Clinical trial NCT04425538
Conditions: COVID-19
Keywords: COVID-19
Sponsor: Tufts Medical Center
Start date: 2020-06-01; Completion date: 2021-01-22
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators hypothesize that early institution of TNFα inhibitor therapy in patients with severe COVID-19 infections will prevent further clinical deterioration and reduce the need for advanced cardiorespiratory support and early mortality. To address this hypothesis, a prospective, single center, phase 2 trial is proposed to assess the efficacy of infliximab or infliximab-abda in hospitalized adult patients with severe or critical COVID-19. Observations from this study will inform the conduct of prospective randomized controlled studies to follow.

Detailed description:
The investigators hypothesize that early institution of TNFα inhibitor therapy in patients with severe COVID-19 infections will prevent further clinical deterioration and reduce the need for advanced cardiorespiratory support and early mortality. To address this hypothesis, a prospective, single center, phase 2 trial is proposed to assess the efficacy of infliximab or infliximab-abda in hospitalized adult patients with severe or critical COVID-19. Observations from this study will inform the conduct of prospective randomized controlled studies to follow.

Infliximab and Infliximab-abda are TNFα inhibitors currently FDA-approved for the treatment of autoimmune disorders, including Crohn's disease and rheumatoid arthritis. The risks and adverse reactions are described in the approved prescribing information for infliximab (or infliximab-abda). Infliximab will be used when available. Should infliximab be unavailable in the pharmacy, infliximab-abda, a biosimilar, will be used.

Treatment with infliximab or infliximab-abda 5mg/kg IV should ideally be administered within 6 hours of enrollment, and no more than 24 hours following enrollment. Pre-medication with Tylenol 650 mg once 30 minutes prior to infusion would be recommended. Other pre-medications may be given at the discretion of the treating physician. These include diphenhydramine 50mg by mouth, as well as prednisone 20mg by mouth, both given 30 minutes prior to infusion. Pulse and blood pressure should be monitored every 30 minutes during the infusion, and patients should be monitored for at least 30 minutes following the infusion.

Retreatment with infliximab is permitted at treating physician discretion 7-21 days following primary therapy and based on initial response; the usual treatment schedule is every 2 weeks, this interval is not strictly enforced given the uncertainty of outcomes with primary therapy.

Arms: arm 1: All patients enrolled into this trial will be assigned to the Infliximab arm. Patients will be treated with infliximab on Day 1, and may be re-treated per protocol and at the discretion of the investigator.
Interventions: intervention 1: Infliximab
Intervention descriptions: intervention 1: Either infliximab or infliximab-abda will be used at the discretion of the investigator

Protocol documents:
Prot_SAP_000.pdf: 
 
Mathew TNFa in COVID-19 Version 22Jun2020  
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STUDY TITLE: A PHASE 2 TRIAL OF INFLIXIMAB IN CORONAVIRUS DISEASE 2019 (COVID-19). 
 
STUDY SPONSOR: Tufts Medical Center 
 
PRINCIPAL INVESTIGATOR  
Name: Paul Mathew, MD 
Department: Hematology & Oncology 
Phone: 1-617-636-2694 
Email: pmathew@tuftsmedicalcenter.org 
 
VERSION DATE: 22 June 2020 
 
NCT: 04425538 
 


 
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Table of Contents – Click on the links below to go directly to the applicable section 
 
A. 
Study Schema ................................................................................................................................................3 
B. 
Introduction .....................................................................................................................................................3 
B.1 Background, Rationale and Therapeutics .......................................................................................................3 
B.2 Risks to Subjects and Study Staff ...................................................................................................................8 
B.3 Potential Benefits to Subjects ..........................................................................................................................9 
B.4 Alternatives ......................................................................................................................................................9 
C. 
Objectives .......................................................................................................................................................9 
D. 
Enrollment and Withdrawal .......................................................................................................................... 10 
D.1 Inclusion Criteria ........................................................................................................................................... 10 
D.2 Exclusion Criteria .......................................................................................................................................... 10 
D.3 Withdrawal of Subjects ................................................................................................................................. 11 
D.4 Recruitment and Retention ........................................................................................................................... 11 
D.4.1 Local Recruitment Methods ................................................................................................................... 11 
D.4.2 Study-Wide Recruitment Methods ........................................................................................................ 11 
All subjects will be recruited by methods under the control of Tufts Medical Center. .................................... 11 
D.4.3 Payment ................................................................................................................................................ 11 
D.4.4 Reimbursement ..................................................................................................................................... 12 
E. 
Costs to Subjects ......................................................................................................................................... 12 
F. 
Study Design ............................................................................................................................................... 12 
F.1 Study Timelines............................................................................................................................................. 12 
F.2 Procedures .................................................................................................................................................... 14 
F.3 Evaluations .................................................................................................................................................... 16 
F.4 Collection and Storage of Human Biological Specimens  ............................................................................ 17 
G. 
Ethics and Protection of Human Subjects ................................................................................................... 17 
G.1 Informed Consent Process ........................................................................................................................... 17 
G.2 Waiver or Alteration of Consent Process ..................................................................................................... 17 
G.3 International Research ................................................................................................................................. 17 
G.4 Confidentiality ............................................................................................................................................... 17 
G.5 Screening Data Collection Form/Screening Log .......................................................................................... 18 
G.6 Provisions to Protect the Privacy Interests of Subjects ................................................................................ 18 
G.7 Provisions to Monitor the Study to Ensure the Safety of Subjects ............................................................... 18 
G.8 Vulnerable Populations ................................................................................................................................ 18 
H. 
Adverse Event Monitoring............................................................................................................................ 19 
H.1 Definitions ..................................................................................................................................................... 19 
H.2 Reporting Procedures ................................................................................................................................... 19 
H.3 Reportable New Information ......................................................................................................................... 20 
I. 
Statistical Considerations ............................................................................................................................ 20 
I.1 Study Endpoints ............................................................................................................................................. 20 
I.2 Statistical Analysis: ........................................................................................................................................ 20 
I.3 Number of Subjects ........................................................................................................................................ 21 
I.4 Data Management .......................................................................................................................................... 21 
I.5 Randomization ............................................................................................................................................... 21 
J. 
Drugs or Devices ......................................................................................................................................... 21 
K. 
Study Administration .................................................................................................................................... 22 
K.1 Setting ........................................................................................................................................................... 22 
K.2 Registration ................................................................................................................................................... 22 
K.3 Resources Available ..................................................................................................................................... 22 
K.4 IRB Review ................................................................................................................................................... 22 
K.5 Multi-Site Research ...................................................................................................................................... 23 
K.6 Community-Based Participatory Research ................................................................................................... 23 
K.7 Sharing Results with Subjects ...................................................................................................................... 23 
L. 
References .................................................................................................................................................. 23 
Appendix A - Tufts Medical Center COVID-19 Treatment Guidance……….………………………………………….27 
Appendix B - Laboratory Manual…………………………………………………………………………………………...30 
Appendix C - Schedule of Assessments…………………………………………………………………………..………32 
 
 
 
 


 
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A. Study Schema 
 
 
 
 
B. Introduction 
 
B.1 Background, Rationale and Therapeutics 
 
On March 30 2020, there were over 720,000 confirmed cases of SARS-COV2 infection 
(COVID-19) globally and 33,000 deaths, with a mortality rate that is10-fold higher than 
that of influenza.1 In the United States, COVID-19 cases and deaths from COVID-19 are 
accelerating rapidly across the nation. Twenty percent of COVID-19 patients present 
with severe illness, defined by presence of dyspnea, respiratory rate ≥30/min, blood 
oxygen saturation ≤93%, partial pressure of arterial oxygen to fraction of inspired 
oxygen ratio (PaO2/FiO2) <300, and/or lung infiltrates >50% within 24 to 48 hours. 
Approximately 50% of admitted patients will require intensive care monitoring for 
cardiorespiratory support. Among those who are admitted to the intensive care unit and 
require intubation, the mortality rate approaches 85%. Death from cardiorespiratory 
Baseline
•Eligibility Confirmation
•Baseline  Assessments
•Cytokine and Inflammatory Profile
Day 1
•Treatment with Infliximab or Infliximab-abda
•Start Daily Review of ventilator use, oxygen use,  vasopressor support
Day 3
•Safety  and Laboratory Assessments for Inflammatory Markers
•Cytokine Profile, Post-Dose
•Continued Daily Review of ventilator use, oxygen use,  vasopressor support
Day 5
•Safety and Laboratory Assessments for Inflammatory Markers
•Continued Daily Review of ventilator use, oxygen use,  vasopressor support
Day 14
•Safety and Laboratory Assessments for Inflammatory Markers
•Continued Daily Review of ventilator use, oxygen use,  vasopressor support
•Cytokine Profile Day 14
Day of 
Discharge
•Safety and Laboratory Assessments for Inflammatory Markers
•Final Review of ventilator use, oxygen use,  vasopressor support, and secondary 
infections
Day 28 
Follow-Up
•Follow-up for Survival


 
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failure is principally due to acute respiratory distress syndrome (ARDS) and myocardial 
depression or cardiogenic shock.2 With the COVID-19 pandemic threatening to 
overwhelm the US healthcare system, there is a dire need for treatment to mitigate 
disease severity and death and also to preserve and ration medical equipment and 
intensive care unit (ICU)-level interventions, including ventilator requirements.3 Lack of 
ICU access and ventilator shortages alone threaten to contribute significantly to the 
excess mortality from COVID-19 disease. 
 
Course of the Lethal Illness and the Role of Cytokine Storm.   
In both inpatient and ambulatory settings, the typical clinical course includes 
stable or improving symptoms over the first 7 to 10 days after symptom onset. 
Beyond this time frame, some patients have a sudden, fulminant clinical 
decompensation requiring emergent intubation and ICU care.4, 5 This rapid 
deterioration with progressive hypoxemia, myocardial depression, and multiorgan 
failure is thought to be secondary to cytokine storm, rather than direct viral 
damage to pneumocytes. Early intervention to prevent or mitigate this 
hyperinflammatory cytokine response may markedly reduce the need for ICU 
level of care, ventilator support, and vasopressors usage and improve survival 
rates in COVID-19 patients.6  
Pathophysiology of the Cytokine Storm in COVID-19 
Strong parallels have been noted between severe COVID-19 and hyperinflammatory 
states, such as cytokine storm and secondary hemophagocytic lymphohistiocytosis 
(sHLH). These illnesses are characterized by aberrant and exorbitant immune 
responses, which can be triggered and amplified by viral infections interacting with 
incompletely determined host factors. A hallmark of the illness is the influx of tissue 
macrophages that generate prodigious amounts of cytokines that suppress cytotoxic T-
lymphocytes and NK cell function and inflict a diverse array of tissue damage.7 Severe 
COVID-19-related multi-organ dysfunction is associated with a cytokine profile 
characterized by increased levels of tumor necrosis factor-alpha (TNFα), interleukin-2 
(IL-2), interleukin (IL-7), interleukin-10 (IL-10), granulocyte colony stimulating factors 
(GCSF), interferon-gamma inducible protein (IP10) and macrophage inflammatory 
protein 1-a (MIP1A).2 The cytokine profile of COVID-19 patients admitted to the ICU 
showed higher levels of TNFα, IL-2, IL-7, and IL-10 than non-ICU patients, correlating 
with disease severity.2 In addition, CRP, IL-6 and ferritin levels were found to be 2-4 fold 
higher in patients who died of COVID-19 relative to those who recovered.8 Moreover, 
flow cytometry analysis of peripheral blood from 28 patients with COVID-19 identified a 
unique monocyte population that expressed macrophage markers and secreted TNFα, 
IL-6 and IL-10. This monocyte population, otherwise absent in healthy controls, had 
readily detectable morphological and inflammation-related phenotypic changes, which 
were more pronounced in patients requiring prolonged hospitalization and ICU 
admission.9 The aberrant and excess inflammatory activation appears to be detrimental 
rather than protective in COVID-19 patients. The hyperinflammatory state that is noted 
in COVID-19 patients resembles virally-triggered secondary HLH (Figure 1), which can 
also result in a fulminant life-threatening course with overlapping patterns of organ 
failure.10 
 


 
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Active therapeutic trials for the Cytokine Storm of COVID-19 and their 
rationale: 
A number of anti-viral drugs that inhibit viral replication are being investigated as 
treatment for COVID-19.11 However, tissue injury in severe COVID-19 appears to 
be principally mediated by pro-inflammatory cytokines6, which suggests that 
blocking cytokine activity at the cellular level is a valid and potent strategy to 
blunt the magnitude of damage from the viral illness. Given the diversity of 
cytokine elevation associated with the illness, identifying a driver or master-
regulator cytokine to target would be essential to this approach. Cytokine 
directed therapies have been used for the treatment of cytokine storms of diverse 
origins, including IL-6, IL-1b and TNFα inhibitors.12-14 Tocilizumab, an IL-6 
inhibitor, has shown efficacy when used for cytokine release syndrome that 
occurs after CAR-T administration.12 Use of tocilizumab for managing cytokine 
storm related to COVID-19 is now gaining mainstream acceptance after 
preliminary data from a study of 21 patients with severe or critical COVID-19 
infection showed rapid defervescence and improved oxygenation after 
administration of a single dose of tocilizumab.15 Current clinical guidance on 
management of severe COVID-19 infections recommends against the use of 
corticosteroids, unless indicated for another reason, and reports insufficient 
evidence to issue any recommendation on the use of any of the following: 
antiviral agents, recombinant interferons, chloroquine/hydroxychloroquine, or 
tocilizumab.16  Clinical trials (NCT04317092, NCT04306705, NCT04320615) are 
currently ongoing to demonstrate the efficacy of IL-6 and IL-1beta antagonism in 
COVID-19.17 In secondary HLH, TNFα-antagonists have demonstrated striking 
efficacy after failure of frontline steroids and etoposide-based chemotherapy.14  
TNFα as a master regulator of the cytokine storm of COVID-19 
There are diverse lines of evidence that implicate TNFα as a master regulator of the 
cytokine storm in COVID-19 and secondary HLH. TNFα is a cytokine produced by 
mononuclear cells, predominantly macrophages/monocytes and plays an integral role in 
the inflammatory cascade associated with infections and autoimmune diseases (Figure 
Figure 1: Pathophysiological 
model of the cytokine storm for 
COVID-19/HLH: NK and CTLs 
fail to eliminate activated 
macrophages, Activated 
macrophages continue to 
secrete excessive amount of 
cytokines and feed back to 
cause CTL proliferation, 
Excessive cytokine production 
(cytokine storm) by 
macrophages, NK cells, and 
CTLs resulting in tissue 
damage and multi-organ failure. 
[Adapted from Rosee et al, 
Blood 2019] 


 
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2).18 Its inflammatory and immuno-regulatory actions are mediated by its binding to TNF 
receptor-1 and TNF receptor-2. TNFα is thought to trigger a febrile reaction by a 
mechanism that involves release of IL-6 and is independent of IL-1β.19 Fever is the 
most common symptom of COVID-19 infection2 which suggests that TNFα may be an 
early mediator in the pathological cascade of the illness. TNFα levels have been found 
to be significantly higher in both ICU and non-ICU patients relative to healthy controls, 
whereas IL-6 levels were only elevated in ICU patients (Figure 3).2 These findings 
suggest that TNFα levels may rise earlier in the disease course and play a critical role in 
the early pathogenesis of severe illness. Additionally, TNFα was found to up-regulate 
the production of ferritin in acute phase state human hepatocyte cultures, as opposed to 
IL-6 and interleukin-lα that did not.20 As with HLH, ferritin elevation was noted in almost 
80% of COVID-19 cases and hyperferritinemia was more common in patients who died 
from the infection.2 Elevated ferritin levels have been identified as a predictor of 
mortality in COVID-19 and thus, indirectly linking TNFα with adverse disease 
outcomes.2, 21 The role of TNFα in the pathogenesis of autoimmune disease such as 
rheumatoid arthritis (RA) is clear.  In a disease model that represents RA, anti-TNF 
agents were shown to inhibit the production of several important pro-inflammatory 
cytokine such as IL-1, IL-6 and GM-CSF from the synovial culture.22 Anti-TNF therapies 
have since become the mainstay of disease modifying therapies for RA. 
 
 
 
The detrimental role of excess TNFα has been established in influenza and 
severe acute respiratory syndrome (SARS)-Coronavirus (CoV). The levels of pro-
inflammatory cytokines (IL-6, TNFα) in patients with influenza correlate with both 
the severity and duration of symptoms.23, 24 Furthermore, single-nucleotide 
polymorphisms (SNPs) in the TNF gene have been associated with severity of 
influenza.25 In preclinical mouse models of influenza, etanercept (which binds to 
circulating TNFα) used in H1N1 infected mice decreased inflammatory cytokines, 
including TNFα, IL-6 and IFN-gamma, reduced inflammatory cell infiltration 
including macrophages and neutrophils, reduced viral replication, and improved 
survival.26 The improved virological outcomes suggest restoration of 
physiological immune surveillance, specifically cytotoxic T cell and NK-function. 
Similarly, early upregulation of key inflammatory mediators, including TNFα and 
Figure	2	
Figure	3	


 
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IL-6, in SARS-CoV infected mice was shown to promote lethal disease with all 
responses being significantly more robust early during infection in the lethal 
isolates.27 This upregulation in TNFα, as well as IL-6, was also noted in SARS 
patients and found to be sustained for every length of the clinical courses 
investigated when compared to healthy controls.28, 29 Infection of St. Jude porcine 
lung (SJPL) epithelial cells with different respiratory viruses significantly 
increased TNFα expression, indicating a role for TNFα in the pathogenesis of 
virus inflicted cellular injury.30 These results indicate that viral lung damage is at 
least in part mediated by TNFα action and TNFα depletion via use of TNFα 
inhibitors may potentially be protective against this direct damage as well.26, 31 
 
ARDS is characterized by diffuse alveolar damage (DAD) and lung capillary endothelial 
injury, and overdrive in the inflammatory response led by inflammatory cytokines has 
been implicated in its evolution. High TNFα levels have been detected in serum and 
bronchoalveolar lavage fluid of patients with ARDS and correlate with severity of lung 
damage.32, 33 Post-mortem analysis of patients who died from COVID-19 shed light on 
the diffuse alveolar damage, cytopathic changes in the pneumocytes and presence of 
mononuclear inflammatory infiltrates, dominated by lymphocytes.34, 35 Immune profiling 
by flow cytometry depicted a higher than expected fraction of pro-inflammatory CCR6+ 
Th17 cells in the blood.35 Th17 cells produce cytokines, including interleukin (IL)-17, IL-
6, IL-21, IL-22 and TNFα and have been identified as a pathogenic factor in RA. Use of 
TNFα inhibitors has been shown to suppress their activity and potentially control the 
inflammatory cascade.36 As ARDS can develop in up to one-third of COVID-19 cases 
and high TNFα levels have been seen in these patients, the role of TNFα inhibitors to 
protect from lung injury should be further contemplated. Cardiac decompensation is 
another hallmark of COVID-19 with pre-existing hypertension and cardiovascular 
disease accounting for the highest risk of death.2, 8 TNFα has been associated with 
myocardial depression and evolution of viral myocarditis and taken together may be 
implicated in the cardiac pathology of lethal COVID-19.37, 38 
 
Taken together, the preclinical and clinical data strongly support the rationale for 
investigating the efficacy and safety of anti-TNFα therapy in patients at risk for rapid 
cardiorespiratory decompensation and early mortality in severe COVID-19 infections. 
Other groups have echoed the need for clinical trials to study this approach.39 Fulfilling 
this need is urgent in the setting of a rapidly accelerating global pandemic with restricted 
availability of effective systemic therapies and access to critical care support.     
 
We hypothesize that early institution of TNFα inhibitor therapy in patients with severe 
COVID-19 infections will prevent further clinical deterioration and reduce the need for 
advanced cardiorespiratory support and early mortality. To address this hypothesis, a 
prospective, single center, phase 2 trial is proposed to assess the efficacy of infliximab 
or infliximab-abda in hospitalized adult patients with severe or critical COVID-19. 
Observations from this study will inform the conduct of prospective randomized 
controlled studies to follow. 
 
B.1.1 Therapeutic Agents – Infliximab and Infliximab-abda 
 
 
Infliximab and Infliximab-abda are TNFα inhibitors currently FDA-approved for the 
treatment of autoimmune disorders, including Crohn’s disease and rheumatoid 
arthritis. The risks and adverse reactions are described in the approved prescribing 


 
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information for infliximab (or infliximab-abda).  Either infliximab or infliximab-abda 
may be used, at the discretion of the investigator.  For the full prescribing information 
for infliximab, please click here.  Full prescribing information for infliximab-abda can 
be found here. 
 
Treatment with infliximab or infliximab-abda 5mg/kg IV should ideally be administered 
within 6 hours of enrollment, and no more than 24 hours following enrollment. Pre-
medication with Tylenol 650 mg once 30 minutes prior to infusion would be 
recommended. Other pre-medications may be given at the discretion of the treating 
physician.  These include diphenhydramine 50mg by mouth, as well as prednisone 
20mg by mouth, both given 30 minutes prior to infusion. Pulse and blood pressure 
should be monitored every 30 minutes during the infusion, and patients should be 
monitored for at least 30 minutes following the infusion. 
 
Patients will be monitored for safety through the infusions of infliximab or infliximab-
abda.  Common adverse drug reactions include infections and infusion related 
reactions.  Signs of infusion related reactions include chest pain, chills, dyspnea, 
fever, hypertension, hypotension, pruritis, urticarial, abdominal pain, coughing, 
fatigue, headaches, nausea, and upper respiratory tract infections.  In the event any 
of these occur during or following the infusion, the relation to infliximab or infliximab-
abda will be determined by the investigator. 
 
In the event of a hypersensitivity reaction, the infusion should be stopped and the 
treating physician should be alerted.  For mild hypersensitivity reactions (localized 
hives, itching, warmth), diphenhydramine 25-50mg IV or orally and famotidine 20mg 
IV should be administered.  For moderate hypersensitivity reactions (generalized 
hives or itching, flushing, diffuse erythema, or mild hypotension), hydrocortisone 
100mg should be administered in addition to diphenhydramine 50mg IV or orally and 
famotidine 20mg IV.  For severe reactions (angioedema, respiratory failure, 
hypotension), 0.3 mg of epinephrine intra-muscular injection should be given in 
addition to the mild and moderate reaction regimens listed above.   
 
Retreatment with infliximab is permitted at treating physician discretion 7-21 days 
following primary therapy and based on initial response; the usual treatment schedule 
is every 2 weeks, this interval is not strictly enforced given the uncertainty of 
outcomes with primary therapy.   
 
B.2 Risks to Subjects and Study Staff 
Infliximab (or Infliximab-abda) is currently FDA-approved for the treatment of a 
number of autoimmune disorders, including Crohn’s disease and rheumatoid 
arthritis. The risks and adverse reactions are described in the approved 
prescribing information for infliximab (or infliximab-abda). In addition to the 
possible side effects and toxicities associated with the use of infliximab (or 
infliximab-abda), the risks of this study include possible unique and unknown 
adverse events or complications related to the use of a TNFα inhibitor in the 
setting of COVID-19, a potential for worsening or accelerated disease 
progression and death, and possible exclusion from receiving other 
immunosuppressive or biologic agents or from enrollment in other trials 
evaluating other therapeutic options. However, reporting to date has indicated 
that cytokine-directed therapies have not resulted in disease worsening in 


 
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COVID-19 and TNF-directed therapies in bacterial sepsis have not resulted in 
adverse outcomes. 
Infliximab may enhance the adverse/toxic effect of live vaccines and diminish the 
therapeutic effect of both live and inactivated vaccines. Live-organism and live-
attenuated vaccines should not be given concurrently with infliximab. Live-
attenuated vaccines should not be given for at least 3 months after infliximab. In 
the absence of any other contraindications, vaccinations per standard of care can 
be given after at least 3 months from the last dose of infliximab which also should 
include a COVID-19 vaccine in the event that becomes available.  
Study investigators and staff may be at risk for contracting COVID-19 while performing 
study procedures.  However, Tufts Medical Center has implemented numerous 
universal precautions to prevent the spread of COVID-19, including reducing the 
number of staff on-site, required use of facemasks at all times, and use of additional 
PPE when interacting with COVID-19 patients. Remote consenting processes have 
obviated the need for in-person interactions by study personnel. 
 
B.3 Potential Benefits to Subjects 
 
Potential direct benefits to an enrolled subject may include a shorter time to 
improvement in oxygenation and breathing, a shorter recovery time, decreasing the 
need for intensive care or ventilator support, and decreased mortality. Possible benefits 
to others include learning if the study drug is safe and effective in the treatment of 
COVID-19 and which subsets of patients with COVID-19 as defined by cytokine profile, 
benefit maximally from the study drug. Furthermore, If the trial meets its endpoints and 
TNFα inhibitor therapy is proven effective in severe cases of COVID-19, it would add a 
critically required therapeutic option, especially in the setting of limited resources, and 
restricted availability and expected shortages in other agents used such as remdesivir 
and IL-6 inhibitors. Repurposing an already approved and well-studied drug for a new 
indication is an efficient and attractive alternative in the setting of an outbreak of this 
magnitude. Given the shortage in critical care resources that will alone account for 
significant excess mortality, effective sparing of ventilator therapy for one patient may 
prove life-saving for two individuals rather than just one.   
 
B.4 Alternatives 
 
Patients may choose not to participate in this research study. There is currently no FDA 
approved treatment available for COVID-19. Alternative treatment options may include 
supportive care alone, palliative care, enrollment in other clinical trials or off-label 
treatment with one of the agents that are part of the Tufts Medical Center COVID-19 
treatment guidelines. .  
 
 
C. Objectives 
Primary endpoint: 
1. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater 
compared to the baseline SpO2/FiO2) sustained for a minimum of 48 hours 
Secondary endpoints: 
1. 28-day mortality 


 
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2. Assessment of cytokine and inflammatory profile at baseline and at 48 hours 
after therapy (TNFα, IL-1b, IL-2, sIL-2r, IL-6, ferritin, ESR, CRP, CPK, 
troponin) 
3. Qualitative and quantitative toxicity  
4. Incidence and duration of supplemental oxygen administration by nasal 
cannula, simple face mask, or other similar oxygen delivery device  
5. Incidence and duration of non-invasive ventilation or by non-rebreather mask 
or high-flow nasal cannula   
6. Incidence and duration of mechanical ventilation 
7. Incidence and duration of vasopressor support 
8. Incidence and duration of extracorporeal membrane oxygenation (ECMO)   
9. Duration of fever 
10. Correlation of cytokine profile to clinical outcomes specified in primary and 
secondary objectives 
11. Duration of hospitalization 
12. Secondary infections 
 
D. Enrollment and Withdrawal  
 
D.1 Inclusion Criteria 
Patients must meet all the following criteria to be eligible:  
1. Age 18 years or older 
2. Able to provide informed consent 
3. Hospitalized adult patients with pneumonia evidenced by chest X-ray or CT scan 
4. Laboratory (RT-PCR) confirmed infection with 2019-nCoV or strongly suspected to be 
infected with SARS-COV2 with confirmation studies pending 
5. And at least one of the following: 
a) Respiratory frequency ≥30/min 
b) Blood oxygen saturation ≤93% on RA 
c) Partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) 
<300 
d) Worsening of lung involvement, defined as an increase in number and/or extension of 
pulmonary areas of consolidation, need for increased FiO2 to maintain stable O2 
saturation, or worsening O2 saturation of >3% with stable FiO2 
 
D.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the trial: 
1. Treatment with any TNFα inhibitor in the past 30 days  
2. Known hypersensitivity to any TNFα inhibitor, murine proteins, or any component of the 
formulation 


 
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3. Presence of any of the following abnormal laboratory values at screening: absolute 
neutrophil count (ANC) less than 1000 mm3, hemoglobin <7.0g/L, platelets <50,000 per 
mm3, or AST or ALT greater than 5 x ULN 
4. Known active or latent Hepatitis B 
5. Known or suspected active tuberculosis (TB) or a history of incompletely treated or latent 
TB. 
6. Pregnancy  
7. Patients with uncontrolled systemic bacterial or fungal infections (Patients with a history of 
positive bacterial or fungal cultures but on enrollment are on appropriate therapy with 
negative repeat cultures may be enrolled) 
8. Serious co-morbidity, including: 
a) Myocardial infarction (within last month) 
b) Moderate or severe heart failure (New York Heart Association (NYHA) class III or IV) 
c) Acute stroke (within last month) 
d) Uncontrolled malignancy 
e) Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated glomerular 
filtration rate (eGFR) < 30 ml /min/1.73 m^2) at baseline  
 
Subject eligibility will be assessed using medical record review and clinical tests.  The 
Principle Investigator and/or Co-Investigator will determine eligibility. Patients may 
participate in other therapeutic studies while participating in this trial but all concomitant 
cytokine-directed, anti-viral and other COVID-19 experimental therapeutics will be 
annotated in reporting.  
 
D.3 Withdrawal of Subjects 
 
Participants may withdraw consent for participation in the study at any time.  
Participants may also be withdrawn from the study if, in the opinion of the investigator, it 
is in the patient’s best interest to do so. Participants who elect to discontinue study 
treatment may still be followed for clinical events as appropriate. 
 
D.4 Recruitment and Retention 
 
D.4.1 Local Recruitment Methods 
 
All eligible COVID-19 patients will be approached as part of their care at Tufts 
Medical Center. All participants will be recruited from the COVID-19 patient 
population at Tufts Medical Center.  All COVID-19 trial investigators collaborate on 
identifying potential subjects and will determine the best course of treatment for 
these patients.   
 
D.4.2 Study-Wide Recruitment Methods 
 
All subjects will be recruited by methods under the control of Tufts Medical Center. 
 
D.4.3 Payment  
 


 
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Subjects will not receive money, gifts, or any other incentive for participating in this    
study. 
  
D.4.4 Reimbursement  
 
Subjects will not be reimbursed for their expenses, such as travel, parking, meals,      
or other related costs. 
                                  
 
E. Costs to Subjects 
 
The drug will be dispensed from the Tufts Medical Center inpatient pharmacy and may be 
billed to the subject or their insurance. Participants will not be charged for research-related 
laboratory tests. 
 
F. Study Design 
 
F.1 Study Timelines 
 
Subjects will participate in the study for up to 28 days.  Enrollment is expected to last for 
approximately 12 weeks.  The estimated date for investigators to complete this study is 
September 2020. 
 
The following procedures will be performed at each study visit: 
Baseline Visit 
 Informed Consent 
 Covid-19 Diagnosis Confirmation 
 Demographic information 
 Chest X-Ray or CT Scan 
 Medical History 
 Vital Signs: blood pressure, heart rate, respiratory rate, temperature, oxygen 
saturation 
 CBC with Differential 
 CMP 
 Coagulation Profile  
 Inflammatory Profile  
 Cytokine Profile  
 Hepatitis Panel  
 Pregnancy Test (for women of child-bearing potential) 
 O2 Requirements 
 Mode of Ventilation 
 Vasopressor Support 
 
Day 1 
 Infliximab or Infliximab-abda Dosing 
 Start Daily AEs of Special Interest/SAE Assessment 
 Start Daily Vital Signs 
 Start Daily O2 Requirements 
 Start Daily Mode of Ventilation 


 
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 Start Daily Vasopressor Support 
 Start Daily CBC, CMP 
 
Day 3 
 
 CBC with Differential 
 Chem-1 
 Coagulation Profile  
 Inflammatory Profile   
 Cytokine Profile (between 48 – 72 hours post-treatment) 
 
Day 5 
 
 CBC with Differential 
 Chem-1 
 Coagulation Profile  
 Inflammatory Profile  
 
Day 14  
 
This visit will be completed only if the subject is still an inpatient at Tufts Medical Center. 
 
 CBC with Differential 
 Chem-1 
 Coagulation Profile  
 Inflammatory Profile  
 Cytokine Profile 
 Infliximab or Infliximab-abda Dosing (at discretion of PI/Co-I +/- 7 days) 
 
Day of Discharge 
 
Day of discharge is the date of discharge from hospital, date of death or day 28, 
whichever occurs first. 
 
 AEs of Special Interest/SAE Assessment 
 Vital Signs 
 O2 Requirements 
 Mode of Ventilation 
 Vasopressor Support 
 CBC with Differential 
 Chem-1 
 Coagulation Profile  
 Inflammatory Profile  
 Cytokine profile (only if discharge is between Day 7 and Day 14) 
 Secondary Infections 
 
Day 28 Follow-Up 
 
 Survival Follow-Up 
 


 
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F.2 Procedures 
 
Patients will be identified as they are seen at Tufts Medical Center. Safety labs and 
procedures will be performed per standard of care. The results of all labs and 
procedures will be reviewed by the study team and the PI. 
 
Source records that will be used to collect data about subjects include documents from 
the Tufts Medical Center Electronic Medical Record, in addition to study coordinator 
checklists and case report forms (CRFs). 
 
The following procedures and tests will be performed solely for research purposes: 
 Blood collection for cytokine profile 
 Informed Consent 
 Treatment with Infliximab or Infliximab-abda 5mg/kg IV (See Section B.1.1) 
 
All other procedures performed on this study are standard of care at Tufts Medical 
Center. 
 
Below is a description of all procedures that will take place during the study: 
 
Informed Consent 
 
Informed Consent will be obtained prior to participation in this study.  Informed consent 
will be obtained according to the Remote Consent Guidelines. 
 
Covid-19 Diagnosis Confirmation 
 
Patients must have a diagnosis of pneumonia by imaging and laboratory confirmed 
COVID-19 or with strong suspicion of COVID-19 with laboratory study pending to be 
eligible.  This will be confirmed at Baseline prior to enrollment. 
 
Adverse Events of Special Interest/Serious Adverse Events 
 
Adverse events of special interest and serious adverse events will be collected from 
Day 1 until Day of Discharge.  For more information see protocol section H.1. 
 
Demographic information 
 
 
Demographic information will be collected at Baseline and includes date of birth, gender 
and race/ethnicity. 
 
Chest X-Ray or CT Scan 
 
An X-Ray or CT Scan of the chest will be performed at any point during the admission 
prior to enrollment to confirm diagnosis of pneumonia. 
 
Medical History 
 
 
Medical history will be documented at Baseline and includes any ongoing medical co-
morbidities (i.e.: cardiovascular, pulmonary, endocrine, oncologic diagnosis). 
 


 
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Vital Signs 
 
 
Vital signs will be collected at baseline and throughout the study while participants are 
inpatients at the hospital.  Vital signs include: heart rate, blood pressure, O2 saturation, 
respiratory rate, temperature, weight, height (on screening only).On the day of 
discharge, the first and last day of fever during the hospitalization will be recorded. 
 
Complete Blood Count with Differential (CBC with Differential) 
 
CBC with Differential will be collected at Baseline, Day 3, Day 5, Day 14, and on date of 
discharge.  These labs may also be collected daily whenever possible or as per 
standard of care. 
 
Complete Metabolic Panel (CMP) 
 
CMP will be collected at Baseline, Day 3, Day 5, Day 14, and on date of discharge.  
Complete metabolic profile (CMP) includes: sodium, potassium, bicarbonate, chloride, 
glucose, creatinine, calcium, magnesium, estimated glomerular filtration rate, lactate 
dehydrogenase, blood urea nitrogen, calcium, magnesium, phosphate, total protein, 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total and 
direct bilirubin.  These labs may also be collected daily whenever possible or as per 
standard of care. 
 
Coagulation Profile 
 
 
Coagulation Profile will be collected at Baseline, Day 3, Day 5, Day 14, and on date of 
discharge. Key elements of the coagulation profile includes D-Dimer and fibrinogen. 
 
Inflammatory Profile 
 
Inflammatory Profile will be collected at Baseline, Day 3, Day 5, Day 14, and on date of 
discharge.  Inflammatory profile includes C-reactive protein, troponin, Creatine 
phosphokinase and ferritin. 
 
Cytokine Profile  
 
A blood sample for cytokine profile testing will be collected at Baseline and at least 48 
hours but no later than 72 hours following the first dose of infliximab or infliximab-
abda.  This will be repeated at Day 14 OR between Day 7 and Day 14 if the patient is 
discharged before Day 14. This cytokine profile includes TNFα, IL2, IL6, and IL1-beta.  
Instructions for sample collection and processing can be found in Appendix B.   
 
Hepatitis Panel 
 
Hepatitis panel will be performed at Baseline and includes: HepBs Ag and Ab, HepBc 
Ab and HepC Ab. 
 
Pregnancy Test 
 
Women of childbearing potential will undergo pregnancy testing at Baseline.  Either a 
urine or serum pregnancy test is acceptable. Both tests are available at Tufts Medical 


 
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Center and the choice of which test is used will be at the discretion of the treating 
physician. 
 
Infliximab or Infliximab-abda Dosing 
 
Treatment with infliximab or infliximab-abda 5mg/kg IV should ideally be administered 
within 6 hours of enrollment, and no more than 24 hours following enrollment. Pre-
medication with Tylenol 650 mg once 30 minutes prior to infusion would be 
recommended.  Retreatment with infliximab is permitted at treating physician discretion 
7-21 days following primary therapy and based on initial response; the usual treatment 
schedule is every 2 weeks, this interval is not strictly enforced given the uncertainty of 
outcomes with primary therapy.  See section B.1.1 for more information regarding 
treatment with infliximab and infliximab-abda. 
 
O2 Requirements 
 
Fraction of inspired O2 will be calculated at Baseline, within 24 hours of the first dose of 
infliximab, and at 24 hour intervals (+/- 12 hours) thereafter until primary end point is 
met, discharge, death or day 28 (which ever occurs first).  
 
Mode of Ventilation 
 
Mode of ventilation will be assessed throughout the study and until the day of discharge, 
death or day 28 (which ever occurs first).  Mode of ventilation includes: none (on room 
air), nasal cannula/simple face mask/other, non-invasive ventilation, non-rebreather 
mask, high-flow nasal cannula, mechanical ventilation, extra-corporeal membrane 
oxygenation (ECMO).  On day of discharge, the incidence and day of initiation and 
discontinuation of each mode of ventilation will be recorded. 
 
Vasopressor Support 
 
The incidence and date of initiation and discontinuation of vasopressor use will be 
recorded throughout the study and on the day of discharge, death or day 28 (which ever 
occurs first). 
 
 
Secondary Infections 
 
Any secondary infections that occur while the subject is an inpatient at Tufts Medical 
Center will be documented on the day of discharge.  Secondary infections include any 
documented bacterial, fungal, parasitic and/or other viral infections. 
 
Survival Follow-Up 
 
Patients will be contacted 28 days following the initial dose of infliximab to assess 
survival status.  This can be done via phone call, clinic visit, or review of medical 
records. 
 
 
F.3 Evaluations 
 


 
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All laboratory tests, excluding the cytokine profile, will be performed as standard-of-care 
at the Tufts Medical Center Laboratory.  Blood samples for cytokine profiles will be 
processed per the lab manual (Appendix B) and stored in the Neely Center laboratory.  
These assays will be performed at an outside facility.   
 
F.4 Collection and Storage of Human Biological Specimens  
 
Specimens for cytokine assays will be stored in the NCCCR laboratory for up to 1 year.  
NCCCR staff and study investigators will have access to the specimens, which are 
stored in a locked laboratory in Tufts Medical Center. 
 
All specimens will be labeled with study ID only, a link to the patient identifier will be 
kept on a secure file accessible only to the principal investigator and study staff. 
IRB approval will be required for use of any specimen obtained from this study for future 
use.  
 
Subjects can withdraw permission for use of their stored specimens and PHI for future 
research in writing, by email or letter, or documented phone conversation. The banked 
specimen will be labeled with a study ID number and we will keep a separate record 
linking the study ID to the patient so we can identify a sample if a participant wants to 
withdraw consent for future research.   
 
G. Ethics and Protection of Human Subjects 
 
G.1 Informed Consent Process 
 
All subjects will be required to provide informed consent. The consent process will take 
place in private areas within Tufts Medical Center. The Principle Investigator or Co-
Investigator will carry out the informed consent process, with the assistance from a 
study coordinator or study nurse.  All patients will have long as necessary to make a 
decision about participation in the study. However due to the nature of the disease, it 
may be limited to 24 to 48 hours. To ensure the safety of study staff and investigators, a 
remote consent process will be used. This will be distributed separately. Study staff will 
ensure ongoing consent at every opportunity. Non-English speakers will be enrolled 
using interpreters and IRB approved Short Forms per the IRB’s Short Form policy. 
 
G.2 Waiver or Alteration of Consent Process 
 
There will not be a request for a waiver or alteration of consent process for this study. 
 
G.3 International Research 
 
This study will only be conducted at Tufts Medical Center.  There will be no additional 
sites, nationally or internationally. 
 
G.4 Confidentiality 
 
All data and specimens will be stored in a secure location only accessible by the 
research team. The PI will ensure that study documents are stored in a manner that 
protects the privacy of subjects and the confidentiality of study data. Signed ICFs and 
source documents will be stored in locked file cabinets in the Neely Center.  De-
identified data will be entered into a RedCap electronic database. Research bio 


 
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specimens will be processed in the NCCCR laboratory.  Stored bio specimens will be 
kept in a locked freezer in the NCCCR laboratory. 
 
Study numbers will be assigned and a codebook stored in a locked cabinet.  Only the 
research team will have access to the file.   
 
All study records will be retained for the timeframe described in the record retention 
policy of the “SOP – Records Retention Timeframe – Investigators”. Long-term storage 
of study materials will take place at SPRY Moving and Storage. 
G.5 Screening Data Collection Form/Screening Log  
 
An IRB approved screening log will be used in this research study.  This will be an 
identifiable screening log that will not be distributed or viewed outside of the institution. 
Only the research study team will have access to this log.  This log will be stored 
securely with all other study documents.  
 
 
G.6 Provisions to Protect the Privacy Interests of Subjects 
 
All discussions with participants will occur in private settings. Study questions will ask 
about general medical information.  Participants can withdraw consent for the study at 
any time, or decline to answer any questions. 
 
G.7 Provisions to Monitor the Study to Ensure the Safety of Subjects 
 
This is treatment-based study and patients will receive standard of care treatment for 
COVID-19 symptoms in addition to treatment with infliximab or infliximab-abda. Safety 
data will be monitored continuously while subjects are inpatients in COVID-19 units at 
Tufts Medical Center.  Additionally, patient data will be reviewed at each study visit.  All 
data will be reviewed by the study PI. A senior physician investigator (Raymond 
Comenzo, MD or Kenneth Miller, MD) within the Hematology & Oncology Division at 
Tufts Medical Center will review the safety data for all subjects enrolled onto this trial. 
 
Case report forms and any clinical findings (sourced from EMR) will be reviewed by the 
PI or Co-Is at each study visit, or as-needed. Data collection will begin as soon as 
participants sign the informed consent form.  Adverse events will be collected until 28 
days following the last dose of study drug. Cumulative data will be analyzed at the end 
of the study period. In the first stage, 17 patients will be accrued. If there are five or 
fewer patients exhibiting improvement in oxygenation in these 17 patients, the study 
may be stopped.  
 
G.8 Vulnerable Populations 
 
This study will not involve enrollment of vulnerable subjects, including pregnant women, 
neonates, minors, prisoners, or students or employees at Tufts Medical Center. Patients 
who are not able to personally provide consent due to cognitive impairment or reduced 
performance status related to a medical condition (i.e. intubated patients, etc) may still 
be enrolled with a Legally Authorized Representative, including those with durable 
power of attorney for health care, court appointed guardian for health care decisions, a 
spouse, a health care proxy, or an adult child.  This will be performed in accordance 
with the local IRBs “SOP: Legally Authorized Representatives, Children, and Guardians 
(HRP-013).” Assent will also be obtained whenever possible.  For these subjects, ability 


 
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to give consent will be monitored continuously by clinic and study staff, and full consent 
would be obtained as soon as the patient is identified as able to provide it.  However, it 
may still not be possible to obtain a signature due to their medical state. Every effort will 
be made to obtain informed consent and assent as appropriate given the condition of 
the patient. We will keep both the LAR and patient informed throughout the study as 
appropriate.  An individual is determined to be capable of consent if at least two 
physicians (the treating physician and one of the investigators or another physician 
team member) determine based on their clinical judgment that the individual is capable 
of making their own decisions. These patients may be withdrawn from the trial if they 
appear to be under undue distress, as determined by the investigator. The investigators 
in collaboration with the clinical care teams will work together to assess withdrawal for 
each patient throughout their participation in the trial. 
 
H. Adverse Event Monitoring 
 
H.1 Definitions 
 
Only adverse events of special interest will be collected for the purposes of this trial. 
Adverse events of special interest include infusion reactions from infliximab treatment, 
anaphylaxis, and any other event deemed by the investigator to be directly related to 
infliximab treatment. 
 
An adverse event or suspected adverse reaction is considered "serious" if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes: Death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. The PI will 
assess each SAE as they become aware.  Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. 
 
Unanticipated problems (UPs) are defined as any incident, experience or outcome that 
meets all of the following criteria: 
 
Unexpected (unforeseen by the researcher or the research participant) in terms of 
nature, severity, or frequency, given the research procedures and the subject 
population being studied; 
 
Related or probably related to participation in the research, or if the event or problem 
probably or definitely affects the safety, rights and welfare of current participants; 
 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic or social harm) than was 
previously known or recognized. 
 
H.2 Reporting Procedures 
 
The PI will review all study data to assess for any AEs possibly related to the research 
procedures.  The PI would report to the IRB within 48 hours if any deaths or SAEs occur 
which could be related or possibly related to the research procedures, or any 
unexpected AEs that may be related to the research procedures. Any AEs possibly 
related to the research procedures will be collected and any unexpected AEs possibly 
related to the research procedures will be reported to the IRB within five business days 


 
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per the Tufts Health Sciences IRB reportable new information policy.  Any unanticipated 
problems possibly related to the research procedures will also be collected and reported 
to the IRB within five business days. 
 
H.3 Reportable New Information 
 
All reportable new information will be reported to the IRB per the Tufts Health Sciences 
IRB’s Reportable New Information policy. 
 
I. Statistical Considerations 
 
I.1 Study Endpoints 
 
Primary endpoint: 
 
Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater 
compared to the baseline SpO2/FiO2) for a minimum of 48 hours 
 
Secondary endpoints: 
1. 28-day mortality 
2. Assessment of dynamic changes in cytokine and inflammatory profile after 
therapy 
3. Qualitative and quantitative toxicity  
4. Incidence and duration of supplemental oxygen administration by nasal cannula, 
simple face mask, or other similar oxygen delivery device  
5. Incidence and duration of non-invasive ventilation or by non-rebreather mask or 
high-flow nasal cannula   
6. Incidence and duration of mechanical ventilation 
7. Incidence and duration of vasopressor support 
8. Incidence and duration of extracorporeal membrane oxygenation (ECMO)   
9. Duration of fever 
10. Correlation of cytokine and inflammatory profile to clinical outcomes  
11. Duration of hospitalization 
12. Secondary infections 
 
I.2 Statistical Analysis:  
 


 
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The design of the study will be based on estimated 75% risk of worsening oxygenation 
for the spectrum of severe COVID-19 lung disease allowed in the study (25% probability 
of improvement). This estimate is based on a mixture of patients with non-invasive and 
invasive oxygenation support. We will target a 50% rate of improvement in oxygenation 
following therapy with the experimental strategy. A Simon's two-stage design will be 
used. The null hypothesis that the true improvement of oxygenation is only 25% will be 
tested against a one-sided alternative. In the first stage, 17 patients will be accrued. If 
there are 5 or fewer patients exhibiting improvement in oxygenation in these 17 
patients, the study will be stopped. Otherwise, 20 additional patients will be 
subsequently accrued for a total of 37 patients. The null hypothesis will be rejected if 13 
or fewer responses are observed in 37 patients. This design yields a type I error rate of 
0.05 and power of 0.9 when the true response rate is 25%. Mean cytokine levels at 
baseline and the mean dynamic change in cytokines between responders and non-
responders will be compared using a t-test. Other secondary endpoints will be 
annotated by descriptive markers. 
 
I.3 Number of Subjects 
 
In the first stage, 17 patients will be accrued. If there are five or fewer patients exhibiting 
improvement in oxygenation in these 17 patients, the study may be stopped. Otherwise, 
20 additional patients will be accrued for a total of 37 patients.   
 
I.4 Data Management 
 
All research coordinators go through training on a regular basis.  All paper records will 
be kept in a locked cabinet and all electronic records will be kept in a password 
protected shared drive and only those directly involved with the study will have access.  
All participants will be assigned a study ID and the RedCap database will have de-
identified data only. The Neely Center study coordinators will input all data into the 
RedCap database.  All data will be reviewed by the PI.   
 
Only the research study team will have access to the data and specimens. The primary 
documents will be stored in a locked cabinet, the electronic files will be kept in a 
password protected shared file on the Tufts Medical Center server and the bio 
specimens and redcap database will use a de-identified study ID number.  The key that 
associates the de-identified study ID number with the patient name will be kept 
separately from the database and bio specimens in a locked location.   
 
Data will remain at Tufts Medical Center.  Bio specimens will be transported by a 
research coordinator to the Neely Center laboratory for specimen processing and 
storage. 
 
Data and/or specimens will be stored for at least 7 years. 
  
I.5 Randomization  
 
Subjects will not be randomized in this trial. 
 
J. Drugs or Devices 
 
This research will involve the use of drugs.  The Tufts Medical Center pharmacy, 
delegated study staff, and the PI/Co-Is will be accountable for the drugs used for the 


 
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study.  Orders will made by the study staff and PI/Co-Is, and will be reviewed and 
signed by PI/Co-I.  This will be completed using the EMR and/or physical order forms. 
 
Patients should not receive any live vaccinations that could lead to a clinical infection 
while on the study.  Additionally, the use of other anti-cytokine agents, anti-viral agents 
or other experimental therapeutics for COVID-19 disease is not prohibited.  However, all 
disease-modifying therapies that occur while the subject is on-study will be 
documented.   
 
Women of childbearing potential should employ the use of effective contraception 
methods to avoid pregnancy for 6 months following the last dose of infliximab/infliximab-
abda, per manufacturer recommendations. 
 
K. Study Administration 
K.1 Setting 
 
All research related activities will take place at Tufts Medical Center.  
 
K.2 Registration 
 
Subject Eligibility Checklists will be used to ensure that a subject is appropriately 
enrolled in the study prior to receiving any study intervention.  Eligibility checklists will 
be reviewed and signed by the PI or Co-I prior to registration.  The Investigators and 
study staff will also ensure consent and other study procedures are documented 
appropriately. 
 
K.3 Resources Available 
 
All study staff will be trained on study procedures on a regular basis.  The PI will ensure 
all study staff are qualified to perform the procedures to which they are delegated. The 
research coordinators will screen patient lists and approach patients for consent along 
with the PI/Co-I.  The PI will supervise the informed consent discussions. Blood and/or 
urine will be collected at the time of standard of care labs for treatment in the inpatient 
setting by the phlebotomist and/or staff nurse.  Research samples will be transported by 
the research coordinators to the NCCCR laboratory for processing and storage. All 
CRFs will be reviewed and confirmed by the study PI.   
 
Dr. Andreas Klein, a Co-I on this study will be the acting PI in the event that the PI is 
away or unavailable.   
 
Medical or psychological resources that subjects might need, such as for emergencies 
or medical issues, will be available for the study. 
 
 
 
K.4 IRB Review 
 
This study will be reviewed and approved by an appropriate IRB registered with the 
OHRP.  Any amendments to the protocol or informed consent documents will be 
reviewed and approved by the IRB prior to use, unless required to eliminate an 
apparent immediate hazard to subjects.   
 


 
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K.5 Multi-Site Research 
 
 
This is not a multi-site study where Tufts is the sponsor, primary grant recipient, or 
coordinating site. 
 
K.6 Community-Based Participatory Research 
 
This study will not involve community-based participatory research. 
 
K.7 Sharing Results with Subjects 
The results of clinical tests performed as part of standard of care and will be reported 
according to routine practice to the patients’ treating physician.  The results of 
exploratory biomarkers will not be given to the participants or treating physicians.  
 
L. References  
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30, 2020). 
 
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 
novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506 
 
3. Emanuel E.J, et al. Fair Allocation of Scarce Medical Resources in the Time of 
Covid-19. New England Journal of Medicine. DOI: 10.1056/NEJMsb2005114. 
 
4. Lauer SA, et al. The incubation period of Coronavirus Disease 2019 from publicly 
reported confirmed cases: Estimation and Application. Ann Intern Med. Published 
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5. Liu Y, et al. Viral dynamics in mild and severe cases of Covid-19. Lancet Infect 
Dis. Published Online March 19, 2020 https://doi.org/10.1016/ S1473-
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6. Shi, Y., Wang, Y., Shao, C. et al. COVID-19 infection: the perspectives on 
immune responses. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-
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7. Crayne CB, et al. The immunology of macrophage activation syndrome. Front 
Immunol 2019 Feb 1;10:119. doi: 10.3389/fimmu.2019.00119. eCollection 2019.  
 
8. Ruan Q, Yang K, Song J. Clinical predictors of mortality due to COVID-19 based 
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2020 Mar 3. doi: 10.1007/s00134 020-05991-x.  
 
9. Zhang D, et al. COVID-19 infection induces readily detectable morphological and 
inflammation-related phenotypic changes in peripheral blood monocytes, the 
severity of which correlate with patient outcome. medRxiv preprint. Posted March 
26, 2020. doi: https://doi.org/10.1101/2020.03.24.20042655 
 


 
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Appendix A – Tufts Medical Center COVID-19 Treatment Guidance Document for 
Inpatients Guideline on Anti-Inflammatory Management 
 
Updated as of 10 April 2020 
 
This is one of a series of collaborative documents developed by members of ID, 
Pulmonary/Critical Care, Hematology, Nephrology, Rheumatology, Pharmacy, Cardiology, 
Radiology, Dermatology, Pediatrics and Pathology Divisions and Departments.  
 
Please note the date at the bottom of the page; this document will be updated as the COVID-
19 pandemic evolves and new data becomes available. There will be changes.  
Please see other existing documents located on intranet for current information on definitions 
of persons under investigation (PUI), testing guidelines, Algorithms for disposition and 
personal protective equipment (PPE), exposures, and FAQ.  
 
There is currently no FDA-approved treatment for COVID-19 or agent with clear benefit at this 
time. 
Changes since last version: 
Addition of Corticosteroid Recommendations 
Revisions to diagnostic criteria and treatment algorithm for cytokine storm 
Requirement for Hematologist Approval for use of anti-cytokine therapy 
 
Corticosteroids 
There is currently uncertain benefit and risk of corticosteroids in the treatment of COVID-
19.  Corticosteroids continue to have a controversial role in the treatment of non-infectious 
ARDS, and data show both detrimental and beneficial impacts on patients with other viral 
pneumonias including those caused by MERS and influenza (Russel CD, et al. Lancet; Li H, et 
al. Influenza Other Respi Viruses).  Preliminary observational data suggests there may be a 
potential benefit of steroids in those with ARDS caused by COVID-19 (Wu C, et al. JAMA 
Internal Medicine) but this data is confounded by the lack of a true comparator. 
Corticosteroids should not be withheld if underlying indication exists (i.e. adrenal insufficiency, 
COPD exacerbation). 
For the management mechanically ventilated patients without ARDS, corticosteroids are not 
thought to be beneficial and may increase risk of mortality. 
For the management of mechanically ventilated patients with ARDS, there is a potential role 
for corticosteroid therapy.  A patient-specific risk vs. benefit decision should be made on a 
case by case basis by the critical care team. 
Cytokine Storm 
Definition: 
Cytokine storm applies to a condition of dysregulated immune activation and cytokine release 
resulting in fever, vasogenic edema, and hypotension which may mimic severe sepsis.  Clinical 


 
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entities associated with massive cytokine release include macrophage activation syndrome 
(MAS) and hemophagocytic lymphochistiocytosis (HLH).  Cytokine storm is believed 
responsible for clinical deterioration and progressive pulmonary damage occurring in severe 
cases COVID-19 infection. 
Diagnosis:  
No formal diagnostic criteria for cytokine storm have been defined in the setting of COVID-19 
but may be suspected on clinical grounds.  The presence of the three criteria below may 
constitute sufficient evidence of cytokine storm to institute anti-cytokine treatment. 
1. Appropriate clinical context: COVID+, progression of symptoms >= 3 days after 
onset of symptoms or positive test 
2. Clinical deterioration: persistent fever and progressive hypoxemia: 
Escalation to ≥ 4-6L/min O2 via NC to maintain saO2 > 92% 
Transitioning from NC to NRB, BiPAP/HFNC or intubation 
BiPAP increased to FiO2 100% 
Increasing HFNC ≥ 60L/min, FiO2 ≥ 80% 
Intubated within 24h 
3. Laboratory evidence of inflammatory state: elevation >2x ULN of any of ferritin, CRP 
or LDH 
 
Laboratory Evaluation:  
Patients suspected with cytokine storm should have the following lab work collected at the time 
of treatment initiation and repeated 48 to 72 hours later for evaluation of effect: 
CBC with differential 
PT, fibrinogen, D-dimer / fibrin split products 
Ferritin, C-reactive Protein, CPK, troponin 
sIL-2R, IL-6 (send out to Viracor) 
Procalcitonin 
Treatment:  
Treatment of cytokine storm is aimed at blocking mediators of inflammation.  Two targets have 
been evaluated and demonstrated responses in clinical practice: IL-6 and IL-1.  In order of 
preference and subject to availability, the following interventions below are suggested.  
Anticytokine therapy may increase the risk of infection or impair the ability to fight concurrent 
bacterial, fungal or mycobacterial infection – use should proceed with caution. 
Sarilumab on clinical trial 
Tocilizumab 4mg/kg IV over at least 1 hour x 1 – give whole 400mg vial, repeat x1 in 6-
12 hours if response inadequate; dose of 8mg/kg (max 800mg) may be considered 
Infliximab 5mg/kg IV over at least 2 hours x 1 (may be preferred for patients with 
particularly high ferritin) 
Unlikely to be available for use 
Siltuximab 11mg/kg IV over 1 hour x 1, repeat x1 in 6-12 hours if response 
inadequate 
Sarilumab 200mg SC x1, repeat x1 in 6-12 hours if response inadequate 
Anakinra 100mg SC daily x 3-5 days, consider in setting of sepsis 
 
 


 
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Consultation: 
Hematology consultation is available 24/7 for questions regarding these guidelines, for 
refractory cases, or where alternative diagnosis is suspected.  Administration of anti-cytokine 
therapy according to the above guidelines does not require a formal hematology consultation, 
but requires approval from one of the following doctors: Andreas Klein, Jason Law, Tishi Shah, 
Hannah Fassel, Cathy Rosenfield, Laura Wiltsie, or Blythe Thompson. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix B – Laboratory Manual 
 
WHEN: Cytokine assays will be collected at baseline and at least 48 hours but no later than 72 
hours following the first dose of infliximab or infliximab-abda.  A Day 14 assay will also be 
drawn on all patients remaining hospitalized whereas for patients who are planned for 
discharge between Day 7 and Day 14, a repeat assay will drawn prior to discharge. Research 
staff will coordinate the orders to be integrated with routine clinical care. 
 
WHERE: These samples will be drawn by qualified inpatient staff at the time of routine 
standard-of-care blood draws whenever possible.  
 
WHAT: For the cytokine panel, approximately 6 mL of blood will be collected in an EDTA tube  
 
HANDLING: A member of the study staff will then gently invert the tube 8-10 times, before 
transporting the specimen from the inpatient unit to the lab for processing. 
 
PROCESSING:  
 
f) Blood samples will then be centrifuged by study staff at 1000 x g for 10 min at 4°C, 
within 30 minutes of blood collection and no later than 2 hours after collection.  
g) Plasma will be collected immediately into two collection tubes: Tube #1 will contain 
0.5 ml of plasma and Tube #2 with 0.5 ml of plasma).  
h) Tubes #1 and #2 will be 0.5 ml Eppendorf Safe-Lock Tubes. 
 
i) Each tube will be labeled alpha numerically with T (T for Tufts) followed by 
consecutive numbers.   
j) Both tubes will then be placed in a -20°C freezer until ready for shipment. 
 
SHIPPING FOR ANALYSIS OF CYTOKINES:  
 
An outside laboratory facility, Eve Technologies Corporation, will conduct the cytokine assays.  
Undiluted tube #1 will be shipped to EVE technologies for Human Cytokine Array / Chemokine 
Array 48-Plex (HD48).  Samples will be batched and shipped weekly using FedEx.  Samples 
can be shipped on Mondays and Tuesdays only.  The contact and shipping information is 
listed below: 
 
Eve Technologies Corporation 
Address: 3415A - 3 Ave., N. W. Calgary, AB. Canada T2N 0M4 
email: admin@evetechnologies.com  
website: www.evetechnologies.com 
Tel:  587-975-8850   
Fax:  587-975-8899 
 
All samples will be shipped frozen on dry ice.  Prior to shipment, samples will be removed from 
the freezer and placed in a plastic or cardboard sample box. The box will then be placed in a 
leak proof bag with absorbent material, which will then be placed in a Styrofoam insulated 
shipping boxes with a corrugated fiberboard outer box with a minimum of 5 kg of dry ice. A 
Class 9 Dry-ice label (UN 1845) will be affixed on outer packaging (with weights and 
addresses filled in). As the samples are infectious category B, UN 3373 label will also be 
affixed on the outer box.  Eve Technologies Corporation will be emailed on the day of shipment 
with the shipment manifest and tracking information.


 
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Appendix C – Schedule of Assessments 
 
 
 
1- Day 1 when anti-TNF therapy is administered, within 6 hours of enrollment and no more than 24 hours following enrollment. 
2- Day of discharge is the date of discharge from hospital, date of death or day 28, whichever occurs first. 
3- It is strongly preferred that all laboratory samples be collected per the schedule above (+/- 24 hours). 
4- Retreatment with infliximab at treating physician discretion 7-21 days following primary therapy and based on initial response; the 
usual treatment schedule is every 2 weeks, this interval is not strictly enforced given the uncertainty of outcomes with primary 
therapy. Follow-up of clinical and inflammatory markers will continue in this context as prescribed following Day 1of therapy.   
5- Pregnancy testing is required at Baseline only for women of childbearing potential.  Either serum or urine testing is acceptable.  
6- Only if discharge date is greater than or equal to Day 7 and less than Day 14 following Day 1 infliximab treatment.
Study Procedures 
Baseline   Day 11 
Day 2 
Day 3 
Day 4 
Day 5 
Day 14 
Day of discharge2 Day 28 
Follow-up 
Informed consent 
X 
 
 
 
 
 
 
 
 
Diagnosis confirmation 
X 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs of special interest/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chest Xray or CT scan 
X 
 
 
 
 
 
 
 
 
Infliximab or Infliximab-abda 
Dosing1, 4 
 
X 
 
 
 
 
X1, 4 
 
 
Required laboratory tests 
Pregnancy Test5 
X 
 
 
 
 
 
 
 
 
CBC with differential3 
X 
 
 
X 
 
X 
X 
X 
 
CMP3 
X 
 
 
X 
 
X 
X 
X 
 
Coagulation profile3 
X 
 
 
X 
 
X 
X 
X 
 
Inflammatory profile3 
X 
 
 
X 
 
X 
X 
X 
 
Cytokine profile3 
X 
 
 
X 
 
 
X 
X6 
 
Hepatitis panel 
X 
 
 
 
 
 
 
 
 
Disease and response assessment 
O2 requirements 
X 
X 
X 
X 
X 
X 
X 
X 
 
Mode of ventilation 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vasopressor support 
X 
X 
X 
X 
X 
X 
X 
X 
 
Secondary infections 
 
 
 
 
 
 
 
X 
 
Follow-up 
Survival Follow-up 
 
 
 
 
 
 
 
 
X 


 
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