Clinical trial NCT04479358
Conditions: COVID-19
Keywords: COVID-19 Tocilizumab
Sponsor: University of Chicago
Start date: 2020-09-10; Completion date: 2025-02-10
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab. arm 2: Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg. arm 3: Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg. arm 4: 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). arm 5: 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. arm 6: 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.
Interventions: intervention 1: Tocilizumab intervention 2: Tocilizumab intervention 3: Standard of Care intervention 4: Standard of Care
Intervention descriptions: intervention 1: Tocilizumab 40mg intervention 2: Tocilizumab 120mg intervention 3: Tocilizumab-Free Standard of Care intervention 4: Tocilizumab 400mg or 8mg/kg

Protocol documents:
Prot_SAP_000.pdf: 
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COVIDOSE-2: A multi-center, randomized, controlled phase 2 trial comparing 
early administration of low-dose tocilizumab to standard of care in hospitalized 
patients with COVID-19 pneumonitis who do not require invasive mechanical 
ventilation 
 
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:  
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 
 
 
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 
 
Ayodeji Adegunsoye, MD MS FCCP 
Bhakti Patel, MD 
Brian Heiss, MD 
Didem Saygin, MD 
Iazsmin Bauer Ventura, MD 
Jennifer Pisano, MD 
Jonathan Trujillo, MD, PhD 
Lauren He, MD 
Mary Strek, MD 
Misha Tran, MD 
Natasha Pettit, PharmD 
Sherin Rouhani, MD, PhD 
Tom Gajewski, MD, PhD 
Victor Kim, MD 
Vivian Lee, MD 
 
Clinical research coordinators:         Shruti Kamath 
Rachel Wright 
 
Statistician:                          
Theodore Karrison, PhD 
 
Dept. of Public Health Sciences, MC2000 
5841 S. Maryland Avenue 
Chicago, IL 60637 
tkarrison@health.bsd.uchicago.edu 


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Protocol Type / Version # 1.3/ Version Date:  02/24/2021 
 
 
 
Study Design:  A multi-center randomized, controlled phase 2 trial studying the use of 
reduced-dose tocilizumab for COVID-19 compared to that of standard of care treatment. 
 
Eligible Patients:  Hospitalized patients with a diagnosis of COVID-19 pneumonitis 
 
Primary Objectives: 
 
1. To establish whether low-dose tocilizumab reduces the time to clinical recovery 
in patients with COVID-19 pneumonitis and hyperinflammation. 
 
Secondary Objectives: 
1. To establish whether low-dose tocilizumab increases the probability of clinical 
recovery at seven days in COVID-19 pneumonitis. 
 
2. To establish whether low-dose tocilizumab decreases signs, symptoms, and 
laboratory evidence of COVID-19 pneumonitis.  
 
To compare the survival, hospital length of stay, rate of progression of COVID-19 
pneumonitis, rate of non-elective mechanical ventilation, number of days to mechanical 
ventilation, number of days requiring mechanical ventilation, rate of vasopressor support 
utilization, number of days to vasopressor support, number of days of vasopressor 
support, and duration of supplemental oxygen requirement higher than prior to 
hospitalization in non-critically ill patients with COVID-19 pneumonitis who receive 
either standard of care treatment (incorporating either no tocilizumab at all or higher-dose 
tocilizumab (equalling 400mg or 8mg/kg)), low-dose tocilizumab 40mg, or low-dose 
tocilizumab 120mg. 
 
 
 


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OVERALL STUDY SCHEMA: 
 
 
 
 


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TABLE OF CONTENTS                                                                                                                       
 
       
PAGE 
Introduction ........................................................................................................................ 8 
 
Background and Rationale .......................................................................................... 8 
1.1
1.1.1 
COVID-19 and Global Pandemic ........................................................................................... 8 
1.1.2 
Risk of Death in COVID-19 Disease ...................................................................................... 8 
1.1.3 
COVID-19 Mortality and Limited Promise of Antiviral Agent Remdesivir Monotherapy .... 9 
1.1.4 
Dexamethasone in COVID-19 ................................................................................................ 9 
1.1.5 
Parallels Between COVID-19 and Chimeric Antigen Receptor T-Cell (CAR-T)- Related 
Cytokine Release Syndrome (CRS) .....................................................................................................10 
 
Tocilizumab ................................................................................................................ 10 
1.2
1.2.1 
Clinical Studies ......................................................................................................................10 
1.2.2 
Drug Shortages in the Treatment of COVID-19 ....................................................................11 
1.2.3 
Risk of Bacterial Infection in Patients with COVID-19 Treated with Tocilizumab ..............11 
1.2.4 
Interventional pharmacoeconomics to increase effective supply ...........................................12 
1.2.5 
A Treatment Strategy Incorporating Low-Dose Tocilizumab ...............................................12 
1.2.6 
Dose-finding Studies for Tocilizumab in COVID-19 ............................................................13 
Preliminary Data from the COVIDOSE-1 Trial ..................................................................................13 
1.2.7 
Early Termination of the COVIDOSE-1 Study .....................................................................15 
 
Endpoints .................................................................................................................... 16 
1.3
1.3.1 
The Need for Rapid Pharmacodynamic Endpoints ................................................................16 
1.3.2 
CRP is correlated with IL-6-axis signaling ............................................................................16 
1.3.3 
CRP and Fever Briskly Respond to Tocilizumab in COVID-19 ...........................................16 
1.3.4 
Justification for CRP Cutoffs .................................................................................................17 
1.3.5 
Incorporation of Ordinal Clinical Endpoints .........................................................................17 
1.3.6 
Selection of an Ordinal Scale Relevant to Tocilizumab ........................................................18 
2 
Objectives and Hypotheses................................................................................... 19 
 
Primary Objective and Hypothesis........................................................................... 19 
2.1
 
Secondary Objectives and Hypotheses ..................................................................... 19 
2.2
3 
Site Selection ........................................................................................................ 20 
4 
Patient Selection ................................................................................................... 20 
 
Number of Subjects .................................................................................................... 20 
4.1
 
Inclusion Criteria ....................................................................................................... 20 
4.2
 
Exclusion Criteria ...................................................................................................... 21 
4.3
 
Gender, Age, Racial and Ethnic Origin of Subjects ............................................... 23 
4.4
5 
Registration and Data Collection/Management ................................................. 23 
 
General Guidelines ..................................................................................................... 23 
5.1
 
Informed Consent Process ......................................................................................... 24 
5.2
 
Exemption from Investigational New Drug Application ........................................ 25 
5.3
 
Registration Process ................................................................................................... 26 
5.4
 
Randomization and Stratification ............................................................................ 27 
5.5
 
Data to Collect ............................................................................................................ 28 
5.6


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Data Submission ......................................................................................................... 31 
5.7
6 
Drug Administration ............................................................................................ 31 
 
Duration of Study ....................................................................................................... 31 
6.1
 
Amount of Treatment ................................................................................................ 31 
6.2
7 
Study Assessments ................................................................................................ 32 
 
Pretreatment Evaluation ........................................................................................... 32 
7.1
 
On-Study Evaluation ................................................................................................. 32 
7.2
 
Off Study Assessments ............................................................................................... 34 
7.3
 
Study Calendar ........................................................................................................... 34 
7.4
7.4.1 
Overall Study Calendar..........................................................................................................34 
8 
Safety .................................................................................................................... 35 
 
Risks ............................................................................................................................ 35 
8.1
9 
Measurement of Effect......................................................................................... 35 
 
Time to Recovery ....................................................................................................... 35 
9.1
 
Achievement of Recovery, 7 days ............................................................................. 36 
9.2
 
Overall Survival, 28 days ........................................................................................... 36 
9.3
 
Hospital LOS .............................................................................................................. 36 
9.4
 
Clinical Response – Maximum Temperature (Tmax) Response, 24 hours ...... Error! 
9.5
Bookmark not defined. 
 
Clinical Response – Rate of Non-Elective Invasive Mechanical Ventilation 
9.6
(RNEIMV) ............................................................................................................................... 36 
 
Clinical Response – Duration of Non-Elective Invasive Mechanical ventilation 
9.7
(DNEIMV) ............................................................................................................................... 36 
 
Clinical Response – Time to Non-Elective Invasive Mechanical ventilation 
9.8
(TNEIMV)................................................................................................................................ 36 
 
Clinical Response – Rate of Vasopressor/Inotrope Utilization (RVIU) ................ 36 
9.9
 
Clinical Response – Duration of Vasopressor/Inotrope Utilization (DVIU) ......... 36 
9.10
 
Clinical Response – Time to Vasopressor/Inotrope Utilization (TVIU) ................ 37 
9.11
 
Clinical Response – Duration of Increased Supplemental Oxygen from Baseline 37 
9.12
 
Biochemical Response - C-reactive Protein Response Rate ................................... 37 
9.13
 
Safety – Rate of Secondary Infection ....................................................................... 37 
9.14
10 
Statistical Plan and Considerations (10) ............................................................. 37 
 
Sample Size Determination ....................................................................................... 37 
10.1
 
Definition of Evaluable Patients ............................................................................... 38 
10.2
 
Statistical Methods ..................................................................................................... 38 
10.3
 
Interim Analyses ........................................................................................................ 39 
10.4


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11 
STUDY MANAGEMENT AND REGULATORY AFFAIRS ............................ 40 
 
Institutional Review Board (IRB) approval ............................................................ 40 
11.1
 
Ethical and Scientific Conduct of the Clinical Study .............................................. 40 
11.2
 
Informed Consent ...................................................................................................... 40 
11.3
 
Data Safety Monitoring ............................................................................................. 41 
11.4
11.4.1 
Data Safety Monitoring by Study Investigators ................................................................41 
11.4.2 
Independent Data Safety Monitoring Board .....................................................................41 
 
Amendments to the Protocol ..................................................................................... 42 
11.5
 
Annual IRB Renewals, Continuing Review and Final Reports ............................. 42 
11.6
 
Record Retention........................................................................................................ 42 
11.7
References: ....................................................................................................................... 44 
 
 
 
 
 
 
 
 
 


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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 15%.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.5,6 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. 
 
Local efforts to control the COVID-19 pandemic have been heterogeneous within 
the United States, such that many communities are experiencing “second waves” 
associated with re-opening strategies and/or insufficient containment measures. Perhaps 
more accurately, the “first wave” was either never experienced or never went away and 
instead the current state is either an elevated plateau or a community’s first real wave. In 
either case, the urgency of the pandemic on a national and to an extent global scale has 
not abated and therapies are urgently needed. 
 
1.1.2 Risk of Death in COVID-19 Disease 
COVID-19 pneumonitis 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. 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.7 
 
 
Figure 1. Clinical and radiographic characteristics of 
patients with Critical COVID-19 disease. 
 
For the purposes of the previous COVIDOSE 
study (IRB20-0515), hereafter referred to as 
COVIDOSE-1 to differentiate it from the 
proposed study, we focused on hospitalized 
patients with signs of COVID-19 pneumonitis 
who were not designated to be “critically ill,” as 
delineated by aforementioned parameters (Figure 1). Based on previously published 
data,8 these remaining hospitalized patients with COVID-19 pneumonitis have risk of 


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clinical decompensation, intensive care utilization, and COVID-19-related mortality. 
These patients 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.  
 
 
1.1.3 COVID-19 Mortality and Limited Promise of Antiviral Agent 
Remdesivir Monotherapy 
Repurposed investigational therapies to this point have been divided into antiviral 
therapies such as hydroxychloroquine, lopinavir/ritonavir, and remdesivir and adjunctive 
anti-inflammatory therapies, including hydroxychloroquine, Janus kinase (JAK) 
inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, immunomodulating biologics such 
as anakinra and immunosuppressive monoclonal antibodies.9 In the preliminary report of 
the Adaptive COVID-19 Treatment Trial (ACTT),10 authors showed remdesivir, the most 
promising antiviral to date, was statistically superior to placebo in reducing hospitalized 
adults’ recovery time by a clinically relevant four days (on an ordinal scale of disease 
severity).10 Although clinically meaningful, the hazard ratio for death with remdesivir 
treatment was 0.70, a result that was not statistically significantly at a threshold p-value 
of 0.05. While the overall survival result may eventually be demonstrated to be 
substantial, the inability of a pharmacologically active antiviral therapy to clearly reduce 
COVID-19 disease’s high mortality suggests additional therapeutic approaches may be 
important, particularly in those patients with more severe disease.10  
 
1.1.4 Dexamethasone in COVID-19 
Recent evidence demonstrates the benefit of dexamethasone in the treatment of 
hospitalized patients with COVID-19. This trial, the RECOVERY trial from the United 
Kingdom, randomized hospitalized patients with COVID-19 of all levels of severity, 
2104 in total, to receive either dexamethasone 6mg daily for up to ten days or to usual 
standard care.11 Arms were well balanced between the two treatment assignments, with 
dexamethasone patients being statistically older than those receiving usual standard of 
care. Those patients receiving dexamethasone had statistically lower probabilities of 28-
day mortality and receipt of invasive mechanical ventilation, with higher probability of 
discharge from hospital within 28 days.11 Subgroup analysis demonstrated that the effects 
may have been most profound in patients receiving supplemental oxygen and invasive 
mechanical ventilation. On the basis of this evidence, it is likely that, similar to acute 
respiratory distress syndrome, steroids are beneficial in the latter stages of COVID-19. 
Steroids, especially in the context of concurrent infection and high risk for 
secondary infection, are not benign medications. Not reported, but of concern, include 
secondary opportunistic and bacterial infections as well as the role of dexamethasone on 
the development of anti-Spike and anti-RBD antibodies against SARS-CoV-2. 
Experience during the initial wave of SARS in the early 2000s raised additional questions 
with respect to steroid use. Diminished bone health, namely avascular necrosis, from 
prolonged steroid use emerged as a significant risk during the SARS epidemic.12,13 Short- 
and long-term steroid-related risks of adrenal insufficiency and diabetes mellitus have 
also been raised during the COVID-19 pandemic.14,15 Taken together, these emerging 
data when viewed in the context of the clear proof-of-principle for reduction of 


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inflammation in COVID-19 established by the RECOVERY trial demonstrate a clear 
need for steroid-sparing immunomodulatory treatment strategies. 
 
1.1.5 Parallels Between COVID-19 and Chimeric Antigen Receptor T-Cell 
(CAR-T)- Related Cytokine Release Syndrome (CRS) 
 
Instead, 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 2).16 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.8,17,18 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 hyperinflammation 
with only a single tocilizumab dose.18 
 
Figure 2. 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.) 
 
Although prospective trials or even large retrospective trials are scant and peer-reviewed 
literature otherwise on the topic is still scarce, what has been gleaned thus far is 
illuminating. First, a randomized, controlled trial conducted at multiple institutions in 
France has, per press release, shown promising signs of tocilizumab’s efficacy in 
COVID-19 treatment.19 Sanofi/Regeneron has released results of phase 2/3 studies of 
sarilumab in COVID-19, with clear signs of clinical benefit in the high-dose sarilumab 
arm of the study.20 Real-world evidence of off-label tocilizumab use also point to its 
benefit.21 
 
 
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 


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based on improvement in the American College of Rheumatology (ACR) 20 score.22 
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.22 
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).22  Response data from Food and Drug 
Administration (FDA) filings, however, suggest a 4 mg/kg dose had similar efficacy 
(table 18).23 Critically, lower doses were not studied.23 No common CRS biomarkers 
such as ferritin or C-reactive peptide (CRP) response were included as part of 
tocilizumab’s FDA filings.23 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”.23 
 
New information suggests a role for tocilizumab in COVID-19 pneumonitis and 
the related CRS. A French multicenter randomized, controlled trial of tocilizumab 
8mg/kg in hospitalized patients with COVID-19 reportedly has demonstrated 
“significant” clinical benefit in patients when compared to standard of care.19 
Additionally, the IL-6R-targeted monoclonal antibody sarilumab has shown signs of 
efficacy in an early industry-sponsored phase 2/3 study.20 
 
Additional evidence derived from platform randomized controlled trials has 
demonstrated mortality benefit with tocilizumab.24,25 Consequently, tocilizumab has been 
adopted as a standard of care treatment in many parts of the industrialized world, 
including the United Kingdom, Canada, and European Union, for patients with incipient 
organ failure or within 24 hours of admission to an intensive care unit and elevated C-
reactive protein. 
 
1.2.2 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.26,27 Moreover, the 
supply of these anti-IL6 therapies may not be efficiently matched to hospitals expected to 
bear the brunt of COVID-19.28 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 increasing manufacturing 
and extending the extant anti-IL-6 therapy as much as possible. 
 
1.2.3 Risk of Bacterial Infection in Patients with COVID-19 Treated with 
Tocilizumab 
There is medical rationale for low-dose tocilizumab in COVID-19.29 In the early era of 
COVID-19 treatment, there was concern that immunosuppression for long periods of 
time of patients expected to have long inpatient hospital stays would increase the risk of 
nosocomial infection or bacterial superinfection, both of which have been concerns in 
patients with coronavirus infections.30-32 Retrospective studies in the COVID-19 space 


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have validated these concerns. Single-center retrospective studies have estimated an 
approximately three-fold increase in the likelihood of secondary bacterial infections (e.g., 
hospital acquired and ventilator associated pneumonias) in patients receiving tocilizumab 
at higher doses.32,33 Higher rates of infection were not identified in large-scale platform 
randomized controlled trials.25 
Lower doses of tocilizumab, with consequent lower peak concentration and 
shorter duration of immunosuppression, may reduce the frequency and the duration of 
these adverse events.29 In the initial COVIDOSE-1 study, the observed rate of secondary 
bacterial infection (e.g., ventilator-associated pneumonia, hospital acquired pneumonia, 
or bacteremia) in patients treated with low-dose tocilizumab was approximately one-
fourth that of mechanically ventilated patients who received tocilizumab approximating 
the labeled dose.33,34 There may still be a marginal increase in the risk of nosocomial 
pneumonia even with low-dose tocilizumab – the likelihood of COVIDOSE-1 patients 
developing serious bacterial infections was approximately equal to that of mechanically 
ventilated patients not treated with tocilizumab.33 How the rates of prospectively-
collected secondary infections compare between low-dose tocilizumab-, high-dose 
tocilizumab (400 mg or 8 mg/kg)-, and dexamethasone-treated patients and their 
respective control populations remains to be seen,11 and carefully conducted prospective 
studies with appropriate biological correlates are much needed in this space. 
 
1.2.4 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.35 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. Extrapolating from IVPE as 
applied to cancer, extending the supply of expensive medications is a particularly useful 
tactic in low- and middle-income countries (LMICs) as well as rural hospitals.36 These 
localities are also expected to bear the brunt of COVID-19’s impact.  
 
1.2.5 A Treatment Strategy Incorporating Low-Dose Tocilizumab 
At an individual patient level, utilizing a practical and effective low dose of a drug can 
optimize efficacy while minimizing 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). 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 
3).27 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.37 


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As with most drugs, tocilizumab baseline supply is matched to baseline demand. In the 
presence of a rapid increase in anticipated demand due to a global pandemic, it is unclear 
if supply could be efficiently increased to match said demand in time to be useful.34 
Roche has increased tocilizumab production, but this production has been for the sake of 
global clinical trials.38 Thus, relative to anticipated demand, tocilizumab is in limited 
supply both domestically and globally.34,39 In this context, we proposed the development 
of alternative treatment regimens to address COVID-19-related hyperinflammation with 
the aim of providing therapy for the greatest number of patients likely to benefit.29 
 
We estimate a priori that a target maximum concentration of tocilizumab likely to 
provide biochemical response as well as clinical benefit for patients with COVID-19 is 
approximately 8g/mL.29 Given the much lower IL-6 concentrations in COVID-19 
compared to CAR-T-related CRS, we hypothesized that single doses less than 400 mg 
would be effective.17,40 In the initial COVIDOSE-1 study, clinical and biochemical 
responses were observed in patients receiving as low as 40mg of tocilizumab, providing 
proof-of-principle for the approach. A minimum effective dose was not identified, but a 
practical and effective low dose of 40mg – representing one-half of tocilizumab’s 
smallest vial size and approximately 10% of the currently accepted standard COVID-19 
dose – was.  
 
1.2.6 Dose-finding Studies for Tocilizumab in COVID-19 
To our knowledge COVIDOSE-1 was the first dose-finding study to be completed for 
tocilizumab in COVID-19 disease or CAR-T-related CRS. COVIDOSE-1 succeeded in 
identifying a practical and potentially effective low dose of tocilizumab for the treatment 
of COVID-19 pneumonitis.  
 
Preliminary Data from the COVIDOSE-1 Trial 
In exploring lower doses of tocilizumab, we initially stratified patients on the basis of 
their perceived risk of clinical decompensation due to COVID-19 for the purposes of 
safety. Patients not meeting definition of critical COVID-19 (Figure 1) were divided into 
Group A (patients with COVID-19 disease who have known epidemiologic risk factors) 
as shown in Figure 3 and biochemicalevidence of incipient hyperinflammation as 
determined by a pre-designated adjudicated CRP level of  75µg/ml) and Group B, 
patients with COVID-19 disease who do not have these known epidemiologic risk factors 
or evidence of incipient hyperinflammation. 
 


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Figure 3. 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. 
 
The crucial role of IL-6 in context of the risk of inhibiting innate antiviral 
response with these high doses of tocilizumab (400mg or 8mg/kg) is not insignificant.41,42 
We therefore believed that a) it was prudent to begin proactive treatment of these patients 
(which is expected to be confirmed with prospective RCT data19) and b) it was reasonable 
to use a tocilizumab dose that is lower than reported by others. We identified efficacious 
doses of 40mg and 120mg in COVIDOSE-1. 
 
 
We have arrived at this dose through the initial COVIDOSE-1 study. The 
majority of patients in both Group A and Group B had clinical and biochemical response 
to the starting doses of 200mg and 80mg, respectively. Based on trial operating 
committee meeting and unanimous decision, the doses were decreased to 120mg and 
40mg. With these lower doses, the majority of patients continued to have clinical and 
biochemical response. 
 
Additionally, post-hoc analysis of recovery time yielded promising results: Time 
to recovery was calculated for enrolled COVIDOSE-1 patients who survived. Median 
time to recovery for the entire COVIDOSE-1 population was 3 days (interquartile range, 
2-5). When stratified by COVIDOSE-1 risk group assignment, Group A patients had 
median time to recovery of 4.5 days (IQR, 2.5-6.75) while those in Group B had median 
time to recovery of 3 days (IQR, 2-4). In the first cross-trial comparison between 
tocilizumab and remdesivir, patients with a requirement for supplemental oxygen who 
received remdesivir had median time to recovery of 7 days (95% CI 6-8),10 while this 


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subpopulation in COVIDOSE-1 had median time to recovery of  4 days (IQR, 3-5) 
despite the COVIDOSE-1 protocol selecting for patients with comorbidities. 
COVIDOSE-1 was a single-arm adaptive phase 2 study and recovery time was evaluated 
post hoc, thus there remains equipoise as to whether low-dose tocilizumab is clinically 
beneficial to patients with COVID-19 pneumonitis – this is the key question to be 
addressed by COVIDOSE-2. 
 
1.2.7 Early Termination of the COVIDOSE-1 Study 
During the course of the COVIDOSE-1 study, industry- and NIH-sponsored studies of 
remdesivir were being conducted worldwide.10,43 The NIH-sponsored study reported, in 
press release form, that remdesivir use was associated with decreased hospital length of 
stay and “trended toward” improvement in survival (~30% decrease in the case-fatality 
rate).10,44 Shortly thereafter, the Food and Drug Administration released an Emergency 
Use Authorization (EUA) letter for remdesivir, making it the antiviral standard of care in 
COVID-19.45 Availability of the medication through the EUA, however, remains 
uncertain and further innovation is necessary. 
 
The originally intended enrollment of COVIDOSE-1 was 50 patients. After the 
enrollment of the thirty-second COVIDOSE patient, however, remdesivir became 
generally available in the United States under the EUA. To that point, COVIDOSE-1 was 
successful in identifying a practical and pharmacodynamically effective low-dose of 
tocilizumab – 40 milligrams – that represents one-half of tocilizumab’s smallest vial, 
making for convenient dosing and scalability. Rather than amend the COVIDOSE-1 
protocol to continue enrollment and seek determination of the minimum effective dose of 
tocilizumab while simultaneously dealing with heterogeneous data to make 
pharmacodynamic inferences, we opted instead to close enrollment of COVIDOSE-1 and 
pivot toward the question of whether low-dose tocilizumab truly has efficacy in COVID-
19 disease, particularly in combination with remdesivir. 
 
 
COVIDOSE-1 identified no concerning safety signals, and there was preliminary 
evidence for both pharmacodynamic and clinical efficacy of low-dose tocilizumab. Even 
in the absence of full accrual, there is equipoise for a randomized, controlled trial. In 
terms of the recently published COVID-GRAM risk score,46 Groups A and B appeared to 
have equivalent risks of decompensation, intensive care utilization, and COVID-19-
related death. Participants in Group A had median (IQR) score of 126.8  (113.5, 151.8) 
while those in Group B had median (IQR) score of 125.2 (102.3, 158.9). These are not 
differences significant enough to justify risk-stratification on the basis of Group A and 
Group B in a randomized, controlled trial. Moreover, COVID-GRAM has not been 
prospectively validated, let alone used for risk stratification purposes in a randomized, 
controlled trial. Finally, it is not clear at this time that a higher dose of tocilizumab is 
needed for patients at higher risk – that is one of the questions being addressed by 
COVIDOSE-2. 
 


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Endpoints 
1.3
1.3.1 The Need for Rapid Pharmacodynamic Endpoints 
COVID-19 disease is a rapidly changing landscape with acute pressures on the US 
healthcare system and individual patients. 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 natural history of COVID-19, we propose incorporation of 24-hour clinical 
and biochemical endpoints. 
 
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-6.17 Cytokines such as IL-6 are not 
universally available in clinical laboratories, however CRP tends to be. 
 
Prior work from the immunology literature demonstrates a strong connection 
between CRP elevation and the presence of IL-6 signaling,47 with IL-6-axis signaling 
serving as the predominant inducer of CRP expression.48 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 (likely due to increased free IL-6 serum concentrations after blockade 
of the IL-6R by tocilizumab),49 CRP declines, suggesting a decrease in effective IL-6 axis 
signaling. Within the context of COVID-19, IL-6 and CRP are correlated, as well.50 
 
1.3.3 CRP and Fever Briskly Respond to Tocilizumab in COVID-19 
Critically ill patients treated with tocilizumab 400mg experience rapid improvement in 
fever and CRP levels.18,51 Based upon our independent evaluation of previously published 
data and an estimated CRP half-life of 19 hours,18,52 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 g/mL within 24 hours 
of dose administration.37 Furthermore, all febrile patients with COVID-19 disease who 
were treated with tocilizumab 400mg experienced resolution of their fever within 24 
hours of dose administration (reconstituted data are available upon request).37 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. 
 
 
This prediction was verified in the COVIDOSE-1 trial, where our preliminary 
data show that approximately 85% and 75% of patients experienced CRP and fever 
decline, respectively, after a single dose of tocilizumab, and only 15% of patients 
required re-dosing. In comparison, a COVIDOSE-1-eligible retrospective control 
population, derived from a de-identified clinical data warehouse, experienced CRP and 
fever decline in 34% and 14% of cases, respectively. In only 12.5% (4 of 32 cases) was 
there discordance between CRP decline and clinical outcome, suggesting the ability of 
COVIDOSE-1’s inclusion and exclusion criteria to identify those patients likely to 
respond to therapy.  


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1.3.4 Justification for CRP 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.53-55 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 g/mL). Moreover, maximal AUROC for CRP from 
early studies of COVID-19 mortality is found at a CRP cutoff of 40 mg/L.50 
Preliminary multivariate regression analysis of clinical and laboratory factors 
suggests CRP is correlated with COVID-19 related morality (unpublished data). 
Validation of these findings at our institution and others using either a test data set or 
prospective cohort study has not yet been completed. The goal of the overarching 
treatment strategy discussed in 1.2.4 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. 
 
1.3.5 Incorporation of Ordinal Clinical Endpoints 
To date, the ideal clinical endpoints for COVID-19-related clinical trials remain 
unknown. Given the nature of this pandemic and the potential for health system collapse, 
therapeutic “success” and “failure” should account for individual patients’ outcomes – 
clinical improvement and survival – as well as outcomes with systems-level implications 
– avoidance of mechanical ventilation, length of hospital stay, and avoidance of 
mechanical ventilation. Under normal circumstances, time to recovery for an individual 
highly likely to recover in the absence of a therapeutic intervention may not be all that 
important a clinical outcome – but these are not normal times. Marginal improvements in 
hospital length of stay and clinical improvement may serve the function of reducing 
hospital crowding, limiting nosocomial transmission, and providing something of a 
backstop for re-opening strategies. 
 
Rather than target certain physiologic parameters in COVID-19, ordinal scales of 
clinical severity are the mainstay of COVID-19 clinical trials, imperfect though they may 
be. The ACTT study, an NIAID-sponsored double-blind, randomized, controlled trial of 
remdesivir in hospitalized patients with COVID-19 that thus far represents the gold 
standard in COVID-19 clinical trial design, incorporates an eight-point ordinal scale of 
disease severity ranging from not hospitalized and without limitation on activities (1) to 
death (8) in its secondary outcome measures, as defined by the first assessment on a 
given study date.10 “Successes” included: 1) Improvement in one category using the 
ordinal scale (as indicated by the secondary outcome measure of ‘time to improvement of 
one category’) and 2) improvement by two categories using the ordinal scale (as 
indicated by the secondary outcome measure of ‘time to improvement of two 
categories’). Time to recovery was defined as achieving one of the three statuses: 
“hospitalized without any requirement for medical care” (category 3), “not hospitalized 
with limitation on activities” (category 2), or “not hospitalized without limitation on 
activities” (category 1).10 
 


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In the Gilead-sponsored randomized, controlled trial of remdesivir, a seven-point 
ordinal scale was incorporated, ranging from death (1) to not hospitalized (7). 
Intermediate points on the scale were otherwise the same as in the ACTT trial. The 
primary outcome measure of this study was the odds ratio representing the odds of 
improvement in the ordinal scale on day 14.43 
 
Large randomized, controlled trials of anti-IL6 axis therapies incorporate a similar 
ordinal framework. The aforementioned COVACTA study utilized the same seven-point 
ordinal scale, with an ill-defined primary outcome measure described as “clinical status”. 
Derivative secondary outcome measures included time to clinical improvement, marked 
by National Early Warning Score of 2 or less, maintained for 48 hours and/or 
improvement of at least 2 categories relative to baseline when using the seven-point 
scale.56 
 
The Sanofi/Regeneron-sponsored adaptive phase 2/3 trial of sarilumab in 
COVID-19 incorporates this same seven-point ordinal scale, with time to improvement 
being the outcme measure and improvement being defined as a two-point improvement in 
the ordinal scale.20 Of note, the phase 3 portion of the sarilumab study will only proceed 
in a population of patients with critical COVID-19.20 
 
The CORIMUNO-TOCI trial incorporates the eleven-point World Health 
Organization (WHO) scale of COVID-19 disease progression, ranging from uninfected 
(0) to death (10).57 The WHO scale utilizes the physiologic parameter of P/F ratio (or 
SpO2/FiO2) as well as use of pressors to separate mechanically ventilated patients into 
three categories (categories 7-9). For the purposes of disease severity, CORIMUNO-
TOCI split its population into two populations on the basis of severity: Group 1, with a 
WHO score of 5 or less, corresponding to nasal cannula supplemental oxygen 
requirement, and Group 2, with a WHO score of 6 or more, corresponding to non-
invasive mechanical ventilation or high-flow nasal cannula.57 
 
Finally, the forthcoming REMDACTA trial studying the combination of 
remdesivir and tocilizumab in patients with severe/critical COVID-19 will incorporate 
the 7-category ordinal scale utilized in Gilead-sponsored studies of remdesivir. 
 
1.3.6 Selection of an Ordinal Scale Relevant to Tocilizumab 
COVIDOSE-2’s primary aim is to identify whether low-dose tocilizumab versus standard 
of care – which is expected to include remdesivir in the majority of patients – confers 
clinical benefit. Although not validated and developed empirically, the ordinal clinical 
scales used above are intuitive and can apply. The ordinal scale’s use as a primary 
outcome measure in the above clinical trials of IL-6 axis-directed therapies limits the 
ambiguity of cross-trial comparisons. The ordinal scale’s use as a primary outcome 
measure in studies of remdesivir may also aid in addressing the hypothesis that 
tocilizumab and remdesivir, by virtue of their different mechanisms of action, may be 
synergistic. Ordinal scales are appropriate for this study. 
 


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We have selected the same ordinal scale used in the Gilead remdesivir 
international trials, a seven-point ordinal scale: 1) Death; 2) Hospitalized, receiving 
invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) 
Hospitalized, receiving non-invasive mechanical ventilation or high flow oxygen devices; 
4) Hospitalized, requiring low-flow supplemental oxygen; 5) Hospitalized, not requiring 
supplemental oxygen but requiring ongoing medical care (COVID-19 related or 
otherwise); 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care 
(ed: used largely for infection control purposes); 7) Not hospitalized (ed: with or without 
limitation on activities and/or requiring home oxygen). 
 
Adapting the definition of clinical recovery from ACTT, our primary outcome 
measure will be the time to recovery as defined by achievement of status 6 or 7 on the 
seven-point ordinal clinical scale of COVID-19 severity, in line with the definition of 
clinical recovery used in the ACTT trial of remdesivir.10 
 
2 
OBJECTIVES AND HYPOTHESES 
 
Primary Objective and Hypothesis 
2.1
 
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: We 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: We hypothesize that low-dose tocilizumab is near-equivalent to 
high-dose tocilizumab (400 mg or 8 mg/kg) in reducing the time to clinical 
recovery in hospitalized, non-invasively ventilated patients with COVID-19 
pneumonitis and hyperinflammation. 
 
 
 
Secondary Objectives and Hypotheses 
2.2
Sub-Study A 
Secondary Objective A1: To establish whether low-dose tocilizumab increases 
the probability of clinical recovery at seven days in COVID-19 pneumonitis. 
 


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Secondary Hypothesis A1: Low-dose tocilizumab increases the probability of 
clinical recovery at seven days in hospitalized, non-invasively ventilated patients 
with COVID-19 pneumonitis and hyperinflammation when compared to a 
tocilizumab-free standard of care. 
 
Secondary Objective A2: To establish whether low-dose tocilizumab decreases 
signs, symptoms, and laboratory evidence of COVID-19 hyperinflammation. 
 
Secondary Hypothesis A2: Low-dose tocilizumab increases the probability of 
fever resolution and CRP decline consistent with IL-6 signaling inhibition at 24 
hours when compared to a tocilizumab-free standard of care. 
 
Sub-Study B 
Secondary Objective B1: To establish whether low-dose tocilizumab is nearly 
equivalent to high-dose tocilizumab  in increasing the probability of clinical 
recovery at seven days in COVID-19 pneumonitis. 
 
Secondary Hypothesis B1: Low-dose tocilizumab is nearly equivalent to high-
dose tocilizumab in increasing the probability of clinical recovery at seven days in 
hospitalized, non-invasively ventilated patients with COVID-19 pneumonitis and 
hyperinflammation. 
 
Secondary Objective B2: To establish whether low-dose tocilizumab is nearly 
equivalent to high-dose tocilizumab in decreasing signs, symptoms, and 
laboratory evidence of COVID-19 hyperinflammation. 
 
Secondary Hypothesis B2: Low-dose tocilizumab is nearly equivalent to high-
dose tocilizumab in increasing the probability of fever resolution and CRP decline 
consistent with IL-6 signaling inhibition at 24 hours. 
3 
SITE SELECTION 
We intend to conduct this trial in collaboration with other medical centers within the 
United States, as well as internationally. We will amend the protocol to add outside sites 
as they are defined. 
4 
PATIENT SELECTION  
 
Number of Subjects 
4.1
We anticipate maximum enrollment of 332 total patients from various medical 
institutions during this adaptive clinical trial, distributed equally between the two sub-
studies. Information published while the trial is being conducted may lead to a firmer 
definition of “standard of care”. In this case, one of the two sub-studies will be prioritized 
and meet accrual target while the other may not. 
 
 
Inclusion Criteria 
4.2
● Adults ≥ 18 years of age 
● Approval from the patient’s primary inpatient service 


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● Hospitalized  
● 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). 
● CRP ≥ 40mg/L 
 
 
Exclusion Criteria 
4.3
 
● Concurrent use of invasive mechanical ventilation or helmet ventilation 
● Concurrent use of vasopressor or inotropic medications 
● Concurrent receipt of convalescent plasma therapy or in the 30 days preceding 
enrollment 
● Previous receipt of tocilizumab or another anti-IL6R or IL-6 inhibitor in the year 
prior. 
● Known history of hypersensitivity to tocilizumab. 
● 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 Bruton’s tyrosine kinase-targeted agent, which include 
the following: 
● 
Acalabrutinib 
● 
Ibrutinib 
● 
Zanubrutinib 
● On active therapy with a JAK2-targeted agent, which include the following: 
● 
Tofacitinib 
● 
Baricitinib 
● 
Upadacitinib  
● 
Ruxolitinib 
● Any of the following biologic immunosuppressive agent (and any biosimilar 
versions thereof) administered in the past 6 months or less:: 
● 
Abatacept 
● 
Adalimumab 
● 
Alemtuzumab 
● 
Atezolizumab 
● 
Belimumab 
● 
Blinatumomab 
● 
Brentuximab 
● 
Certolizumab 


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● 
Daratumumab 
● 
Durvalumab 
● 
Eculizumab 
● 
Elotuzumab 
● 
Etanercept 
● 
Gemtuzumab 
● 
Golimumab 
● 
Ibritumomab 
● 
Infliximab 
● 
Inotuzumab 
● 
Ipilimumab 
● 
Ixekizumab 
● 
Moxetumomab 
● 
Nivolumab 
● 
Obinutuzumab 
● 
Ocrelizumab 
● 
Ofatumumab 
● 
Pembrolizumab 
● 
Polatuzumab 
● 
Rituximab 
● 
Rituximab 
● 
Sarilumab 
● 
Secukinumab 
● 
Tocilizumab 
● 
Tositumumab 
● 
Tremelimumab 
● 
Urelumab 
● 
Ustekinumab 
● History of bone marrow transplantation (including chimeric antigen receptor T-
cell) or solid organ transplant 
● Known history of Hepatitis B or Hepatitis C (patients who have completed 
curative-intent anti-HCV treatments are not excluded from trial) 
● Positive result on hepatitis B or C screening 
● Known history of mycobacterium tuberculosis infection at risk for reactivation 
● Known history of gastrointestinal perforation 
● Known history of or active diverticulitis 
● Multi-organ failure as determined by primary treating physicians 
● Any other documented serious, active infection besides COVID-19 – including 
but not limited to: lobar pneumonia consistent with bacterial infection, 
bacteremia, culture-negative endocarditis, or current mycobacterial infection – at 
the discretion of primary treating physicians 
● Pregnant patients or nursing mothers 


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● CRP < 40 mg/L 
 
 
 
Gender, Age, Racial and Ethnic Origin of Subjects 
4.4
 
Men and women of all races and ethnic groups are eligible for this trial. 
 
5 
REGISTRATION AND DATA COLLECTION/MANAGEMENT 
 
General Guidelines 
5.1
Patients will be identified as potential participants in this clinical trial by in silico 
screening of patients via electronic medical records (EMRs) when available. Primary 
teams and emergency department teams are encouraged to securely send medical record 
numbers of potentially eligible patients to study investigators at their respective 
institutions. When EMR not available, we recommend primary inpatient treating health 
care teams or emergency department teams make the study investigators aware of eligible 
patients.   
 
Prior to approaching the patient for recruitment, we will approach the patient’s 
treating team for permission and to discuss the standard of care (SOC) treatment plan as 
well as the study design. As indicated in the study schematic on page 4, the study consists 
two sub-studies that each include 3 arms. 
 
Sub-study A:         
 SOC (routine treatment plan 
includes no tocilizumab) 
 Tocilizumab 40mg 
 Tocilizumab 120mg 
Sub-study B: 
 SOC (routine treatment plan includes 
tocilizumab 400mg or 8mg/kg) 
 Tocilizumab 40mg 
 Tocilizumab 120mg 
 
Sub-study assignment for each subject is done in collaboration with the patient’s 
treating physican team. The treating team will be given the option to choose which sub-
study might be most appropriate for their patient based on their intended treatment plan. 
For example, if the team did not intend to use tocilizumab as part of their treatment plan, 
they would likely choose Sub-study A. However, if the intended treatment plan was to 
include tocilizumab (at the emerging Covid-19 standard of care doses of 400mg or 
8mg/kg), then they would likely choose sub-study B. Once the sub study has been 
assigned, randomization occurs (1:1:1) within the respective sub study. 
 
Before any study-specific evaluations are performed, all patients must have given 
informed consent for the study. Patients must meet all of the eligibility requirements 
listed in Section 3.0. Eligible patients will be entered into the University of Chicago’s 
REDCap database used for both registration and data collection.58 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. 
 


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(1) Patient screened: by investigators electronically via EMR or after primary 
inpatient or emergency department teams make investigators aware of patient 
eligibility 
(2) Sub-study designation: Study investigators confirm with primary team the 
decision regarding appropriate sub-study for patient.  
(3) Reciept of Informed consent: Informed consent from patient received and 
confirmed  
(4) Randomization: Pre-designated study investigator(s) will perform the 
randomization within the aforementioned sub-study to determine which dose 
of tocilizumab (if any) patient will receive – and relay this information to 
primary clinical team in real time (as to avoid delay of drug administration).  
(5) Recording in REDCap: Patient eligibility and patient information recorded 
into REDCap database through the use of online REDCap report 
 
 
Informed Consent Process 
5.2
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, using exclusively electronic means to obtain consent: 
 
Electronic consent: 
1. Screening via electronic medical records and/or collaboration via primary clinical 
team regarding patient eligibility 
2. Study investigators confirm with primary team the sub-study designation the 
primary team feels appropriate for patient 
3. Patient called by study investigators to determine if patient willing to discuss 
research opportunity and willing to receive consent via email. If the patient does 
not have access to email at the time, a paper form can be delivered directly to the 
subject. 
4. Discussion between study investigators and patient while reading through 
consent.  
5. If patient agrees and willing to participate, the subject will be asked to verify 
identity by providing their date of birth, and last four digits of social, which will 
be verified against records in Epic. We will then obtain written consent via 
electronic signature through RedCAP. 
Paper Consent: 
If consent signature through RedCAP is not possible, a written consent via signed paper 
copy will be obtained, using safe practices as determined by individual institutional 
policies. 
  
Proxy Consent 
Electronic Consent: 


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In the event of the patient’s inability to provide informed consent for the study, an 
appropriate surrogate decision-maker (e.g., next of kin or legally authorized 
representative) may make the consent decision on the patient’s behalf. This will be 
performed in the following manner: 
1. Screening via electronic medical records and/or collaboration via primary clinical 
team regarding patient eligibility 
2. Study investigators confirm with primary team the sub-study designation the 
primary team feels appropriate for patient 
3. Clarification of patient’s consentability. 
4. If patient cannot be consented, patient’s surrogate decision-maker is called by 
study investigators to discuss further.   
5. On video call, surrogate decision-maker will verify his/hers/their identity by 
showing  ID during video conference (surrogate physically shows their ID 
card/license)  
6. Once surrogate decision-maker identity verified, study investigator will discuss 
surrogate decision-maker’s willingness to to discuss research opportunity and 
receive consent via email. 
7. Surrogate decision-maker sent email with consent form, with appropriate copying 
of the patient if email is available. 
8. Discussion between study investigators and surrogate decision-maker while 
reading through consent.  
9. If surrogate decision-maker agrees and is willing to provide informed consent for 
the patient on his/her behalf, we will obtain written consent via electronic 
signature through RedCAP.  
 
Paper Consent: 
If consent signature through RedCAP is not possible, a written consent via signed paper 
copy will be obtained either in person or via traditional mail. A conversation will take 
place between a member of the study team and the subject’s surrogate, explaining the 
study and answering any questions (either in person, over the phone or over video call) 
before signing the consent form. The proxy will be provided with a final signed copy of 
the consent (if traditional mail is used, the proxy will mail the signed copy of the consent 
to the study team, who will sign and mail a copy back to the proxy). 
 
 
 
Exemption from Investigational New Drug Application 
5.3
Investigational New Drug (IND) is not required at this time, on the basis of September 
2013 Food and Drug Administration Guidance 59, 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. 


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● 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% 8. 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 doses under 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. 
 
Tocilizumab is currently used off-label around the world for management of COVID-
19 pneumonitis, including domestically, in Europe, and in Asia. At present time, 
however, there is no level 1 evidence of tocilizumab’s benefit on either time to clinical 
recovery or overall mortality in COVID-19 pneumonitis. It is possible that randomized 
controlled trial evidence reported in the near future will show that tocilizumab is better 
than no additional drug therapy. 
 
The response of investigators to new tocilizumab-related evidence and government 
action should be proportional to the strength of evidence. In the event of EMA or FDA 
approval of tocilizumab for the treatment of COVID-19 pneumonitis, study investigators 
would suspend enrollment and amend the trial protocol. Note that Emergency Use 
Authorization (EUA) definitionally does not require the same level of evidence and/or 
quality control as a normal, “peacetime” FDA approval. As such, there remains 
ambiguity as to whether the drug is truly beneficial even following EUA. Given this 
ambiguity, therefore, the presence of an EUA for tocilizumab will not lead to trial 
suspension and protocol amendment. 
 
 
Registration Process 
5.4
To complete the registration process, a member of the study team will: 
 
1.) Confirm with treating physicians the assignment for sub-study (A or B) the 
treating clinical team feels appropriate for patient. This will essentially designate 
whether the patient receives no tocilizumab (sub-study A) or high-dose 
tocilizumab (sub-study B) if randomized to the standard of care arm. 
2.) Assign the patient a study number coded to the study site and sub-study (e.g. first 
University of Chicago patient on sub-study A would be UC-A-001) 
3.) Register the patient on the study (and relevant sub-study) 


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4.) Randomize the patient to low-dose tocilizumab 40mg, low-dose tocilizumab 
120mg, or standard of care arm. 
5.) Record the values of pre-treatment laboratory studies as below. 
 
When registering a subject, the following must occur: 
● The patient must have signed the consent form (or his/her proxy/surrogate/legally 
authorized representative will have completed the electronic consent form via 
REDCap) or evidence of a signed paper consent. 
● 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 the secure, password protected, and regularly 
backed up REDCap clinical trials database. All data will be entered into the REDCap 
database. Collaborating institutions will complete daily summaries for the trial using the 
RedCAP secure web survey interface, thereby ascribing the same level of data protection 
and convenience to trial form completion that will be used in the consent process. Data 
will be stored in RedCap using the patient-study number. 
 
 
Randomization and Stratification 
5.5
The patient’s primary treating team will determine which of the two sub-studies in which 
to enroll the patient, Sub-study A or Sub-study B.  Following the determination of sub-
study assignment, all patients will be randomized to one of three respective arms in 1:1:1 
ratio. 
 
Sub study A:         
 SOC (routine treatment plan 
includes no toci) 
 Tocilizumab 40mg 
 Tocilizumab 120mg 
Sub study B: 
 SOC (routine treatment plan includes toci 
400mg or 8mg/kg) 
 Tocilizumab 40mg 
 Tocilizumab 120mg 
 
 
 
Randomizations will be generated by the study statistician using the method of 
permuted blocks, stratified by 1) the presence or absence of expanded use access (EUA) 
remdesivir and 2) the presence or absence of systemic corticosteroid administration (at a 
dose higher than the patient’s pre-hospitalization baseline steroid use) in order to achieve 
overall balance between the arms in terms of their exposures to presumed efficacious 
antivirals and baseline, pre-treatment severity. Randomization will be implemented using 
the randomization module present in the REDCap software suite and readily available to 
study investigators who are participating in the consenting process. 
 
 
Patients will remain on their allocated arm for the study’s duration. Clinical 
decompensation to the point of requiring additional use of IV tocilizumab or any other 
anti-inflammatory monoclonal antibody (e.g., siltuximab, anakinra, sarilumab) by 


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primary team for therapy of hyperinflammation secondary to COVID-19 will qualify as a 
failure. 
 
 
Patients and their primary teams will be notified by investigators of the patient’s 
randomized group assignment within 2 hours of randomization, with the patient receiving 
his/her baseline CRP laboratory draw and tocilizumab dose (if applicable) on the same 
calendar day. Delays in treatment initiation – for example, due to a patient no longer 
being eligible for study or withdrawing consent – should be discussed with the Principal 
Investigator. 
 
 
Data to Collect 
5.6
The following baseline clinical variables will be collected and recorded on the Eligibility 
and Registration Form: 
- 
Sub-study assignment 
- 
Age 
- 
Sex 
- 
Race and Ethnicity, self-identified 
- 
COVID-19-related medications (including antiviral, anti-inflammatory, and 
immunomodulatory drugs) 
- 
Complete medication list (pre-hospitalization and during hospitalization) 
- 
Complete medical history, with particular attention to the following medical 
comorbidities: 
● 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 
● Prior to admission 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 
● Baseline supplemental oxygen required (in 24hrs prior to first tocilizumab 
dose) >6L/min Nasal cannula 
 


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The following laboratory data are required to be collected within 24 hours prior to 
tocilizumab administration will be reviewed and tracked by investigators. The following 
data are required for eligibility, safety and clinical management purposes: 
- 
White blood cell count 
- 
Absolute lymphocyte count (ALC) 
- 
Absolute neutrophil count (ANC) 
- 
Hemoglobin 
- 
Platelets 
- 
AST (SGOT) 
- 
ALT (SGPT) 
- 
BUN 
- 
Creatinine  
The following laboratory data are recommended to be collected within 24 hours prior to 
tocilizumab administration will be reviewed and tracked by investigators. The following 
data are recommended for clinical management purposes and secondary analysis:  
- 
D-dimer 
- 
Fibrinogen 
- 
Lactic dehydrogenase (LDH) 
- 
Westergren sedimentation rate (ESR) 
- 
Ferritin 
- 
IL-6 
- 
Triglycerides 
- 
High-sensitivity troponin 
 
The following laboratory data is required to be collected within 12 hours prior to 
tocilizumab administration to determine eligibility and will be reviewed and tracked by 
investigators: 
- 
C-reactive protein (CRP) 
 
In addition, all patients are required to have the following baseline laboratory data 
collected in the 2 hours prior to administration of tocilizumab. It will be used for 
assessment of pharmacodynamic response and may be used for clinical management: 
- 
CRP 
 
For the first post-tocilizumab follow-up, investigators require the following laboratory 
be performed at 27 +/- 3 hours following tocilizumab administration for assessment of 
pharmacodynamic response and may be used for clinical management: 
- 
CRP 
Investigators strongly recommend the following laboratory study to be collected at 24-
hour intervals during the patient’s hospitalization (or with clinical decompensation) for 
the purposes of clinical management, safety, and consequently adverse event 
reporting: 
- 
White blood cell count 


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- 
Absolute lymphocyte count (ALC) 
- 
Absolute neutrophil count (ANC) 
- 
Hemoglobin 
- 
Platelets 
- 
AST (SGOT) 
- 
ALT (SGPT) 
- 
BUN 
- 
Creatinine  
Regarding these aforementioned labs: no labs will be drawn solely for research purposes 
if not available through clinical care (even if denoted as “required”). 
 
Optional Sample 
For the purposes of secondary analysis and identification of predictors of tocilizumab 
response, University of Chicago Medicine patients will have the option (as a separate line 
item in the consent document) to allow investigators to use leftovers from tubes of blood 
drawn for clinical tests that would otherwise be discarded. This will apply to any blood 
collected during that respective hospital stay as well as up to 1 year after study 
enrollment. The following correlates will be analyzed: 
- 
Cytokine analysis 
- 
Measurement of anti-SARS-CoV-2 antibodies 
All labs and tocilizumab doses while inpatient will be collected on the Labs and 
Tocilizumab Administration Form, which will be made available to collaborating 
institutions in the RedCAP web interface. 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, which will be made available to collaborating institutions in 
the RedCAP web interface. If the patient subsequently improves and no longer requires 
the critical care parameter(s),  please complete a second Patient Change in Clinical Status 
Labs Form, which will be made available to collaborating institutions in the RedCAP 
web interface. For every dose of tocilizumab administered, please record the details (dose 
amount, date, time, etc.) on the Labs and Tocilizumab Administration Form, which will 
be made available to collaborating institutions in the RedCAP web interface. 
 
 
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, which will be made available to 
collaborating institutions in the RedCAP web interface. 
 
 
On a daily basis the clinical status of the patient will be assessed by CRC/clinicians. 
Based on the assessment and documentation of the clinical team of record caring for the 
patient, the ordinal score will be assigned by study team. Key phrases to distinguish 
between a category 5 patient (“Hospitalized, not requiring supplemental oxygen but 
requiring ongoing medical care (COVID-19 related or otherwise)”) – and a category 6 


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patient (“Hospitalized, not requiring supplemental oxygen or ongoing medical care”) 
would include the following (or approximate versions thereof): “Awaiting disposition”, 
“pending placement”, “awaiting transport”, “awaiting negative test for placement”, or 
“requires negative test for dialysis center”. Any patients who do not meet these would 
need to be adjudicated by DMC in order to be made category 6. Patients who are 
hospitalized will be assumed to be category 5 unless proven otherwise. 
 
 
 
Data Submission 
5.7
All forms collected for the trial will be entered into the REDCap database. 
6 
DRUG ADMINISTRATION  
Treatment will be administered to the patient on the day of their enrollment and while 
they are admitted. Tocilizumab is commercially available and will not be provided by the 
study. 
 
In sub-study A, therapy will consist of tocilizumab administered at doses of 40mg 
(low-dose tocilizumab arm 1) or120mg (low-dose tocilizumab arm 2), or no tocilizumab 
at all. In sub-study B, therapy will consist of tocilizumab administered at doses of 40mg 
(low-dose tocilizumab arm 1), 120mg (low-dose tocilizumab arm 2), or 400 mg will be 
utilized, as discussed in sections 4.1 and 4.5. 
 
 
Duration of Study 
6.1
Therapy with a one-time dose of tocilizumab will proceed unless one of the following 
events occurs: 
1. Treating physician determination prior to dose administration that the risks 
or downsides of tocilizumab administration outweigh the potential 
benefits. 
2. Patient withdraws consent prior to dose administration 
3. Patient is withdrawn from the study prior to dose administration at the 
discretion of the investigator or the patient’s attending physician. 
Patients will be followed for overall survival for 28 days after tocilizumab administration 
or liberation from mechanical ventilation, whichever occurs latest. 
 
 
Amount of Treatment 
6.2
Patients will receive only one on-protocol dose of tocilizumab. Patients will not be re-
dosed as part of the trial protocol regardless of whether they have improvement in their 
biochemical and/or clinical parameters. If randomized to either of the low-dose 
tocilizumab arms of the study, the patient remains eligible to receive high-dose 
tocilizumab (400mg or 8mg/kg) at the discretion of primary treating physicians. 
 


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7 
STUDY ASSESSMENTS 
 
Pretreatment Evaluation 
7.1
The following laboratory data are required to be collected within 24 hours prior to 
tocilizumab administration will be reviewed and tracked by investigators. The following 
data are required for eligibility, safety and clinical management purposes: 
- 
White blood cell count 
- 
Absolute lymphocyte count (ALC) 
- 
Absolute neutrophil count (ANC) 
- 
Hemoglobin 
- 
Platelets 
- 
AST (SGOT) 
- 
ALT (SGPT) 
- 
Blood urea nitrogen 
- 
Creatinine  
- 
Chest radiograph (CXR) (portable single-view is acceptable) or computed 
tomography (CT) of chest 
The following laboratory data are recommended to be collected within 24 hours prior to 
tocilizumab administration will be reviewed and tracked by investigators. The following 
data are recommended for clinical management and secondary analysis purposes:  
- 
D-dimer 
- 
Fibrinogen 
- 
Lactic dehydrogenase (LDH) 
- 
Westergren sedimentation rate (ESR) 
- 
Ferritin 
- 
IL-6 
- 
Triglycerides 
- 
High-sensitivity troponin 
 
The following laboratory data is required to be collected within 12 hours prior to 
tocilizumab administration to determine eligibility and will be reviewed and tracked by 
investigators: 
- 
C-reactive protein (CRP) 
 
The patient’s score on the seven-point ordinal clinical scale (described in section 1.3.6) is 
required at the following timepoints: 
- 
Study enrollment 
- 
Randomization 
 
 
On-Study Evaluation 
7.2
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 


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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-19, and CT 
scans or chest x-rays as necessary for routine care. 
 
Patients will have the following laboratory study is required to be collected in the 2 
hours prior to administration of tocilizumab and this value will be deemed the pre-
tocilizumab or baseline value. It will be used for assessment of pharmacodynamic 
response and may be used for clinical management: 
- 
CRP 
 
For the first post-tocilizumab follow-up, investigators require the following laboratory 
be performed at 27 +/- 3 hours following tocilizumab administration for assessment of 
pharmacodynamic response and may be used for clinical management: 
- 
CRP 
The patient’s score on the seven-point ordinal clinical scale (described in section 1.3.6) is 
required at the following timepoints: 
- 
Tocilizumab administration (if applicable) 
- 
Daily during patient’s hospitalization 
- 
28 days following randomization and tocilizumab administration 
 
In line with standard of care clinical management of COVID-19 patients, investigators 
strongly recommend the following laboratory study to be collected at 24-hour intervals 
during the patient’s hospitalization (or with clinical decompensation) for the purposes of 
clinical management, safety, and consequently adverse event reporting: 
- 
White blood cell count 
- 
Absolute lymphocyte count (ALC) 
- 
Absolute neutrophil count (ANC) 
- 
Hemoglobin 
- 
Platelets 
- 
AST (SGOT) 
- 
ALT (SGPT) 
- 
BUN 
- 
Creatinine 
 
For the purposes of secondary analysis and identification of predictors of tocilizumab 
response, University of Chicago Medicine patients will have the option (as a separate line 
item in the consent document) to allow investigators to use leftovers from tubes of blood 
drawn for clinical tests that would otherwise be discarded. This will apply to any blood 
collected during that respective hospital stay as well as up to 1 year after study 
enrollment. The following correlates will be analyzed: 
- 
Cytokine analysis 
- 
Measurement of anti-SARS-CoV-2 antibodies 


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Collection and Handling of Specimens: 
Clinical labs will be drawn and processed normally as per standard of care. No additional 
labs will be drawn solely for research purposes if not collected as part of clinical care. 
 
Labs collected for secondary analysis will be stored in the University of Chicago Human 
Immune Monitoring Core Facility.  Samples will be labeled with a unique study patient 
identifier, which will be linked to the patient’s identifying information in a secure 
RedCap database.  Barcodes reflecting the unique study patient identifier may be used on 
some blood samples to automate sample processing.  There will not be any other 
identifying PHI on the stored samples.  Blood samples will be stored at or below –
80°C.  After the study has been completed, samples will be de-identified and the linkage 
between the unique patient study ID and the patient’s identifying information on RedCap 
will be removed.  De-identified study samples may be stored indefinitely. 
 
 
 
 
 
Off Study Assessments 
7.3
Enrolled patients will be followed throughout their hospital course, and for survival for 
28 days after receiving the first dose of tocilizumab. 
 
 
Study Calendar 
7.4
7.4.1 Overall Study Calendar 
 
 
Eligibility 
Assessment 
 
Consent and 
Study 
Enrollment 
Randomization 
Pre-
Tocilizumab 
Assessment 
Post-
Tocilizumab 
Assessment, 
27 +/- 3 hours 
Daily 
assessment after 
randomization, 
while 
hospitalized 
Patient Intubated 
OR  
Patient transferred 
to ICU 
OR  
Patient change in 
clinical status 
Patient 
Extubated 
OR  
Patient 
transferred from 
ICU 
28 Days 
following 
tocilizumab  
 
Written 
Informed 
Consent 
 
X (require) 
 
 
 
 
 
 
 
Lab set 1a 
X (require) 
 
 
 
X 
(recommend) 
X 
(recommend) 
X (recommend) 
X 
(recommend) 
 
Lab set 2b 
X (require) 
 
 
X (require) 
X (require) 
X 
(recommend) 
X (recommend) 
X 
(recommend) 
 
Lab set 3c 
 
X 
(recommend) 
 
 
X 
(recommend) 
 
X (recommend) 
X 
(recommend) 
 
Imagingd 
X (require) 
 
 
 
 
 
X (recommend) 
X 
(recommend) 
 
Clinical 
Ordinal 
Status 
Assessmente 
X (require) 
X (require) 
X (require) 
X (require) 
X (require) 
X (require) 
X (require) 
X (require) 
X (require) 
Eligibility 
Confirmation 
X (require) 
X (require) 
X (require) 
X (require) 
 
 
 
 
 
 
a Set 1: WBC, ALC, ANC, hemoglobin, platelets, AST, ALT, BUN, Creatinine. 
b Set 2: CRP. 
c Set 3: D-dimer, fibrinogen, LDH, ESR, ferritin, IL-6, triglycerides, high-sensitivity troponin.  
d For baseline assessment, imaging study should be completed within 48 hours of initial tocilizumab administration. 
e Seven-point ordinal clinical scale as described in section 1.3.6. For each calendar day that the patient is enrolled on 
study, the patient’s worst ordinal clinical status should be recorded and submitted along with all relevant study records. 
a, b, c, d No imaging or labs will be conducted solely for research purposes if not conducted as part of clinical care. 


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8 
SAFETY  
 
Risks  
8.1
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 
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 
this dose to a reduced dose, there is a risk that the administration of reduced dose may be 
associated with poorer clinical outcomes for patients. Patients will be informed of this 
possibility. 
 
Side effects and theoretical risks associated with tocilizumab include:  
- 
Serious infections, including but not limited to: 
- 
Opportunistic infections such as tuberculosis, Cryptococcus, aspergillosis, 
candidiasis, and pneumocystis 
- 
Secondary bacterial infection such as ventilator-associated pneumonia (if 
later requiring mechanical ventilation), hospital-acquired pneumonia, 
bloodstream infection, urinary tract infection, cellulitis, herpes zoster, 
gastrointestinal infection, diverticulitis, septic arthritis 
- 
Gastrointestinal perforation 
- 
Hypersensitivity reaction, including anaphylaxis and death 
- 
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 the adaptive antiviral immune system, resulting in progression of 
COVID-19 
9 
MEASUREMENT OF EFFECT  
 
Time to Recovery 
9.1
Day of recovery is defined as the first day on which the patient achieves one of the 
following two categories from the 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. 
 


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Achievement of Recovery, 7 days 
9.2
This will be defined as the percentage of patients in a given arm of the study achieving 
one of the above two categories on the ordinal scale on day 7 after randomization. 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. 
 
 
Overall Survival, 28 days 
9.3
This will be defined as the percentage of patients in a given arm of the study who are 
alive 28 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. 
 
 
Hospital LOS 
9.4
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. 
 
 
 
Clinical Response – Rate of Non-Elective Invasive Mechanical Ventilation 
9.5
(RNEIMV) 
This will be a binary outcome defined as worsening COVID-19 disease resulting in the 
use of non-elective invasive mechanical ventilation during the course of the patient’s 
COVID-19 infection. 
 
 
Clinical Response – Duration of Non-Elective Invasive Mechanical 
9.6
ventilation (DNEIMV) 
This will be a continuous outcome defined by the amount of time between initiation and 
cessation of non-elective non-elective invasive mechanical ventilation.  
 
 
Clinical Response – Time to Non-Elective Invasive Mechanical ventilation 
9.7
(TNEIMV) 
This will be a continuous outcome defined by the amount of time between randomization 
and the initiation of non-elective invasive mechanical ventilation. This will be treated as a 
time-to-event with possible censoring. 
 
 
Clinical Response – Rate of Vasopressor/Inotrope Utilization (RVIU) 
9.8
This will be a binary outcome defined as utilization of any vasopressor or inotropic 
medication. 
 
 
Clinical Response – Duration of Vasopressor/Inotrope Utilization (DVIU) 
9.9
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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 Clinical Response – Time to Vasopressor/Inotrope Utilization (TVIU) 
9.10
This will be a continuous outcome defined by the amount of time between randomization 
and the initiation of any vasopressor or inotropic medication. This will be treated as a 
time-to-event with possible censoring. 
 
 Clinical Response – Duration of Increased Supplemental Oxygen from 
9.11
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. 
 
 Biochemical Response - C-reactive Protein Response Rate 
9.12
This will be a binary outcome defined as the presence or absence of a decline in CRP of ≥ 
25% from baseline CRP in the 27 +/- 3 hours after tocilizumab administration, as 
compared to pre-treatment baseline. 
 
 Safety – Rate of Secondary Infection 
9.13
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. 
10 STATISTICAL PLAN AND CONSIDERATIONS (10) 
 Sample Size Determination 
10.1
 
The primary endpoint is time to recovery (TTR) as defined in section 8.1 above.  Each 
subject will be followed for a minimum of 28 days. As in the ACTT-1 analysis,10 patients 
who die or are discharged to hospice will be censored as of day 28 (or the longest follow-
up time if >28 days). As a result patients censored on day >28 will reflect both any who 
did not recover as well as those who died. Kaplan-Meier curves will be generated and 
compared between the treatment arms using a logrank test stratified by remdesivir use 
and clinical status at enrollment as determined on the seven-point clinical ordinal scale.60 
Separate analyses will be performed for the two sub-studies, i.e., those whose standard of 
care includes no tocilizumab (superiority study) and those whose standard of care 
includes 400mg or 8mg/kg tocilizumab (near-equivalence study). 
 
For the superiority study, patients will be randomized in a 1:1:1 ratio to 0mg, 40mg, or 
120mg tociluzmab. The initial analysis will pool the 40mg and 120mg dose groups and 
contrast their TTR with the control arm (0mg). Sample size calculations are based on the 
results of the ACTT-1 trial. We assume that in our study population 25%, 65%, and 10% 
will fall into the risk strata depicted in Figures 2B, 2C, and 2D of the published results, 
corresponding to, respectively, patients not receiving supplemental oxygen at enrollment, 
patient receiving low-flow supplemental oxygen at enrollment, and patients receiving 
high-flow oxygen or noninvasive mechanical ventilation at enrollment.10 The median 


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TTRs in the corresponding placebo and remdesivir groups were 6 vs. 5 days, 9 vs. 7 days, 
and 22 vs. 16 days, respectively. Assuming the distributions are roughly symmetrical, this 
implies a median/mean TTR for the non-remdesivir-treated, control arm patients in our 
study of 0.25(6)+0.65(9)+0.10(22)=9.6 days. For the remdesivir-treated subgroup, the 
median/mean will be assumed to be 0.25(5)+0.65(7) +0.10(16)=7.4 days. Finally, we 
predict 85% of our population will receive remdesivir and 15% will not, giving an overall 
median/mean TTR in the control arm of 0.85(7.4)+0.15(9.6)=7.7 days. Since patients will 
be assessed daily, we will assume a median control TTR of 8 days. In order to have 80% 
power to detect a reduction in the median TTR of 3 days with 40/120mg tocilizumab 
(rate ratio for recovery of 1.60), a sample size of 132 patients is required (44 per arm), 
based on a one-sided test at the alpha=0.05 signficance level.  
 
In the near-equivalence study, patients will be randomized in a 1:1:1 ratio to 40mg, 
120mg, or higher-dose (400mg or 8mg/kg) tocilizumab. Here the same sample size of 
132 patients will provide 80% power to determine whether the true TTR under the 400mg 
dose is 3 days less than that for the pooled 40/120mg arms. It is recognized that our 
sample size will not be sufficient to formally establish non-inferiority of the lower 
doses—this would entail a much larger study. Thus the secondary endpoints—in 
particular, rate of secondary infection and toxicity as well as CRP as an efficacy 
biomarker—will also have an important role. As noted by Tannock et al, “there is usually 
minimal consideration of other measures of benefit due to ALT, such as reduced drug 
exposure and toxicity, or reduced cost leading to greater access. Non-inferiority trials can 
‘fail’, because the sample size is too small to provide the pre-specified level of statistical 
confidence for non-inferiority, even if the best estimates of efficacy of ALT and new-
SOC are similar.”61 (Here “ALT” would correspond to the lower dose levels and “new-
SOC” to the 400mg dose.) Thus the totality of evidence, including the estimated 
difference in TTR afforded by the higher dose together with its 95% confidence interval, 
the effects on secondary endpoints, toxicity, and the reduced cost and wider accessibility 
of the lower dose levels will be considered in the interpretation of the results. 
 
 Definition of Evaluable Patients 
10.2
 
Patients are considered eligible for analysis if they have enrolled in the study and been 
randomized. 
 
 Statistical Methods 
10.3
 
Time to recovery (TTR) will be estimated by the Kaplan-Meier method and compared 
between groups using a stratified logrank test.60 As noted above, patients who die or 
transferred to hospice will be censored at 28 days—effectively, their TTR is infinity. A 
Cox proportional hazards regression model will be fit to estimate the rate ratio for 
recovery and its 95% confidence interval and to examine and adjust for the effects of 
covariates (remdesivir use, age, co-morbidities, and ordinal category status at the time of 
randomization).62 The Cox procedure will also be used to model the dose-response 
relationship between TTR and tocilizumab dose. If the proportional hazards assumption 


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is violated,63 as an alternative summary metric we will compare restricted mean survival 
times.64,65 
 
Secondary time-to-event endpoints (overall survival and 28-day survival, 7-day TTR, 
length of hospital stay, TNEIMV, and TVIU) will calculated by the Kaplan-Meier  
method and compared between groups using a log-rank test.60 In the analysis of hospital 
length of stay (LOS), patients who die or are discharged to hospice will be analyzed in 
two ways: (i) censored as of the date of death/discharge to hospice, and (ii) scored higher 
than the maximum LOS observed with the data analyzed using nonparametric, rank-
based tests. Binary outcomes (Tmax response, RNEIMV, RVIU, CRP response, and 
secondary infection) will be compared between groups using chi-square and Fisher exact 
tests as well as logistic regression modeling to estimate odds ratios and to assess and 
adjust for the effects of covariates. DNEIMV and DVIU among those requiring 
ventilation and vasopressor/inotrope utilization, respectively, will be compared using 
two-sample t-tests. Since these comparisons condition on having had the event, 
nonparametric tests will also be performed in which patients without an event are 
assigned a score of 0. The duration of increased supplemental O2 requirement from 
baseline will be treated as an ordinal variable and compared between groups by fitting 
proportional odds models.66 Finally, adverse event rates will summarized by type, grade, 
and attribution to tocilizumab treatment and compared between groups using chi-square 
and Fisher exact tests. 
 
 Interim Analyses 
10.4
 
An interim analysis will be performed after one-half of the targeted number of patients 
have been enrolled and followed for 28 days in the near-equivalence study to confirm that 
400mg is not clearly better than the lower doses. The rate ratios for recovery will be 
compared between the 400mg and 120mg groups and between the 400mg and 40mg 
groups and a conservative O’Brien-Fleming boundary applied (p < 0.0054). If the 
boundary is exceeded for the 400mg vs. 120mg comparison, the trial will be terminated.  
If the boundary is exceeded for the 400mg vs. 40mg comparison, the 40mg dose will be 
dropped and 1:1 randomization performed between the 400mg and 120mg arms for the 
remainder of the study. Use of the O’Brien-Fleming boundary will lead to minimal power 
loss and allow the final analyses to be performed at the conventional 0.05 [0.025] level 
with negligible inflation of the type I error. 
 
In the the superiority study, an interim analysis will likewise be performed after 
one-half of the patients have been randomized and followed for 28 days to compare TTR 
between the pooled tocilizumab dose arms and the 0mg control group using the O’Brien-
Fleming boundary. 
 
Finally, in both sub-studies we will assess wither the higher dosage(s) are associated 
with significant excess toxicity relative to the lower dose level(s). Specific toxicities to be 
monitored are grade 3 or 4 higher gastrointestinal perforation, liver injury, culture-proven 
bacterial infection (pneumonia or bacteremia), hepatotoxicity, neutropenia, or 
thrombocytopenia. Comparsions will be made using chi-square and Fisher exact tests 


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with the p-value for significance set at p < 0.01 to control for multiplicity. An 
independent Data and Safety Monitoring Board (DSMB) will be assembled to review the 
interim analyses. 
11 STUDY MANAGEMENT AND REGULATORY AFFAIRS  
   Institutional Review Board (IRB) approval  
11.1
 
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).67 
 
 Ethical and Scientific Conduct of the Clinical Study 
11.2
 
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 
11.3
 
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 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. 
  
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 


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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. 
 
 Data Safety Monitoring  
11.4
 
11.4.1 Data Safety Monitoring by Study Investigators 
 
The study investigators will meet at regular intervals throughout the trial as 
deemed necessary to review on-protocol and enrolled subjects of the clinical trial. 
Items that will be discussed will include (but not be limited to) the following:  
 Enrollment rate relative to expectations, characteristics of participants 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 Adverse events 
 
Protocol deviations are to be documented using the Protocol Deviation Form 
and sent via email to PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that 
are considered major because they impact subject safety or alter the risk/benefit 
ratio, compromise the integrity of the study data, and/or affect subjects’ 
willingness to participate in the study must be reported within 7 days. Please 
contact 
the 
University 
of 
Chicago 
CRA 
(PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to 
report deviations.  All major protocol deviations should also be reported to the 
local IRB of record according to their policies and procedures. 
 
 
11.4.2 Independent Data Safety Monitoring Board 
 
Unless otherwise specified, this protocol will undergo additional review by an 
independent DSMB composed of about 3-4 multi-disciplinary faculty from 
different institutions outside of University of Chicago Medical Center. This 
independent DSMB will likely include a pulmonologist/intensivist, 
rheumatologist, infectious disease specialist and a statistician well-versed in 
clinical trial methodology and protocols, COVID-19 and updated literature in 
addition to their subspecialty of expertise.   
 
This Indepdent DSMB will convene via teleconference after the first 10 subjects 
are 3 days after drug dose and then at 10% enrollment, 25% enrollment, 50% 
enrollment and 75% enrollment, unless extenuating circumstances require 
meeting(s) otherwise.  
 
As delineated by Clinial Trials Transformation Inititaive Recommendations, 
“DMC members will report any activities or connections with [trial investigators] 
that could be perceived as a conflict of interest. If any such activity or connection 


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is deemed to undermine the member’s independence, that member may need to 
resign from the DMC.” (www.ctti-clinicaltrials.org) 
 
Recommendations and proposed modifications by the Indepdent DSMB will be 
relayed to this trial’s predesignated leadership group which includes: Drs. Jennifer 
Pisano, Mary Strek, Mark Ratain, Theodore Karrison and Pankti Reid.  
 
The DSMB will review in an unmasked fashion items related to (but not limited 
to) the following: 
 
 Outcomes measures 
 Recruitment progress 
 Effectiveness of data collection 
 Adherence to protocol 
 Adverse events (serious, nonserious) and Mortality 
 
  Amendments to the Protocol 
11.5
 
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. All participating sites will require approval of amendments made by Study Lead 
PI at University of Chicago. 
 
 Annual IRB Renewals, Continuing Review and Final Reports 
11.6
 
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 
11.7
 
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). 
  


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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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