The RESCUE 1-19 Trial: Radiation Eliminates Storming Cytokines and Unchecked Edema as a 1-Day Treatment for COVID-19
Phase: PHASE1
Conditions: Pneumonia, Coronavirus Infection in 2019 (COVID-19), Severe Acute Respiratory Syndrome (SARS) Pneumonia
Sponsor: Emory University

 
Winship Protocol #: RAD5049-20; Protocol: [Original / Final Version/ 06.11.2020] 
 
Radiation Eliminates Storming Cytokines and Unchecked Edema as a 
1-Day Treatment for COVID-19 (RESCUE 1-19): A Randomized Phase 
III  Trial of Best Supportive Care versus Whole Lung Low-Dose 
Radiation Therapy in Hospitalized Patients with COVID-19 
 
Principal Investigator(s): 
 
 
 
 
 
   
Clayton B. Hess, MD, MPH  
Assistant Professor, Radiation Oncology 
Emory University SOM 
cbhess@emory.edu 
 
Mohammad K. Khan MD, PhD (Contact PI) 
Associate Professor, Radiation Oncology 
Emory University SOM 
m.k.khan@emory.edu 
 
Co-Investigators: 
Department of Radiation Oncology 
 
 
Walter J Curran Jr, MD 
Professor and Chair 
Emory University SOM 
wcurran@emory.edu 
William Stokes MD 
Assistant Professor 
Emory University SOM 
wastoke@emory.edu 
Zachary Buchwald MD Ph.D 
PGY 5 Resident 
Radiation Oncology 
zachary.scott.buchwald@emory.edu 
Translational Science: 
Tahseen Nasti Ph.D 
Postdoctoral Fellow 
Immunology/Microbiology 
tah.nasti@emory.edu 
Intensivits: 
David Murphy MD 
Associate Professor  
Pulmonary Critical Care 
Emory University Hospital 
david.j.murphy@emory.edu 
 
Radiology:  Brent Weinberg, MD 
Assistant Professor 
Department of Radiology 
brent.d.weinberg@emory.edu 
 
Infectious Disease: 
Jesse Jacob MD 
Associate Professor 
Division of Infectious Disease 
jtjacob@emory.edu  
 
Ighovwerha Ofotokun MD, MSc 
Professor, Medicine 
Division of Infectious Disease 
iofotok@emory.edu 
Ramzy Rimawi MD 
Asst. Professor, Emory Critical Care 
Emory University Hospital 
ramzyrimawi@emory.edu 
 
St Joseph Radonc 
Tony Eng, MD 
Associate Professor 
Emory University SOM 
t.y.eng@emory.edu 
Biostatistics:  
Jeff Switchenko PhD, MS 
Assistant Professor 
Biostatistics and Bioinformatics 
Rollins School of Public Health 
jswitch@emory.edu  
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................. 2 
1 
PROTOCOL SUMMARY................................................................................................ 4 
1.1 
Synopsis ...................................................................................................................4 
1.2 
Schedule of Activities (SoA) ...................................................................................5 
2. 
INTRODUCTION .......................................................................................................... 6 
2.1 
Study Rationale ........................................................................................................6 
2.2 
Background ..............................................................................................................6 
2.3 
Potential Risks and Benefits ..................................................................................17 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................... 21 
4. 
STUDY DESIGN ......................................................................................................... 22 
4.1 
Overall Design .......................................................................................................22 
4.2 
End of Study Definition .........................................................................................24 
5. 
STUDY POPULATION ................................................................................................. 24 
5.1 
Inclusion Criteria ...................................................................................................25 
5.2 
Exclusion Criteria ..................................................................................................25 
6. 
REGISTRATION PROCEDURES .................................................................................... 26 
6.1 
Local Winship Procedures .....................................................................................26 
6.2 
Study Enrollment ...................................................................................................26 
7. 
STUDY INTERVENTION .............................................................................................. 27 
7.1 
General Concomitant Medication and Supportive Care Guidelines ......................27 
7.2 
Duration of Follow Up ...........................................................................................27 
7.3 
Withdrawal from the Study ....................................................................................27 
8. 
STUDY ASSESSMENTS AND PROCEDURES .................................................................. 29 
8.1 
Schedule of study procedures ................................................................................29 
8.2 
Description of study procedures ............................................................................29 
9. 
STATISTICAL CONSIDERATIONS ................................................................................. 31 
9.1 
Study Design/Endpoints.........................................................................................31 
9.2 
Sample Size/Accrual Rate ......................................................................................31 
9.3 
Stratification Factors ..............................................................................................31 
9.4 
Analysis of Endpoints ............................................................................................31 
9.5 
Interim analysis ......................................................................................................32 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................................ 33 
10.1 
Comprehensive Adverse Events and Potential Risks List .....................................33 
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10.2 
Definition of Adverse Events (AE)........................................................................33 
10.3 
Definition of Serious Adverse Events (SAE) ........................................................33 
10.4 
Classification of an Adverse Event ........................................................................33 
10.5 
Adverse Event and Serious Adverse Event Reporting ..........................................35 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS ................................................... 38 
11.1 
Data Reporting .......................................................................................................38 
11.2 
Data and Safety Monitoring Plan ...........................................................................38 
12. 
ETHICS AND PROTECTION OF HUMAN SUBJECTS ....................................................... 40 
12.1 
Ethical standard ......................................................................................................40 
12.2 
Institutional review board ......................................................................................40 
12.3 
Informed consent/Assent .......................................................................................40 
12.4 
Participant and data confidentiality .......................................................................41 
12.5 
Research use of stored samples, specimens, or data ..............................................41 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ....................................................... 48 
APPENDIX B GLASCOW COMA SCALE ................................................................................ 49 
APPENDIX C CHARLESON COMORDBITIY INFEX ................................................................. 50 
 
 
 
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1  
PROTOCOL SUMMARY 
1.1 
Synopsis  
 
 From ClinicalTrials.gov Protocol Data Element Definitions available at:  https://prsinfo.clinicaltrials.gov/definitions.html.  
 
 
 
 
 
 
 
 
 
 
 
Title: 
Radiation Eliminates Storming Cytokines and Unchecked Edema as a 1-Day Treatment for 
COVID-19 (RESCUE 1-19): A Randomized Phase III  Trial of Best Supportive Care Plus 
Provider’s Treatment Choice versus Best Supportive Care Plus Low-Dose, Whole-Lung 
Radiation in Hospitalized Patients with COVID-19 
Study 
Description: 
Hypothesis: Low-dose, whole-lung radiation therapy (LD-RT) improves clinical status in 
patients with COVID-19.  
This study investigates LD-RT as a anatomically-targeted, anti-inflammatory treatment to 
induce local suppression of pulmonary immuno-toxicity within viral pneumonia infiltrates 
in hospitalized patients with COVID-19. 
Objectives: 
 
To compare treatment of COVID-19 between best supportive care plus provider’s 
treatment choice  versus best supportive care plus low-dose, whole-lung radiation 
therapy. 
Endpoints: 
Primary Endpoint: Time to Clinical Recovery (TTCR).   
Secondary Endpoints: Time to Hospital Discharge, Radiographic Changes, Serological 
Biomarker Changes, Inflammatory Biomarker Changes, Freedom from Intubation, 
Freedom from ICU admission, Overall Survival, Toxicity. 
Study 
Population: 
Hospitalized COVID-19 patients with pulmonary infiltrates pre-inbutation who require 
supplemental oxygenation use. 
Phase: 
Phase III, preplanned analysis after first 8 patients treated on each arm at day 14.  
Sites/Facilities 
Enrolling 
Participants: 
Emory University Hospital, Clifton Road, Atlanta, GA 
Emory University Hospital Midtown, Peachtree Road, Atlanta, GA 
Emory St. Joseph’s Hospital, Atlanta , GA 
Description of 
Study 
Intervention: 
Whole Lung Radiation to a dose of 1.5 Gy 
Study 
Duration: 
6 months 
Participant 
Duration: 
6 months  
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1.2 
Schedule of Activities (SoA) 
 
 
Procedures 
Screening 
Day -7 to -1 
LD-RT Day 0 
 
Follow-up day 1 
Follow-up day 2 
Follow-up day 3 
Follow-up day 4 
Follow-up day 5 
Follow-up day 6 
Follow-up day 7 
Follow-up day 14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics* 
X 
 
 
 
 
 
 
 
 
 
Medical history & Pregnancy 
test* 
X 
 
 
 
 
 
 
 
 
 
Physical exam*  
X 
X 
 
 
 
 
 
 
 
x 
Vitals and O2 sat needs* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
Performance status* 
X 
X 
 
 
X 
 
 
 
X 
x 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
Comorbidity Index* 
X 
 
 
 
 
 
 
 
 
 
Serum chemistry * 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
Glasgow Coma Scale* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood gases * 
X 
 
X 
 
X 
 
 
 
X 
x 
Serologic immune markers*,## 
X  
 
X 
X 
X  
X 
X 
X 
X  
      X  
Low-Dose Radiation Therapy* 
 
X 
 
 
 
 
 
 
 
 
Chest Imaging (CT and/or CXR) * 
X 
(Both) 
 
X (chest 
xray) 
 
X (chest 
xray) 
 
 
 
X (both) X (both) 
Clinical Assessment* 
X 
X 
 
 
X 
 
 
 
X 
x 
 
All procedures are considered to follow standard of care procedures and timelines, and marked 
above with (*), unless otherwise noted with (##).  The exact dates/timings of these may vary based 
evolving clinical circumstances and on patients’ clinical course. These are only suggested timelines.   
 
## 4 extra vials of 8 ml tubes will be extracted on days 0, 3, and 7 for additional correlative analysis 
(which may include CD 8 Tell, CD 4 T cells, cytokine analysis,  and/or other immunological 
biomarkers, as well as any additional RNA/DNA sequencing on the blood samples).   Day 14 are 
optional collections.   All blood draws can be off by +/- 2 days for logistical reasons and to minimize  
extraneous blood draws for patients.   Day 28 blood draw is optional;  
 
*all day 14  activites listed in table are optional, especially if a patient is discharged from the 
hospital.  
*A day 28 follow-up as inpatient or outpatient is encouraged, but at discretion of treating physicans. 
This would also be standard of care post RT check. A day 28 blood sample collection may also take 
place at discretion of the treating physician, but is not required. This is optional.  
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2. INTRODUCTION 
 
2.1 
Study Rationale  
 
Main Points 
 
• 
Mortality from cascading inflammatory lung injury for intubated COVID-19 patients is 50-80%.   
 
• 
Immunomodulating LD-RT eliminates cytokine storms and cured past pneumonias. 
 
• 
There is precedent to use RT to treat a wide breadth of benign or inflammatory conditions.  
 
• 
COVID-19 injurious mechanisms resemble those of histiocytosis, which has  response rates of 
>90% following LD-RT 
 
• 
Radiation is routinely used in modern days to treat a histiocytosis disorder, especially the 
Langerhan’s cell subtype. We suspect it may also help with the hemophagocytic 
lymphohistiocystosis  (HLH)like syndrome that occurs in COVID-19 patients.  
 
The novel coronavirus in 2019 (COVID-19) is associated with severe acute respiratory syndrome (SARS), 
intensive-care unit admission, and high mortality.1,2  There is little awareness among modern investigators 
that low doses of ionizing radiation therapy (LD-RT) were successfully used to induce localized anti-
inflammatory states as treatment of various types of infections during the first half of the 20th century, 
including pneumonia, sinus infection, and skin infection.3-5 Anecdotally, RT reduced inflammation and 
reversed clinical decline at doses considerably lower than those currently used for oncologic purposes.3 
Abruptly in the early 1940’s and for ensuing decades, the role of RT in treating pneumonia and other infections 
was eclipsed by the emergence of antibiotics.3 In 2020, however, in an era of increasing antibiotic resistance,6 
a novel viral threat has emerged. The SARS from coronavirus in 2019 (SARS-COVID-19) pandemic has shut 
down the global economy.7,8 COVID-19 is thought to induced a hyper-immune cytokine storm leading to 
pneumocyte injury and profound pulmonary edema. With mortality rates of 2-3% for all documented infected 
persons but around 50-80% for severe cases requiring ventilation support, bilateral patchy ground glass 
opacities have been reported in most patients with 97% diagnostic sensitivity.8-11 Spread of the contagion has 
risen dramatically with a reproduction number of 2.2, and the global health care system has been further 
strained by dramatic shortages of critical medical supplies, most notably ventilators.8 Given existing antiviral 
resistance, historical reports of success using LD-RT to treat pneumonia, the alarming mortality seen with 
COVID-19, and the need to preserve ventilator capacity, this study proposes to re-evaluate LD-RT as a localized 
anti-inflammatory treatment for COVID-19 pneumonia in critically ill patients following ICU admission.  
 
2.2 
Background  
 
Between 1905 and 1946, 700 pneumonia patients underwent LD-RT and subsequently experienced 
measurable clinical improvements in the hours and days following treatment. One to three treatments of LD-
RT to cumulative doses of approximately 50 to 550 Roentgen (~44 to 482 cGy) yielded reduction in 
inflammatory markers, improved respiration, down-trending fever, resolution of radiographic consolidations, 
and reduction in mortality. At acute onset, observed success rates for lung irradiation were highest when RT 
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was delivered early in the disease process, with observed improvements after 5 days of pneumonia, and 
further still after 14 days, implying that the best responses were seen when RT was implemented early in the 
disease process.3   
 
Table 1 (left). From Calabrese, et al. 2013.3  Case series and case reports of observational data utilizing LD-RT 
for clinical pneumonia. These studies included a variety of control arm techniques including alternating 
treatment between patients, historical controls, and institutional cohort controls, but pre-dated wide 
implementation of modern clinical trial or randomization designs. Please see full publication for bracketed 
references.   
Figure 1 (right). From Rousseau, et al. 1942.12  “Lobar pneumococcic pneumonia; 200 roentgens to anterior 
right chest immediately after admission. Prompt response to irradiation, with complete recovery, 
temperature, pulse, and respiration showing gradual disease decline to normal of three-day interval.” 
The anecdotal reports from these studies are provocative: 
“A patient with a high fever, severe dyspnea, and cyanosis is irradiated. A few hours later, often 
within a period of six hours, he states that he can breathe more easily, and he takes some 
nourishment. After twelve to twenty-four hours the fever abates, in most cases by crisis, 
breathing is no longer painful, and dyspnea decreases or disappears entirely. In most of the 
cases reacting favorably, a normal condition is re-established in twenty-four to forty-eight 
hours. In some cases the fever does not resolve by crisis but falls in two long steps; in some 
there is a gradual decline to normal. In all these cases the decline of temperature, 
disappearance of dyspnea, general improvement, and indeed the whole course of the disease 
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appear to have been definitely hastened by irradiation. And as this observation was made 
consistently, it would seem to be an established fact.”3 (Fried, et al 1941, cited in Calabrese, et 
al, 2013) 
 
Another notable example among these studies was published in Radiology in 1942, which compared two 
sequential cohorts before and after the advent of antibiotics in 1939: LD-RT alone versus LD-RT following 
sulfonamides.  At hospital admission for pneumonia with mean time from symptom onset of 2 days), 
patients received 200 R (~175 cGy) every 36 hours for 1, 2, or 3 treatments (as needed) while laying supine 
in bed using 2-D planning anterior-posterior and posterior-anterior (APPA) alternating fields (anterior beam 
for first treatment, posterior beam for second treatment). No other intervention was given. The 
investigators followed vital signs, white blood cell count, and chest x-ray imaging across time following 
administration of LD-RT. Of 104 patients treated, 98 recovered, and mortality was 5.7% against a backdrop 
of historical mortality rates of ~25-30%. The authors quoted, “X-ray therapy has been strikingly free from 
any toxic side-effects…Many theories have been advanced by various investigators, and sooner or later 
conclusive proof of how and why small doses of x-rays have a favorable influence on inflammatory 
processes will be established.”  
 
At the time, the mechanism by which LD-RT achieved these gains was not known. By the late 1940’s, however, 
LD-RT disappeared as a treatment for infectious pneumonia as penicillin mass production marked the dawn 
of the modern antibiotic era. Since that time, few have even contemplated treating pneumonia with radiation, 
but discovery of the mechanisms and pathways of LD-RT’s immune-modulating effects now elucidates how 
LD-RT may have helped treat pneumonia 80 years ago. Nearly a century later, 2020 has witnessed the rise of 
a novel pathogenic threat, the COVID-19 pandemic. Mortality rates hover near 50-80% for the most severe 
cases requiring ventilation support. The virus can induce an acute respiratory distress syndrome (ARDS) via 
macrophage activation of a cytokine storm that leads to immune-mediated and sometimes fatal organ 
damage. Anti-infectious agents are limited. Health care resources including intensive care units, personal 
protective equipment, and personnel are under unprecedented strain, highlighting the need for new 
strategies to reduce this burden. Faced with the prospect of overwhelmed health care systems, clinicians have 
a moral imperative to reassess readily-available treatment approaches that they may not have considered in 
non-pandemic times. 
 
Preliminary Interim Analysis at day 7 from Phase I/II Trial (i.e. Cohort 1 @ day 7: Figure 1) 
 We are the first in the world (to our knowledge) to have conducted a small prospective IRB-approved pilot 
trial at Emory University. In this phase I/II single-arm trial, patients deemed to be clinically deteriorating and 
therefore in need of “rescue” were enrolled.  We enrolled primarily elderly patients who were generally in 
their 90s with multiple co-morbidities, were COVID+ at time of admission, required supplemental oxygen, and 
had radiographic pulmonary infiltrates.  The primary hospitalist team caring for these patients were asked to 
refer patients they felt were decompensating or refractory to non-invasive measures, and  would therefore 
be good candidates for a novel intervention. The principal investigators and/or study coordinators informed 
hospitalists of eligibility criteria and were not involved in selecting candidates; this decision was ultimately 
decided by the primary hospitalist. 
 
We treated five patients, ranging in age from 64 to 94, median 90 years. At enrollment, their Charlson 
comorbidity index ranged from 2-8 (average 5.6), and their Glasgow coma scale ranged from 9-15 (average 
11.6). All underwent LD-RT. Within 24-48 hours, the average Glasgow coma scale had improved to 14.8, a 
27.5% improvement. Four (80%) of the patients were weaned off supplemental oxygen within 72 hrs and were 
noted to have at least one level of ARDS improvement on their 24 hour chest x-ray.  The oxygen saturations 
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within the 72 hours following LD-RT for all 5 patients are plotted in figure 2 below, along with a representative 
chest x-ray showing significant improvement within 24 hours. All patients had 50% or more of their serological 
biomarkers improve within 72 hrs. There was no increase in acute skin, GI, GU, pulmonary, or cardiovascular 
toxicity; as of day 7 post treatment, all patients were alive and four (80%) were anticipating discharge by the 
time of the preplanned day 7 interim analysis of the initial five patients (manuscript submitted for publication) 
 
 
 
 
Figure 2: Oxygen Saturation and Chest X-ray Pre and Post Radiotherapy, within 72 hrs (lightning bold indicates 
radiation administration). 
 
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Full Pilot Data From Phase I/II Trial (see updated Figure 1 below with all 10 patients data plotted together); 
 
 As of May 28th, 2020, we have completed the Phase I/Phase 2 trial, and now request approval for phase 3.  
We have completed the treatments of Cohort 1 (5 patients) and Cohort 2 (5 patients), for a total of 10 patients. 
We found that low-dose radiation delivered prior to intubation may yield a clinical improvement time of just 
3 days in a cohort of patients older, sicker, and more oxygen dependent (1-6L) at baseline with worse X-ray 
findings in the lungs compared to other recently published studies.  Our mortality at Day 14 is 0%. [Of note, 
patient 5 died at Day 15]; This represents an overall survival of 90% as of May 28th, 2020 for all 10 patients 
treated on our pilot phase 1/2 Trial. Given the older age, severe COVID disease, oxygen dependency, and the 
multiple comorbidities of our patient cohorts, we are strongly encouraged by a 90% overall survival rate.  
 
The mean time to discharge is 11 days. 83% of all biomarkers showed serologic recovery (safety endpoint) 
over 7 days. For patients age 65 and older (n=7),  100% percent of patients got off of oxygen within 96 hours, 
100% percent of altered patients improved in mental status at 24 hours,  100% showed improvement in 
follow-up radiographs (day 3-28),  100% of patients recovered, despite large co-morbidity burden, older age, 
nursing home placement issues over COVID-19 immunity. The finding in our older patient is extremely 
encouraging. Certainly, much better than what was anticipated when we first conceptualized he trial.  
 
For patients under age 65 (n=3), these patients appear to present with much higher burden of disease. We 
suspect that this may reflect pulmonary reserve, which allows these patients to develop extreme amount of 
disease before presenting to the hospital. All of these younger patients were treated at time of impending ICU 
admission or rapid clinical decline. Thus, we clinically expected them to be the worse actors, and enrolled 
them anyway on our pilot trial. Despite this, we note a 66% survival (2 out of 3) and rescue from impending 
ICU admission/intubation. Both patients were weaned off oxygen in a median time of 8 days. We noted 
signficiant evidence of infiltrate re-absorption at day 7 CT chest.   
 
Full data on Oxygenation Improvement in all 10 patients: 
 
 
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Radiation Therapy for Benign Diseases, Including LCH and HLH 
While most clinicians are familiar with the use of RT in the management of malignant neoplasms, curious 
practitioners of radiation medicine, based primarily in Europe, have broadened the applicability of RT to a 
variety of benign indications.  
Low to modest doses of RT have proven efficacious in the treatment of immune-mediated inflammatory 
processes such as Graves orbitopathy. Multiple studies indicate that delivery of 10 to 30 Gy to the orbital 
tissue behind the eyes, typically via fractions of 1-2 Gy per day, leads to clinically significant improvements, 
both in subjective symptom scores and objective measurements including eye motility and oculomotor 
muscle size.13-15 Long-term follow up of these patients up to and beyond 10 years indicates an acceptably 
low incidence of complications.16,17 Randomized evidence comparing RT with systemic corticosteroids 
demonstrates that RT delivers comparable symptom relief with a lower toxicity burden, suggesting a steroid-
sparing benefit with RT.13 
Other proliferative disorders successfully managed with RT include Morbus Dupuytren, Morbus Ledderhose, 
and Peyronie’s disease. For each of these entities, characterized by fibrotic contractures of the palm(s), 
sole(s) and penile shaft, respectively, focal RT delivered in 1.5-3 Gy fractions to a cumulative dose of 12-36 
Gy has proven effective in reducing pain and in arresting or even reversing the fibrotic deformity in most 
treated patients.18-23 
German investigators have explored multiple dose-fractionation schema to treat refractory pain from 
plantar fasciitis. Both older retrospective series and more recent randomized trials indicate that optimal 
analgesia occurs at a modest cumulative dose of 3-6 Gy with negligible acute or long-term toxicity.24-26 
A benign application of RT familiar to radiation clinics on both sides of the Atlantic is the prevention of 
heterotopic ossification (HO). As a dysregulated inflammatory process supposedly mediates formation of 
this dystrophic bone,27 investigators have explored multiple anti-inflammatory strategies to disrupt the 
process. As compared to systemic non-steroidal anti-inflammatory drugs, RT is equally, if not more 
efficacious in reducing the incidence of HO, especially when delivered at a moderate dose of 7 Gy in a single 
fraction.28-30 As for Graves orbitopathy, RT for HO exerts a local immunomodulatory effect that avoids the 
undesirable non-local effects of systemic anti-inflammatory treatment. 
It should be noted that the indications for RT in the aforementioned patient populations are far from life-
threatening, but that RT nevertheless proved both effective in reducing symptoms and safe with a low 
toxicity burden. This favorable risk/benefit ratio in these low-acuity settings justifies the consideration of RT 
in patients suffering from higher-acuity disease processes, for whom the potential benefits are considerably 
higher and the risks are certainly no greater. 
Pertinently, focal thoracic RT has been recently used by intrepid American investigators to treat patients 
suffering from ventricular tachycardia refractory to medical management. This approach, which entails the 
delivery of a single fraction of 25 Gy directly to an arrhythmogenic focus of the heart, dramatically reduced 
arrhythmia burden and improved quality of life while causing negligible toxicity in a prospective trial.31,32 
Numerous mechanisms of action have been proposed to explain the observed anti-inflammatory and anti-
fibrotic effects of LD-RT, including depletion through ionizing damage, exudative reduction, and wavelength 
vibrations causing immune and pathogenic cell disruptions.3  
COVID-19 Infectious Pathway 
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The COVID-19 infectious mechanism of action is currently being investigated but is thought to be mediated 
by inhaled viral particles infecting airway alveolar type II pneumocytes using angiotensin-converting enzyme 
(ACE) receptor entry points, leading to iterative viral production and a cascading inflammatory event.33 
Macrophage- and monocyte-dominated local infiltration can lead to localized cytokine storms, pulmonary 
edema, exudative infiltrative inflammation, diffuse alveolar damage, and inflammatory-led myocardial 
injury.34-37 It can lead to fatal acute lung injury from inflammatory response for which ACE-receptor 
modulators, and both steroidal and non-steroidal anti-inflammatories have been proposed.34,38 Anti-
inflammatory agents that are given systemically have to be carefully balanced with adverse unintended 
consequences (see discussion below about competing clinical trials). While these may be susceptible to 
systemic anti-inflammatory agents, based on the experience using glucocorticoids in the 2002 SARS 
epidemic, the World  Health Organization (WHO) has advised caution and currently recommends avoidance 
of glucocorticoid treatments.36,39   
 
Figure from Fu, et al.34 
 
ARDS Pathways and Interventional Mechanisms 
 
Acute respiratory distress syndrome (ARDS) in COVID-19 patients appears to be induced by a 
hyperinflammatory syndrome similar to secondary hemophagocytic lymphohistiocystosis (sHLH) or 
macrophage activation syndrome (MAS).40 sHLH and MAS are cytokine storm-like syndromes most 
commonly associated with rheumatologic disorders;,41,42 however, viral disease in both preclinical models 
and in the clinic have been shown to induce a similar phenomenon.43,44 Pre-clinical data has shown CD8+ T-
cell dysfunction is critical for sHLH development following a viral infection with CD8+ T-cell secreted IFN-
gamma being an important mediator.43 Mehta et al. noted that severe COVID-19 patients have a cytokine 
profile similar to sHLH characterized by increased IL-2, IL-6, and interferon-gamma.40 
 
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The data governing the role of induced  immunosuppression in COVID-19 is currently mixed. There are on-
going clinical trials evaluating blockade of IL-6 (ChiCTR2000029765). No current clinical evidence suggests a 
net benefit for ARDS mitigation with globally immunosuppressive corticosteroids in SARS-CoV, MERS-CoV or 
SARS-CoV2 infections,45 although this may depend on the timing of steroid administration.46 It is 
conceivable, however, that focal immunosuppression with local radiation to areas of immunopathology (i.e. 
the lung) may avoid globally immunosuppressing the systemic anti-viral response while mitigating the 
pulmonary inflammation. 
 
Lymphocytes, a main mediator of sHLH, are exquisitely sensitive to ionizing radiation with a D90 (dose required 
to reduce the surviving lymphocyte population to 90% of initial values) of 0.5 Gy.47 Additionally, fractionated 
radiotherapy can induce lymphopenia.48 We and others have shown that fractionated radiation to a murine 
lymph node can deplete irradiated lymphatic tissue for up to one week and induce local immunosuppression 
with a decreased local anti-tumor CD8+ T-cell response (Buchwald et al., Under Review).49 Interestingly, the 
data evaluating pulmonary irradiation and inflammatory infiltrates is highly dose- and timing- dependent.  
Paun et al. showed increased lymphocytic lung tissue infiltration at day 1 and 7 following 18 Gy to the whole 
thorax.50 In contrast, Zheng et al. showed that 2.5 Gy TBI induces a delayed pulmonary inflammatory 
reconstitution with a CD8+ T-cell minima at 3 days post irradiation.51 Importantly Zheng et al. did not show a 
rebound increase in lung T-cell infiltrates at later time points following RT. This suggests that a low radiation 
dose may be effective at inducing transient lympho-depletion within the lungs without inducing a subsequent 
pro-inflammatory rebound. 
 
The probability that lymphoid-depleting LD-RT will have clinical effect in reducing the HLH-mediated cytokine 
storm in COVID-19 patients is arguably most well-informed by the published outcomes of patients irradiated 
for other histiocytic disorders. Among these, clinical experience with LD-RT for the treatment of Langerhan’s-
cell Histiocytosis (LCH) is most robust. Investigators report phenomenal response rates of over exceeding 90% 
of among patients with LCH. Complete responses range from 76%-93% with the majority of those remaining 
the remainder experiencing partial responses following LD-RT to doses typically ranging from 6 to 20 Gy.52,53 
Non-LCH histiocytoses are comparatively rare, with HLH being the next most common and clinically 
characterized by hyperactivation of ordinary macrophages and lymphocytes leading to the systemic hyper-
inflammatory syndrome discussed previously.54 We suspect that if the efficacy of radiotherapy is so effective 
in treating LCH, it should also help may also extend to mitigate the sHLH in COVID-19 patients.  
 
In still further support of our mechanistic hypothesis, LD-RT has actually been used for the treatment of HLH 
itself in select case reports.  Shinoda et al reported successfully treating a 5-year-old girl with HLH isolated to 
the central nervous system with complete resolution of the disease and improvement in neurological 
symptoms.55  Fischer et al. reported described theon successful treatment of four patients with 
erythrophagocytic lymphohistiocytosis that were successfully treatment withusing a  multifaceted treatment 
approach combination therapy that involved included cranial irradiation;56 Hale et al reported on 5 children, 
2 with LCH and 3 with HLH, who were successfully treated with LD-RT-based conditioning regimen, where 
total body irradiation (TBI) was the essential component of successful treatment.57 Hege et al reported 
successful treatment using a reduced-intensity regiment based on 4 Gy TBI in a recurrent HLH patient who 
previously failed a non-TBI based conditioning regimen. Nishi et al reported on use of reduced intensity TBI-
based conditioning regimen (using 2-4 Gy) to successfully treat 13 patients with familial hemophagocytic 
lymphohistocytosis (FHL) and no significant grade > 2 treatment related toxicity.58  
 
Thus, it is plausible that radiotherapy may alter the course of the sHLH-mediated inflammatory storm 
observed in COVID-19 and therefore warrants further study. 
 
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Inflammatory hallmarks of COVID-19  (Table 2) 
The clinical course of COVID-19 entails three phases;59 the viremia phase; acute phase (viral pneumonia); and 
either a recovery phase or severe/critical phase. Given an appropriate immune response during the first two 
phases, there is a high likelihood that the patient will clear the virus and recover. 
However, if the immune response is disproportional, a severe phase and criticality can occur, characterized 
by a hyperinflammatory state associated with mortality 60, 1, 61. In this severe phase, a systemic inflammatory 
response develops that is characteristically the result of cytokine storm, in which there is excessive production 
and systemic release of the pro-inflammatory cytokines interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-
α 40 (see further table 2 below). 
 
This state resembles that observed in other hyperinflammatory conditions, such as cytokine storm after CAR-
T-cell therapy, thus, blocking of the IL-1 and/or the IL-6 receptor may be an effective treatment option in 
COVID-19 patients 62, 63. We advocate that, these immunomodulatory drugs should be used cautiously, as they 
may prolong viral shedding and can be associated with infectious complications. 
Anti-inflammatory effects of LD-RT (Table 2) 
LD-RT is known to affect both immune and endothelial cells. In vitro, LD-RT results in apoptosis and decreased 
adhesion of leukocytes to endothelial cells (when administered at doses of 0.1 – 0.5 Gy) 64. This decreased 
adhesion may be caused by a lower expression of E-selectin, an adhesion molecule expressed by endothelial 
cells (which has been shown to occur, after exposure to 0.3 – 0.5 Gy) 65. In a mouse model of collagen-induced 
arthritis, an increase in regulatory T cells, which is capable of dampening immune responses, was observed 
after treatment with LD-RT 66.  
Of interest, LD-RT has been shown to mitigate the proinflammatory effects of macrophages in murine studies. 
Prior to stimulation with lipopolysaccharide and interferon (IFN)-γ, LD-RT reduced the secretion of nitric oxide 
by macrophages 67. Furthermore, proinflammatory cytokine production by macrophages in response to 
stimulation with lipopolysaccharide was shown to be suppressed by LD-RT 68. Similarly, the secretion of 
reactive oxygen species by macrophages was depressed by LD-RT when administered at doses between 0.3 
and 0.6 Gy 69. 
Calabrese et al suggested that LD-RT induces polarization of M1-type macrophages to the anti-inflammatory 
M2-type 70. This polarization distribution is probably not absolute, but rather represents a combinatory state 
of differing macrophage phenotypes. This M1- to M2- phenotypic conversion may be important to clinical 
outcomes of inflammatory disease, as the M2-type macrophage secrete anti-inflammatory cytokines, IL-10 
and TGF-β1 and suppress IL-6. 
Patients felled by critical COVID-19 illness (i.e.- hyperinflammation) have been shown to have high levels of 
cytokines, particularly IL-6 60 as constituent to cytokine storm. In this light, we opine that LD-RT may be 
beneficial in reducing the pro-inflammatory effects and multi-organ manifestations of cytokine storm. Table 
2 specifically addresses the pro-inflammatory cytokines LD-RT have shown to reduce, as compared to the 
inflammatory cytokines upregulated in COVID-19. We posit that low radiation doses of 1.5 Gy may suppress 
the inflammatory environment and mitigate or prevent the severe/critical phase of COVID-19, including ARDS. 
Table 2 
Pro-inflammatory Cytokines 
14 | P a g e  
 

Increased in COVID-
19 
Reduced with LD-
RT 
TNF-α [40,7171] 
TNF-α [7272] 
IL-1β [7171,38*] 
IL-1β [7272]  
IL-2/R [7171,38*] 
IL-2 [7373] 
IL-6 [7171,38*] 
IL-6 [7474] 
IL-8 [7171] 
IL-8 [7575] 
INF-γ [7171,42*] 
INF-γ [7676] 
References for Table 2 (need add to reference database); 
[38] Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in 
the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives 
of clinical immunologists from China. Clin Immunol 2020;214:108393. 
https://doi.org/10.1016/j.clim.2020.108393. 
 
[42] Liu C, Zhou Q, Li Y, Garner LV, Watkins SP, Carter LJ, et al. Research and Development on 
Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. 
ACS Cent Sci 2020;6:315–31. https://doi.org/10.1021/acscentsci.0c00272. 
 
The Landscape of Competing Trials 
Since the December 2019 outbreak of COVID-19, the academic community has collectively responded to the 
virus’ evolutionary evasion of immune defenses with its own iterative counter punches in the form of 
observational and therapeutic investigations and clinical trials.  Agents currently under investigation include 
mechanism that act on the innate or adaptive immune response pathway (IL-6 blockade with Siltuximab, 
Tocilizumab), protease inhibition of viral replication (Oseltamivir, Favipiravir), pH modification for enzymatic 
lysosomal inhibition (anti-malarial drugs hydroxychloroquine and chloroquine), convalescent serum/plasma, 
angiotensin-converting enzyme (ACE) Inhibition and angiotensin-II type 1 receptor blockade (ARB), non-
steroidal anti-inflammatory drugs (cautionary), steroidal anti-inflammatory drugs (cautionary) and 
vaccination development. Other efforts include but are not limited to phosphodiesterase enhancement 
(sildenafil), BCG vaccine, bevacizumab, and iron chelation with deferoxamine.77 
 
Globally, as of May 2020, more than 3.3 million have been infected leading to over 240,000 deaths.  Early data 
from Lopinavir-Ritonavir phase 3 randomized trial demonstrated a mean time to clincial improvement of 15 
days, which was no different than than the observation arm of 16 days.  The average age in this trial was 58 
yrs old, and the 28 day mortality was 25% in the experimental arm vs 19.2% in the experimental arm.  23% 
of the patients died within 12 days after onset of symptoms.  Only 6% in the experimental arm had 
improvements within 7 days in the experimental arm and only 2% in the observation arm.  
 
Of note, patients in the lopinavir-ritonavir trial (NEJM, Cao et al. PMID 32187464) were only required to have 
less oxygen needs than our patients. The inclusion criteria was that if they were on room air, and if they 
saturated at or below 94%, the were allowed to go on the trial. Our patients, however, had to be dependend 
15 | P a g e  
 

on oxygen, and had to have bilateral xray findings.  Despite our elderly patients (mean age 82), higher glasgow 
coma scale, higher Charleston comorbidities score, and higher requirements to be on our trial, the response 
rate of clinical improvement were much faster with low dose whole lung radiotherapy.  Mean mean time for 
clinical improvement on he current Remdesevir trial was 11 days. We observed a mean time to clinical 
recovery of around 1.5 days in 80% of our patients. For statistical considerations, we will use a more 
conservative estitmate (see stats section).  
 
No Current Standard Of Care Treatments Exist for COVID 
As of June 2020, there are no standard of care treatment for hospitalized COVID patients. There has been no 
therapy that has shown any signficaint success in terms of increasing a patient’s ability to get out of the 
hospital any faster, prevent them from going to the ICU, or extend their overall survival.  The recently 
published randomized double blinded placebo controlled multicenter trial that tested remdesivr vs placebo 
conducted amongst 10 hospitals in China in 237 patients did not show any signficaint clinical benefit (Wang 
et al. Lancet. 2020. May. 395(10238):1694;  Another trial from the United States (Biegel et al. NEJM. May 2020. 
DOI:10.1056/NEJMMoa2007764) changed its primary endpoint during the trial, and found that remdesivir 
was superior to placebo in shortenting time to recovery based on improvement in oxygen status in 
hospitalized CVOID-19 patients. However, there are several scientific criticisms regarding this trial, and many 
leading scientist have concluded that this still does not define the standard of care for COVID -19 patients (i.e. 
personal communication with Dr Aneesh Mehta, one of the co-authors on this paper).  Furthermore, there was 
no benefit in the subgroup not receiving oxygen, and patients on high blow oxygen or were on non-invasive 
mechanical ventilation. Additionally, this minor improvement on oxygen dependency in a subgroup of 
patients did not translate into early hospital discharge, prevention of ICU admission, and/or extended survival 
in the patients that received Remdesivir.   Thus, there is currently, no standard of care therapy for hospitalized 
COVID patients. Furthermore, there has been no vaccines or therapeutic prevention methods that have 
received FDA approval based on any phase 3 data.  Thus, we believe that our phase 3 trial of best supportive 
care plus physician’s choice vs best supportive care plus whole long LD-RT is reasonable. 
 
Expected risks with radiotherapy: 
Risk of radiotherapy are minimal in the near term. A single fraction of 1.5 Gy to the whole lung rarely causes 
any acute side effects. There is a small chance of mild fatigue and skin reaction. However, we did not observe 
this in our small cohort. On the contrary, most of our patients actually improved as their oxygen status 
improved.  There is a hypothetical risk of worsening the cytokine storm in the short term. However, this was 
not noted in our patients, as more than 50% of biomarkers improved.  In the long term, there is small risk for 
secondary cancer. However, radiotherapy is commonly used in many cancer and non-cancer indications with 
much lower mortality rates. And we accept the risk for secondary cancer in these indications. An example is a 
keloid patient, which have a very (nearly 100%) long term chance of surviving from their keloid. We use 
radiotherapy primarily for cosmetic reasons to provid local control, and we accept a very small risk of 
radiation induced cancer many years later. Furthermore, the radiotherapy uses for keloid patients is on a 
order 20-30 times higher than what we are using in our COVID cohort 
 
Ventilator-dependence need for ICU admission, and mortality of the critically ill are extremely high in COVID-
19 patients. Intubation rates are 70-75% of those admitted to the ICU, the mortality 50-70% and the 
extubation rate was only 20% at 3-4 weeks post ICU admission (including at EUH, personal communication).78 
Among those with cardiomyopathy, mortality rates in ICU patients have been reported at 70%.79 Ventilator 
duration was estimated at 1-2 weeks for non-survivors and longer for survivors.78    Thus, if we can improve 
and/or prevent hospitalized patients from becoming dependent on a ventilator by improving their oxygen 
needs earlier in the course of treatment, we would have provided significant medical value and the benefits 
of radiotherapy would outweigh the potential long risk of a secondary malignancy, in a population with very 
high early mortality rates.  
 
 
16 | P a g e  
 

2.3 
Potential Risks and Benefits  
 
EXACERBATION OF EXISTING COVID-19 SEQUELAE 
 
Investigation into the safety of whole-lung low-dose radiation in critically-ill patients with SARS-COVID-19 
requires prediction of potential interactions between low-dose ionization events and all previously-reported 
symptoms and adverse outcomes associated with SARS-COVID-19.  Low-dose radiation therapy is a well-
tolerated and well-studied treatment.  150cGy is unlikely to cause acute toxicity other than fatigue and 
transient cytopenia, and is much lower than what has been previously used in reduced intensity 
conditioning TBI-based regiments to treat HLH.   
 
Symptoms 
 
Fever, cough, myalgia, fatigue, sputum production, headache, hemoptysis, diarrhea, dyspnea have all been 
reported with COVID-19.1  Radiation therapy to the whole lung at a dose of 150cGy is associated with very 
low rates of acute toxicity with symptom onset, with the possible exception of fatigue.  Radiation may 
exacerbate the pre-existing fatigue of COVID-19 patients. Otherwise, few acute toxicities are anticipated 
with low dose lung radiotherapy. 
 
Adverse Outcomes 
 
To date, the virus has been associated with high mortality,  as well as adverse sequelae including but not 
limited to lymphopenia, leukocytosis, leukopenia, hypoalbuminemia, pneumonia, abnormal chest CT, acute 
cardiac injury, acute respiratory distress syndrome, secondary infection, lung parenchyma destruction, 
diffuse alveolar damage, cardiomyopathy, brain injury, pleurisy, pericarditis, shock, and cytopenia.1,80,81 
Brain injury data is anecdotal and limited and will not be further discussed since at the time of protocol 
preparation, too little data has been published to inform discussed of the potential impact of LD-RT on 
neurologic injury -- likely negligible. 
 
ARDS/Lung Parenchyma Destruction/Pulmonary Edema/ Pleurisy/Pneumothorax (45-80%) 
Pneumocyte hyperplasia, focal Inflammation, and diffuse alveolar damage with exudates have been 
reported in COVID-19 patients, with predominantly lymphocytic, and multinucleated giant cells seen 
alongside large atypical pneumocytes.80  Whole-lung irradiation is unlikely to contribute to this inflammatory 
damage because of the very low dose of 150 cGy per fraction.  Pneumonitis constraints for lung radiation 
treatments limit the total lung volume receiving 5 Gy of radiation to be 60%or less (V5<60%). This is 
unquestionable achievable so long as no COVID-19 patient receives more than 3 fractions of 1.5 Gy (4.5 Gy 
total).82  
 
Cardiomyopathy/Myositis/Heart Failure/Pericarditis (15-30%) 
Patient with SARS-COVID-19 can develop cardiac injury diagnosed through elevated troponin levels.1 
Evidence of this injury has been strongly correlated with mortality in initial studies of early disease cohorts 
from Wuhan, China.81 Mortality rates for those with underlying cardiovascular disease and elevated 
troponin levels is reported by numerous authors at 70%.35,79  Proposed mechanisms include increase 
myocardial load,  immune-cell disruption, dislodgement of existing atherosclerotic plaque, and even direct 
myocardial muscle invasion by viral pathogen.79  Radiation therapy can induce late toxicity wherein the risks 
of accelerated atherosclerosis, but this is unlikely to occur in the acute phase of acute pulmonary infection 
and thus LD-RT is unlikely to exacerbating COVID-related cardiac morbidity. 
17 | P a g e  
 

 
Liver + Biliary Dysfunction (60%) 
SARS-COV-2 shares 82% and 50% genetic homology to prior coronavirus infections SARS-COV and MERS, 
which each reported liver injury incidences of around 60%.83 In 14-62% of COVID-19 patient, elevated AST 
and ALT were observed.1,84  Radiation-induced liver injury (RILD) is a rare late radiation toxicity typically 
avoided by liver constraints that preserve portions the whole liver dose to 30 Gy.84  Our proposed dose of 
1.5 Gy may overlap with the upper portion or perhaps all of the liver, but our dose is 10-20 times lower than 
the published tolerance and thus unlikely to contribute significantly to COVID-related liver injury. Gamma-
glutamyl transferase (GGT), a marker of cholangiocytic injury, as well a AST/ALT can monitor for liver/biliary 
injury in COVID-19 patients undergoing whole lung LD-RT. 
 
Hypovolemic Shock//Cardiogenic Shock/Septic Shock (20-35% in ICU patients) 
There is increasing data that COVID-19 infection can lead to shock through a variety of mechanisms 
including cardiac injury, superinfection, and superimposed hypovolemia.85 Radiation therapy has little 
impact on the volume status or fluid balance and is unlikely to exacerbate this COVID sequelae. 
 
Cytopenia/Lymphocytopenia/Splenic atrophy (80%)86 
Radiation to the whole lungs has the potential to exacerbate cytopenia, since thoracic radiation alone is 
known to induce lymphocytopenia and could worsen this outcome in COVID-19 patients.87Decreased 
numbers of lymphocyte, cell degeneration and necrosis have been observed in the autopsy reports of 
spleens following lethal COVID-19 infection. The propensity for low-dose radiation therapy to focally deplete 
the immune system is both the mechanism objective of this protocol, but also could deplete the lymphocyte 
stores in the adjacent spleen – although likely transiently - which could hypothetically exacerbate splenic 
necrosis and further deplete lymphocytes outside of the intra-pulmonary cytokine storm,36 but this is 
unlikely and has not previously been observed at such low doses. 
 
Steroid-related Injury  
 
Systemic anti-inflammatory medications have been deemed contra-indicated in SARS-COVID-19 by the 
World Health Organiztion.39 Numerous reports have reported higher rates of adverse outcomes with the 
addition of systemic corticosteroids, including shock, acute kidney injury, high plasma viral load, prolonged 
viremia, and secondary infection.1,2  These adverse events are particularly relevant to our investigation as 
adverse outcomes associated with anti-inflammatory interventions were somewhat surprising but 
sufficiently consistent to prompt the WHO to recommend against them. The current protocol proposes anti-
inflammatory intervention but at the local level rather than systemic precisely to assess whether local anti-
inflammatory effect and focal immune modulation can rapidly improve outcomes as it did in lobular, viral, 
and interstitial pneumonias the pre-antibiotic era.3 
 
INHERENT RISKS OF LOW-DOSE RADIATION THERAPY ARE LOW 
 
Whole Lung Dose 
 
Lung irradiation is a well-studied treatment for both childhood and adult malignancies. Lung RT has well-
established dosimetric threshold limits for the avoidance of toxicities such as radiation pneumonitis.88,89  
Children with metastatic cancer such as Wilm’s tumor or Ewing sarcoma have been receiving whole-lung 
irradiation to doses of 15-18 Gy for decades, delivered in 1.5 Gy daily fractions over 10-13 treatments.90  Total-
body irradiation (TBI) for marrow ablation is common in the setting of stem cell transplant, utilizing doses 
around 12-14 Gy, but again typically delivered in smaller fractions of 1.5-2.5 Gy per day with lung blocks to 
18 | P a g e  
 

reduce pulmonary exposure.91 Safety parameters for single-fraction radiation therapy has, more recently, 
been established for palliation of lung metastases at dose ranges of around 8 Gy per fraction or as high as 34 
Gy per fraction for peripheral non-small lung cancers.92,93  The proposed single-fraction dose (1.5 Gy in a single 
treatment) is considerably lower than any of these published lung toxicity thresholds. Even if multiple fractions 
were delivered, -dose volume constraints (V5<60%) would not be violated, and even these were not predictive 
of pneumonitis in a recent large trial.82 Given this plethora of clinical experience, there is little risk of acute or 
late pulmonary toxicity following 150 cGy delivered in single fraction. Yet, this low  dose of 1.5 Gy 
approximates an equivalence dose similar to the range of radiation doses reported as effective for various 
infections in the pre-antibiotic era (50-550 Roentgen).3,88   
 
Risk Mitigation Strategies 
 
Delivery of external radiotherapy to COVID-19 positive patients is within the standard operating procedures 
of the Winship Cancer Institute.  However, there is risk of COVID-19 transmission to healthcare workers and 
contemporaneous COVID-19 negative patients.  Risk mitigation strategies continue to evolve as new clinical 
data and best practice guidelines become available.   Strict adherence to the most up to date intuitional 
guidelines for distancing, personal protective equipment, and disinfection is critical. 
 
Mechanisms of transport 
Patient transport to the department of Radiation Oncology will be at the discretion of the patient’s primary 
intensivist.  Adequate monitoring of patients during transportation and treatment in Radiation Oncology is 
required.  Monitoring during transport guidelines will be established by the intensive care unit.  In general, 
the patient’s ICU nurse is recommended to travel with the patient and remain present throughout treatment 
and transport back to the ICU.  EMS transportation may be required per ICU guidelines. Standard of care 
transport and monitoring guidelines will be followed.  
 
The pathway through the department and into the designated treatment room will be clearly marked with 
signage.  Radiation therapy staff will escort the patient from the doors of the department to the treatment 
room. 
 
Pre-arrival strategy 
This experimental radiotherapy will be delivered entirely outside of normal clinical hours.  This will 
dramatically reduce the risk of transmission to COVID-19 negative patients and staff.  Experimental treatments 
will be blocked together as much as feasible in order to minimize the total number of treatment sessions.  A 
single treatment session is preferred. 
 
All staff and providers are required to have completed all institutional PPE training. Prior to each treatment 
session, the radiotherapy treatment care team will meet to review PPE guidelines, including donning and 
doffing, clinical care plan, and post-treatment disinfection plan.  At a minimum all staff and providers will wear 
N95 masks, approved face or eye shields, double gloves and gowns.   
 
A single treatment machine will be designated for all treatments in the session.  Clear plastic coverings will be 
placed over the radiation therapy treatment consoles, keyboards, and mouses and follow department 
standard operative procedures for COVID+ patients.  
 
Using all available diagnostic imaging, a preliminary treatment plan will be generated by the treating radiation 
oncologist and dosimetry staff for each patient.   
19 | P a g e  
 

 
Strategy during RT delivery and planning 
The clinical care plan will strive to minimize the time required to plan and deliver radiotherapy.  The treating 
Radiation Oncologist will be available throughout the treatment session without other required clinical 
responsibilities.  A medical physicist and dosimetrist will be available remotely as well. 
 
Patients will be treated in the gurneys in which they are transported if at all possible, but moved onto the 
treatment table, if necessary, taking care to safely maintain the endotracheal tube and all lines.  The ventilator 
will be positioned that such that the readout screen and vital signs are visible through the video monitoring 
system.  During treatment planning, the patient will remain secured in his or her gurney on the treatment 
table. The radiation therapy staff will take special care to ensure no loose hanging materials (e.g. sheets, lines, 
etc.) come into contact with the linear accelerator during imaging or treatment.  Radiation therapists will be 
instructed not to handle the in-room control wand to move the treatment couch or gantry. 
 
Post-departure strategy 
Once the patient has departed the Radiation Oncology area, the staff will change outer gloves but otherwise 
maintain all other PPE for the next scheduled patient.  Standard cleaning procedures of the treatment room 
will be followed between patients.  Staff and providers will be instructed to avoid entering any areas outside 
of the designated path and treatment area. Standard departmental procedures for COVID + patients will be 
followed.  
 
At the conclusion of the treatment session, a deep cleaning procedure will be instituted that will include the 
treatment room, the treatment console area, and the entire pathway of transportation used during the 
session.  Radiation Oncology staff will personally observe cleaning of these areas by environmental services.  
Approved cleaning materials will be used as referenced in the Emory Ambulatory Cleaning Protocol 
(http://www.ourehc.org/departments/communicable-diseases/ambulatory/cleaning-algorithm.pdf). 
 
All high touch surfaces will be cleaned including but not limited to the following: 
 
• 
Door knobs or door open/close buttons 
• 
Treatment Table (including control wand) 
• 
Cabinet handles 
• 
Countertop 
• 
All faucet handles 
• 
All treatment keyboards, mouses, and control panels (following disposal of clear plastic coverings) 
• 
All patient hand rails throughout the path from door to treatment room 
 
The designated linear accelerator will not be used for any patient treatments for at least 12 hours after the 
last COVID-19 positive treatment patient. However, once the linear accelerator is cleaned per departmental 
protocols, the linear accelerator may be used thereafter.  
 
20 | P a g e  
 

3. OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
PHASE III  
 
 
To investigate clinical recovery, radiographic, and 
immune outcomes in critically-ill patients with COVID-
19 pneumonia following best supportive care plus 
provider’s treatment choice versus best supportive 
care plus low-dose whole-lung radiation therapy (LD-
RT). 
   
Clinical  
• 
time to clinical recovery* 
• 
freedom from intubation 
• 
temperature 
• 
heart rate 
• 
blood pressure 
• 
oxygen saturation 
• 
supplemental oxygenation need* 
• 
respiratory rate 
• 
Glasgow Comma Scale pre and post tx 
• 
performance status 
• 
time to hospital discharge 
• 
freedom from ICU admission 
• 
survival 
 
Radiographic  
• 
serial chest x-rays SARS scoring 
• 
Changes on CT scans pre and post RT 
 
Inflammatory and serologic markers 
• 
CRP/ESR/LDH/D-Dimer/ IL-6 
• 
serum chemistry + CBC with differential 
• 
blood gases (when available) 
• 
albumin/ potassium 
• 
procalcitonin 
• 
AST/ALT/bilirubin 
• 
creatine kinase/ myoglobin 
• 
PT/PTT 
• 
troponin 
• 
lactate 
• 
NT-pBNP (cardiac injury) 
• 
Gamma-glutamyl transferase (GGT) 
• 
Triglycerides  
• 
Fibrinogen/Ferritin 
• 
may include CD 8 Tell, CD 4 T cells, 
cytokine analysis, other immunological 
biomarkers, RNA/DNA sequencing 
* statistical analysis endpoint.  
21 | P a g e  
 

 
4. STUDY DESIGN  
 
4.1 
Overall Design 
 
Phase III Clinical Trial 
 
Primary Objective: Time to Clinical Recovery based on reducing the need of supplementary oxygenation in 
COVID 19 patients.  
Secondary Objectives: To investigate (1) clinical, (2) radiographic, and (3) immune marker response to best 
supportive care plus whole-lung LD-RT compared to best supportive care plus provider’s treatment choice. 
Will monitor improvement in chest xrays, changes in glasscow comma scale, time to hospital discharge, 
overall survival, freedom from intubation, freedom from ICU admission, and changes in biomarkers.   
 
Intervention: LD-RT will be delivered to the bilateral whole lungs using a clinical set up to a dose of 150 cGy 
in one fraction. All patients be approached for enrollment within the 5 (+/- 2) days immediately preceding 
the designated treatment.  Patients will be treated in subsequent 30 minute- time slots on the linear 
accelerator using a hand-calculation of dose and the required machine monitor units for their individual 
source-to-surface distance (SSD), field size, and soft tissue thickness.  Hand calculations will be prepared 
prior to patient arrival to department and will be based on patient separation as determined from prior 
diagnostic CT scan, so as to expedite treatment delivery. Patients will be treated while laying flat or sitting 
upright at angle of optimal respiration.The gantry may be rotated perpendicular to this position and 
positioned at extended SSD so as not avoid transfer from gurney to treatment table, when needed. 
Treatment will be delivered with open fields with jaws set below the diaphragm and above the lung apices 
as seen by light fields or kV/mV imaging with lateral skin flash. Treatment will be delivered in anAPPA 
technique. 
 
22 | P a g e  
 

 
Figure 3. Representative Lung Fields. 
 
 
Personnel present 
Qualified medical physicist (in person and/or remote) 
Faculty radiation oncologist x 1 (PPE protected) 
Radiation Therapists x 2 (PPE protected) 
Equipment needed 
Megavoltage linear accelerator 
Shielded vault 
Computerized dosimetry 
Patient positioning 
Supine or inclined at angle for optimal respiration in transport gurney with arms secure laterally 
at the patient’s sides not overlapping the thorax. 
Patient imaging 
 
Kilovoltage or megavoltage (kV/mV) on- board imaging 
Manual calculation of dose  
As per TG-51 recommendations94 
 
Population: The study population will be divided into two cohorts using central randomization approach 
once a patient has signed consent. The first cohort will undergo best supportive care plus provider’s choice 
of available treatments (which would couldbe, azithromycin, remdesivr, etc. and/or whatever FDA approved 
treatment may be at that time). The second cohort will proceed with best supportive care plus low dose 
radiotherapy on this trial.   
 
Stopping Rule: For the experimental arm, we would evaluate the first 8 patients treated on radiation arm 
for toxicity or worsening cytokine storm, and their outcomes will be compared with the first 8 patients 
treated on the provider’s choice arm (i.e. remdesivir, etc).  See stats section below. 
23 | P a g e  
 

 
Interim efficacy analysis:  
 
1) We would do an interim anlysis after the first 8 patient treated on each arm to compare for primary 
and secondary endpoints at day 14. See stats section.  
 
Intervention sites: Winship Cancer Institute, Emory University Hospital, and Emory University Hospital 
Midtown, Emory Saint Joseph’s Hospital.  
 
The investigational nature and objectives of the trial, the procedures involved, their attendant risks and 
discomforts will be carefully explained to the subject or the subject’s parents or guardian if the subject is a 
child, and a signed informed consent and assent will be obtained according to institutional guidelines. 
 
Patients and/or their legal surrogates will provide written informed consent/assent to participate in the study 
before completing any protocol-specified procedures or evaluations not considered to be part of the patient’s 
standard care.  Procedures that were performed for standard of care prior to signing informed consent may 
be used for screening purposes (e.g., full physical exam).   
 
After signing the ICF, patients will be evaluated for entry criteria during the screening period.  Rescreening 
after screen failure will be allowed.  Documentation of the informed consent for screening will be maintained 
in the subject’s research chart. 
 
 
4.2 
End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last visit or the last scheduled procedure  as shown in the Schedule of Activities (SoA), Section 
1.2 OR if the trial has achieved superiority of one arm over another for the primary endpoint and/or secondary 
endpoints.  If the primay endpoint is met, the trial may still continue to see if secondary endpoint differences 
also tend to occur or not. At this point, the trial may undergo an expansion and repowering for the secondary 
endpoint (but, only after IRB re-approval).  
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
 
5. STUDY POPULATION 
 
Patients are expected to be hospitalized, possibly incapacitated,sedated, or otherwise unable to provide 
informed consent for themselves.  Next of kin or legal surrogate will be approached to screen for 
enrollment. Since no visitors are allowed in COVID ICU units, telephone-based or video-conference based 
consents will be obtained. 
 
24 | P a g e  
 

5.1 
Inclusion Criteria 
 
Inclusion criteria for the patients must  
 
a. Be age 18 or over; Not pregnant (will undergo pregnancy testing if below age 50);  
 
b. Have had a positive test confirming the diagnosis of COVID-19* 
 
c. Have had clinical signs of severe acute respiratory syndrome or pneumonia (ie. dyspnea, cough, 
fever) that primary team feels like patient needs rescuing with treatments.** 
 
d. Have visible consolidations/ground glass opacities on chest imaging.*** 
 
e. Requiring supplemental oxygen**** 
 
f. Willingness and ability of the subject to comply with scheduled visits, protocol-specified laboratory 
tests, other study procedures, and study restrictions. 
 
g. Evidence of a signed informed consent/assent indicating that the subject is aware of the infectious 
nature of the disease and has been informed of the procedures to be followed, potential risks and 
discomforts, potential benefits, and other pertinent aspects of study participation. 
 
It is encouraged but not required that: 
* patients have tested COVID positive within 72 hours of enrollment  
** patients be enrolled and randomized within their first week (7 days) of hospital admission +/- 2 days. 
*** patients have bilateral infiltrates or peripheral ground glass opacities. 
**** patients undergo attempted weaning of supplemental oxygen prior to enrollment and demonstrate 
inability to tolerate room air for a 12-hour period wherein they consistently maintaining saturations >90%. 
 
 
5.2 
Exclusion Criteria 
 
a. 
Use of disallowed medications prior to randomization, including remdesivir,  hydroxycholooquine, 
glucocorticoid steroids or other COVID-directed therapies. This does not apply to azithromycin given 
its lack of published efficacy. Azithromycin must be discontinued at the time of enrollment but does 
not exclude a patient from study participation. After enrollment, patients randomized to receive best 
supportive care plus provider’s choice of therapy may receive any COVID-directed therapy at provider 
discretion. However, administration of COVID-directed therapies is prohibited for patients 
randomized to the interventional arm of best supportive care plus radiation, with one exception. If a 
patient who has received radiation therapy experiences clinical decline after radiation delivery and 
requires intubation or mechanical ventillation, he or she may thereafter receive any COVID-directed 
therapy at providers’ discresion.   
b. 
Pregnant and/or planned to be pregnant within in next 6 months. (will undergo pregnancy testing) 
 
25 | P a g e  
 

6. REGISTRATION PROCEDURES 
 
Patients will be registered after meeting all entry requirements and signing of the informed consent 
document. 
 
6.1 
Local Winship Procedures 
 
Study personnel will notify Winship Central Subject Registration (WCSR) by email at 
winshipcsr@emory.edu, once subject has been consented for a trial.  
Email notification must be done within 24 hours after consent has been obtained and it will include 
scanned copies of: 
 
• 
Signed patient consent form 
• 
HIPAA authorization form 
• 
Emory Research Management System (ERMS; https://erms.emory.edu) Enrollment Fax Cover  
 
The WCSR will enter the subject into the OnCore Research Management System, which is the system of record 
for Winship Cancer Institute Clinical Trials. 
 
6.2 
Study Enrollment 
 
Enrolling a subject requires careful screening and determination of eligibility.  
Subjects may be enrolled on the study once all eligibility requirements for the study have been met. Subjects 
who give informed consent for the protocol should not be enrolled until the screening is completed and they 
are determined to meet all eligibility criteria. 
Eligible patients will be enrolled on study centrally at Winship Cancer Institute by the Study Coordinator.   
When all required test results are available, complete the eligibility checklist and provide the checklist and the 
supporting documentation to the IRB approved investigator for review and sign-off.  
Once the investigator (sub-investigator, Co-Investigator) has signed the eligibility checklist, enrollment may 
proceed. Oncore and ERMS must be updated to reflect eligibility and “on study” status.  
The date protocol procedures are projected to start must be no later than 14 calendar days after the date of 
study enrollment. Subjects must not receive any protocol blood draws prior to enrollment. 
All clinical data required for determining eligibility of a subject enrolled on this trial must be available in the 
subject’s medical or research record which will serve as the source document for verification at the time of 
audit. 
 
 
 
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7. STUDY INTERVENTION  
 
7.1 
General Concomitant Medication and Supportive Care Guidelines 
 
Best supportive care will be administered by direction of supervising internist or intensivist. 
 
COVID-directed therapies (remdesivir for example, or other drugs) are allowed on the control arm 
receiving best supportive care plus provider-directed therapies. The use of COVID-directed therapies 
prior to enrollment is  exclusionary and prohibited in patients randomized to the investigational arm 
with a severity exception (see section 5.2 above).    
 
 
7.2 
Duration of Follow Up 
 
Patients will be followed until the patient’s withdrawal of consent or loss to follow up, death, or study 
termination, planned for 14 days following first administration of LD-RT as listed on work flow table.  
• All patients will be contacted during day 3 (+/- 2 days) of the first week following the last intervention, day 
7 (+/-2 days), and at day 14 day (+/- 1 week). Blood draws will occur at baseline, before RT delivery, at days 3 
(+/- 2 days) and 7 (+/- 2 days) following RT delivery, and one convalesce lab draw after disease recovery.  Blood 
drays at day 14 is optional (but encouraged). Blood draws can be off by +/- 3 days due to logistical reasons.  
• In case of a clinically significant AE, patient will be followed for safety until resolution or permanent sequelae 
of all toxicities attributable to study procedures. If the patient discontinues study drug for a clinically 
significant AE, the patient will be followed until resolution of the AE or the event is considered to be stable 
and/or chronic.  
A participant will be considered lost to follow-up if one fails to return for three scheduled visits and is unable 
to be contacted by the study site staff after three attempts at contact by phone.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort 
to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified 
letter to the participant’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he will be considered to have withdrawn from the 
study with a primary reason of lost to follow-up. 
 
7.3 
Withdrawal from the Study 
 
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Participants, upon request, are free to withdraw or discontinue from participation in the study at any time, 
for any reason, and without prejudice to treatment. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• Occurrence of a clinically significant AE found to be unacceptable or non-resolution of clinically significant 
AEs or other medical condition or situation occurs such that continued participation in the study would not 
be in the best interest of the participant.  
• Symptomatic deterioration, disease progression which requires discontinuation of the study procedures.  
• Significant noncompliance of the patient with protocol-mandated procedures based on the judgment and 
agreement of the Investigator.  
• If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation. 
• Continued participation is no longer in the patient’s best interest in the opinion of the Investigator.  
• Withdrawal of consent.  
 
In the event of a patient’s withdrawal, the Investigator will make every effort to complete the EOT procedures 
specified in the Schedule of Events. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report 
Form (CRF).  
Subjects who sign the informed consent form but do not proceed to the study procedures may be replaced.   
 
 
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8. STUDY ASSESSMENTS AND PROCEDURES 
 
 
 
8.1 
Schedule of study procedures 
 
Screening Phase 
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any study-specific 
screening procedures are performed.  After signing the ICF, completing all screening procedures, and being 
deemed eligible for entry, subjects will be enrolled in the study.  Procedures that are performed prior to the 
signing of the ICF and are considered standard of care may be used as screening assessments if they fall within 
the screening window.  
The following procedures will be performed during the Screening Visit: 
• 
Informed Consent 
• 
Review of eligibility criteria 
• 
Medical history and demographics 
• 
Prior anti-infectious medications for current COVID-19 course of disease 
• 
Complete physical exam  
• 
ECOG Performance Status,  
• 
Glasgow Comma Scale assessment 
• 
Use of any supplemental oxygen and O2 saturations. 
• 
Vitals signs, weight and height  
• 
Review of prior/concomitant medications 
• 
Serologic studies 
• 
Chest imaging 
 
 
8.2 
Description of study procedures 
 
Medical history 
Findings from medical history (obtained at screening) and physical examination shall be given a baseline grade 
according to the procedure for AEs. Increases in severity of pre-existing conditions during the study will be 
considered AEs, with resolution occurring when the grade returns to the pre-study grade or below. 
 
Physical examination 
Physical examinations should be conducted according to the Schedule of Events.  Full physical examinations 
should be conducted at screening/baseline, and EOT (evaluate all major organ systems, including the following 
categories:  general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, 
29 | P a g e  
 

extremities, integumentary, neurologic, and psychiatric). Other examinations may be focused, at the 
discretion of the Investigator, to identify changes from baseline or evaluate changes based on the patient’s 
clinical symptoms.  
 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to the 
assessment schedules.  Body weight is also recorded along with vital signs.  A communication order will be 
placed in the chart of each enrolled patient to ensure proper measurement of fever, stating, “Clinical trial 
patient. No Tylenol.” 
 
Oxygenation 
Both arms will follow identical standardized oxygenation weaning processes: 
1. Oxygenation weaning will be attempted following enrollment for all patients with the exception of 
any patient whose oxygenation requirement or dyspnea has increased within the prior 12 hours.  
Patients with escalating symptoms are excempt from weaning until they have experienced  
stabilization of oxygen requirements for 12 hours. 
2. For patients who have not required an increase in oxygenation in the immediately preceeding 12 
hours, weaning will be attempted at least twice daily (at least one attempt per 12-hour nursing shift) 
over the 14-day trial.  
3. To achieve this, a communication order will be placed into the chart requesting door signage that 
reads: “Clinical trial patient: attempt oxygen wean twice daily (at start of each nursing shift). Maintain 
sats above 90%.”  
4. Patients in both arms will be allowed to request additional weaning as tolerated. 
5. Designation as having returned to room air will require that a patient remain on ambient air for 12 
consecutive hours with no more than one documented transient drop below 90%. A second 
documented drop below 90% in the same 12-hour period will re-set the monitoring period. Any drop 
below 85% will reset the monitoring period. Worsening patient dyspnea or work of breathing that 
clinically merits a return to a higher oxygen level also resets the 12-hour monitoring period.  
6. Patients who required chronic home oxygen supplementation at baseline and who were admitted 
with oxygenation requirements above baseline will be considered clinically recovered when their 
oxygen requirements return to their baseline use for a minimum of 12 consecutive hours. 
 
Clinical laboratory tests 
The following clinical laboratory tests may be performed (see the Schedule of Assessments) 
• 
Hematology and Clinical Chemistry 
• 
COVID-19 testing. 
• 
Viral testing using standard of care clinical procedures and timelines, which may include BAL, NP swaps, 
mouth swabs, etc to determine viral loads.  
 
 
 
 
 
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9. STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
Phase III investigation of efficacy of one-time low-dose radiation treatment for COVID-19 pneumonia.  Our 
primary endpoint is the time to clinical improvement. We suspect that the mean time to wean off oxygen 
will be shorter in the experimental arm compared with the provider’s choice arm.  Secondary endpoints, 
such as clinical status (Glasgow coma scale, toxicity, radiographic, and immune biomarkers, time to 
discharge, freedome from ICU, freedome from intubation, time to hospital discharge, overall survival) will 
also be explored.  
 
9.2 
Sample Size/Accrual Rate 
 
 
The required sample size is 16 patients for provider’s choice arm, and an additional planned enrollment 
for 16 patients in experimental arm.  We would also include another 20 patients for screen failure, for a 
total sample size of 52 .  Patients will be randomized 1:1 to treatment arms using blocked randomization 
with a block size of 4. 
 
In our pilot data, our mean time to clincial improvement was 4 days. Conservatively, we have assumed a 
mean time to clinical improvement of 7 days with a 4-day standard deviation. The provider’s choice arm, 
driven by recent remdesivir data had a mean time of approval of 11 days (assuming all patients on the 
physician’s choice arm may be receiving remedesivir and/or other FDA approved drugs at time of 
enrollment).  Thus, with a sample size of 32, assuming a standard deviation of 4 days, we would have a 
80% power to detect a statistically significant 4-day  difference assuming a Type I error of 0.05.  This 
calculation assumes one interim analysis for efficacy with the use of O’Brien-Fleming stopping boundaries. 
 
9.3 
Stratification Factors 
 
 
 
There are no stratification factors. 
 
9.4 
Analysis of Endpoints 
 
Primary endpoint: The primary endpoint is time to clinical improvement based on weaning from oxygen 
use and hospital discharge.  Clinical improvement will be defined as meeting at least one of the following: 
1) reduction in oxygen use back to baseline  status prior to being hospitalized for COVID and/or [see 
section 8.2 above] 2) hospital discharge.  Mean time to clinical improvement will be compared between 
the two treatment arms using a two-sample z-test, with a known population standard deviation of 4.  If 
the test statistic is greater than 1.97, then we will reject the null hypothesis and conclude the experimental 
arm is superior using a two-sided Z-test.  If Z-test assumptions are not valid, a Mann-Whitney U non-
parametric test will be used.  Difference in mean time to clinical improvement, and a 95% confidence 
interval will be reported. 
31 | P a g e  
 

 
Secondary endpoints: Secondary endpoints include toxicity, radiographic, immune biomarker, and overall 
survival endpoints. Point improvement on the Glasgow Coma scale,  ARDS xray scale, and performance 
status. We would also analyze time to hospital discharge, freedom from ICU, and freedom from 
intubation, and changes on CT scans. All endpoints will be summarized descriptively, using mean, median, 
interquartile range, minimum/maximum, and standard deviation for continuous endpoints, and 
frequency and percentage for categorical endpoints. For time-to-event endpoints, we will use the Kaplan-
Meier method to estimate survival. 
 
9.5 
Interim analysis 
 
 
Stopping Rule for Efficacy:  After 16 patients have been enrolled, treated, and evaluated, an interim look 
will be conducted to stop for efficacy of the experimental arm over the provider’s choice arm.  The boundary 
is determined using the O’Brien-Fleming group sequential method.  If the critical value for a 2-sided Z-test is 
greater than 2.96, the primary endpoint will be considered completed and secondary endpoint will be 
pursued, including time to hospital discharge, etc. The study will acknowledge the efficacy of the 
experimental arm over the provider’s choice arm in achieving clinical recovery, but will not be stopped. If at 
any point in the study, overall survival is found to be statistically superior, the study will be stopped.  This 
analysis assumes a known population standard deviation of 4/group. 
 
Analysis Populations: 
 
The Efficacy and Safety populations include all subjects enrolled in the study and who receive best 
supportive care plus radiotherapy and best supportive care plus provider’s treatment choice.  The Efficacy 
Population will be used for analysis of the primary and secondary endpoints.   
 
 
 
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10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
and the characteristics of an observed AE will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List 
 
The Adverse Event and Potential Risks list provides a single list of reported and/or potential adverse events 
(AE) associated with an agent using a uniform presentation of events by body system.   
 
10.2 
Definition of Adverse Events (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)). 
10.3 
Definition of Serious Adverse Events (SAE)  
 
An adverse event (AE) 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 
• 
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 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. (Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse). 
 
10.4 
Classification of an Adverse Event 
 
10.4.1 Severity of Event 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be 
used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
33 | P a g e  
 

• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”. 
• 
 
10.4.2 Relationship to Study Intervention 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained 
by concurrent disease or other drugs or chemicals. The response to withdrawal of the study 
intervention (dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may 
have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the study intervention) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician.] 
 
10.4.3 Expectedness  
 
Investigators will be responsible for determining whether an adverse event (AE) is expected or unexpected.  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
 
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10.5 
Adverse Event and Serious Adverse Event Reporting  
 
10.5.1 Adverse Event Reporting  
 
From the time of study entry through 14 days following last visit, all adverse events, that begin or worsen after 
informed consent, must be recorded by the investigator or designee at each examination on the Adverse 
Event case report forms/worksheets.   
The investigator will make every attempt to follow all subjects with non-serious adverse events for outcome. 
Conditions that were already present at the time of informed consent should be recorded in the Medical 
History page of the patient’s CRF/worksheet. 
 
Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. Grade 1 to 5 will be used to characterize the severity of the Adverse Event.  
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-
threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be used. Information 
about any deaths (related to an Adverse Event or not) will also be collected through a Death form (or 
EOT/SEC/Survival Information in NOVDD). The occurrence of adverse events should be sought by non-
directive questioning of the patient (patient) during the screening process after signing informed consent and 
at each visit during the study. Adverse events also may be detected when they are volunteered by the patient 
(patient) during the screening process or between visits, or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine:  
1. The severity grade (CTCAE Grade 1-5)  
2. Its duration (Start and end dates)   
3. Its relationship to the study intervention (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study intervention (none, temporarily interrupted, permanently discontinued, 
unknown, not applicable).  
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 10.3 
 
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved with 
sequelae, fatal, unknown)   
  
If the event worsens the event should be reported a second time in the CRF noting the start date when the 
event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a lower grade is 
determined a new entry for this event should be reported in the CRF noting the start date when the event 
improved from having been Grade 3 or Grade 4.   All adverse events should be treated appropriately. If a 
concomitant medication or non-drug therapy is given, this action should be recorded on the Adverse Event 
CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study treatment, the interventions required to treat it, and the 
outcome.  
Progression of malignancy (including fatal outcomes), if documented by use of appropriate method (for 
example, as per RECIST criteria for solid tumors), should not be reported as a serious adverse event.  
 
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Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded on the Adverse Events CRF. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported as 
adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless it 
meets the definition of serious as defined below and/or as per investigator’s discretion.  
 
10.5.2 
Serious Adverse Event Reporting  
 
For the time period beginning at study intervention through 14 days following last visit, any serious adverse 
event, or follow up to a serious adverse event, including death due to any cause whether or not related to the 
study drug, must be submitted on an SAE form and assessed by PI in order to determine reporting criteria to 
regulatory authorities, IRB, DSMC, or FDA.  
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
regulatory authority and should be provided as soon as possible. The investigator will be responsible for 
notifying FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but 
in no case later than 7 calendar days after the initial receipt of the information. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
Any additional information for the SAE including complications, progression of the initial SAE, and recurrent 
episodes must be reported as follow-up to the original episode within 24 hours of the investigator receiving 
the follow-up information.  
An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously 
reported one should be reported separately as a new event.  
Any SAEs experienced after the reporting period described above should only be reported to FDA/IRB if the 
investigator suspects a causal relationship to the study intervention.    
 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. The investigator must 
assess and record the relationship of each SAE to each specific study treatment (if there is more than one 
study treatment), complete the SAE Report Form, and submit the completed form.   
Each reoccurrence, complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation.  
 
If Reported to FDA, all SAE must be recorded on a MedWatch 3500 Form. SAE reports and any other relevant 
safety information are to be forwarded to the following  
 
MedWatch 3500 Reporting Guidelines: 
Note:  MedWatch 3500 forms and other information related to MedWatch reporting are available at 
http://www.fda.gov/medwatch/index.html. 
 
 
 
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10.5.3 
Definition of unanticipated problems (UP) and reporting requirements 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or an outcome that meets all the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
This study will use the OHRP definition of unanticipated problems. Incidents or events that meet the OHRP 
criteria for UPs require the creation and completion of a UP report form. It is the site investigator’s 
responsibility to report UPs to their IRB. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
The Investigator will make an assessment of whether the event constitutes an unanticipated problem posing 
risks to subjects or others (UP). This assessment will be provided to the Emory University IRB.  If the Emory 
IRB determines an event is a UP it will notify the appropriate regulatory agencies and institutional officials. 
37 | P a g e  
 

 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
11.1 
Data Reporting 
 
Study staff are responsible for submitting data and/or data forms in the clinical management system - 
Online Collaborative Research Environment (ONCORE)- per Winship SOP 4.2 Data Completion Metrics.  
Data completion will be reviewed monthly. In situations where there are significant delays of data 
completion, the Associate Director of Clinical Research or the Director of Clinical Trials may temporarily 
suspend enrollment. Data entry is to be completed within the designated timeframe, not to exceed 30 
days of the subject visit.  
Queries will be resolved by the research staff within the time frame specified by the protocol, not to 
exceed 2 weeks.  
 
11.1.1 Source data and documents 
 
In accord with section 1.51 of the ICH E6 document all information in original records and certified copies 
of original records or clinical findings, observations, or other activities necessary for the reconstruction 
and evaluation of the trial is considered source data. Source data are contained in source documents, 
which can be original records or certified copies of hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects' diaries of evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
Case Report Forms (CRFs) - Source data may be collected in the source documents or entered directly 
onto the case report forms. 
Protocol Adherence 
By signing the Form FDA 1572, the Investigator agrees to conduct the study according to the protocol and 
the FDA regulations set forth in 21 CFR Parts 50, 54, 56, and 312. 
Retention of Study Documents 
All documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence will be maintained for at least 2 years after the investigation is completed. 
 
11.2 
Data and Safety Monitoring Plan 
 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide oversight 
for the conduct of this study. The DSMC functions independently within Winship Cancer Institute to 
conduct internal monitoring functions to ensure that research being conducted by Winship Cancer 
Institute Investigators produces high-quality scientific data in a manner consistent with good clinical 
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Winship Protocol #: 
Version Date: 
practice (GCP) and appropriate regulations that govern clinical research. Depending on the risk level of 
the protocol, the DSMC review may occur every 6 months or annually. For studies deemed High Risk, 
initial study monitoring will occur within 6 months from the date of the first subject accrued, with 2 of the 
first 5 subjects being reviewed. For studies deemed Moderate Risk, initial study monitoring will occur 
within 1 year from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed. 
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety Monitoring Plan 
(DSMP).  
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with the 
protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal 
Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, accuracy and 
availability of source documents, AEs/SAEs, and essential regulatory documents. Following the monitoring 
review, monitors will provide a preliminary report of monitoring findings to the PI and other pertinent 
individuals involved in the conduct of the study. The PI is required to address and respond to all the 
deficiencies noted in the preliminary report. Prior to the completion of the final summary report, monitors 
will discuss the preliminary report responses with the PI and other team members (when appropriate). A 
final monitoring summary report will then be prepared by the monitor. Final DSMC review will include the 
final monitoring summary report with corresponding PI response, submitted CAPA (when applicable), PI 
Summary statement, and available aggregate toxicity and safety data.  
Study staff will get approval by the DSMC for opening the second cohort and provide an update on all 
relevant safety data of patients entered to cohort 1 when opening the of second cohort is planned. 
The DSMC will render a recommendation and rating based on the overall trial conduct. The PI is 
responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB. 
Continuing Review submissions will include the DSMC recommendation letter. Should any revisions be 
made to the protocol-specific monitoring plan after initial DSMC approval, the PI will be responsible for 
notifying the DSMC of such changes. The Committee reserves the right to conduct additional audits if 
necessary. 
 
 
 
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Winship Protocol #: 
Version Date: 
12. ETHICS AND PROTECTION OF HUMAN SUBJECTS 
 
12.1 
Ethical standard 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, as 
well as the federal regulations pertaining to ICH E6. 
 
12.2 
Institutional review board 
 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
 
12.3 
Informed consent/Assent 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant 
(or their legal representative/next of kin/surrogate) and written documentation of informed consent is 
required prior to starting intervention/administering study product.  Because intubated patients who 
would be eligible for this trial are not able to provide informed consent, legal representatives/next of 
kin/surrogate will be invited to the hospital to meet with investigators and provide consent in-person or 
they will be offer the option of electronic consent on behalf of patients. This process will require a video 
or telephone conference with the patient’s surrogate to review the consent form in detail. 
 
Informed consent is a process that is initiated prior to the individual consent to participate in the study 
and continues throughout the individual’s participation. Extensive discussion of risks and 
possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB 
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. 
 
The participants should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by emphasizing 
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to them that the quality of their medical care will not be adversely affected if they decline to participate 
in this study. 
 
12.4 
Participant and data confidentiality 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and research staff 
will be secured and password protected. At the end of the study, all study databases will be de-identified 
and archived. 
 
12.5 
Research use of stored samples, specimens, or data 
 
Samples and data collected under this protocol may be used to study COVID-19. Access to stored samples 
will be limited to IRB-approved investigators. Samples and data will be stored using codes assigned by the 
investigators or their designees. Data will be kept in password-protected computers. Only investigators 
will have access to the samples and data. 
All stored samples will be maintained in the laboratory to which it was sent initially for analysis. Study 
participants who request destruction of samples will be notified of compliance with such request and all 
supporting details will be maintained for tracking. 
 
 
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References 
 
 
1. 
Huang C, Wang Y, Li X, et al: Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet 395:497-506, 2020 
 
2. 
Bhatraju PK, Ghassemieh BJ, Nichols M, et al: Covid-19 in Critically Ill 
Patients in the Seattle Region - Case Series. N Engl J Med, 2020 
 
3. 
Calabrese EJ, Dhawan G: How radiotherapy was historically used to treat 
pneumonia: could it be useful today? Yale J Biol Med 86:555-70, 2013 
 
4. 
Calabrese EJ, Dhawan G: The historical use of radiotherapy in the 
treatment of sinus infections. Dose Response 11:469-79, 2013 
 
5. 
Calabrese EJ: X-Ray treatment of carbuncles and furuncles (boils): a 
historical assessment. Hum Exp Toxicol 32:817-27, 2013 
 
6. 
Dodds DR: Antibiotic resistance: A current epilogue. Biochem Pharmacol 
134:139-146, 2017 
 
7. 
Subbaraman N: Coronavirus tests: researchers chase new diagnostics to 
fight the pandemic. Nature, 2020 
 
8. 
Fauci AS, Lane HC, Redfield RR: Covid-19 - Navigating the Uncharted. 
N Engl J Med, 2020 
 
9. 
Wang D, Hu B, Hu C, et al: Clinical Characteristics of 138 Hospitalized 
Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA, 2020 
 
10. 
Bai Y, Yao L, Wei T, et al: Presumed Asymptomatic Carrier Transmission 
of COVID-19. JAMA, 2020 
 
11. 
Ai T, Yang Z, Hou H, et al: Correlation of Chest CT and RT-PCR Testing 
in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology:200642, 
2020 
 
12. 
Rousseau JP, Johnson WM, GT H: The Value of Roentgen Therapy in 
Pneumonia Which Fails to Responde to the Sulfonamides. Radiology 38:281-9, 1942 
 
13. 
Prummel MF, Mourits MP, Blank L, et al: Randomized double-blind trial 
of prednisone versus radiotherapy in Graves' ophthalmopathy. Lancet 342:949-54, 1993 
 
14. 
Seegenschmiedt MH, Keilholz L, Gusek-Schneider G, et al: [Endocrine 
orbitopathy: comparison of the long-term result and classification after radiotherapy]. 
Strahlenther Onkol 174:449-56, 1998 
 
15. 
Kahaly GJ, Rosler HP, Pitz S, et al: Low- versus high-dose radiotherapy 
for Graves' ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab 85:102-8, 
2000 
 
16. 
Marquez SD, Lum BL, McDougall IR, et al: Long-term results of 
irradiation for patients with progressive Graves' ophthalmopathy. Int J Radiat Oncol Biol Phys 
51:766-74, 2001 
 
17. 
Wakelkamp IM, Tan H, Saeed P, et al: Orbital irradiation for Graves' 
ophthalmopathy: Is it safe? A long-term follow-up study. Ophthalmology 111:1557-62, 2004 
 
18. 
Betz N, Ott OJ, Adamietz B, et al: Radiotherapy in early-stage 
Dupuytren's contracture. Long-term results after 13 years. Strahlenther Onkol 186:82-90, 2010 
 
19. 
Heyd R, Dorn AP, Herkstroter M, et al: Radiation therapy for early stages 
of morbus Ledderhose. Strahlenther Onkol 186:24-29, 2010 
 
20. 
Incrocci L, Wijnmaalen A, Slob AK, et al: Low-dose radiotherapy in 179 
patients with Peyronie's disease: treatment outcome and current sexual functioning. Int J Radiat 
42 | P a g e  
 

Winship Protocol #: 
Version Date: 
Oncol Biol Phys 47:1353-6, 2000 
 
21. 
Niewald M, Wenzlawowicz KV, Fleckenstein J, et al: Results of 
radiotherapy for Peyronie's disease. Int J Radiat Oncol Biol Phys 64:258-62, 2006 
 
22. 
Schuster J, Saraiya S, Tennyson N, et al: Patient-reported outcomes after 
electron radiation treatment for early-stage palmar and plantar fibromatosis. Pract Radiat Oncol 
5:e651-8, 2015 
 
23. 
Seegenschmiedt MH, Attassi M: [Radiation therapy for Morbus 
Ledderhose -- indication and clinical results]. Strahlenther Onkol 179:847-53, 2003 
 
24. 
Niewald M, Seegenschmiedt MH, Micke O, et al: Randomized, 
multicenter trial on the effect of radiation therapy on plantar fasciitis (painful heel spur) 
comparing a standard dose with a very low dose: mature results after 12 months' follow-up. Int J 
Radiat Oncol Biol Phys 84:e455-62, 2012 
 
25. 
Ott OJ, Jeremias C, Gaipl US, et al: Radiotherapy for benign 
calcaneodynia: long-term results of the Erlangen Dose Optimization (EDO) trial. Strahlenther 
Onkol 190:671-5, 2014 
 
26. 
Prokein B, Holtmann H, Hautmann MG, et al: Radiotherapy of painful 
heel spur with two fractionation regimens : Results of a randomized multicenter trial after 48 
weeks' follow-up. Strahlenther Onkol 193:483-490, 2017 
 
27. 
Zeckey C, Hildebrand F, Frink M, et al: Heterotopic ossifications 
following implant surgery--epidemiology, therapeutical approaches and current concepts. Semin 
Immunopathol 33:273-86, 2011 
 
28. 
Kienapfel H, Koller M, Wust A, et al: Prevention of heterotopic bone 
formation after total hip arthroplasty: a prospective randomised study comparing postoperative 
radiation therapy with indomethacin medication. Arch Orthop Trauma Surg 119:296-302, 1999 
 
29. 
Kolbl O, Knelles D, Barthel T, et al: Randomized trial comparing early 
postoperative irradiation vs. the use of nonsteroidal antiinflammatory drugs for prevention of 
heterotopic ossification following prosthetic total hip replacement. Int J Radiat Oncol Biol Phys 
39:961-6, 1997 
 
30. 
Sell S, Willms R, Jany R, et al: The suppression of heterotopic 
ossifications: radiation versus NSAID therapy--a prospective study. J Arthroplasty 13:854-9, 
1998 
 
31. 
Cuculich PS, Schill MR, Kashani R, et al: Noninvasive Cardiac Radiation 
for Ablation of Ventricular Tachycardia. N Engl J Med 377:2325-2336, 2017 
 
32. 
Robinson CG, Samson PP, Moore KMS, et al: Phase I/II Trial of 
Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia. 
Circulation 139:313-321, 2019 
 
33. 
He F, Deng Y, Li W: Coronavirus disease 2019: What we know? J Med 
Virol, 2020 
 
34. 
Fu Y, Cheng Y, Wu Y: Understanding SARS-CoV-2-Mediated 
Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virol Sin, 2020 
 
35. 
Guo T, Fan Y, Chen M, et al: Cardiovascular Implications of Fatal 
Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol, 2020 
 
36. 
Yao XH, Li TY, He ZC, et al: [A pathological report of three COVID-19 
cases by minimally invasive autopsies]. Zhonghua Bing Li Xue Za Zhi 49:E009, 2020 
 
37. 
Zhang W, Zhao Y, Zhang F, et al: The use of anti-inflammatory drugs in 
the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of 
43 | P a g e  
 

Winship Protocol #: 
Version Date: 
clinical immunologists from China. Clin Immunol 214:108393, 2020 
 
38. 
Del Rio C: Coronavirus (COVID-19) Update: Early Safety Signals 
Around Ibuprofen and Renin-Angiotensin Inhibitors, 2020, pp https://edhub-ama-assn-
org.proxy.library.emory.edu/jn-learning/audio-player/18329925 
 
39. 
Organization WH: Clinical Management of Severe Acute Respiratory 
Infection when Novel Coronavirus (nCoV) Infection is Suspected, 2020 
 
40. 
Mehta P, McAuley DF, Brown M, et al: COVID-19: consider cytokine 
storm syndromes and immunosuppression. Lancet 395:1033-1034, 2020 
 
41. 
Bracaglia C, Prencipe G, De Benedetti F: Macrophage Activation 
Syndrome: different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online J 
15:5, 2017 
 
42. 
Grom AA, Horne A, De Benedetti F: Macrophage activation syndrome in 
the era of biologic therapy. Nat Rev Rheumatol 12:259-68, 2016 
 
43. 
Jordan MB, Hildeman D, Kappler J, et al: An animal model of 
hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential 
for the disorder. Blood 104:735-43, 2004 
 
44. 
Morimoto A, Nakazawa Y, Ishii E: Hemophagocytic lymphohistiocytosis: 
Pathogenesis, diagnosis, and management. Pediatr Int 58:817-25, 2016 
 
45. 
Russell CD, Millar JE, Baillie JK: Clinical evidence does not support 
corticosteroid treatment for 2019-nCoV lung injury. Lancet 395:473-475, 2020 
 
46. 
Tokunaga A, Sugiyama D, Maeda Y, et al: Selective inhibition of low-
affinity memory CD8(+) T cells by corticosteroids. J Exp Med 216:2701-2713, 2019 
 
47. 
Nakamura N, Kusunoki Y, Akiyama M: Radiosensitivity of CD4 or CD8 
positive human T-lymphocytes by an in vitro colony formation assay. Radiat Res 123:224-7, 
1990 
 
48. 
Yovino S, Kleinberg L, Grossman SA, et al: The etiology of treatment-
related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating 
lymphocytes explains clinical observations and suggests methods of modifying the impact of 
radiation on immune cells. Cancer Invest 31:140-4, 2013 
 
49. 
Marciscano AE, Ghasemzadeh A, Nirschl TR, et al: Elective Nodal 
Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and 
Immunotherapy. Clin Cancer Res 24:5058-5071, 2018 
 
50. 
Paun A, Kunwar A, Haston CK: Acute adaptive immune response 
correlates with late radiation-induced pulmonary fibrosis in mice. Radiat Oncol 10:45, 2015 
 
51. 
Zheng X, Guo Y, Wang L, et al: Recovery Profiles of T-Cell Subsets 
Following Low-Dose Total Body Irradiation and Improvement With Cinnamon. Int J Radiat 
Oncol Biol Phys 93:1118-26, 2015 
 
52. 
Olschewski T, Seegenschmiedt MH: Radiotherapy for bony 
manifestations of Langerhans cell histiocytosis. Review and proposal for an international 
registry. Strahlenther Onkol 182:72-9, 2006 
 
53. 
Laird J, Ma J, Chau K, et al: Outcome After Radiation Therapy for 
Langerhans Cell Histiocytosis Is Dependent on Site of Involvement. Int J Radiat Oncol Biol 
Phys 100:670-678, 2018 
 
54. 
Classen CF, Minkov M, Lehrnbecher T: The Non-Langerhans Cell 
Histiocytoses (Rare Histiocytoses) - Clinical Aspects and Therapeutic Approaches. Klin Padiatr 
228:294-306, 2016 
44 | P a g e  
 

Winship Protocol #: 
Version Date: 
 
55. 
Shinoda J, Murase S, Takenaka K, et al: Isolated central nervous system 
hemophagocytic lymphohistiocytosis: case report. Neurosurgery 56:187, 2005 
 
56. 
Fischer A, Virelizier JL, Arenzana-Seisdedos F, et al: Treatment of four 
patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, 
steroids, intrathecal methotrexate, and cranial irradiation. Pediatrics 76:263-8, 1985 
 
57. 
Hale GA, Bowman LC, Woodard JP, et al: Allogeneic bone marrow 
transplantation for children with histiocytic disorders: use of TBI and omission of etoposide in 
the conditioning regimen. Bone Marrow Transplant 31:981-6, 2003 
 
58. 
Nishi M, Nishimura R, Suzuki N, et al: Reduced-intensity conditioning in 
unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis. Am 
J Hematol 87:637-9, 2012 
 
59. 
Lin L, Lu L, Cao W, et al: Hypothesis for potential pathogenesis of SARS-
CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes 
Infect 9:727-732, 2020 
 
60. 
Zhou F, Yu T, Du R, et al: Clinical course and risk factors for mortality of 
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 
395:1054-1062, 2020 
 
61. 
Ruan Q, Yang K, Wang W, et al: Clinical predictors of mortality due to 
COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 
46:846-848, 2020 
 
62. 
Luo P, Liu Y, Qiu L, et al: Tocilizumab treatment in COVID-19: A single 
center experience. J Med Virol, 2020 
 
63. 
Dimopoulos G, de Mast Q, Markou N, et al: Favorable Anakinra 
Responses in Severe Covid-19 Patients with Secondary Hemophagocytic Lymphohistiocytosis. 
Cell Host Microbe, 2020 
 
64. 
Kern PM, Keilholz L, Forster C, et al: Low-dose radiotherapy selectively 
reduces adhesion of peripheral blood mononuclear cells to endothelium in vitro. Radiother Oncol 
54:273-82, 2000 
 
65. 
Hildebrandt G, Maggiorella L, Rodel F, et al: Mononuclear cell adhesion 
and cell adhesion molecule liberation after X-irradiation of activated endothelial cells in vitro. Int 
J Radiat Biol 78:315-25, 2002 
 
66. 
Nakatsukasa H, Tsukimoto M, Ohshima Y, et al: Suppressing effect of 
low-dose gamma-ray irradiation on collagen-induced arthritis. J Radiat Res 49:381-9, 2008 
 
67. 
Hildebrandt G, Seed MP, Freemantle CN, et al: Mechanisms of the anti-
inflammatory activity of low-dose radiation therapy. Int J Radiat Biol 74:367-78, 1998 
 
68. 
Tsukimoto M, Homma T, Mutou Y, et al: 0.5 Gy gamma radiation 
suppresses production of TNF-alpha through up-regulation of MKP-1 in mouse macrophage 
RAW264.7 cells. Radiat Res 171:219-24, 2009 
 
69. 
Schaue D, Marples B, Trott KR: The effects of low-dose X-irradiation on 
the oxidative burst in stimulated macrophages. Int J Radiat Biol 78:567-76, 2002 
 
70. 
Calabrese EJ, Dhawan G, Kapoor R, et al: Radiotherapy treatment of 
human inflammatory diseases and conditions: Optimal dose. Hum Exp Toxicol 38:888-898, 
2019 
 
71. 
Ye Q, Wang B, Mao J: The pathogenesis and treatment of the `Cytokine 
Storm' in COVID-19. J Infect 80:607-613, 2020 
 
72. 
Arenas M, Sabater S, Hernandez V, et al: Anti-inflammatory effects of 
45 | P a g e  
 

Winship Protocol #: 
Version Date: 
low-dose radiotherapy. Indications, dose, and radiobiological mechanisms involved. Strahlenther 
Onkol 188:975-81, 2012 
 
73. 
Gyuleva I, Djounova J, Rupova I: Impact of Low-Dose Occupational 
Exposure to Ionizing Radiation on T-Cell Populations and Subpopulations and Humoral Factors 
Included in the Immune Response. Dose Response 16:1559325818785564, 2018 
 
74. 
Li J, Yao ZY, She C, et al: Effects of low-dose X-ray irradiation on 
activated macrophages and their possible signal pathways. PLoS One 12:e0185854, 2017 
 
75. 
Schroder S, Broese S, Baake J, et al: Effect of Ionizing Radiation on 
Human EA.hy926 Endothelial Cells under Inflammatory Conditions and Their Interactions with 
A549 Tumour Cells. J Immunol Res 2019:9645481, 2019 
 
76. 
Pandey R, Shankar BS, Sharma D, et al: Low dose radiation induced 
immunomodulation: effect on macrophages and CD8+ T cells. Int J Radiat Biol 81:801-12, 2005 
 
77. 
Health NIo: Clinical Trials.gov, 2020 
 
78. 
, !!! INVALID CITATION !!! 2,67 
 
79. 
Bonow RO, Fonarow GC, O'Gara PT, et al: Association of Coronavirus 
Disease 2019 (COVID-19) With Myocardial Injury and Mortality. JAMA Cardiol, 2020 
 
80. 
Hanley B, Lucas SB, Youd E, et al: Autopsy in suspected COVID-19 
cases. J Clin Pathol, 2020 
 
81. 
Shi S, Qin M, Shen B, et al: Association of Cardiac Injury With Mortality 
in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol, 2020 
 
82. 
Chun SG, Hu C, Choy H, et al: Impact of Intensity-Modulated Radiation 
Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis 
of the NRG Oncology RTOG 0617 Randomized Clinical Trial. J Clin Oncol 35:56-62, 2017 
 
83. 
Zhang C, Shi L, Wang FS: Liver injury in COVID-19: management and 
challenges. Lancet Gastroenterol Hepatol, 2020 
 
84. 
Russell AH, Clyde C, Wasserman TH, et al: Accelerated hyperfractionated 
hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose 
escalating protocol. Int J Radiat Oncol Biol Phys 27:117-23, 1993 
 
85. 
Alhazzani W, Moller MH, Arabi YM, et al: Surviving Sepsis Campaign: 
Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-
19). Crit Care Med, 2020 
 
86. 
Yang X, Yu Y, Xu J, et al: Clinical course and outcomes of critically ill 
patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational study. Lancet Respir Med, 2020 
 
87. 
Joseph N, McWilliam A, Kennedy J, et al: Post-treatment 
lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with 
radical radiotherapy. Radiother Oncol 135:115-119, 2019 
 
88. 
Pollom EL, Chin AL, Diehn M, et al: Normal Tissue Constraints for 
Abdominal and Thoracic Stereotactic Body Radiotherapy. Semin Radiat Oncol 27:197-208, 2017 
 
89. 
Zhao J, Yorke ED, Li L, et al: Simple Factors Associated With Radiation-
Induced Lung Toxicity After Stereotactic Body Radiation Therapy of the Thorax: A Pooled 
Analysis of 88 Studies. Int J Radiat Oncol Biol Phys 95:1357-1366, 2016 
 
90. 
Suzuki G, Ogata T, Aibe N, et al: Effective heart-sparing whole lung 
irradiation using volumetric modulated arc therapy: a case report. J Med Case Rep 13:277, 2019 
 
91. 
Wong JYC, Filippi AR, Dabaja BS, et al: Total Body Irradiation: 
Guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat 
46 | P a g e  
 

Winship Protocol #: 
Version Date: 
Oncol Biol Phys 101:521-529, 2018 
 
92. 
Topkan E, Yildirim BA, Guler OC, et al: Safety and palliative efficacy of 
single-dose 8-Gy reirradiation for painful local failure in patients with stage IV non-small cell 
lung cancer previously treated with radical chemoradiation therapy. Int J Radiat Oncol Biol Phys 
91:774-80, 2015 
 
93. 
Videtic GM, Paulus R, Singh AK, et al: Long-term Follow-up on NRG 
Oncology RTOG 0915 (NCCTG N0927): A Randomized Phase 2 Study Comparing 2 
Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I 
Peripheral Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 103:1077-1084, 2019 
 
94. 
Almond PR, Biggs PJ, Coursey BM, et al: AAPM's TG-51 protocol for 
clinical reference dosimetry of high-energy photon and electron beams. Med Phys 26:1847-70, 
1999 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely 
disabled, 
hospitalization 
indicated.  Death not imminent. 
4 
100% 
bedridden. 
 
Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
 
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APPENDIX B 
GLASCOW COMA SCALE 
 
https://www.cdc.gov/masstrauma/resources/gcs.pdf 
 
 
 
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APPENDIX C 
CHARLESON COMORDBITIY INFEX 
 
https://www.rtog.org/LinkClick.aspx?fileticket=8o6FpyC8s9w%3D&tabid=290 
 
 
 
 
 
 
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