochemical outcome measures of time to CRP normalization for the individual patient and the rate of patients whose CRP normalize.
2. To establish proof of concept that low-dose tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients without clinical risk factors for clinical decompensation, intensive care utilization, and death, as determined by the clinical outcome of resolution of fever and the biochemical outcome measures of time to CRP normalization for the individual patient and the rate of patients whose CRP normalize.

Detailed description:

Arms:
arm 1: Hospitalized, non-critically ill patients with COVID-19 pneumonitis with risk factors for decompensation arm 2: Hospitalized, non-critically ill patients with COVID-19 pneumonitis without risk factors for decompensation

Interventions: intervention 1: Tocilizumab intervention 2: Tocilizumab
Intervention descriptions: intervention 1: 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:

1. Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND
2. CRP decrease is \< 25% at 24 hours following tocilizumab administration and CRP \> 40mg/L intervention 2: 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:

1. Increasing supplemental oxygen requirement or Tmax higher than baseline in the 24h following initial tocilizumab administration AND
2. CRP decrease is \< 25% at 24 hours following tocilizumab administration and CRP \> 40mg/L

Protocol document:
Prot_SAP_001.pdf: 
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Early Institution of Tocilizumab Titration in Non-Critical Hospitalized COVID-19 
Pneumonitis (COVIDOSE) 
 
Lead Principal Investigator: 
Pankti Reid, MD, MPH 
 
University of Chicago, Department of Medicine 
 
Section of Rheumatology 
 
5841 S. Maryland Ave.  
Chicago, IL 60637 
 
pankti.reid@uchospitals.edu 
 
 
Co-Investigators:  
Brian Heiss, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
 
bheiss@medicine.bsd.uchicago.edu 
 
 
Garth W Strohbehn, MD, MPhil 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
 
gstrohbehn@uchicago.edu 
 
 
Alec Kacew, BA 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
 
 
 
Mark J. Ratain, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
 
mratain@medicine.bsd.uchicago.edu 
 
 
Tom Gajewski, MD, PhD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
 
tgajewsk@medicine.bsd.uchicago.edu 
 
 
 
Sherin Rouhani, MD, PhD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
Sherin.Rouhani@uchospitals.edu 


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Jonathan Trujillo, MD, PhD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
 
jtrujillo@medicine.bsd.uchicago.edu 
 
 
Cuoghi Edens, MD 
 
University of Chicago, Department of Medicine and
 
Pediatrics 
 
Section of Rheumatology and Pediatric Rheumatology 
 
5841 S. Maryland Ave. 
 
cedens@peds.bsd.uchicago.edu 
 
 
Reem Jan, MD 
 
University of Chicago, Department of Medicine 
 
Section of Rheumatology 
 
5841 S. Maryland Ave. 
Chicago, IL 60637 
 
rjan@medicine.bsd.uchicago.edu 
 
 
Iazsmin Ventura, MD 
 
University of Chicago, Department of Medicine 
 
Section of Rheumatology 
 
5841 S. Maryland Ave. 
Chicago, IL 60637 
 
Iazsmin.Ventura@uchospitals.edu 
 
 
Mary Strek, MD 
 
University of Chicago, Department of Medicine 
 
Section of Pulmonary/Critical Care 
 
5841 S. Maryland Ave. 
Chicago, IL 60637 
 
mstrek@medicine.bsd.uchicago.edu 
 
 
Natasha Pettit, PharmD 
 
University of Chicago, Department of Medicine 
 
Section of Infectious Disease 
 
5841 S. Maryland Ave. 
Chicago, IL 60637 
 
Natasha.Pettit@uchospitals.edu 
 
 
Jennifer Pisano, MD 
 
University of Chicago, Department of Medicine 
 
Section of Infectious Disease 
 
5841 S. Maryland Ave. 
Chicago, IL 60637 
 
jpisano@bsd.uchicago.edu 
 
 


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Spring Maleckar 
Alexandra Weiss 
Rachel Wright 
Adriana Koziol 
Bhakti Patel, MD 
Lauren Wall 
Bethany Martell 
David Pitrak, MD 
Karli Molignoni 
David Beiser, MD 
 
 
 
Statistician:                          
Theodore Karrison, PhD 
 
Dept. of Public Health Sciences, MC2000 
5841 S. Maryland Avenue 
Chicago, IL 60637 
tkarrison@health.bsd.uchicago.edu 
 
 
Trial Operating Committee: 
Voting Members: 
Pankti Reid, MD, MPH 
Mark Ratain, MD 
Mary Strek, MD 
Jennifer Pisano, MD 
 
Non-Voting Members: 
All other investigators 
Ad hoc consultative expertise 
 
 
 


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Protocol Type / Version # 1.6/ Version Date:  04/20/2020 
 
 
 
 
Study Design:  An operating committee-guided multi-arm, multi-step dose escalation/de-
escalation trial.  
 
Eligible Patients:  Hospitalized, non-critically ill patients with a diagnosis of COVID-19 
pneumonitis 
 
Primary Objectives: 
1. To establish proof of concept that tocilizumab is effective in decreasing signs, 
symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-
critically ill patients with clinical risk factors for clinical decompensation, intensive care 
utilization, and death. 
 
2. To establish proof of concept that low-dose tocilizumab is effective in decreasing 
signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, 
non-critically ill patients without clinical risk factors for clinical decompensation, 
intensive care utilization, and death. 
 
3. To estimate the minimum effective dose of tocilizumab, as assessed by early clinical 
and biochemical markers of resolution of hyperinflammation, in hospitalized, non-
critically ill patients with moderate COVID-19 pneumonitis, with and without clinical 
risk factors for clinical decompensation, intensive care utilization, and death. 
 
Secondary Objectives: 
To evaluate 28-day overall survival, survival to hospital discharge, rate of progression of 
COVID-19 pneumonitis, rate of non-elective mechanical ventilation, number of days to 
mechanical ventilation (invasive and non-invasive), number of days requiring mechanical 
ventilation, rate of vasopressor support utilization, number of days to vasopressor 
support, and number of days of vasopressor support in non-critically ill patients with 
COVID-19 pneumonitis who are treated with tocilizumab. 
 
 
 


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OVERALL STUDY SCHEMA: 
 
 
 
 
 
 
 
 
 


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PROPOSED TREATMENT AND RE-DOSING STRATEGY FOR LOW-DOSE 
TOCILIZUMAB: 
 
 
 


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TABLE OF CONTENTS                                                                                                                            
PAGE 
1 
Introduction ............................................................................................................ 9 
 
Background and Rationale .......................................................................................... 9 
1.1
1.1.1 
COVID-19 and Global Pandemic ........................................................................................... 9 
1.1.2 
COVID-19 Disease Risk-Stratification .................................................................................. 9 
1.1.2.1 
Defining the Subpopulation of Critically Ill Patients with COVID-19 Pneumonitis ...... 10 
1.1.3 
Parallels Between COVID-19 and Chimeric Antigen Receptor T-Cell (CAR-T)- Related 
Cytokine Release Syndrome (CRS) .....................................................................................................12 
1.1.4 
Justification for C-Reactive Protein Cutoffs ..........................................................................13 
1.1.5 
Anticipated Drug Shortages in the Treatment of COVID-19 ................................................13 
1.1.6 
Interventional pharmacoeconomics to increase effective supply ...........................................14 
 
Tocilizumab ................................................................................................................ 14 
1.2
1.2.1 
Clinical Studies ......................................................................................................................14 
1.2.2 
A Treatment Strategy Incorporating Low-Dose Tocilizumab ...............................................15 
1.2.3 
Dose-finding Studies for Tocilizumab in COVID-19 ............................................................17 
1.2.4 
Justification for Proposed Tocilizumab Dosing .....................................................................17 
1.2.5 
Justification for Proposed Changes to Tocilizumab Dosing ..................................................18 
 
Endpoints .................................................................................................................... 19 
1.3
1.3.1 
The Need for Rapid Endpoints ..............................................................................................19 
1.3.2 
CRP is correlated with IL-6-axis signaling ............................................................................19 
1.3.3 
CRP and Fever Briskly Respond to Tocilizumab in COVID-19 ...........................................19 
2 
Objectives .............................................................................................................. 20 
 
Hypotheses .................................................................................................................. 20 
2.1
 
Primary Objectives .................................................................................................... 20 
2.2
3 
Patient Selection ................................................................................................... 21 
 
Number of Subjects .................................................................................................... 21 
3.1
 
Inclusion Criteria ....................................................................................................... 21 
3.2
 
Exclusion Criteria ...................................................................................................... 21 
3.3
 
Assignment of eligible patients to Group A or Group B ........................................ 23 
3.4
 
Gender, Age, Racial and Ethnic Origin of Subjects ............................................... 24 
3.5
4 
Registration and Data Collection/Management ................................................. 24 
 
General Guidelines ..................................................................................................... 24 
4.1
 
Informed Consent Process ......................................................................................... 24 
4.2
 
Exemption from Investigational New Drug Application ........................................ 25 
4.3
 
Registration Process ................................................................................................... 26 
4.4
 
Data to Collect ............................................................................................................ 26 
4.5
 
Data Submission ......................................................................................................... 28 
4.6
5 
Drug Administration ............................................................................................ 28 
 
Duration of Treatment ............................................................................................... 28 
5.1
 
Duration of Study ....................................................................................................... 29 
5.2


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Study Operating Committee ..................................................................................... 29 
5.3
6 
Study Assessments ................................................................................................ 31 
 
Pretreatment Evaluation ........................................................................................... 31 
6.1
 
On-Study Evaluation ................................................................................................. 31 
6.2
 
Collection and Handling of Specimens: ................................................................... 32 
6.3
 
Off Study Assessments ............................................................................................... 32 
6.4
 
Study Calendar ........................................................................................................... 32 
6.5
6.5.1 
Overall Study Calendar..........................................................................................................32 
7 
Safety .................................................................................................................... 32 
 
Risks ............................................................................................................................ 32 
7.1
8 
Measurement of Effect......................................................................................... 33 
 
Clinical Response – Response in Maximum Temperature (Tmax) ....................... 33 
8.1
 
Biochemical Response - C-reactive protein Response ............................................ 33 
8.2
 
28-Day Overall Survival ............................................................................................ 34 
8.3
 
Survival to Hospital Discharge ................................................................................. 34 
8.4
 
Progression of COVID-19 Pneumonitis ................................................................... 34 
8.5
 
Rate of Non-elective Mechanical Ventilation .......................................................... 34 
8.6
 
Duration of mechanical ventilation .......................................................................... 34 
8.7
 
Time to Mechanical ventilation ................................................................................ 34 
8.8
 
Rate of Vasopressor or Inotropic Medication Utilization ...................................... 34 
8.9
 
Duration of Vasopressor of Inotropic Medication utilization ................................ 34 
8.10
 
Time to Vasopressor or Inotropic Utilization .......................................................... 35 
8.11
 
Number of ICU Days ................................................................................................. 35 
8.12
 
Duration of Increased Supplemental Oxygen Requirement from Baseline .......... 35 
8.13
9 
Statistical Plan and Considerations (10) ............................................................. 35 
 
Sample Size Determination ....................................................................................... 35 
9.1
 
Definition of Evaluable Patients ............................................................................... 35 
9.2
 
Statistical Methods ..................................................................................................... 35 
9.3
10 
STUDY MANAGEMENT AND REGULATORY AFFAIRS ............................ 36 
 
Institutional Review Board (IRB) approval ............................................................ 36 
10.1
 
Ethical and Scientific Conduct of the Clinical Study .............................................. 36 
10.2
 
Informed Consent ...................................................................................................... 36 
10.3
 
Amendments to the Protocol ..................................................................................... 37 
10.4
 
Annual IRB Renewals, Continuing Review and Final Reports ............................. 37 
10.5
 
Record Retention........................................................................................................ 37 
10.6


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11 
References: ........................................................................................................... 38 
 
 
 
 
 
 
 
1 
INTRODUCTION 
 
Background and Rationale 
1.1
1.1.1 COVID-19 and Global Pandemic 
 
The global pandemic of coronavirus disease-2019 (COVID-19), secondary to the severe 
acute respiratory syndrome coronavirus-2 (SARS-CoV-2), represents an emergent threat 
to public health, with a quoted mortality rate among inpatients greater than 25% (1). 
Containment strategies have been employed to varying degrees and effects in Western 
nations, now necessitating mitigation strategies in overwhelmed hospitals to effectively 
address COVID-19. Limited intensive care unit- (ICU) level resources such as 
mechanical ventilation and other in-hospital resources such as bedding space have played 
a significant role in the poor clinical outcomes associated with COVID-19 (2-4). 
Moreover, the throughput and length of hospitalization of patients requiring acute care 
beds may play a role in the “logjam” of available resources in a pandemic. Therefore, 
early identification of patients at risk for clinical decompensation, imminently preventing 
their decompensation so as to preserve as many ICU-level resources as possible, and 
decreasing the length of stay of non-critically ill patients are all crucial at a public health 
level to navigate the COVID-19 pandemic.   
 
1.1.2 COVID-19 Disease Risk-Stratification 
Varying clinical presentations of COVID-19 disease exist. The pneumonitis associated 
COVID-19 disease exists on a continuum, ranging from (on one extreme) bilateral 
infiltrates and associated respiratory failure, hyperinflammation, and septic shock leading 
to death to (at the other extreme) absence of pulmonary infiltrates and very mild 
symptoms. For the purposes of this study, patients meet diagnostic criteria for COVID-19 
pneumonitis when they have: 1) positive SARS-CoV-2 viral polymerase chain reaction 
test and 2) evidence of an infiltrate on chest imaging. Patients with COVID-19 disease 
may be admitted to the hospital for varying reasons. It is possible that patients with 
COVID-19 disease may be admitted to the hospital and not have COVID-19 
pneumonitis. Those patients with COVID-19 disease who do not have pulmonary 
infiltrates are generally at low risk for progression to pneumonitis and clinical 
decompensation, ICU resource utilization, and death. For the purposes of our study, we 
will focus primarily on hospitalized patients with signs of COVID19 pneumonitis who 
are not designated to be critically ill as delineated by aforementioned parameters (Figure 
1). Based on previously published data, (1) we can broadly risk-stratify patients who 
meet diagnostic criteria for pneumonitis according to their risk of clinical 
decompensation, intensive care unit (ICU) utilization, and death. The first division in the 
risk stratification schema is between patients who are critically ill (Figure 1) and those 


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who are not. Within the subpopulation who are not critically ill, there are those with 
relatively high risk for decompensation, ICU utilization, and COVID-19-related mortality 
(Group A; Figure 2) and those with relatively low risk for these same outcomes (Group 
B; Figure 3).  
 
1.1.2.1 Defining the Subpopulation of Critically Ill Patients with COVID-19 
Pneumonitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Clinical and radiographic characteristics of patients with Critical COVID-19 disease. 
 
 
First are critically ill patients with COVID-19 pneumonitis who are already utilizing 
near-ICU or ICU-level resources. These patients (Figure 1) have polymerase chain 
reaction (PCR)-proven SARS-CoV-2 infection, radiographic evidence of infiltrates, and 
physiologic signs of pneumonitis and COVID-19 related hyperinflammation marked by 
one or more of either respiratory rate greater than or equaled to 30 per minute, oxygen 
saturation of 93% or less in ambient air (for patients without baseline supplemental 
oxygen requirement), or a partial pressure of oxygen (PaO2)-fraction of inspired oxygen 
(FiO2) ratio of less than or equal to 300 mmHg. In addition, critical patients will be 
defined as having one or more of either respiratory failure requiring mechanical 
ventilation (invasive or non-invasive), shock of any form requiring the use of a 
vasopressor medication, or multi-organ failure. 
 
 
1.1.2.2 Defining and Risk-Stratifying within the Subpopulation of Non-Critically Ill 
Patients with COVID-19 Pneumonitis 
 
The remaining patients with COVID-19 pneumonitis who are admitted to the hospital are 
those non-critically ill patients who do not meet criteria for critical COVID-19 disease. 
These patients have risk, however, of clinical decompensation, utilization of ICU-level 
resources, and ultimately COVID-19 disease-related mortality. This population of 
patients can itself be thought of as two subpopulations: One has relatively high risk for 
progression to critical COVID-19 disease and ultimately COVID-19 disease-related 


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mortality (Figure 2) (hereafter ‘Group A’). Risk factors, as determined by a consensus of 
a multi-disciplinary panel of experts, include epidemiologic risk factors related to 
medical history and laboratory-based signs of hyperinflammation. The second 
subpopulation is comprised of patients (hereafter ‘Group B’) (Figure 3) who have 
COVID-19 disease but lack the epidemiologic or laboratory-based risk factors known to 
marginally increase the probability of progression to critical COVID-19 disease or 
COVID-19-related mortality. Both groups have risk of clinical decompensation, 
utilization of ICU-level resources, and COVID-19 disease-related mortality and may 
benefit from early treatment with medications aimed at managing COVID-19 disease-
related CRS. As a public health measure, early treatment may help to preserve limited 
ICU resources.  
 
Figure 2. Group A. Clinical, laboratory, and epidemiologic characteristics of hospitalized, non-
critically ill patients with COVID-19 pneumonitis at higher risk for clinical decompensation, ICU 
utilization, and COVID-19 disease-related mortality. 
 
>6L/min


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Figure 3. Group B. Clinical and laboratory characteristics of hospitalized, non-critically ill patients 
with COVID-19 pneumonitis at relatively lower risk for clinical decompensation, ICU utilization, 
and COVID-19 disease-related mortality. 
 
1.1.3 Parallels Between COVID-19 and Chimeric Antigen Receptor T-Cell 
(CAR-T)- Related Cytokine Release Syndrome (CRS) 
 
COVID-19’s high mortality may in part be driven by hyperinflammation resembling the 
cytokine storm often identified in hemophagocytic lymphohistiocytosis and cytokine 
release syndrome (CRS), offering the hope that immunosuppressive therapies commonly 
used to treat CRS – such as the interleukin-6 (IL-6) receptor-targeted monoclonal 
antibodies tocilizumab or sarilumab and IL-6 targeted monoclonal antibody siltuximab – 
can be used to reduce mortality in COVID-19 (Figure 4) (5). Emerging evidence shows 
marked elevation of serum IL-6, C-reactive protein (CRP), lactic dehydrogenase, and 
ferritin in patients with COVID-19, with the degree of elevation correlating with severity 
of disease (1, 6, 7). Early data suggest IL-6 axis suppression has promise. Retrospective 
analysis of severe to critical COVID-19 patients receiving tocilizumab 400 mg 
(approximately 6.67 mg/kg using average Chinese body weight) demonstrated that 
greater than 75% of patients had rapid resolution (i.e., within 24-72 hours following 
administration) of both clinical and biochemical signs (fever and CRP, respectively) of 
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hyperinflammation with only a single tocilizumab dose (6). To date, no prospective 
investigation on the topic – tocilizumab for the treatment of COVID-19 associated CRS – 
has been published. 
 
 
 
 
 
Figure 4. Interleukin-6 signaling in cytokine release syndrome 
(CRS) in chimeric antigen receptor T-cell (CAR-T). In normal 
circumstances (panel A), classic IL-6 signaling, marked by IL-6 
binding only to cell-bound IL-6 receptors (IL-6R), predominates. 
IL-6-axis signaling typically only occurs in neutrophils, 
macrophages, hepatocytes, and select T-cells. Under 
circumstances such as CAR-T-mediated CRS (B) and possibly 
COVID19-mediated CRS, IL-6 levels are markedly elevated, 
leading to pro-inflammatory trans IL-6-axis signaling and 
resultant systemic inflammation akin to sepsis.  (Image first 
published in Lee et al, Blood, 2014. Legend is independently 
written.) 
 
 
 
 
 
 
1.1.4 Justification for C-Reactive Protein Cutoffs 
 
Evidence collected thus far in COVID-19 suggests C-reactive protein (CRP) as a useful 
proxy marker for serum IL-6 levels as well as COVID-19 disease-related inflammation in 
hospitalized patients, both critically ill and non-critically ill (8-10). Early reports from the 
University of Chicago experience demonstrate that admission CRP is elevated in 
approximately 90% of hospitalized patients with COVID-19 disease (using an 
institutional normal range of < 5 ug/mL). Critically ill patients with COVID-19 disease 
tend to have higher CRP than non-critically ill patients (mean, 91 vs 66 ug/mL) (Natasha 
Pettit, COVID-19 Response Team, personal communication). The goal of the 
overarching treatment strategy discussed in 1.2.2 is to provision potentially efficacious 
therapy to the greatest number of patients likely to benefit from tocilizumab while still 
preserving an adequate supply for critically ill patients. Approximately 50% of 
hospitalized, non-critically ill patients with COVID-19 have CRP of < 40 ug/mL. 
(Natasha Pettit, COVID-19 Response Team, personal communication). An additional 
30% of patients have CRP between 41 and 75 ug/mL, with the final 20% of hospitalized, 
non-critically ill COVID-19 patients having CRP greater than 75 ug/mL (Natasha Pettit, 
COVID-19 Response Team, personal communication). 
 
1.1.5 Anticipated Drug Shortages in the Treatment of COVID-19 
 
Even if immunosuppressive monoclonal antibodies are efficacious therapies, challenges 
remain. As in the case of hydroxychloroquine, aggregate demand for anti-IL6 therapies 
driven by off-label utilization could quickly outstrip available supplies(11, 12). 


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Moreover, the supply of these anti-IL6 therapies may not be efficiently matched to 
hospitals expected to bear the brunt of COVID-19 (13). To overcome the drug 
supply/demand mismatch, three challenges must be overcome: 1) demand must be 
reduced through maximal containment measures, 2) the available medication’s 
distribution channels must be improved, and 3) the effective supply of the medications 
must be increased by ramping up manufacturing and extend anti-IL-6 therapy as much as 
possible. 
 
1.1.6 Interventional pharmacoeconomics to increase effective supply 
 
We can draw on lessons from the new field of interventional pharmacoeconomics (IVPE) 
to increase the effective supply of anti-IL-6 therapy (14). Many monoclonal antibodies 
used in both oncologic and rheumatologic indications in the outpatient setting have 
labeled doses and schedules aimed at maintaining a therapeutic concentration for weeks. 
In contrast, in the inpatient setting, where a patient’s primary problem is expected to be 
temporary and on the order of days, a lower and more frequent dosing of a monoclonal 
antibody is preferable. This approach helps to minimize the total amount of medication 
used and reduce the frequency and/or duration of adverse events. This pharmacological 
line of reasoning is germane to COVID-19 and is a plausible strategy to conserve use of 
potentially efficacious and supply-limited anti-IL6 therapies. Moreover, there is medical 
rationale in COVID-19: Immunosuppression for long periods of time of patients who are 
expected to have long inpatient hospital stays may increase their risks of nosocomial 
infection or bacterial superinfection, both of which have been concerns in patients with 
coronavirus infections (15, 16).  
 
 
Tocilizumab 
1.2
1.2.1 Clinical Studies 
 
Tocilizumab was originally developed for outpatient, every four-weeks administration in 
rheumatoid arthritis (RA), giant cell arteritis, polyarticular juvenile idiopathic arthritis, 
and systemic juvenile idiopathic arthritis at a labeled dose of 8 mg/kg, with approval 
based on improvement in the American College of Rheumatology (ACR) 20 score (17). 
Dose-finding studies revealed a dose-related reduction in Disease Activity Score in 28 
joints (DAS28) beyond 4 weeks at doses 4mg/kg and 8mg/kg (17). In its subsequent new 
drug application for treating CRS in chimeric antigen receptor T cell  (CAR T) therapy, 
no formal dose-finding study was performed and tocilizumab was approved after the 
8mg/kg dose, provisioned up to four times at least eight hours apart, led to resolution of 
CRS within a 14-day period of time (the primary outcome measure for these purposes) 
(17).  Response data from Food and Drug Administration (FDA) filings, however, 
suggest a 4 mg/kg dose had similar efficacy (table 18, reference 5) (18). Critically, lower 
doses were not studied (18). No common CRS biomarkers such as ferritin or C-reactive 
peptide (CRP) response were included as part of tocilizumab’s FDA filings (18).  The 
FDA’s own review stated: “It was notable that some patients in the Treated Population 
had resolution of CRS by day 14 after receiving tocilizumab 4 mg/kg, suggesting that a 
dose lower than recommended might be effective” (18).  
 


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1.2.2 A Treatment Strategy Incorporating Low-Dose Tocilizumab 
 
At an individual patient level, utilizing the minimally effective dose of a drug 
(tocilizumab) can optimize efficacy with minimalization of adverse events. On a more 
global scale, the logic behind a grand strategy for COVID-19 pandemic mitigation efforts 
is to proactively utilize one rare resource (tocilizumab) to prevent utilization of another, 
more limited resource (ICU-level care), rather than waiting until a patient is already 
committed to the most limited resource (ICU-level care) to then expend another limited 
resource (tocilizumab). The goal of the overarching treatment strategy is to provision 
potentially efficacious therapy to the greatest number of patients likely to benefit from 
tocilizumab while still preserving an adequate supply for critically ill patients (Figure 5) 
(12).  
 
 
 
Figure 5. Utilization of low-dose tocilizumab in hospitalized, non-critically ill patients with COVID-19 disease 
to prevent clinical decompensation, ICU utilization, and COVID-19-related death. 
 
Tocilizumab’s effectiveness in CRS after CAR-T therapy has led to off-label treatment of 
CRS from COVID-19 infections with preliminary evidence showing efficacy (6). 
Unfortunately, as previously stated, tocilizumab is in limited supply.  In this context, we 
have proposed the development of alternative treatment regimens for supportive care of 
COVID-19 (Figure 5) with the aim of providing therapy for the greatest number of 
patients likely to benefit. Hospitalized, non-critically ill patients with COVID-19 with 
and without risk factors for developing severe disease may be prime candidates for 
treatment with tocilizumab. Given the much lower IL-6 concentrations in COVID-19 
compared to CRS, we envision that single doses less than 400 mg will be effective (7, 
19). To date, tocilizumab 400 mg is the adopted standard of care dose, representing a 


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dose of approximately 5 mg/kg (based on average body weight in the United States). The 
speed with which both clinical and biochemical improvements in COVID-19-related 
hyperinflammation are seen in patients with COVID-19 treated with tocilizumab suggests 
rapid readout within 24 hours is possible (Figure 5) (6). Patients will be reassessed at 24 
hour intervals. Factors assessed will include: overall clinical status (specific focus on 
maximum supplemental oxygen required over the preceding 24 hours, fever curve and 
maximum temperature over the preceding 24 hours) as well as biochemical parameters 
that parallel IL-6 axis-suppression (with focus on C-reactive peptide (CRP) measured at 
approximate 24 hours after the initial dose and then daily thereafter) (6). Similar 
approaches may be useful in safely reducing the labeled doses of other IL-6 axis-
suppressing therapies and IL-1 antagonists (e.g., anakinra) to more COVID-19-
appropriate doses, thereby increasing effective supply.  
 
Patients will be considered for a total of 2 doses of tocilizumab.  Participants will be 
followed up evaluation of re-dosing 24-48 hours after first tocilizumab dose. Patients will 
be considered for re-dosing of tocilizumab if they meet one or more of the clinical criteria 
and the biochemical criteria below: 
 
Clinical criteria 
o Increased maximum supplemental oxygen required over approximately 24 
hours following the first tocilizumab dose compared to pre-dosing or 
baseline supplemental oxygen requirements and determined to be 
associated with COVID19 pneumonitis as determined by primary team 
or 
o Increased maximum temperature over approximately 24 hours following 
the first tocilizumab dose compared to maximum temperature in the 24 
hours prior to first tocilizumab administration  
 
  AND 
 
 
Biochemical criteria 
o CRP decrease of <25% of baseline CRP and >40mg/L: 
 
This follow-up CRP will be measured >=24 hours post first 
tocilizumab dose and >=24 hours since the draw of the CRP within 
2 hours of first dose administration. 
 
Baseline CRP 
 
If pre-drug CRP was within 2 hours prior to first 
tocilizumab administration, this will be the baseline CRP  
 
If pre-drug CRP was within 2-6 hours prior to first 
tocilizumab administration and a repeat CRP was ordered 
at the time of ordering tocilizumab, the baseline CRP will 
be the higher of these two values 
 


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1.2.3 Dose-finding Studies for Tocilizumab in COVID-19 
 
No dose-finding studies have been completed for tocilizumab in COVID-19 disease or 
CAR-T-related CRS. 
 
1.2.4 Justification for Proposed Tocilizumab Dosing 
 
Group A 
Hospitalized, non-critically ill patients with COVID-19 disease who have known 
epidemiologic risk factors and/or evidence of incipient hyperinflammation represent a 
group with significantly higher than baseline risk for clinical decompensation, utilization 
of ICU-level resources, and COVID-19 disease-related mortality. The risk of inhibiting 
innate antiviral response with high- or standard of care dose tocilizumab is not 
insignificant. We therefore believe it prudent to begin proactive treatment of these 
patients with a tocilizumab dose that is lower than reported by others. The current 
adopted standard of care dose in the critical setting is 400mg (20, 21). We propose a 
starting dose of 200mg. 
 
Group B 
Hospitalized, non-critically ill patients with COVID-19 disease who do not have known 
epidemiologic risk factors and evidence of incipient hyperinflammation represent a group 
of patients with risk for clinical decompensation, utilization of ICU-level resources, and 
COVID-19 disease-related mortality that is higher than that of the global population 
(which includes all patients with COVID-19, both inpatient and outpatient) but lower 
than the mean risk of the inpatient population (critically-ill COVID-19 patients and 
Group A patients). This is a non-trivial, albeit relatively smaller risk of clinical 
decompensation, utilization of ICU-level resources, and COVID-19 disease-related 
mortality. We believe it merits provision of a dose of tocilizumab approximately 
proportional to this population’s risk. 
 
Clinical guidance comes from the rheumatoid arthritis literature in the perioperative 
period in order to understand a) the impact and b) the dose of tocilizumab to reduce fever 
Re-dose if meets both clinical and biochemical parameters met:
1. Patient would meet clinical parameter if 
Follow-up-Tmax* > Pre-TCZ Tmax
or
Follow-up-O2-required* > Pre-TCZ O2 required
2. Patient would meet biochemical parameter if 
Follow-up-CRP†>40mg/L  
and  
Follow-up CRP† decrease is <25% of Baseline CRP#
*Max in 24hours postTCZ compared to Max value in 24hours preTCZ and associated with COVID19 per primary team
†Follow up CRP will be >= 24 hours after first tocilizumab dose and >=24 hours after baseline CRP
#Baseline CRP will be defined according to when results in reference to drug administration as follows: 
∙
If pre-drug CRP was within 2 hours prior to first tocilizumab administration, this will be the baseline CRP 
∙
If pre-drug CRP was within 2-6 hours prior to first tocilizumab administration and a repeat CRP was ordered at the 
time of ordering tocilizumab, the baseline CRP will be the higher of these two values


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and inflammatory markers in patients undergoing a major physiologic stressor. In a case-
control study of patients with rheumatoid arthritis, investigators identified 22 patients 
with rheumatoid arthritis who received tocilizumab 8mg/kg as outpatients in the run-up to 
surgery (22). Mean time of tocilizumab provisioning prior to surgery was 16 days. 
Tocilizumab-treated patients had increases in body temperature on post-operative days 1 
and 2 that were approximately one-half of rheumatoid arthritis control patients not treated 
with tocilizumab (22). Tocilizumab-treated patients also achieved suppression of the 
post-operative doubling in CRP identified in patients with rheumatoid arthritis who did 
not receive tocilizumab (22). Based on prior pharmacokinetic work and Food and Drug 
Administration review, the tocilizumab drug concentration at this time (16 days following 
administration) in patients treated with tocilizumab is predicted to be approximately 30 
ug/mL (23). We infer that this concentration of tocilizumab is sufficient to blunt 
temperature and CRP increases in times of physiologic stress. The pharmacologically 
implied one-time dose of tocilizumab needed to achieve a Cmax of 30 ug/mL is between 
50 and 100mg. Given this line of pharmacologic reasoning and tocilizumab’s vial sizes of 
80mg, 200mg, and 400mg, we therefore propose beginning with a dose of 80mg in Group 
B patients. 
 
1.2.5 Justification for Proposed Changes to Tocilizumab Dosing 
 
Prior investigations show there is no material difference in the rates of resolution of CRS 
at 14 days, the clinically relevant endpoint, between tocilizumab 4 mg/kg and 8 mg/kg, 
opening the possibility that a significantly lower dose could be used, especially given the 
lower levels of IL6 in COVID-19 infection CRS than in CAR-T-related CRS (18).  
Additionally, CRS symptoms from CAR-T usually resolved with only 1 or 2 doses of 
tocilizumab (18). Warning signs, then, of inefficacy likely will not become apparent until 
a truly ineffective dose of tocilizumab is reached. De-escalation of the tocilizumab dose 
therefore will be guided by rapidly ascertainable clinical and biochemical endpoints 
(1.3.1) and cautious de-escalation is warranted. To that end, de-escalations from cohort to 
cohort will be determined by the study’s Operating Committee (discussed in section 5.3) 
and will not exceed 50%. Therefore, if evidence of efficacy of tocilizumab 200mg in the 
first Group A study cohort, the dose may be reduced to a minimum of 100mg in the 
second Group A study cohort. If evidence of efficacy of tocilizumab 100mg in the second 
Group A study cohort, the dose may be reduced to a minimum of 50mg in the third Group 
A study cohort, and so on. The same logic will apply to Group B study cohorts, with a 
starting dose of 80mg (1.2.3). Given the risks associated with excessive 
immunosuppression in patients with known viral infection, dose increases will be 
approached similarly but with a maximum cohort-to-cohort increase of 100%: For 
example, if evidence of inefficacy of tocilizumab 200mg in the first Group A study 
cohort, the dose may be increased to a maximum of 400mg in the second Group A study 
cohort. Dosing changes will be at the discretion of the trial’s Operating Committee 
(discussed in section 5.3).  


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Endpoints 
1.3
1.3.1 The Need for Rapid Endpoints 
 
COVID-19 disease is a rapidly changing landscape with acute pressures on the US 
healthcare system and individual patients. Anecdotes – but not yet evidence – abound of 
patients rapidly decompensating after many hours, and sometimes days, of clinical 
stability. In a rapidly evolving situation, the presence of new clinical data points 
including changes in vital signs and laboratory parameters are necessary to guide clinical 
decisions. By the same token, evaluation of the efficacy of provisioned medications is 
necessary so as to guide clinical and study management. In line with the treatment 
strategy described in 1.2.2 and the behavior of critically ill patients with COVID-19 who 
were treated with tocilizumab (6), as well as given the circumstances of expected drug 
shortages and a need to make rapid decisions about redosing and dose changes, we 
propose incorporation of 24-hour clinical and biochemical endpoints. Mechanism-
specific endpoints such as cytokine panels or direct measurement of IL-6 levels are send-
out labs at the University of Chicago Medicine and therefore cannot be relied upon in the 
clinical context to make judgments about the efficacy of a given dose of tocilizumab. 
 
1.3.2 CRP is correlated with IL-6-axis signaling 
 
Prior literature on serologic markers of inflammation in COVID-19 disease show 
markedly elevated levels of both CRP and IL-6.(7) Cytokines are not frequently obtained 
at the University of Chicago Medicine. Because of turnaround time of > 48 hours (itself 
driven by pre-analytic variable of having to be sent to a reference laboratory), IL-6 
cannot be directly measured and used as a dynamic measure of tocilizumab activity in 
clinical practice at the University of Chicago Medicine. 
 
Prior work from the immunology literature demonstrates a strong connection between 
CRP elevation and the presence of IL-6 signaling (24), with IL-6-axis signaling serving 
as the predominant inducer of CRP expression (25). In the rheumatoid arthritis disease 
state in which the IL-6 axis is not targeted with therapy, CRP and IL-6 are tightly 
correlated, as well. Though tocilizumab administration is typically followed by a rise in 
serum IL-6 levels (23), CRP declines, suggesting a decrease in IL-6 axis signaling. 
Within the context of COVID-19, IL-6 and CRP are correlated, as well (8). 
 
1.3.3 CRP and Fever Briskly Respond to Tocilizumab in COVID-19 
 
Emerging evidence from the COVID-19 disease literature suggests critically ill patients 
treated with tocilizumab 400mg experience rapid improvement in fever and CRP 
levels(6, 26).  Based upon our independent evaluation of the data available from the Xu, 
et al  preprint and an estimated CRP half-life of 19 hours,(27) we infer that 
approximately 85% of critically ill patients with COVID-19 treated with tocilizumab 
400mg would experience either a CRP decline of > 25% or a normalization of CRP to < 
10 ug/mL within 24 hours of dose administration ((6), reconstituted data are available 
upon request). Furthermore, all febrile patients with COVID-19 disease who were treated 


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with tocilizumab 400mg experienced resolution of their fever within 24 hours of dose 
administration ((6), reconstituted data are available upon request) On the basis of these 
data and the absence of a dose-response relationship for tocilizumab in CAR-T-related 
CRS (1.2.4), any effective dose of tocilizumab should have clinical and biochemical 
effects similar to those of the 400mg dose. 
 
2 
OBJECTIVES 
 
Hypotheses 
2.1
 
1. Tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence 
of COVID-19 pneumonitis in hospitalized, non-critically ill patients with clinical 
risk factors for clinical decompensation, intensive care utilization, and death. 
 
2. Low-dose tocilizumab is effective in decreasing signs, symptoms, and laboratory 
evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients 
with and without clinical risk factors for clinical decompensation, intensive care 
utilization, and death. 
 
3. There is a minimum effective dose of tocilizumab, lower than that of the Food 
and Drug Administration-labeled dose for the mitigation of CAR-T-related CRS, 
for the prevention of COVID-19 pneumonitis-related CRS in hospitalized, non-
critically ill patients admitted for COVID-19 pneumonitis. 
 
 
Primary Objectives 
2.2
 
1. To establish proof of concept that tocilizumab is effective in decreasing signs, 
symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, 
non-critically ill patients with clinical risk factors for clinical decompensation, 
intensive care utilization, and death, as determined by the clinical outcome of 
resolution of fever and the biochemical outcome measures of time to CRP 
normalization for the individual patient and the rate of patients whose CRP 
normalize. 
 
2. To establish proof of concept that low-dose tocilizumab is effective in decreasing 
signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in 
hospitalized, non-critically ill patients without clinical risk factors for clinical 
decompensation, intensive care utilization, and death, as determined by the 
clinical outcome of resolution of fever and the biochemical outcome measures of 
time to CRP normalization for the individual patient and the rate of patients 
whose CRP normalize. 
 
3. To estimate the minimum effective dose of tocilizumab, as assessed by early 
clinical and biochemical markers of resolution of hyperinflammation, in 
hospitalized, non-critically ill patients with COVID-19 pneumonitis, with and 
without clinical risk factors for clinical decompensation, intensive care utilization, 


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and death, as determined by the clinical outcome of resolution of fever and the 
biochemical outcome measures of time to CRP normalization for the individual 
patient and the rate of patients whose CRP normalize. 
 
a. Failure rates, determined at 24-hour intervals following tocilizumab 
administration 
b. Biochemical and clinical response rates, determined at 24-hour intervals 
following tocilizumab administration 
c. Time to discharge 
d. Utilization of and length of utilization of ICU-level resources (mechanical 
ventilation, vasopressors) 
e. Overall survival at 28 days following administration of tocilizumab 
 
3 
PATIENT SELECTION  
 
Number of Subjects 
3.1
 
We anticipate enrollment of 5 patients in Group A and 5 patients in Group B in the first 
two weeks of the study’s opening. Further enrollment will be determined by the trial’s 
Operating Committee. The trial’s Operating Committee will meet within the first two 
weeks of the start of study (and likely sooner) and at least every two weeks thereafter 
(and likely more frequently). Further enrollment, dose changes, and changes to 
stratification criteria or redosing parameters (based on iterative assessments, as detailed 
in 5.3) will be determined by the Operating Committee by unanimous consent of the four 
voting members.  
 
 
Inclusion Criteria 
3.2
 
● Adults ≥ 18 years of age 
● Approval from the patient’s primary service 
● Admitted as an inpatient to University of Chicago Medicine 
● Fever, documented in electronic medical record and defined as: T  ≥ 38*C by any 
conventional clinical method (forehead, tympanic, oral, axillary, rectal)    
● Positive test for active SARS-CoV-2 infection 
● Radiographic evidence of infiltrates on chest radiograph (CXR) or computed 
tomography (CT) 
● Ability to provide written informed consent on the part of the subject or, in the 
absence of decisional capacity of the subject, an appropriate surrogate (e.g. a 
legally authorized representative). 
 
 
Exclusion Criteria 
3.3
 
● Concurrent use of invasive mechanical ventilation (patients receiving non-
invasive mechanical ventilation [CPAP, BiPap, HHFNC] are eligible) 
● Concurrent use of vasopressor or inotropic medications 


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● Previous receipt of tocilizumab or another anti-IL6R or IL-6 inhibitor. 
● Known history of hypersensitivity to tocilizumab. 
● Patients who are actively being considered for a study of an antiviral agent that 
would potentially exclude concurrent enrollment on this study. 
● Patients actively receiving an investigational antiviral agent in the context of a 
clinical research study. 
● Diagnosis of end-stage liver disease or listed for liver transplant. 
● Elevation of AST or ALT in excess of 10 times the upper limit of normal. 
● Neutropenia (Absolute neutrophil count < 500/uL). 
● Thrombocytopenia (Platelets < 50,000/uL). 
● On active therapy with a JAK2-targeted agent, which include the following: 
● 
Tofacitinib 
● 
Baricitinib 
● 
Upadacitinib  
● 
Ruxolitinib 
● On active therapy with a biologic immunosuppressive agent, which include the 
following biologics and any biosimilar versions thereof: 
● 
Alemtuzumab 
● 
Blinatumomab 
● 
Brentuximab 
● 
Daratumumab 
● 
Elotuzumab 
● 
Ibritumomab 
● 
Obinutuzumab 
● 
Ofatumumab 
● 
Ocrelizumab 
● 
Rituximab 
● 
Inotuzumab 
● 
Gemtuzumab 
● 
Tositumumab 
● 
Moxetumomab 
● 
Polatuzumab 
● 
Abatacept 
● 
Adalimumab 
● 
Belimumab 
● 
Certolizumab 
● 
Eculizumab 
● 
Etanercept 
● 
Golimumab 
● 
Infliximab 
● 
Ixekizumab 
● 
Rituximab 


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● 
Sarilumab 
● 
Secukinumab 
● 
Tocilizumab 
● 
Ustekinumab 
● History of bone marrow transplantation or solid organ transplant. 
● Known history of Hepatitis B or Hepatitis C. 
● Known history of mycobacterium tuberculosis infection at risk for reactivation. 
● Known history of gastrointestinal perforation or active diverticulitis. 
● Multi-organ failure as determined by primary treating team 
● Any other documented serious, active infection besides COVID-19. 
● Pregnant patients and nursing mothers 
● Patients who are unable to discontinue scheduled antipyretic medications, either 
as monotherapy (e.g., acetaminophen or ibuprofen [aspirin is acceptable]) or as 
part of combination therapy (e.g., hydrocodone/acetaminophen, 
aspirin/acetaminophen/caffeine [Excedrin®]) 
● CRP < 40 mg/L (or ug/mL) 
 
 
Assignment of eligible patients to Group A or Group B 
3.4
 
Patients will be assigned to Group A if: 
● C-reactive protein (CRP) ≥ 75 ug/mL 
 
AND 
 
Any one of the following criteria are met: 
● Previous ICU admission 
● Previous non-elective intubation 
● Admission for heart failure exacerbation within the past 12 months 
● History of percutaneous coronary intervention (PCI) 
● History of coronary artery bypass graft (CABG) surgery 
● History of cerebrovascular accident with residual, patient-reported neurologic 
deficit 
● Diagnosis of pulmonary hypertension 
● Baseline requirement for supplemental O2 
● Diagnosis of interstitial lung disease (ILD) 
● Admission for chronic obstructive pulmonary disease (COPD) exacerbation 
within the past 12 months 
● Asthma with use of daily inhaled corticosteroid 
● History of pneumonectomy or lobectomy 
● History of radiation therapy to the lung 
● History of HIV 
● Cancer of any stage and receiving active treatment (excluding hormonal therapy) 
● Any history of diagnosed immunodeficiency 
● End-stage renal disease (ESRD) requiring peritoneal or hemodialysis 
● BMI >30 kg/m2 


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● Baseline supplemental oxygen required (in 24hrs prior to first tocilizumab dose) 
>6L/min Nasal cannula 
 
All other patients meeting study eligibility criteria will be assigned to Group B. 
 
 
Gender, Age, Racial and Ethnic Origin of Subjects 
3.5
 
Men and women of all races and ethnic groups are eligible for this trial. 
 
4 
REGISTRATION AND DATA COLLECTION/MANAGEMENT 
 
General Guidelines 
4.1
 
Patients will be identified as potential participants in this clinical trial through medical 
record screening and collaboration with the COVID-19 clinical team. Primary teams and 
Emergency Department teams will be encouraged to send the medical record numbers of 
potentially eligible patients to investigators (PDR, GWS, BH) using the UCM secure 
paging system (Spok). Information sheets will be posted in Internal Medicine team rooms 
and in strategic locations of the Emergency Department (determined by DB) for nurses 
and physicians.  
 
Before any study-specific evaluations are performed, all patients must have given written 
informed consent for the study.  Patients must meet all of the eligibility requirements 
listed in Section 3.0.  Eligible patients will be entered on study by the University of 
Chicago into a REDCap database used for both registration and data collection (28). 
 
An investigator will confirm eligibility criteria and the informed consent process and a 
member of the study team will complete the registration case report form. 
 
 
Informed Consent Process 
4.2
 
Given the unique nature of the COVID-19 pandemic and the risk for transmission to 
health care and research staff, we will obtain informed consent from possible participants 
by the following process: 
 
1. Prospective study participants/representatives identified by an investigator will 
receive two (physical) copies of the written informed consent form (ICF) for their 
review from the research team, to be delivered by unit staff caring for the patient. 
ICFs delivered for review will have been signed by an investigator.  A patient’s 
representative may alternatively be provided a link to the consent in RedCap. 
2. Phone or video conference will be scheduled between a member of the research 
team and the prospective study participant/representative. Research team and 
prospective study participant/representative will discuss the ICF and intent of the 
study as well as risks/benefits to participation. This conversation will be 
witnessed by the unit staff caring for the prospective participant/representative. 


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3. If the prospective study participant/representative understands the risks/benefits of 
the study and is interested in participating, study participant or his/her designated 
representative will sign both copies of the ICF. The witness will sign both copies 
of the ICF.  If the consent is delivered through RedCap, this signature process 
happens electronically within the RedCap system. 
4. The research staff will document the informed consent conversation in the 
electronic medical record as a Telephone Encounter note in parallel with the 
conversation in an Epic Telephone Encounter created for the purposes of research. 
A standard note form (dot-phrase) will be used for all study participants 
(Appendix A).  
5. At this time, two fully executed ICFs will exist. The study 
participant/representative will keep one of them in his/her possession as proof of a 
fully executed ICF. The other fully executed ICF will be bio-bagged in the 
patient’s room and immediately bio-bagged once more upon exit and will be kept 
for filing by research staff.  If the consent process occurred electronically, then 
the fully executed consent will be an electronic file PDF/RedCap document. 
 
 
Exemption from Investigational New Drug Application 
4.3
 
Investigational New Drug (IND) is not required at this time, on the basis of September 
2013 Food and Drug Administration Guidance (29), section IV.A. This study meets all 
conditions set forth: 
● It studies a drug product, tocilizumab, legally marketed in the United States. 
● The intent of the study is not to report to FDA a well-controlled study in support 
of label change. 
● The intent of the study is not to support a change in marketing practices. 
● This study focuses on the COVID-19 patient population who have been admitted 
to the hospital. The mortality for COVID-19 among inpatients is quoted as greater 
than 25% (1). Though it is a new clinical situation in which to study tocilizumab, 
it is not prohibitively high-risk. Moreover, it does not represent a prohibitively 
large increase in risk over the baseline risk faced by this unique and ill patient 
population. Despite the presence of the global COVID-19 pandemic, tocilizumab 
continues to be administered at doses nearly an order of magnitude higher than 
the doses proposed in this study to patients with rheumatologic conditions such as 
rheumatoid arthritis, systemic juvenile idiopathic arthritis, and polyarticular 
juvenile idiopathic arthritis. If the risk/benefit calculus of the practice of 
continuing high-dose tocilizumab is acceptable at this time, then this study, with 
its comparable risk/benefit calculus, is as well. Furthermore, an emerging 
standard of care in critical COVID-19 disease is the use of tocilizumab at a dose 
significantly higher than the dose proposed in this study. 
● The study will be reviewed and conducted under the jurisdiction of an 
Institutional Review Board in accordance with 21 CFR part 56 and will have 
informed consent as described below, in accordance with 21 CFR part 50. 
● The study is not intended to promote or commercialize tocilizumab. 
 
 


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Registration Process 
4.4
 
To complete the registration process, a member of it the study team will: 
 
1.) Assign the patient a study number (e.g. patient would be UC-001) 
2.) Register the patient on study 
3.) Collect pre-treatment laboratory studies as below 
4.) Assign study participant to Group A or Group B. 
When registering a subject, the following must occur: 
● The patient must have signed the consent form. 
● The date the patient is registered will be considered the patient’s “On Study 
Date.” The patient’s subject ID will be assigned and a confirmation of registration 
will be issued by REDCap on this date.   
The University of Chicago will maintain a secure, password protected, and regularly 
backed up REDCap clinical trials database.  All data will be entered into the REDCap 
database.  Data will be stored in RedCap using the patient-study number. 
 
 
Data to Collect 
4.5
 
The following baseline clinical variables will be collected and recorded on the Eligibility 
and Registration Form: 
- 
Age 
- 
Sex 
- 
Race 
- 
Complete medical history 
 
The following laboratory data collected within 24 hours of tocilizumab will be reviewed 
by investigators: 
- 
Complete blood count (CBC) with automated differential (followed by manual 
differentiation as dictated per UCM clinical protocols) 
- 
Basic metabolic panel (BMP) 
- 
Liver function tests (LFT) 
- 
D-dimer 
- 
Fibrinogen 
- 
Lactic dehydrogenase (LDH) 
- 
C-reactive protein (CRP) 
- 
Westergren sedimentation rate (ESR) 
- 
Ferritin 
- 
Cytokine panel/IL-6 
- 
Triglycerides 
 
Patients will have the following laboratory studies performed in the 6 hours prior to 
administration of tocilizumab and at the time of tocilizumab dosing if more than 2 hours 
prior to the administration of the tocilizumab: 
CRP 


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In line with emerging standard of care clinical management of COVID-19 patients at 
UCM, investigators will review the results of the following laboratory studies, performed 
at 24-hour intervals during the patient’s hospitalization (or with clinical decompensation): 
- 
Complete blood count (CBC) with automated differential (followed by manual 
differentiation as dictated per UCM clinical protocols) 
- 
BMP 
- 
LFT 
- 
CRP 
 
Investigators advise but do not require the following laboratory and imaging studies be 
performed to monitor clinically: 
 
Laboratory studies performed at 24-hour intervals during the patient’s hospitalization 
(or with change in clinical status): 
- 
ESR 
- 
Ferritin 
 
 
Laboratory studies performed at 48-hour intervals during the patient’s hospitalization 
(or with change in clinical status): 
- 
D-dimer 
- 
Fibrinogen 
- 
LDH 
- 
Triglycerides 
 
Laboratory study performed 120 hours after tocilizumab administration: 
- 
Cytokine panel 
Imaging study performed 24, 72, and 120 hours (+/- 6 hours for each) following 
administration of tocilizumab (or with change in clinical status): 
- 
CXR (portable single-view is acceptable), or 
- 
CT chest 
The details of these results will be recorded on the Imaging Form. 
 
All labs and tocilizumab doses while inpatient will be collected on the Labs and 
Tocilizumab Administration Form.  If the patient has a change in clinical status requiring 
the use of invasive mechanical ventilation, initiation of vasopressor support, or (for 
patients not requiring non-invasive mechanical ventilation upon admission) the use of 
non-invasive mechanical ventilation, please record labs on the Patient Change in Clinical 
Status Labs Form.  If the patient goes to the ICU and is subsequently transferred out, 
please complete a second Patient Change in Clinical Status Labs Form. 
 
For every dose of tocilizumab administered, please record the details (dose amount, date, 
time, etc.) on the Labs and Tocilizumab Administration Form. 
 


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When a patient is in follow-up, they will be followed for survival for 28 days following 
the first dose of tocilizumab or hospital discharge, whichever occurs latest.  The details 
will be recorded on the Follow-Up Form. 
 
 
Data Submission 
4.6
 
All forms collected for the trial will be entered into the REDCap database. 
5 
DRUG ADMINISTRATION  
 
Treatment will be administered to the patient while they are admitted to a University of 
Chicago Medicine.  Tocilizumab is commercially available and will not be provided by 
the study. 
 
Therapy will consist of tocilizumab administered at doses determined by the Principal 
Investigator, as based on the most recent Operating Committee meeting. For the initial 
patients (i.e., prior to the first Operating Committee meeting), doses of 200 mg (Group A) 
and 80 mg (Group B) will be utilized, as discussed in section 1.2.4. 
 
The study Operating Committee (discussed in 5.2) will guide subsequent enrollment and 
dosing decisions in response to local constraints such as medication supply. We 
anticipate initial enrollment of five patients each in both Groups A and B in the first two 
weeks of the study. 
 
 
 
Duration of Treatment 
5.1
 
Patients will be considered for a total of 2 doses of tocilizumab.  Participants will be 
followed up evaluation of re-dosing 24-48 hours after first tocilizumab dose. Patients will 
be considered for re-dosing of tocilizumab if they meet one or more of the clinical criteria 
and the biochemical criteria below: 
 
Clinical criteria 
o Increased maximum supplemental oxygen required over approximately 24 
hours following the first tocilizumab dose compared to pre-dosing or 
baseline supplemental oxygen requirements and determined to be 
associated with COVID19 pneumonitis as determined by primary team 
or 
o Increased maximum temperature over approximately 24 hours following 
the first tocilizumab dose compared to maximum temperature in the 24 
hours prior to first tocilizumab administration  
 
  AND 
 
 
Biochemical criteria 
o CRP decrease of <25% of baseline CRP and >40mg/L: 


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 
This follow-up CRP will be measured >=24 hours post first 
tocilizumab dose and >=24 hours since the draw of the CRP within 
2 hours of first dose administration. 
 
Baseline CRP 
 
If pre-drug CRP was within 2 hours prior to first 
tocilizumab administration, this will be the baseline CRP  
 
If pre-drug CRP was within 2-6 hours prior to first 
tocilizumab administration and a repeat CRP was ordered 
at the time of ordering tocilizumab, the baseline CRP will 
be the higher of these two values 
 
 
  
 
 
 
Duration of Study 
5.2
 
Therapy with tocilizumab will continue unless one of the following events occurs: 
1. Severe allergic or infusion reaction occurs 
2. Treating physician determination that the risks or downsides of 
tocilizumab administration outweigh the potential benefits. 
3. Patient withdraws consent. 
4. Patient is withdrawn from the study at the discretion of the investigator or 
the patient’s attending physician. 
Note:  Patients will be followed for overall survival for 28 days after tocilizumab 
administration or liberation from mechanical ventilation, whichever occurs latest. 
 
 
 
Study Operating Committee 
5.3
 
To account for the constantly changing conditions caused by the COVID-19 pandemic, 
with resultant expectation of drug shortage, and the possibility of unexpected results in 
Re-dose if meets both clinical and biochemical parameters met:
1. Patient would meet clinical parameter if 
Follow-up-Tmax* > Pre-TCZ Tmax
or
Follow-up-O2-required* > Pre-TCZ O2 required
2. Patient would meet biochemical parameter if 
Follow-up-CRP†>40mg/L  
and  
Follow-up CRP† decrease is <25% of Baseline CRP#
*Max in 24hours postTCZ compared to Max value in 24hours preTCZ and associated with COVID19 per primary team
†Follow up CRP will be >= 24 hours after first tocilizumab dose and >=24 hours after baseline CRP
#Baseline CRP will be defined according to when results in reference to drug administration as follows: 
∙
If pre-drug CRP was within 2 hours prior to first tocilizumab administration, this will be the baseline CRP 
∙
If pre-drug CRP was within 2-6 hours prior to first tocilizumab administration and a repeat CRP was ordered at the 
time of ordering tocilizumab, the baseline CRP will be the higher of these two values


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provisioning tocilizumab to COVID-19 patients despite sound biologic and mechanistic 
rationale, we propose a study Operating Committee to guide governance and conduct of 
this study. 
 
The primary role of this committee is to discuss study progress and determine specifics 
for next steps in the study. These are expected to include questions of study continuation, 
enrollment in the next cohort, and dosing decisions. Prior to initiation of the study, the 
Operating Committee agrees to be bound by certain parameters: 
- 
Size of next cohort 
- 
Possible increases in doses, which will not increase from one cohort to the next by 
more than 100% 
- 
Possible decreases in doses, which will generally not decrease from one cohort to 
the next by more than 50% 
 
The voting members of the Operating Committee will be Drs. Reid, Pisano, Ratain, and 
Strek, with all decisions requiring unanimous consent, including enrollment beyond the 
initial 5 patients in each Group. All other study investigators will be non-voting members 
of the Operating Committee. Additional expert consultation will be requested on an as 
needed basis, at which point expert consultants will be ex officio, non-voting members of 
the Operating Committee. The first Operating Committee meeting will occur no later 
than 14 days from the first patient and thereafter at least every two weeks (and likely 
more frequently). It is mandatory for voting members to be present each time the 
Operating Committee convenes, as a 100% consensus is needed from the voting members 
before a decision is implemented into the next steps for the study.   
 
The Operating Committee will also be tasked with making decisions about the success or 
failure of a given dose level within a study cohort. The Committee will be guided by the 
performance of the drug in the previously discussed strategy (Figure 5). Success will be 
defined by a low rate of re-dosing and high rate of clinical and biochemical resolution. 
Metrics will be assessed by the Operating Committee and whatever consultants deemed 
necessary. Decisions will require unanimous consent among the Operating Committee’s 
voting members. 
 
Further enrollment decisions will be made by the trial’s Operating Committee. Further 
enrollment will be determined by the Operating Committee by unanimous consent of the 
voting members.  
 
The Operating Committee will assess the most up-to-date clinical information for each of 
the enrolled patient and also have the task of altering stratification criteria between group 
A and group B as well as redosing parameters as study continues, only via unanimous 
vote by the voting members and without any dissension from non-voting members. This 
is to ensure the utmost safety of the patient by being able to enact on evaluation of 
patient’s hospital courses in real time: allocate patients in appropriate drug dosing group 
(group A versus group B) and avoid inappropriate redosing.  
 


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6 
STUDY ASSESSMENTS 
 
Pretreatment Evaluation 
6.1
 
Investigators will review the following studies, collected within 24 hours prior to 
treatment with the first dose of tocilizumab as part of routine clinical care: 
- 
Complete blood count (CBC) with automated differential (followed by manual 
differentiation as dictated per UCM clinical protocols) 
- 
Basic metabolic panel (BMP) 
- 
Liver function tests (LFT) 
- 
D-dimer 
- 
Fibrinogen 
- 
Lactic dehydrogenase (LDH) 
- 
C-reactive protein (CRP) 
- 
Westergren sedimentation rate (ESR) 
- 
Ferritin 
- 
Cytokine panel/IL-6 
- 
Triglycerides 
- 
12-lead EKG 
 
Patients will have the following laboratory studies performed in the 6 hours prior to 
administration of tocilizumab and at the time of tocilizumab dosing if more than 2 hours 
prior to the administration of the tocilizumab: 
CRP 
  
Within 12 hours prior to treatment with the first dose of tocilizumab administration, the 
patient will have had a chest radiograph (CXR) (portable single-view is acceptable) or 
computed tomography (CT) of chest performed. 
 
 
On-Study Evaluation 
6.2
 
On-study evaluation refers to measurement of vital signs and laboratory studies before 
and after a patient has received tocilizumab. Subjects will be monitored during and 
following the drug infusion to monitor for any complications or reactions. As part of 
routine care, subjects will be seen daily while in the hospital and will be monitored 
through blood tests for general health as well as liver function. Vital signs will be 
monitored daily while in the hospital, physical exams, assessment of COVID infection, 
and CT scans or chest x-rays as necessary for routine care. 
 
Patients will have the following laboratory studies performed in the 6 hours prior to 
administration of tocilizumab and at the time of tocilizumab dosing if more than 2 hours 
prior to the administration of the tocilizumab: 
CRP 
  
Investigators will review the results of the following laboratory studies, performed at 24-
hour intervals during the patient’s hospitalization (or with clinical decompensation): 
- 
CRP 


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Other laboratory studies collected as part of the routine clinical care of COVID-19 
patients, as determined by institutional standards and the UCM COVID-19 Working 
Group, will be monitored by investigators, as well. 
 
 
Collection and Handling of Specimens: 
6.3
 
Clinical labs will be drawn and processed normally as per standard of care.  
 
 
 
 
Off Study Assessments 
6.4
 
Enrolled patients will be followed throughout their hospital course, and for survival for 
28 days after receiving the first dose of tocilizumab.  
 
 
Study Calendar 
6.5
6.5.1 Overall Study Calendar 
 
 
Baseline 
standard 
of care 
labsa  
Regist-
ration 
 
Standard of 
care labs 
collected prior 
to 
administration 
of tocilizumab 
 Standard of 
care lab 
assessments 
every 24 hours 
after 
tocilizumab 
Labs we 
advise but do 
not require 
every 48 
hours after 
tocilizumab 
Patient 
Intubated 
OR Patient 
transferred to 
ICU 
OR Patient 
change in 
clinical status 
Patient 
Extubated 
OR Patient 
transferred 
from ICU 
Follow Up 
Period 28 Days 
from Drug 
Administration 
 
Written 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Lab set 1b 
X 
 
X 
 
 
 
 
 
Lab set 2c 
X 
 
 
X 
 
X 
X 
 
Lab set 3d 
X 
 
 
 
X 
X 
X 
 
Imaginge 
X 
 
 
Xe 
 
X 
X 
 
Eligibility 
Confirmation 
X 
X 
 
 
 
 
 
 
Survival 
Follow Up 
 
 
 
 
 
 
 
X 
a In addition to the baseline labs, standard of care 12-lead EKG and cytokine panel/IL-6 will be obtained. 
b CRP Lab to be collected by the primary team within 6 hours (and at time of drug administration if 2-4 hours prior to 
tocilizumab administration) prior to and/or at the time of tocilizumab administration  
c Standard of care labs to be collected by the primary team every 24 hours or if there is a change in clinical status of 
patient are CBC, BMP, LFT, and CRP. Investigators advise ESR and ferritin. 
d Labs advised to be collected by the primary team every 48 hours or if there is a change in clinical status of patient are 
D-dimer, fibrinogen, LDH, and triglycerides. 
e Likely standard of care imaging will consist of CXR or CT chest. For baseline assessment, imaging study should be 
completed within 12 hours of initial tocilizumab administration.  Imaging that may occur as part of standard of care 
(advised by investigators) at 24, 72, and 120 hours following tocilizumab. 
Note: Investigators advise a cytokine panel performed at 120 hours after tocilizumab administration. 
 
7 
SAFETY  
 
Risks  
7.1
 
Tocilizumab is a commercially available drug approved for the treatment of diseases 
other than COVID-19. To date, there is no prospective, randomized controlled trial data 


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suggesting tocilizumab’s efficacy in COVID-19. There is no standard dose of tocilizumab 
for COVID-19. The FDA-labeled dose of tocilizumab for CRS is 8 mg/kg. In comparing 
a standard of care dose to reduced dose, there is a risk that the reduced dose will lead to 
poorer clinical outcomes for patients. Patients will be informed of this possibility. 
Patients assigned to low-dose tocilizumab blocks may receive an additional dose of 
tocilizumab if there is no evidence of clinical or biochemical improvement. 
 
Side effects and theoretical risks associated with tocilizumab include:  
- 
Serious infection 
- 
Gastrointestinal perforation 
- 
Hypersensitivity reaction, including anaphylaxis and death 
- 
Immunosuppression and increased risk for secondary infection (urinary tract 
infection, bacterial pneumonia, cellulitis, herpes zoster, gastrointestinal infection, 
diverticulitis, septic arthritis, and, rarely, opportunistic infections) 
- 
Neutropenia 
- 
Thrombocytopenia 
- 
Elevated liver enzymes 
- 
Elevated lipids 
- 
Immunogenicity (development of antibodies against tocilizumab) 
- 
Hepatitis B virus reactivation 
- 
Rarely, nervous system problems such as multiple sclerosis. 
- 
Tocilizumab may increase your risk of cancer 
- 
Tocilizumab may harm unborn or nursing babies 
Theoretical risks associated with tocilizumab in the context of COVID-19 infection 
include: 
- 
Suppression of innate antiviral immunity, resulting in progression of COVID-19 
disease 
8 
MEASUREMENT OF EFFECT  
 
Clinical Response – Response in Maximum Temperature (Tmax) 
8.1
 
Tmax Response. Maximum temperature within 24-hour period of time (0:00-23:59) on 
the day prior to, day of, and every 24 hours after tocilizumab administration. The primary 
endpoint is absence of Tmax greater than or equal to 38ºC in the 24-hour period 
following tocilizumab administration. 
 
 
Biochemical Response - C-reactive protein Response 
8.2
 
Time to CRP normalization. Calculated as the number of hours between tocilizumab 
administration and first normal CRP value. 
 
Rate of patients whose CRP normalize. Calculated as the ratio of the number of 
patients who achieve normal CRP value following tocilizumab administration and total 
number of patients who receive tocilizumab. 
 


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28-Day Overall Survival 
8.3
 
28-Day Overall Survival is defined as the status of the patient at the end of 28 days 
starting from the time of the first dose of tocilizumab.  
 
 
Survival to Hospital Discharge 
8.4
 
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.   
 
 
Progression of COVID-19 Pneumonitis 
8.5
 
This will be a binary outcome defined by worsening COVID-19 pneumonitis resulting in 
transition from Group A or Group B to critical COVID-19 pneumonitis during the course 
of the patient’s COVID-19 infection. 
 
 
Rate of Non-elective Mechanical Ventilation 
8.6
 
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. 
 
 
Duration of mechanical ventilation 
8.7
 
This will be a continuous outcome defined by the amount of time between initiation and 
cessation of mechanical ventilation (invasive and non-invasive). 
 
 
Time to Mechanical ventilation 
8.8
 
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. 
 
 
Rate of Vasopressor or Inotropic Medication Utilization 
8.9
 
This will be a binary outcome defined as utilization of any vasopressor or inotropic 
medication. 
 
 Duration of Vasopressor of Inotropic Medication utilization 
8.10
 
This will be a continuous outcome defined by the amount of time between initiation of 
first and cessation of last vasopressor medications. 


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 Time to Vasopressor or Inotropic Utilization 
8.11
 
This will be a continuous outcome defined by the amount of time between initiation of 
first and cessation of last vasopressor medications. This will be treated as a time-to-event 
with possible censoring. 
 
 Number of ICU Days 
8.12
 
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. 
 
 Duration of Increased Supplemental Oxygen Requirement from Baseline 
8.13
 
This will be an ordinal outcome defined by the number of days 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. 
 
9 
 STATISTICAL PLAN AND CONSIDERATIONS (10) 
 
Sample Size Determination 
9.1
 
The sample size is not formally determined at this time. Given expected constraints 
related to the COVID-19 epidemic, it is unclear whether drug shortages will limit 
enrollment and provisioning of tocilizumab. Continued enrollment in the context of drug 
shortages will be determined by the Operating Committee. 
 
 
Definition of Evaluable Patients 
9.2
 
Patients are considered eligible for analysis if they have enrolled in the study and 
received at least one dose of tocilizumab. 
 
 
Statistical Methods 
9.3
 
Primary endpoints will be Tmax response (<38C), time to CRP normalization, and rate 
of patients whose CRP normalize in the study population. 
 
Secondary endpoints including overall survival and survival to hospital discharge, which 
will be calculated by the Kaplan-Meier (26) method and compared between groups using 
a log-rank test. Rate of progression of COVID-19 pneumonitis, rate of non-elective 


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mechanical ventilation, number of days to mechanical ventilation (invasive and non-
invasive), number of days requiring mechanical ventilation, rate of vasopressor support 
utilization, number of days to vasopressor support, number of days of vasopressor 
support, and ICU time in non-critically ill patients with COVID-19 pneumonitis who are 
treated with tocilizumab will be assessed using descriptive and nonparametric statistics. 
 
10  STUDY MANAGEMENT AND REGULATORY AFFAIRS  
   Institutional Review Board (IRB) approval  
10.1
 
The investigator will obtain, from the University of Chicago Institutional Review Board 
(IRB), prospective approval of the clinical protocol and corresponding informed consent 
form(s); modifications to the clinical protocol and corresponding informed consent 
forms, and advertisements (i.e., directed at potential research subjects) for study 
recruitment.   
  
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is 
to eliminate an apparent immediate hazard to the research subject(s).  In such 
circumstances, the investigator will promptly notify the University of Chicago IRB of the 
deviation. 
  
The University of Chicago IRB operates in compliance with FDA regulations at 21 CFR 
Parts 50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice (CGP) (30). 
 
 Ethical and Scientific Conduct of the Clinical Study 
10.2
 
The clinical study will be conducted in accordance with the current IRB-approved 
clinical protocol; ICH Guidelines on GCP; and relevant policies, requirements, and 
regulations of the University of Chicago IRB, University of Chicago and UCMC, State of 
Illinois, and applicable federal agencies. 
  Informed Consent 
10.3
 
The investigator will make certain that an appropriate informed consent process is in 
place to ensure that potential research subjects, or their authorized representatives, are 
fully informed about the nature and objectives of the clinical study, the potential risks and 
benefits of study participation, and their rights as research subjects.  The investigator, or a 
sub-investigator(s) designated by the sponsor-investigator, will obtain the written, signed 
informed consent of each subject, prior to performing any study-specific procedures on 
the subject. The date and time that the subject signs the informed consent form will be 
recorded. The -investigator will retain the original copy of the signed informed consent 
form, and a copy will be provided to the subject. 
  


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The investigator will make certain that appropriate processes and procedures are in place 
to ensure that ongoing questions and concerns of enrolled subjects are adequately 
addressed and that the subjects are informed of any new information that may affect their 
decision to continue participation in the clinical study.  In the event of substantial 
changes to the clinical study or the risk-to-benefit ratio of study participation, the 
sponsor-investigator will obtain the informed consent of enrolled subjects for continued 
participation in the clinical study. 
  Amendments to the Protocol 
10.4
 
All modifications to the protocol or consent form will be submitted to the University of 
Chicago IRB for review and approval.  A list of the proposed modifications or 
amendments to the protocol and/or an explanation of the need of these modifications will 
be submitted, along with a revised protocol incorporating the modifications. Only the 
Study Lead PI can authorize any modifications, amendments, or termination of the 
protocol.   
 Annual IRB Renewals, Continuing Review and Final Reports 
10.5
 
A continuing review of the protocol will be completed by the University of Chicago IRB 
and the participating institutions’ IRBs at least once a year for the duration of the study. 
The annual IRB renewal approvals for participating institutions should be forwarded 
promptly to the Regulatory Manager. If the institution’s IRB requires a new version of 
the consent form with the annual renewal, the consent form should be included with the 
renewal letter. 
 Record Retention 
10.6
 
Study documentation includes all case report forms (CRFs), data correction forms or 
queries, source documents, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
  
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
 
 
 
 
 


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FDA. Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational 
New Drug Applications (INDs) — Determining Whether Human Research Studies Can 
Be Conducted Without an IND. 2013. 
30. 
FDA. CFR-Code of Federal Regulations Title 21. 2018. 
 
 
 
 
 
 
 
 
 
Appendix A: Informed Consent Documentation: Telephone Note Template 


IRB20-0515  
Tocilizumab to prevent clinical decompensation in hospitalized, non-critically ill patients with COVID-19 pneumonitis 
 
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NB: ‘***’ is an optional field. Either the prospective participant of his/her designated 
representative’s name will be listed in the body of the text. “@NAME@” refers to the 
name of the patient. “@HIS@” refers to smartphrase use of “his” or “her” in the 
document. “@HE” refers to smartphrase use of “he” or “she” in the document. 
“@TODAYDATE@” refers to smartphrase use of the date on which the note was 
drafted. 
 
--- 
 
Informed Consent Documentation for IRB *** 
Investigating the role of tocilizumab in the prevention of clinical decompensation in 
non-critically ill patients hospitalized with COVID-19 pneumonitis 
 
Name: @NAME@ 
Member of Research Team Obtaining Informed Consent: @ME@ 
 
I discussed the above-referenced research study with @NAME@ *** @HIS@ 
designated representative *** 
via telephone/videoconference on @TODAYDATE@. @NAME@ *** @HIS@ 
designated representative *** exhibited understanding of the research study and its 
risks/benefits. 
 
We assured the patient that @HE@ is free to withdraw from the study at any time. All 
questions were answered to the patient's satisfaction. 
 
After consideration of the risks/benefits, @NAME@ *** @HIS@ designated 
representative *** provided written informed consent as well as verbal consent to 
participate in the study. Written informed consent was provided on @TODAYDATE@ at 
***:***. The presence of a physical signature was confirmed with the patient's bedside 
nurse.  
 
The signed informed consent form will be scanned and uploaded to the Media tab of 
Epic. A copy of this note and the signed informed consent form (together comprising a 
fully executed informed consent document) will be provided to @NAME@ *** @HIS@ 
designated representative ***. 
 
 
Garth W Strohbehn MD MPhil 
Fellow, Hematology/Oncology  
 
on behalf of the research team for IRB *** 
“Investigating the role of tocilizumab in the prevention of clinical decompensation in 
non-critically ill patients hospitalized with COVID-19 pneumonitis”