Sarilumab for Patients With Moderate COVID-19 Disease: A Randomized Controlled Trial With a Play-The-Winner Design
Phase: PHASE2
Conditions: COVID
Sponsor: Westyn Branch-Elliman

Sarilumab for Patients with Moderate COVID-19 Disease: A Randomized Controlled Trial with a Play-The-
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Sarilumab for Patients with Moderate COVID-19 Disease: A Randomized 
Controlled Trial with a Play-The-Winner Design. 
 
Principal Investigator:  Westyn Branch-Elliman 
 
Phone: 857-203-5116 
 
E-mail:  Westyn.Branch-Elliman@va.gov 
Protocol Version Number:  8.0 
Protocol Version Date:  January 28, 2021 
 
Funding Mechanism:  pending 
Industry Support provided by:  none 
ClinicalTrials.gov number: NCT04359901 
 
IND:  Exemption Granted by FDA 
 
 
 

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TABLE OF CONTENTS 
 
1. Protocol Summary/Abstract ................................................................................................3 
2. Aims/Objectives .................................................................................................................3 
3. Background Information .....................................................................................................4 
4. Rationale and Purpose ........................................................................................................5 
5. Relevance to Veterans Health .............................................................................................6 
6. Study Design.......................................................................................................................6 
7. Study Subject Selection .......................................................................................................6 
a. 
Sample Description ....................................................................................................6 
b. 
Subject Inclusion Criteria............................................................................................6 
c. 
Subject Exclusion Criteria ...........................................................................................7 
d. 
Recruitment ..............................................................................................................7 
8. Data Collection/ Study Measures ........................................................................................8 
9. Statistical Analysis Plan ..................................................................................................... 16 
10. Ethical Issues .................................................................................................................... 21 
a. 
Risks ........................................................................................................................ 21 
b. 
Potential Benefits .................................................................................................... 21 
c. 
Analysis of Risks in Relation to Benefits .................................................................... 22 
d. 
Stopping Rules ......................................................................................................... 22 
11. Safety Monitoring Plan ..................................................................................................... 22 
12. Adverse Event/Unanticipated Problems Reporting Plans.................................................... 27 

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1.  Protocol Summary/Abstract  
 
Objectives: 
To determine whether blockade of IL-6R is beneficial in patients 
with COVID-19 infection of moderate severity. 
Research Design: 
Randomized, controlled trial.  Two-arm trial comparing standard 
care alone to standard care with addition of sarilumab (anti-IL6R). 
The trial will use a randomized play-the-winner design, in which 
randomization becomes weighted toward the arm that was more 
effective in previous subjects in the trial. 
Methodology 
Hospitalized patients meeting clinical criteria for moderate disease 
and testing positive for coronavirus infection.  Interventions:  
sarilumab, 400 mg subcutaneous injection.  Standard care is not 
pre-specified, may vary among patients, and may include agents 
with anti-viral activity, such as remdesivir or hydroxychloroquine, 
among others.  Up to 120 patients, primary outcome intubation or 
death within 14 days.  Secondary outcomes will include new onset 
delirium, ICU admission, new onset heart failure, new onset 
arrhythmia, new or worsening renal failure, and thromboembolic 
disease. All data will be extracted remotely from the EHR. 
Clinical Implications: 
The study has potential to establish IL-6R blockade, delivered 
subcutaneously, as standard of care in reducing progression to 
critical illness in patients with moderate COVID-19 disease. 
 
 
2. Aims/Objectives 
 
The effectiveness of blockade of IL-6R in treating patients with COVID-19 disease of moderate severity 
will be tested in a pragmatic and adaptive randomized trial.  The primary outcome is intubation or death 
within 14 days of enrollment OR administration of a rescue dose of IL-6 inhibition if the patient is 
DNR/DNI and the primary team determines it is appropriate based on clinical deterioration.  Secondary 
outcomes include time to hospital discharge if alive, time to clinical recovery as was defined in a recent 
study [1], ICU length of stay, time to return to normal or baseline oxygen saturation without subsequent 
new or increasing supplemental oxygen before hospital discharge, and changes in laboratory 
biomarkers.  Secondary outcomes will include new-onset delirium, ICU admission, new onset heart 
failure, new onset arrhythmia, new or worsening renal failure, and thromboembolic disease.  Secondary 
clinical outcome status of a subject at will be assessed at time of randomization, time of discharge from 
hospital, and 30 days post-randomization, utilizing a seven-point ordinal scale [2] as follows1. 
<4 Alive, not hospitalized 
4 Hospitalized, no oxygen therapy 
5 Hospitalized, oxygen by nasal prongs or mask 
6 Hospitalized high-flow O2 or non-invasive ventilation 
7 Intubated or ECMO 

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1 Note: Points 1-3 of this scale are defined as: 1, not hospitalized and no limitations of activities; 2, not 
hospitalized, with limitation of activities, home oxygen requirement, or both; 3, hospitalized, not 
requiring supplemental oxygen and no longer requiring ongoing medical care.  As clinical outcome status 
will be determined utilizing remote data collection from the electronic medical record, it is not feasible 
to assign statuses corresponding to Points 1-3.  Other researchers (Beigel et al) have noted that 
consideration of Points 1-3 as indicators of a single outcome (defined as “recovery”) is acceptable in the 
context of COVID-19. 
 
3. Background Information 
 
SARS-COV-2 is a novel human pathogen that emerged at the end of 2019 and rapidly spread worldwide. 
Clinical disease caused by this novel infection has a high mortality rate, particularly in older adults and in 
patients with underlying cardiopulmonary disease, populations that are highly prevalent within the VA 
healthcare system. This creates an urgent need for the VA to quickly and efficiently identify effective 
therapies to reduce mortality and spread of the disease. Based on in vitro and in vivo data, potential 
treatment options include anti-viral drugs (such as antimalarials or medications originally developed to 
treat HIV infection (e.g., lopinavir/ritonavir, remdesivir)), anti-inflammatory drugs, including IL-6 
inhibition, and innovations in supportive care, such as placing patients in prone positioning while awake 
and not intubated.  Importantly, in the context of the global pandemic and exponential spread of the 
disease, clinical trials must be designed in a manner that 1) optimizes outcomes for Veterans, and 2) 
produces rapid answers, so that effective treatments can be deployed quickly to reduce unnecessary 
deaths.  Based on a review of 384 ongoing clinical trials by the Centre for Evidence-Based Medicine, and 
a daily search of open clinical trials, many conventional controlled clinical trials of antiviral drugs and 
cytokine-blocking drugs are in progress and are likely to be completed within a few months; however, it 
is possible that these trials, which may take months to implement and report results, will not yield any 
information about how to treat patients until after the peak of the pandemic is over. A secondary 
challenge is that it is important to identify what works and what does not work quickly, so that 
manufacturers can understand what medications need to be produced so that supply chains are 
adequate for treating all patients who might benefit from an intervention. Thus, innovative clinical trial 
methodologies are needed in order to produce answers in a highly compressed time frame to inform 
medical decision-making and supply chain management.   
 
This novel and innovative proposal concerns use and comparison an existing drug (sarilumab) that 
blocks the receptor for the inflammatory cytokine IL-6.  Most studies of IL-6 pathway blockade are using 
IV medications and include restrictive eligibility criteria and are directed towards patients with severe 
disease.  We hypothesize that patients earlier in the disease course – prior to severe respiratory 
decompensation – might benefit the most from IL-6 inhibition, and thus are the population included in 
this pragmatic trial. This study will expand our knowledge and understanding about how IL-6 inhibition 
can be used to prevent disease progression in patients with moderate disease. It will use a more readily 
available subcutaneous, longer-acting formulation directed towards patients with moderate disease, of 
whom 25-35% can progress to severe disease, often rapidly.  Eligibility criteria allow for a broad range of 
underlying choices of other medications, including antiviral medications such as remdesivir and 
hydroxychloroquine, among others, baseline laboratory values, and comorbidities, reflecting likely real-
world clinical use.  Thus, this pragmatic project would fill a major gap in research about the clinical care 
of patients with COVID-19. 
 

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Release of preliminary results to the popular press already necessitated revision of this protocol after 
only 9 subjects had been enrolled.  Interim analysis of a study of sarilumab by its manufacturer has led 
to revision of the study population and treatment arms.  Originally, two doses (200 mg and 400 mg) 
were tested, and patients with either severe (oxygen requirement and other poor prognostic features) 
or critical (mechanical ventilation) disease were included.  Interim analysis indicated benefit only with 
400 mg in critical disease, so that will be the design of the remainder of that trial.  In contrast, a study of 
a relatively high dose of tocilizumab (8 mg/kg) was reported to be beneficial in a controlled trial of 
patients varying in severity from critical illness to merely requiring supplementary oxygen.  In response, 
the current study has been modified to allow routine escalation of dosing among a broad range of 
“moderate” severity short of critical illness.  For patients who are critically ill, it is expected that off-label 
use of a wide range of “heroic” therapies will be tried, including but not limited to cytokine blocking 
therapies, so exclusion of such patients from this trial does not limit the therapeutic options for such 
patients, and from a research perspective, such patients have become the focus of the largest ongoing 
study of sarilumab. 
 
4. Rationale and Purpose  
 
Severe COVID-19 disease is characterized by a severe acute respiratory distress syndrome (ARDS) 
followed by a severe cardiomyopathy in many cases. Based on currently available data, it is unclear how 
much of the respiratory damage in COVID-19 is due to direct effects of SARS-COV-2, or if the primary 
driver of severe disease is the inflammatory response generated in response to the virus.   The key role 
of inflammation in the progression of the disease is highlighted by recent studies, which demonstrate 
that patients who progress to requiring ICU-level care no longer have detectable virus present in their 
respiratory tract. Thus, identifying drugs that could dampen the inflammatory response prior to severe 
clinical decompensation without adversely affecting clearance of virus would be clinically useful and 
lead to improved outcomes.  Elevated biomarkers of severe inflammation (such as IL-6, CRP, ferritin, and 
lymphopenia) have been strongly associated with severe disease and increased mortality in patients 
with COVID-19 [3,4], and early development of a strong IgG response may paradoxically be a poor 
prognostic sign during the acute phase of the disease.  In contrast, viral load in upper respiratory 
secretions at baseline is only modestly associated with clinical outcomes, and viral load declines in most 
patients after presentation, independent of the clinical course of the disease [5].  Severe disease 
typically arises more than 2 weeks after symptom onset, a time at which virus is usually no longer 
detectable.  These findings suggest that progression to severe disease may be driven more by the 
inflammatory response to the disease than a direct viral effect and point to anti-inflammatory drugs as 
potentially critical therapeutic options.  Importantly, high dose glucocorticoids have been found to be 
ineffective in severe COVID-19 and are associated with somewhat worse outcomes, so other more 
targeted anti-inflammatory options are urgently needed. 
 
Blockade of IL-6 signaling is a particularly attractive approach.  Sarilumab and tocilizumab are antibodies 
to the IL-6 receptor (IL-6R), FDA-approved for long-term treatment of rheumatoid arthritis.  Tocilizumab 
has been used open-label with enough anecdotal success in enough patients in China [6] that the 
manufacturers of sarilumab and tocilizumab have rapidly opened clinical trials in multiple countries at 
assess efficacy in patients with severe COVID-19 disease.  Tocilizumab has also demonstrated efficacy in 
reducing mortality associated with the cytokine release syndrome in patients receiving CAR-T treatment 
for cancer, in which the pathogenic pathway is widespread T-cell activation, which leads to production 
of pleiotropic inflammatory cytokines such as IL-6 by monocytes.  Although trials attempting to rescue 

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patients with severe COVID-19 with ARDS and/or cardiomyopathy are essential and are in progress, the 
ideal population for clinical use may be patients who are not yet critically ill but are at high risk of clinical 
deterioration due to secondary inflammation.  
 
5. Relevance to Veterans Health 
 
COVID-19 has a high mortality rate of 2-3% among symptomatic patients.  It is expected to have a 
particularly high mortality in Veterans, because age >60, underlying cardiovascular or lung disease, and 
obesity are significant risk factors for mortality and clinical deterioration.  Thus, advances in care of 
patients sick enough to be hospitalized yet prior to intubation are expected to have particular benefit for 
Veterans. 
 
6. Study Design 
 
Sites.  VA Boston Healthcare System, VA Connecticut Healthcare System, White River Junction VA 
Medical Center, Providence VA Medical Center, VA Maine Medical Center – Togus. 
 
Design.  Prospective, randomized, unblinded interventional clinical trial. 
 
Two arms:  standard care, based on established practices within the medical center, or standard care 
plus subcutaneous sarilumab.   
 
Assignment Strategy: Randomized play-the-winner design, such that randomization becomes weighted 
toward the arm that was more effective in previous enrolled subjects.  The probability of randomization 
to a specific arm (standard of care or standard of care plus intervention) will be updated based on 
outcomes in blocks of 15 subjects (see Planned Statistical Analyses).  The protocol does not include 
administration of sarilumab or tocilizumab as a “rescue” medication if a patient randomized to standard 
of care alone deteriorates to the point that the primary outcome (intubation) is met, or if the patient is 
DNR/DNI and the patient’s primary clinical team determines intubation would be performed if the 
patient’s goals of care included intubation. Such patients may receive any treatment per the judgment 
of their treating physician, and such treatment might include sarilumab or tocilizumab. Use of sarilumab 
or tocilizumab in this setting will simply be regarded as a treatment failure and not as a protocol 
deviation. 
 
Data will be extracted remotely from the EHR.  No data will be generated specifically for study purposes.  
 
7. Study Subject Selection 
 
a. Sample Description 
Study subjects will be inpatients with confirmed SARS-CoV-2 testing. Testing is performed at the 
discretion of the treating physician.  Only Veterans will be enrolled. 
  
b. Subject Inclusion Criteria 
1. Positive testing for active infection with novel coronavirus SARS-CoV-2019  
2. Patients with moderate COVID-19 disease as defined clinically:   

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a. Score of 1-3 (out of 3) on a modified Brescia COVID respiratory severity score (BCRSS), 
elements of which include wheezing or inability to speak complete sentences without 
effort, respiratory rate ≥22, O2 saturation ≤94% with or without oxygen 
supplementation, or requiring ≥2L supplemental oxygen to maintain O2 Sat >94% in 
patients without previously documented hypoxia or baseline oxygenation requirement; 
either is equal to one point on the score) all within a 24-hour period prior to enrollment, 
and/or any worsening of chest X-ray (CXR) findings after COVID-19 diagnosis. 
b. Worsening of baseline oxygenation by at least 3%, or increase in oxygen requirement by 
at least 2L, in patients with pre-existing hypoxemia or receiving supplemental oxygen 
chronically. 
c. The BCRSS risk calculation score is available at: https://www.mdcalc.com/brescia-covid-
respiratory-severity-scale-bcrss-algorithm 
 
c.  Subject Exclusion Criteria 
1. Critical disease, defined by need for mechanical ventilation 
2. Expected death within 48 hours 
3. Patients taking any of the following for chronic inflammatory diseases:  glucocorticoids 
equivalent to prednisone > 10 mg/day (methylprednisolone > 8 mg/day, dexamethasone > 2 
mg/day), a JAK inhibitor (tofacitinib, baricitinib, upadacitinib), or a biologic  
a. Use of chronic inhaled steroids is NOT an exclusion 
b. Current or recent short-term use of glucocorticoids for chronic conditions such as 
COPD or gout is NOT an exclusion. 
c. Current use of glucocorticoids for COVID-19 is NOT an exclusion 
d. Use of biologics for non-inflammatory diseases is NOT an exclusion 
4. Receipt of any IL-6 inhibitor within 3 months prior to enrollment in the trial  
5. Pregnancy, due to lack of fetal monitoring capabilities  
6. Patients enrolled in other interventional clinical trials, including for COVID-19. Patients 
enrolled in non-interventional studies or receiving non-FDA-approved drugs for 
compassionate use are not excluded. 
7. Patients whose goal of care is comfort measures only 
8. Inability to provide informed consent, or absence of a legally authorized representative to 
provide informed consent. 
9. Severe psychiatric disease that prevents compliance with typical medical care. 
10. Initial positive test for active infection with novel coronavirus SARS-CoV-2019 was >4 
weeks prior to current admission. 
 
d.  Recruitment 
 
Recruitment will occur in-person or over the phone in the inpatient areas at participating sites. At 
VHABHS, this will be at the West Roxbury campus.  The possibility of eligible participants will be 
made by notification of the PI, co-investigators, or study staff by the treating physician and/or by 
surveillance of any locally developed tracking database available to study investigators, e.g. COVID 
TRACKER at VHABHS. 
 
Patients identified as likely to have COVID-19 will be approached about participation when they are 
clinically stable. Study materials delivered to patients may include a plain-language letter explaining 

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the rationale for the study and what involvement might entail. Potential participants may be 
approached in person or usually over the telephone to minimize risk of staff exposure to the highly 
infectious agent, SARS-CoV-2, using approved mechanisms to obtain consent in this way (see Section 
8b, Informed Consent Process).  Patients who are not currently eligible for inclusion based on clinical 
stability, but who may become eligible in the near future (e.g., patients with a Brescia score of 0 
who may progress to 1-2), will also be consented.  Approaching patients at an early time point for 
informed consent is preferable both for the purposes of recruitment and for ethical reasons, since 
patients actively in the process of becoming more ill may not be able to make well-informed 
decisions, and urgent medical care will take precedence.  Patients who have indicated interest in 
enrollment, but initially failed screening will be considered eligible if they subsequently meet criteria 
even if it would not be possible or appropriate to discuss the study again due to clinical 
decompensation.  Of course, patients can, if able, have the opportunity to ask additional questions 
or can withdraw.  A Legally Authorized Representative (LAR) may alternatively be approached about 
the study and asked to provide consent. 
 
8.  Data Collection/ Study Measures 
 
Study Procedures 
 
a. Screening 
• 
COVID-19 laboratory testing 
• 
Brescia COVID Respiratory Severity Score (1-3 on a scale of 0-3) any time during the 24-hour 
period prior to enrollment 
• 
Exclusion criteria related to concurrent or recent use of immunosuppressive drugs 
• 
Exclusion based on CMO status, expected death within 48 hours, severe psychiatric disease 
limiting ability to comply with recommended treatments 
• 
Exclusion criterion of participation in another interventional clinical trial for COVID-19 
 
b. Informed consent process.  As noted above under Recruitment, patients may be approached about 
the study and sign the ICF and HIPAA authorization if they meet eligibility criteria, or if it is 
suspected or known that they are not yet eligible, i.e. if disease is not severe enough for enrollment 
but too severe for the patient to be discharged.  The process of informed consent will most often be 
performed remotely by a member of the study staff with a witness when the patient is in an 
inpatient room, usually over the telephone and/or video call via VA Video Connect (VVC) or other VA 
approved video-based platform (e.g. Facetime, Zoom). A copy of the Informed Consent and HIPAA 
Authorization will be provided to the patient by the clinical team prior to the call. The process is 
expected to take 20 minutes and is the only study-related procedure that requires time or attention 
from the patient.  Due to risk of infection for study staff and hospital personnel, it is usually going to 
be inappropriate to conduct the informed consent process face-to-face, or to collect and store the 
signed informed consent document. If the patient wishes to participate, they will be asked to 
confirm their intent and sign the consent and HIPAA forms. Documentation of written informed 
consent and HIPAA authorization when conducted remotely will be obtained in one of several ways, 
in compliance with guidelines from the VA Office of Research and Development.   
 
i. 
Photograph or screen capture using a VA phone or laptop, of the patient’s signature on the 
paper informed consent and HIPAA Authorization and a copy of the informed consent 

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signed, electronically or manually, by the person obtaining consent and witness with a 
notation of how consent was obtained and confirmation that the patient signed the consent 
document. The signed documents will either be printed and stored with other study 
documents or will be uploaded to a secure server.  
ii. 
Photograph taken by the patient, of his/her signature on the paper informed consent form 
and HIPAA authorization and sent to the investigator/delegated study team member. The 
photograph will either be printed and stored with other study documents or will be 
uploaded to a secure server 
iii. 
DocuSign may be utilized to obtain informed consent and HIPAA authorization from a 
patient or the patient’s LAR.  VA Office of Research and Development has approved 
DocuSign for use in the VA and specifically for use in this study. 
 
Face-to-Face Options for Obtaining Written Informed Consent 
As mentioned above direct interaction with the patient by the study team will rarely occur but if 
there is such an opportunity the following methods are approved to obtain written informed 
consent: 
 
iv. 
The person obtaining consent in the presence of the patient and a witness (in the room or 
on the phone) will review the consent document and address any questions. If the patient 
wishes to participate, they will be asked to confirm their intent and sign the consent and 
HIPAA forms. The person obtaining consent and witness will also sign the consent form. A 
copy of the signed documents will be collected by 1) obtaining a photo of the signed 
documents or 2) placing the signature page of the ICF in a sealed, clear plastic bag. After 
leaving the room, the plastic bag will be decontaminated (e.g., with UV light sanitizer, 
alcohol swab, CAVI wipe, or other antiviral disinfectant wipe). After decontamination, the 
signature page will be either copied, and a copy of the signature will be maintained in the 
study files, or the signature page will be scanned into a PDF file and stored in the study 
folder. Due to the risks of losing the paper form, and the potential for privacy breaches that 
might arise from misplaced study documents with PHI, after the signature page is copied or 
scanned, the document will be destroyed (e.g., shredded), and a note will be made in the 
study file that the original was destroyed and a copy was maintained. This process will 
maintain staff safety and limit risks of breach of confidentiality for study participants. 
 
v. 
Use of iMed Consent, an electronic version of the consent created in CPRS includes the 
same language as is on the approved informed consent form. Use of the iMed consent 
would require a face-to-face interaction with the patient by the person obtaining consent 
and witness and then rolling in a computer cart into the patient’s room to provide the Epad 
to sign the consent document electronically. Use of iMed automatically generates a note in 
CPRS to serve as documentation. While an iMed version of the consent document has been 
prepared it may not be practical to implement given the current COVID-19 recommended 
precautions. 
 
Obtaining Informed Consent from a Legally Authorized Representative 
If a LAR is providing consent, the consent form and HIPAA Authorization will be emailed to them 
using Azure RMS encrypted email, and the informed consent process will be conducted by phone or 
video call using approved VA platforms. The LAR will be asked to print and sign the ICF and either 

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scan or take a picture of the signature page and send it back to the study team. Alternatively, a 
screen capture of the LAR’s signature will be witnessed using VA-approved technologies such as VVC 
or Zoom as approved by the ISSO.  
 
In the instance that a LAR does not have access to a printer, the study team will overnight the 
documents to the LAR with instructions to sign the documents and as above send a photo of the 
signed ICF and HIPAA forms.  
 
Study staff will enter a standardized note in CPRS that describes the conduct of the informed 
consent process and how written informed consent was obtained.  If eligibility criteria are met, then 
randomization may proceed as below.  If criteria are not met (i.e., BCRSS score = 0), then 
randomization may be initiated later, when BCRSS > 0) by adding an addendum to this note or an 
additional note. 
 
c. Physical examination, laboratory testing and chest imaging will be performed as indicated clinically 
and will be directed based on the treating physicians and will not be conducted specifically for 
research purposes.  Exam findings (respiratory effort, wheezing, respiratory rate, oxygen saturation) 
and chest imaging are included in the BCRSS score but are not beyond standard clinical practice. 
 
d. Randomization.  Will be performed by a member of the study staff, using an online tool built by the 
coordinating center, after eligibility criteria have been confirmed as above.  First, a dialog box will 
appear that is only visible to the study staff and is linked to a URL that will perform randomization 
and fill a box for either “Randomized to usual care” or “Randomized to sarilumab plus usual care”.  
Each of these will generate a note in CPRS.  Randomization to “sarilumab plus usual care” generates 
a prompt and link to order the medication, which can only be done by an investigator.  
Randomization to “usual care” includes text in the note that the patient may be declared a 
treatment failure by the treating physicians before the primary outcome (intubation) is met, or if 
they are DNR/DNI and the primary team feels death is certain otherwise but may be avoidable with 
treatment.   The primary team may choose to order tocilizumab if available in the medical center 
but is not encouraged to do so as part of this protocol. 
 
In the event that the randomization application is not functioning, randomization will be performed 
by the statistician or a designee not involved in the screening or enrollment of subjects, with the 
result then communicated to the study team. 
 
e. The pharmacy will be notified immediately when the patient is randomized to receive subcutaneous 
sarilumab and the order has been placed. A copy of the signed consent form will also be sent to the 
research pharmacist. 
 
f. Intervention.  Sarilumab 400 mg subcutaneous injection, or no injection.  Sarilumab is provided in 
prefilled syringes/pens containing 200 mg each as is used clinically, and both injections will be given 
as soon as is convenient after the patient has decided to enroll. Standard of care as directed by the 
treating clinicians will be offered in both arms.   
 

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g. Clinical follow-up.  The primary and secondary endpoints are all objective and will be extracted from 
the EHR remotely rather than through interaction with the study subject.  All blood draws are done 
for clinical purposes only.  The lab data collected are consistent with standard of care, but since 
practice may vary among treating physicians, missing lab data will not be considered protocol 
deviations.  No sensitive data will be collected.  There are no follow-up study visits or contact with 
study subjects, but the EHR will be monitored for medical problems for 6 months after surviving 
patients have been discharged.  These data will be considered study data and will not be reported as 
adverse events.  
 
Clinical data 
• 
Demographics:  age in years, sex, race/ethnicity if available in the EHR, body mass index 
if available in the EHR, smoking status if available in the EHR  
• 
Comorbidities of interest:  coronary artery disease, heart failure, cardiac arrhythmia 
history, COPD, asthma, bronchiectasis, pulmonary fibrosis, diabetes, hypertension  
• 
Date of intubation if applicable 
• 
Date of symptom onset 
• 
Reason the patient was screened for infection with SARS-CoV-2 (e.g., symptoms or high-
risk exposure, community-based screening) 
• 
Date of use of rescue IL-6 inhibition in a patient randomized to standard care, if 
applicable 
• 
Date of death if applicable 
• 
Cause of death if applicable (Note: Cause of death will be manually adjudicated if death 
occurs within the first four weeks after patient randomization.  If death occurs beyond 
the first four weeks after patient randomization, cause of death will be extracted from 
the EHR) 
• 
Date of hospital discharge if living 
• 
Date of return to oxygen saturation >94% without supplemental oxygen, or to the 
patient’s baseline if that baseline is <95% 
• 
Date of clinical recovery, defined as body temperature <37.2degC and slight/no cough 
per patient report, each for 72 hr [1] 
• 
Administration of antibacterial antibiotics, including type, duration, and indication 
• 
Administration of a “rescue” dose of tocilizumab or sarilumab 
• 
Diagnosis/treatment of bacterial pneumonia (at 1 month and 6 months) 
• 
Administration of other medications for COVID-19  
• 
Date(s) of post-hospital discharge visits to VA Emergency Department and 
reason(s)/indication(s) for visit 
 
Laboratory data 
• 
Results of COVID-19 test for active infection, including date of first positive 
• 
CRP 
• 
Ferritin 
• 
D-dimer 
• 
CBC with differential: WBC, Hgb, platelets, total neutrophil count, total lymphocyte 
count 
• 
Liver function tests 

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• 
Blood chemistry 
• 
Troponin 
• 
CPK 
• 
Procalcitonin 
• 
Microbiology results, including results of sputum cultures, blood cultures, and urine 
cultures 
  
 
Imaging data 
• 
CT findings 
• 
CXR findings 
 
h. Regulatory / Privacy Aspects. No sensitive data will be collected.  No samples are collected for 
research purposes only.  No study data will be released to non-VA investigators unless a de-
identified or limited dataset is released later upon publication of findings, as described in the DMAP. 
 
Data Collection 
 
Data collection will be via VA electronic medical records and administrative data. Assessment of 
outcomes and relevant data elements as well as adverse events is by active or passive collection of data 
in electronic health records; the study will not attempt to generate any additional tests or procedures. 
All outcome processing will be conducted by investigators at the Boston CSPCC unaware of treatment 
group. In this section we describe our approach to ascertainment and assessment of such outcomes.  
 
Data on the primary outcome will also be obtained in parallel by review of the EHR on a daily basis by 
study staff. Chart review will be necessary, at some point in the study, to accurately determine the 
timing of the primary endpoint. Doing so during study treatment is essential to determine whether the 
primary team is considering use of open-label tocilizumab. Because the primary endpoint is objective, 
there is little or no possibility of bias being introduced by the study staff reviewing charts for this 
outcome in an unblinded manner. 
 
Site study staff will surveil for Serious Adverse Events for 30 days and record data on an Excel 
spreadsheet template, located in a site-specific folder with limited access and maintained in a secure 
server space.  Sites will report SAEs to their local IRBs of Record as appropriate/required and will provide 
the IRB submission forms to the CSPCC via SharePoint as the primary record of this information. 
 
Surveillance for additional safety events between 31 days and six months will be performed by the 
Coordinating Center using data pulls. These will not be reported as Serious Adverse Events. 
 
As noted above under Recruitment, identifying potentially eligible study subjects will be performed by 
manual review of the COVID TRACKER database.  Thus, advanced methods for identifying outcomes will 
be focused primarily on potential adverse events during the study and medical complications during the 
6 months after the study is completed. 
 
a. Background 
 

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The Boston MAVERIC Center has 20 years of experience in ascertainment and assessment of outcomes 
using the VA electronic health record (EHR) data.  We will build on this extensive experience to refine a 
specific procedure for doing the same in this trial in order to accurately identify and assess 
outcomes.  The process involves several clearly defined steps.  First, we develop a method to screen the 
EHR of all participants on a periodic basis for potential cases.  This screening consists of comparing 
diagnosis and procedure codes for enrolled patients to a list of outcome-relevant ICD 10 and CPT 
codes.  Codes that do not match codes on our list will be considered non-events.  The development of 
the screening process and the algorithms for confirming cases follows a systematic approach that we 
have used at MAVERIC for a number of years.  The screening approach is used to identify all potential 
cases using key elements in the EHR.  The screening tool varies for each outcome (i.e. outcome-specific 
administrative diagnosis codes).  
   
Second, algorithms are developed to collect and analyze data elements that are used to confirm or 
refute the potential cases (e.g. presence of imaging during a stroke).  The algorithms are based on 
elements of the clinical definitions of the outcomes and are applied to potential cases to determine if 
the case is confirmed, refuted, or deemed indeterminate.  Algorithms for cases are constructed using 
“gold standard” cases (identified by manual chart review) and data elements obtained from the medical 
record that are found in the outcome definitions, such as cardiac enzymes for MI.  Once the algorithm 
for a specific case is defined, the algorithm’s accuracy is checked by manual review of cases identified by 
the algorithm.     
 
Third, indeterminate cases undergo manual adjudication via chart review by a trained clinician. We 
expect to be left with a relatively small number of events that cannot be resolved by the algorithm, but 
all of these will be referred for adjudication to an outcomes committee. This greatly lessens the 
workload for manual adjudication. All patients will be followed until death or 6 months after the end of 
the subject’s participation in the study (even if the primary outcome is determined to have occurred) to 
collect secondary outcomes.   
 
As an example, a pilot study using VA EHR in the Diuretic Comparison Project (CSP #597) was conducted 
to determine the availability of potential cases and core data elements that would be needed to develop 
algorithms to assess the primary cardiovascular outcomes and to test this system.  A total of 150 
medical records were reviewed, 30 in each category for stroke, myocardial infarction and urgent 
coronary revascularization and 60 records of patients with a diagnosis of acute heart failure.  A medical 
record abstraction form for each outcome was developed based on standard diagnostic definitions that 
included information on symptom presentation, physical findings, critical laboratory values, radiographic 
or imaging findings, electrocardiographic results, hemodynamic data and administration of medications 
and therapeutic interventions. 
 
b. Adjudication of events  
 
In addition to the review of indeterminate cases, we will also manually adjudicate serious adverse 
events and the secondary outcomes that occur during a subject’s participation in the study.    
 
c. Data Collection and Data Sources   
 

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Data for this study will be obtained from the medical and administrative data that are collected and 
maintained by the United States Department of Veterans Affairs (VA) Corporate Data Warehouse 
(CDW).  This database covers the entire veteran population that utilizes the VA and contains individual 
information on demographic factors, medical history, key laboratory values, procedure codes, and 
diagnoses (inpatient and outpatient) coded with the ICD-9-CM and ICD-10 classification systems. 
Healthcare encounters outside of the VA system will not be captured as a part of this project. Data from 
the various VA databases will be linked together using a unique veteran identification number that is 
assigned to each veteran at entry into the system.  
 
Vital status will be ascertained, in part, from and cross-referenced with the VA Vital Status File. This file 
allows for complete ascertainment of death as it pulls data from multiple sources, including: the 
Beneficiary Identification and Records Locator Subsystem database; the Death Master File from the 
Social Security Administration; and the National Patient Care Database.  Ascertainment of death with 
this method has demonstrated 98% sensitivity and 98% agreement with the National Death Index. Cause 
of death will be collected from the National Death Index, as the VA Vital Status File does not aggregate 
cause of death across the aforementioned data sources.  
 
d. Data Management and Data Security Plans  
Boston CSPCC will employ the use of several data management and analysis tools throughout the 
conduct of the study including Microsoft SQL Server Management Studio and SAS. Additional 
information on the use of tools for the analysis of study data can be found in the study specific DMAP 
and Statistical Analysis Plan.  
The Boston CSPCC will create and maintain an electronic study database to manage the trial data.  All 
study data will be collected electronically from CPRS and/or CDW and a study-specific web application 
by the Coordinating Center throughout the duration of the study.  There will be limited paper-based 
study documents.  
Study data is housed on secure VA servers, encrypted and protected in accordance with VA policies 
compliant with FDA requirements, Federal Information Security Management Act and the HIPAA Privacy 
and Security rules.  Data for this study will be stored in two locations: 1) on a VINCI-hosted server and 2) 
on a MAVERIC-hosted server.  Boston CSPCC personnel manage the data access request process for the 
electronic systems to ensure that data access is appropriate for each individual and the level of the 
individual access.  Study project management will manage the Data Access Request Tracker (DART) 
activities associated with granting VINCI access to study databases.  VA’s Office of Information & 
Technology (OI&T) is responsible for managing other VA system access and ensuring the security and 
integrity of VA information systems, including the databases and servers housing study data.  In 
accordance with VA Handbooks and Directives, OI&T is responsible for ensuring that appropriate 
firewalls and data security is implemented and maintained, that data backups are performed and that 
data may be restored in the event of a system malfunction.  
 
Data security incidents will be reported according to 1058.01. All Boston CSPCC staff will be expected to 
report data security incidents to the responsible authority immediately after they become aware of the 
breach. Whenever possible, the reporting of data security incidents will be handled by the Boston CSPCC 
Associate Center Director for Quality Assurance (ACDQA). This will be done to facilitate communication 

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between the center and the oversight bodies. In the event that an incident must be reported by a staff 
member other than the ACDQA, all communication after the initial report will be handled by the 
Boston CSPCC Center Director, the Boston CSPCC ACDPOC, or the Boston CSPCC ACDQA. [Note: all new 
and current Boston CSPCC personnel will be trained on reporting data security incidents.]    
 
All local data security incidents will be reported in accordance with VA policy immediately upon 
discovering the incident to:  
 
1. The Boston Information Security Officer (ISO)   
2. The Boston Privacy Officer (PO)   
3. The Boston ACOS for Research   
4. The Boston CSPCC Quality Assurance department  
 
Data security incidents will be treated as unanticipated problems by the Boston CSPCC and will be 
reported as such to the VA IRB.  
 
Study data will be coded and stored using a unique study identifier for each participant. Identifiable 
information will be collected for patient tracking and safety purposes, and kept in an encrypted, 
password protected file to which a small number of people will have access. Access to the crosswalk file 
linking the participant's identifiers and their study data will be restricted to the approved personnel at 
the CSP coordinating center. At the end of the study, study data will be stored according to CSP 
guidelines and procedures. Retention of data will be conducted according to CSP operating procedures 
and federal and local VA regulations. This file will be destroyed according to CSP policy well after the 
close of the study.  
  
Access to the study data is restricted to individuals with CSP approval. Study team members must be 
properly credentialed research staff and must be compliant with VA security trainings (e.g. HIPAA, Rules 
of Behavior, and Good Clinical Practices). Once formal training is completed, user accounts for a study-
specific web application utilizing a URL specific to the study to access and use the system and enter 
patient data will be activated for project management, and study nursing staff.. Accounts will be 
password protected and unique to each user. The account permissions will correspond with the users' 
functional study group.  Furthermore, the permissions of the electronic systems are heavily restricted. 
Only properly approved Coordinating Center personnel will have the ability to copy and export data. 
These individuals have received training on the local standard operating procedure (SOP) governing their 
permissions. Access to protected health information (PHI) will be restricted to individuals approved by 
CSP to have access to the data.  
 
At the Boston CSPCC the following staff will have access to all forms of PHI:  
 
1. Center Director  
2. Study Director  
3. Project Management  
4. Study Nurses   
5. Data Management  
6. Biostatisticians  
7. Quality Assurance Officer  

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8. SAS/Database Programmer  
9. Research Assistant  
10. Clinical Applications Coordinator  
11. Informatics Team  
 
Periodic access control assessments will be made by Coordinating Center Quality Assurance personnel 
to verify that access is controlled and appropriate for personnel. In addition, the CSPCC QA group will 
provide continuing education on good clinical practices compliance and will evaluate clinical site 
operations for violations of VA policies including VA data security policies and GCP.  
 
At the end of the study, the data for this trial will remain property of the investigators and be stored and 
shared according to CSP guidelines and procedures. Retention and destruction of data will be conducted 
according to CSP operating procedures and federal and local VA regulations. This will include electronic 
data stored at the MAVERIC CSPCC, and at the VA facility housing our servers. Identifiable data will be 
kept according to CSP policy as outlined in the "CSP Investigator Guidelines for the Planning and Conduct 
of Cooperative Studies”. 
 
e. Data Management and Access Plan  
 
Upon final analysis of the stated objectives in this protocol, the study plans to submit results for 
publication in scientific peer-reviewed journals and provide summary results on ClinicalTrials.gov. 
Results will be posted on ClinicalTrials.gov no later than one year after the last patient has been 
followed for 6 months after hospital discharge. After acceptance of the primary and other stated 
analyses by a journal, the Boston CSPCC will make these publication(s) available via the National Library 
of Medicine’s PubMed Central within one year of the date of publication.  
 
Digital data underlying primary scientific publications from this study will be held as part of a data 
sharing resource maintained by the CSPCC. Study data held for this purpose may include data, data 
content, format, and organization. The data may contain but are not limited to individually identifiable 
information, other PHI, and study codes. The data may be available to the public and other VA and non-
VA researchers under certain conditions and consistent with the informed consent and CSP policy that 
prioritize protecting participants’ privacy and confidentiality to the fullest extent possible. A detailed 
plan for data sharing will be developed in accordance with current technology, infrastructure, best 
practices, and policies and procedures in place at the time of oversight committee reviews (e.g., Privacy 
Board, Information Security, and Information Technology standards). The plan will include how data will 
be discovered, retrieved, analyzed, and managed and will note the materials that are available in 
machine-readable formats. This plan may be revised to ensure consistency with VA, including CSP, 
policies and standards for overall data sharing.  
 
9.  Statistical Analysis Plan 
 
The proposed clinical trial is a prospective, randomized, controlled study.  A total of up to 120 subjects 
will be randomized, stratified by study center, using response adaptive randomization based on the 
posterior probability of the active treatment (Treatment A) being superior to the standard of care 
(Treatment C) treatment. 
 

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The trial is designed to assess the superiority of treatment A compared to standard of care (treatment C) 
with respect to the primary endpoint, a composite endpoint of intubation or death during the 
hospitalization due to SARS-CoV-2 infection. 
 
A Bayesian approach using a Beta-Binomial conjugate model is employed to (1) formally assess the 
superiority of Treatment A to Treatment C, and (2) to adaptively change the randomization ratio to favor 
the treatment arm favored by the data collected data.   
 
This protocol is a major revision of an initial protocol that compared a dose of 200 mg of Sarilumab as 
the active treatment to standard of case. Release of preliminary interim results of an external study led 
to a change in dose from 200 mg to 400 mg. Before the change 9 subjects had been enrolled. Since no 
other major changes in the I/E criteria were made, the data of these 9 subjects enrolled under the 
previous protocol will be used in the analyses of the results for this study. It is our determination that 
this represents a conservative approach, because, when compared with SOC, the relative effect with 400 
mg dose is expected to be at least as large as the one with 200 mg. 
 
a. Study Objectives 
 
The objective of this study is to assess the safety and efficacy of the active treatment in the treatment of 
subjects with moderate COVID-19 disease as defined by positive testing for SARS-CoV-2 
 
b. Primary Endpoint 
 
The primary endpoint is a composite endpoint of intubation or death within 14 days of enrollment, 
during hospitalization due to SARS-CoV-2 infection.  To facilitate the adaptive approach described 
below, the primary endpoint will be assessed 7 days after approximately the 30th patient has been 
enrolled and approximately every additional 15th patient thereafter.  The endpoint at day 7 is expected 
to be highly correlated with the endpoint at day 14, and data regarding that assumption will be 
collected.  
 
We propose a standard Bayesian approach to calculate the current (posterior) probability that the 
primary endpoint event rate with treatment A is lower than the primary event rate with treatment C, 
given the accruing data so far. We assume that in each treatment group, the presence of the primary 
event outcome follows a Bernoulli distribution.  
 
c. Random Adaptive Assignment of Patients 
 
Patients are assigned to one of two treatment arms using an adaptive randomized scheme. Initially, the 
randomization will be balanced, then as data are accrued, assignment probabilities will be shifted in 
favor of arm that is performing better. 
 
The first batch of subjects will be assigned using equal allocation (1:1) to both study arms (A = Active and 
C = SOC).   Then, at each interim evaluation, the posterior probability, 𝜋, that the Event Rate in Group A 
is smaller than the Event Rate in Group C  will be computed 
 
𝜋=  𝑃(Event Rate in Group 𝐴< Event Rate in Group 𝐶|Data), 

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where Data represents all cumulative outcome data available at the interim evaluation. 
Thereafter, the value of 𝜋 will determine the random assignments to treatment. In particular, 
 
 𝑃(next subject assigned to 𝐴) ∝𝜋𝜂 and 𝑃(next subject assigned to 𝐵) ∝ 1 −𝜋𝜂 . 
 
where 𝜂= 0.5, is a calibration parameter. 
 
The update for the value of 𝜋 will occur every time the dataset of outcomes is updated, but for logistical 
simplicity the update will happen approximately after every 15 subjects enrolled.  
 
d. Stopping Rule 
 
We set two parameters 𝛿𝑈 and 𝛿𝐿 that govern how to stop the experiment either for overwhelming 
superiority or overwhelming futility, using the rules:  
 
- 
STOP for superiority if:   𝜋> 𝛿𝑈 
 
- 
STOP for futility if:            
 
 
𝜋1 = 𝑃(Event Rate in Group 𝐴 <  Event Rate in Group 𝐶 +  3%|Data)   
satisfy 
 
𝜋1  < 1 −𝛿𝐿 
 
These two parameters are chosen so that the Type I error is <10%.   We propose to calculate and set a 
maximum value for the total accrual, based on an extensive simulation study (see section f).  
 
e. Statistical Methods  
 
The null hypothesis is that the Active treatment will have a primary endpoint rate equal to or exceeding 
that of the SOC group. 
 
The alternative hypothesis is that the Active treatment will have primary endpoint rate less than the SOC 
group rate.  Specifically: 
H0: 𝜋𝐴−𝜋𝐶≥0 
 
HA: 𝜋𝐴−𝜋𝐶< 0 
 
Where 𝜋𝐴 is the true primary event rate for the Active treatment, 𝜋𝐶 is the true primary event rate for 
the SOC arm. 
 
Statistical analyses for the primary endpoint will be conducted using a statistical test for superiority of 
proportions based on posterior probability. Within each treatment group, a Beta (3, 12) prior will be 

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assumed for the true primary endpoint rate, 𝜋𝐴 and 𝜋𝐶. This prior was selected to have a mean of 20% 
which is the average of the assumed rates under the alternative hypothesis and express a priori 
skepticism of the alternative hypothesis being true; indeed, under this prior, the prior probability of the 
alternative hypothesis is 50%, while the probability of observing an improvement in the true rate of 20% 
(the hypothesized improvement) is only 7.8%. Thus, a reversal in this prior skeptical stance could only 
be due to strong support for the Active treatment in the data collected during the study. With this 
choice regarding the prior distribution, in each group, the posterior probability distribution of the 
primary event rates will be Beta (3+# of events,12+#non-events). The criterion for success is based on 
the posterior probability of the alternative hypothesis (i.e., of superiority being met). The Active group 
will be declared superior to the SOC group if the posterior probability of the alternative hypothesis HA is 
large, that is 
𝑃(𝐻1|𝐷𝑎𝑡𝑎) = 𝑃(𝜋𝐴−𝜋𝐶< 0|Data) > 𝛿𝑈. 
 
Similarly, the Active group will be declared inferior to the SOC group if the posterior probability  
 
𝑃(𝜋𝐴−𝜋𝐶< 3%|Data) < 1 −𝛿𝐿. 
 
The thresholds, 𝛿𝑈 and 𝛿𝐿 are a pre-specified level of evidence we require to declare the alternative 
hypothesis true. The thresholds will be selected such that the overall type I rate for testing the primary 
hypothesis of superiority is bounded by 10%.  
 
A balanced randomization will be employed for approximately the first 30 subjects, after which the 
randomization probability will be assessed. A maximum of 6 interim looks will be scheduled after 
approximately each 15 enrolled subjects enter the study and have finished follow-up. At each interim 
analysis, the alternative hypothesis of superiority and the null hypothesis of inferiority will be evaluated. 
A final analysis will be conducted if no decision has been reached at the interim evaluations after 120 
subjects have been enrolled. 
 
f. Sample Size Determination 
 
The assumptions for the calculations were elicited assuming a treatment dose of 200mg. It is our 
determination that this represents a conservative approach, because, when compared with SOC, the 
relative effect with 400 mg dose is expected to be at least as large as the one with 200 mg. 
The assumptions for this analysis are: 
• 
True primary event rate in the Active treatment group, 𝜋𝐴 is 10.0%  
• 
True primary event rate in the SOC treatment group, 𝜋𝐶 is 30.0% 
• 
Power 85%. 
• 
Six (6) interim analyses and a final analysis will be conducted to evaluate both the superiority 
and futility 
• 
Superiority assessment will be assessed using the posterior probability of the alternative 
hypothesis as specified above, where 𝛿𝑈= 0.95  
• 
Futility assessment will be assessed using the posterior probability of the alternative hypothesis 
as specified above, where 𝛿𝐿= 0.95  
• 
Randomization will be carried out in an adaptive Bayesian fashion. The randomization ratio will 
be evaluated at each of the 6 interim analyses  
 

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Rejection of the null hypothesis will signify that the Active is superior to the SOC with regards to primary 
endpoint event rates.  A maximum total of 120 subjects, adaptively assigned to treatment A or C will 
have 85.7% power to reject the above null hypothesis in favor of the alternative under the stated 
assumptions. Since we are using the adaptive assignment, the group sizes are a function of the data and 
therefore random. Under the alternative hypothesis, it is expected that at the time when the decision is 
made, the median group size will be 42 in treatment A and 27 in treatment C; thus, if treatment A is 
superior to treatment C, more subjects will be treated with the more efficacious treatment. The one-
sided type I error estimates are 9.4%.  Additional operating characteristics of this design are presented 
in the shaded column of Table 1 (under the alternative hypothesis) and shaded column of Table 2 (under 
the null hypothesis). In the same tables, the operating characteristics of the proposed design are 
presented under additional scenarios (Scenarios A1 – A3). From the table, it can be seen that the power 
with the proposed method is sufficient under alternative scenarios. 
 
Table 1: Operating characteristics of the Proposed Design (Alternative Hypothesis); Group A – Active 
Treatment, Group C – Standard of Care 
 
  
Primary 
Scenario 
Scenario A1 
Scenario A2 
Scenario A3 
True rate (Group A) 
10.00% 
5.00% 
5.00% 
5.00% 
True rate (Group C) 
30.00% 
30.00% 
25.00% 
20.00% 
Exit Probability (Group 
A) 
85.7% 
98.1% 
93.4% 
80.9% 
Exit Probability (Group 
C) 
0.0% 
0.0% 
0.0% 
0.0% 
Final Analysis (No 
Decision) 
14.3% 
1.9% 
5.0% 
81.0% 
Mean Sample Size 
74 
57.3 
68.0 
82.1 
Median Group A Size 
42 
30 
38 
49 
Median Group C Size 
27 
21 
24 
30 
 
 
Table 2: Operating characteristics of the Proposed Design (Null Hypothesis); Group A – Active 
Treatment, Group C – Standard of Care 
  
Primary 
Scenario 
True rate (Group A) 
30.00% 
True rate (Group C) 
30.00% 
Exit Probability (Group A) 
7.1% 
Exit Probability (Group C) 
2.1% 
Final Analysis (No Decision) 
90.6% 

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Mean Sample Size 
115.3 
Median Group A Size 
58 
Median Group C Size 
60 
 
 
10. Ethical Issues 
 
a. Risks 
 
The major risks to participation in this study include 1) immunosuppression, 2) possibly bowel 
perforation, and 3) adverse reaction to the medication. Medications that cause immunosuppression 
make patients more susceptible to certain kinds of infections, particularly bacterial infection.  
Although risks associated with sarilumab have only been observed in conditions in which the drug is 
given repeatedly (usually every 2 weeks) for a chronic disease, it is possible that one dose of 
sarilumab, which in this study twice as high (400 mg) as the dose that is used chronically (200 mg), 
might lead to a severe bacterial infection, necessitating treatment with antibiotics, treatment in the 
intensive care unit, or death. It is also possible that sarilumab might make SARS-CoV-2 infection 
worse, which could result in worsening respiratory failure, admission to the intensive care unit, or 
death.  
 
Sarilumab is associated with a small increase in the risk of bowel perforation.  This risk has only been 
observed so far in conditions in which the drug is given at the 200 mg dose repeatedly.  
 
As of this version of the protocol, no study of the use of IL-6 inhibition for COVID-19 has reported an 
increase in the risk of bacterial infection following administration of anti-IL-6-R therapy, and no 
studies have reported bowel perforations in patients with COVID-19 pneumonia. 
 
Individual participating sites and their respective IRB/R&D/Research Committee will decide whether 
this information warrants changes in the section on risk in the informed consent form. 
 
As with any medication, there is the potential for an allergic reaction or an injection site reaction, 
although based on previous data both are rare with sarilumab.  The subcutaneous injection may also 
cause discomfort. 
 
In addition to the risks listed above, there may be previously unknown risks or side effects. 
 
 
b. Potential Benefits 
 
Because SARS-Co-V-2 emerged very recently, there is very limited data to guide clinical decision 
making. Anecdotal data strongly suggest that clinical decompensation is driven by a cytokine storm; 
thus, it is possible that early intervention with an IL-6 inhibitor might prevent progression to severe 
SARS-CoV-2. However, these medications also have side effects, including immunosuppression, that 
could worsen outcomes. The study is designed as a pragmatic, adaptive clinical trial with a play-the-
winner design, which means that as time goes on, participants are more likely to receive the 

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treatment that is most likely to benefit them clinically. This design is chosen because it 1) provides 
rapid results, and 2) ensures that the highest proportion of patients benefit from participation in the 
clinical trial.   
 
c. Analysis of Risks in Relation to Benefits 
 
We currently do not know the best way to treat SARS-CoV-2 infection, although there is mounting 
evidence that the inflammatory response to the disease plays a major role in disease progression. 
This trial will help to answer if IL-6 inhibition, started early in the course of disease, can prevent 
progression and improve outcomes when added to standard of care.  The randomization procedure 
includes a play-the-winner design, which gradually increases the number of patients who receive the 
treatment arm that yields the most benefit. Thus, the study is designed to 1) provide rapid results 
and 2) to optimize management. Given all this potential, we believe there is sufficient clinical 
equipoise to conduct this trial. 
 
d. Stopping Rules 
 
A participant may always withdraw their participation at any time.   
• 
The study has stopping rules, based on futility; see Section 9, Statistical Analysis Plan 
• 
A participant will be withdrawn from the study if the treating physician or investigator feels 
it is in the participant’s best interest. 
 
 
11.  Safety Monitoring Plan   
 
Good Clinical Practices and Site Review Program  
 
a. Role of Good Clinical Practice  
 
This trial will be conducted in compliance with the currently approved protocol, with the standards from 
the International Conference on Harmonisation Efficacy Guideline 6: Good Clinical Practice (ICH E6), and 
with applicable regulatory requirements. The intent of these regulations is to ensure the rights and well-
being of trial participants are protected, and reported trial data are accurate, complete, and verifiable.  
 
b. Clinical Monitoring  
 
The Boston CSPCC Quality Assurance Team will monitor and assist investigators in complying with the 
above applicable regulations, GCP requirements, and VA policies. Study staff will receive GCP orientation 
at a study kickoff meeting (and/or subsequent meetings), or via computerized educational modules. QA 
Team members will provide training and materials to assist study personnel in organizing study files and 
will be available throughout the trial to advise and assist investigators regarding GCP issues.  
 
Study site monitoring will be a combination of site visits, remote (off-site) monitoring performed by 
Boston CSPCC Quality Assurance staff, and centralized statistical monitoring. These visits and activities 
will be conducted according to the study’s risk-based/integrated monitoring plan that will include 
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the site, findings identified during onsite or remote visits, and interaction with the local study site staff. 
All monitoring feedback will be reviewed periodically and the monitoring plan will be assessed for 
adequacy and effectiveness at least annually. The monitoring plan will be revised as necessary to reflect 
identified protocol-specific risks.   
 
c. Quality Control through the Boston CSPCC Quality Management System  
 
The Quality Management System (QMS) in place at the CSPCC will ensure further quality control for the 
trial. The Quality Assurance Department of the CSPCC will subject the data to risk-based audits and 
monitoring that will verify and validate data elements according to internal SOPs. In brief, a sample of 
the data will be verified at routine intervals. If errors are identified they will be referred to the data 
management team for resolution. If the error level rises to a predefined threshold, then the entire 
record or data element type will be subjected to verification and validation. Further, the CSPCC will 
conduct internal audits to ensure the quality of clinical trial processes and procedures. If deviations or 
non-conformances are identified they will be remedied through the internal corrective 
action/preventive action system of the QMS.  
 
Risk based monitoring and auditing will also allow for the early systematic identification of problems 
that require remediation at the local site level. If problems are identified, the CSPCC will work with the 
study staff to create a remediation plan to address the issues. If problems persist after remediation, the 
site may be recommended for termination to the EC.  
 
Study Organization and Administration  
 
a. Administration  
 
The administrative structure of this study is similar to others in the ‘CSP model’ and includes:  
 
The CSPCC and the Study Chairs’ offices jointly will perform day-to-day scientific and administrative 
coordination of the study. These activities include developing and revising the study operational 
protocol, ICFs, and CRFs, ensuring the appropriate support for the participating center(s), scheduling 
meetings and conference calls, answering questions about the protocol, and conducting site visits. The 
CSPCC will also prepare interim and final progress reports, reports on metrics, and archive study data at 
the end of the study. Archiving study records per VHA Handbook 1200.05 requires all study records be 
retained until disposition instructions are approved by the National Archives and Records Administration 
and are published in VHA‘s Records Control Schedule (RCS 10-1). Study DMC reports will be produced 
approximately every 6 months (exact frequency dependent on DMC determination) and other reports 
will be produced at intervals determined by the study team. Participant accrual, participant safety, and 
data quality will be monitored closely by the CSPCC at least annually (or at an interval determined by the 
DMC) to ensure the study is progressing satisfactorily. Further delineation of responsibilities will be 
documented in communications with the Study Chairs’ and CSPCC offices.  
 
 
 
b. Monitoring  
 

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The following groups monitor various aspects of the study. These committees will meet according to 
current CSP guidelines as a model.  
 
The Executive Committee (EC) is responsible for oversight of the operations of the study, including 
protocol amendments, and overall management of the study. It will be headed by the Study Chairs and 
Study Directors and will include the study Biostatistician, CSPCC Center Director, selected participating 
investigators, and outside consultants as needed. This committee will meet regularly to review data and 
may take the following actions: recommend changes to the study, help determine outcomes for sites 
whose performance is substandard, initiate any sub-protocols, and discuss publication of the study 
results. This Committee must grant permission before any study data may be used for presentation or 
publication.  
 
The Data Monitoring Committee (DMC) will review the progress of the study and monitor participant 
intake, outcomes, AEs, and other issues related to participant safety. Interim, independent, and 
unbiased reviews of study progress will be provided. The DMC consists of experts in the study’s subject 
matter field(s), clinical trials, biostatistics, and ethics. These individuals will not be participants in the 
trial and will not have participated in the planning of the protocol. The DMC will consider safety or other 
circumstances as grounds for early termination, including compelling internal or external evidence of 
treatment differences or the unfeasibility of addressing the study hypothesis (e.g., poor participant 
intake, poor adherence to the protocol). The DMC will monitor the primary endpoint at pre-determined 
intervals and recommend whether the trial should be stopped for efficacy.  
 
At each of its meetings during the study period, the DMC will review randomization rates and assess the 
difference between actual and projected rates, as well as the impact of these assessments on overall 
sample size. If the study enrollment is inadequate, the reasons for exclusion may be scrutinized and 
actions may be suggested. An assessment of whether the trial should continue will be made followed by 
recommendations, as appropriate. All SAEs will be reported regularly at these meetings for DMC review. 
The study Biostatistician will provide the appropriate data to the DMC at specified intervals for this 
purpose. Conditional power estimates may be provided at their request to assist the DMC in making 
decisions and recommendations. To help them make assessments, the Study Chairs, Study Directors and 
the study Biostatistician will furnish the DMC with appropriate monitoring data before each meeting. 
The DMC makes recommendations after each meeting to the CSP Director about whether the study 
should continue or be stopped.  
 
The VA Boston Institutional Review Board will monitor the study’s SAEs on a continual basis. They may 
conduct annual reviews of the study. 
  
The CSPCC Human Rights Committee (HRC) is a diverse committee composed primarily of individuals 
from varying demographic and professional backgrounds and includes a number of Veteran members. 
The HRC is responsible for ensuring participant’s rights and safety are upheld prior to study initiation 
and during the conduct of the study. The committee reviews all new protocols, informed consent 
documents, select protocol amendments, periodically makes site visits to participating centers to  
monitor firsthand the progress of the study and may be asked to review any ethical and human rights 
issues that arise during the conduct of the study.  
 
c. Safety Monitoring Plan  

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Monitoring side effects and adverse events in the traditional manner of usual clinical trials is not feasible 
for this clinical trial. First, this is an embedded pragmatic Point of Care study in which all data is captured 
actively or passively through the EHR, and thus real-time reporting is not possible, except for deaths that 
occur during hospitalization for COVID-19. Second, during the COVID-19 national pandemic we need to 
reduce the exposure of study staff to infected patients. The only study-related burden bringing 
additional risk of exposure to clinical staff is the need for the injections of sarilumab, which is similar in 
nature to other aspects of standard clinical care.  Finally, real-time monitoring will not assure adequate 
(or timely) safety of human subjects beyond that already done by the medical staff as part of routine 
medical care on this acutely ill inpatient population. Accordingly, we propose an alternative safety 
reporting plan for this study that ensures protection of the participants and that complies with VHA 
Policy (i.e., VHA Directive 1200.05 and VHA Handbook 1058.01).  
 
The participant’s physicians, nurses, and other health providers will continue their usual monitoring of 
the subject throughout the course of his/her treatment. If any treatments are indicated, they will be 
provided by health providers as a part of the participant’s routine medical care. The CSPCC staff will 
collect safety data from the medical record from the time of consent through the end of the study 
period.  The safety data will then be aggregated and classified according to ICD-10 codes.   
 
d. Safety Reporting  
 
Aggregated safety data will be reported to the Data Monitoring Committee, the study Executive 
Committee, and the VA IRB.   
 
Definitions and recording requirements for this trial are based on the International Conference on 
Harmonisation Efficacy Guideline 2a: Pharmacovigilance: Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting (ICH-E2A), the Code of Federal Regulations (21 CFR 312.32) and 
CSP Global Standard Operation Procedure (SOP) 3.6.  
 
Given the comorbidity expected in this acutely ill study population, it is anticipated that a large 
number of AEs will be observed, most of which will not be related to study drug. For this reason, the 
study will collect reports of all SAEs, but only those non-serious AEs that, in an investigator’s clinical 
judgment, are at least possibly attributed to a study drug and cannot be attributed to non-study 
intervention causes (e.g., to comorbid conditions, the disease that is the subject of the study, or non -
study drugs). A list of expected AEs is included below.  
 
1. Adverse Events  
 
Adverse events will be collected using the 21 CFR 312.32, International Conference on Harmonisation 
(ICH) for Clinical Safety Data Management (ICH-E2A), and CSP Global SOP 3.6 definitions.  Adverse  
events (AEs) are defined by the 21 CFR 312.32 as "any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related." According to ICH-E2A, ”an AE, 
therefore, can be any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the study interventions.”  
 
Expected adverse events of interest will be culled from the EHR as part of the outcome ascertainment 
activities of this protocol. The expected AEs of interest as identified in this trial are:  

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• 
Neutropenia: neutrophil count <1000 mcL 
• 
Thrombocytopenia (low platelet count): <75,000 mcL 
• 
Non-COVID related bacterial, fungal, or mycobacterial infection 
• 
Oral herpesvirus infection, herpes zoster infection, cytomegalovirus infection 
• 
 ALT >3-fold increase above the upper limit normal (ULN)  
• 
Bowel perforation 
   
These safety events are monitored and treated as part of routine medical care. These events and 
outcomes will be identified by the CSPCC through the EHR.  For the first 30 days after randomization 
CSPCC staff will review the EHR daily or every one to two days for the first 14 days and then weekly for 
the remainder of the 30-day period to assess for potential effects of the study drug. Data will be entered 
on an Access form and uploaded to a secure server space. Beyond the 30 days informatics staff at the 
Boston CSPCC will extract medical record data on all subjects and identify adverse events through ICD-
10 codes, laboratory values, and medication files.  Expected adverse events will be reported to the DMC 
in semi-annual reports. The DMC also reserves the right to request reporting on additional safety data 
not specified above, as relevant to the study.  Data will be in the form of aggregated data tables 
detailing the frequencies of these events by blinded treatment group.  These events will be reported to 
the IRB in blinded aggregate form at the time of continuing review.  
 
Adverse events which develop into Serious Adverse Events, as defined below, will be reported as such.  
 
2. Expected Serious Adverse Events  
 
Serious adverse events (SAEs) are a subset of adverse events defined in 21 CFR 312.32(a) and VA 
Handbook 1058.01 paragraph 4(w), as follows:  
 
Definition of SAE from CFR 312.32 (a): Serious adverse event. 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. 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.   
 
Definition of SAE according to VA Handbook 1058.01: An SAE is an AE in human research that results in 
death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent 
or significant disability or incapacity, congenital anomaly, or birth defect. An AE is also considered  
serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an 
outcome.  
 
This study will not use MedDRA coding of AE and SAE data.  The study team will define events using the 
data sources described above and categorize events by system organ class, major diagnostic category, or 
assessment type for reporting.  
 

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Note: Intubation is a study outcome but may also be reported as an SAE depending on local IRB 
requirements. Death is also a study outcome but could be a result of COVID-19 infection or a result of 
another process. All deaths will be reported to the IRB on the same timeline as SAEs, with description to 
allow determination whether they should be considered purely as study outcomes (progression of 
COVID-19 to respiratory failure or multi-organ-system failure) or also as treatment-emergent SAEs.    
 
 
3. Unanticipated Problems Involving Risks to Subjects and Others  
 
Any unanticipated problems involving risks to subjects or others (UPRs), but not qualifying as a serious 
adverse event by definition (such as errant distribution of study medication), will also be reported. 
Unanticipated problems related to the study design will be reported to the IRB in an expedited fashion 
per IRB policies (within 5 business days of identifying the problem).  Examples of possible events include 
failure to distribute study drug or serious adverse drug reactions.  Informatics staff at the Boston CSPCC 
will extract medical record data on all subjects regularly allowing for the identification of UPRs at fixed 
intervals.  Study reports will be circulated to appropriate members, including the study chair.  
 
 
12.   Adverse Event/Unanticipated Problems Reporting Plans 
 
The Principal Investigator will report Unanticipated Problems, Adverse Events, and safety monitors’ 
reports to the IRB in accordance with VHA Handbook 1058.01 and VABHS IRB SOP.    
 
All serious adverse events as defined above that are feasibly identified through the medical record will 
be reported to the VHABHS IRB as they occur and in aggregate form per the timelines specified by the 
IRB.  SAEs will also be reported in aggregate to the DMC at 6-month intervals. Study reports will also be 
circulated to appropriate study team members, including the study investigators and the DMC.  
 
UPRs that are related to the research, including those that result in an SAE, pursuant to the definition 
above, will be reported to the VA Boston IRB within 5 business days by the Boston CSP Coordinating 
Center after becoming aware of the event.  
 
  
13. References 
 
1. Chen Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized 
controlled trial. 2020 [online pre-print]. 
2. Beigel J, et al.  Remdesivir for the treatment of Covid-19 – Final report.  N Engl J Med 2020 Nov 
5;383(19):1813-1826.  doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8. 
3. Chen G, et al. Clinical and immunologic features in severe and moderate coronavirus disease 
2019. J Clin Invest 2020 [online ahead of print]. 
4. Deng Y, et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 
(COVID-19) in Wuhan, China: a retrospective study. Chin Med J 2020 [online ahead of print]. 

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5. To KKW, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and 
serum antibody responses during infection with SARS-CoV-2: an observational cohort study. 
Lancet Infect Dis 2020 [online ahead of print]. 
6. Xu X, et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. 2020 [online pre-
print, http://chinaxiv.org/abs/202003.00026].