Safety and Efficacy of the Treatment of Hospitalized Patients With COVID 19 Infection With an Inhibitor of IL-4 and IL-13 Signaling: A Phase IIa Trial
Phase: PHASE2
Conditions: COVID-19
Sponsor: University of Virginia

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Title: Impact of dupilumab use for treatment of acute moderate to severe COVID-19 on post recovery long haul 
syndrome  
 
Study Center: University of Virginia 
 
PRINCIPAL INVESTIGATORS 
William A. Petri, Jr., MD, PhD (ID) 
University of Virginia 
Division of Infectious Disease and International Health 
Department of Medicine 
Charlottesville, VA 22908 
Tel #: 434-924-5621 
E-mail: wap3g@virginia.edu 
 
CO-PRINCIPAL INVESTIGATOR 
Jennifer Sasson, MD (ID) 
University of Virginia 
Division of Infectious Disease and International Health 
Department of Medicine 
Charlottesville, VA 22908 
Tel #: 585-752-1707 
E-mail: jms7uq@hscmail.mcc.virginia.edu 
 
IND SPONSOR  
William A. Petri, Jr., MD, PhD (ID) 
University of Virginia 
Division of Infectious Disease and International Health 
Department of Medicine 
Charlottesville, VA 22908 
Tel #: 434-924-5621 
E-mail: wap3g@virginia.edu 
 
SUB-INVESTIGATORS 
Alex Kadl, MD (P&CCM) 
University of Virginia 
Division of Pulmonary and Critical Care Medicine 
Charlottesville, VA 22908 
Tel #: 434-924-9682 
E-mail: ak5sc@virginia.edu 
 
Mary Young, BS 
University of Virginia 
Division of Infectious Disease and International Health 
Department of Medicine 
Charlottesville, VA 22908 
Tel #: 434-924-5167 
E-mail: myk4n@virginia.edu 
 
BIOSTATISTICS  
Jennie Z. Ma, PhD 
University of Virginia 

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Department of Public Health Sciences 
Po Box 800717 
Charlottesville, VA 22908 
jzm4h@virginia.edu 
 
Uma Nayak, PhD 
University of Virginia 
Center of Public Health Genomics 
Po Box 800717 
Charlottesville, VA 22908 
un8x@virginia.edu 
 
 
1.0 SUMMARY 
 
Background: Our research group has shown that high interleukin (IL)-13 is associated with respiratory failure in 
COVID-19 and that IL-13 inhibition protects in a mouse model of SARS-CoV-2 infection1. IL-13 is a known 
cause of pulmonary inflammation in asthma and interstitial lung disease2. We have discovered that IL-13 
neutralization lessens the severity of COVID-19 and reduces hyaluronan (HA), an extracellular matrix 
polysaccharide previously implicated in other inflammatory pulmonary diseases, deposition in mouse lung 
parenchyma1,3. It is therefore biologically plausible that IL-13 contributes to the long-haul pulmonary compromise 
seen in patients with severe COVID-19, potentially through promotion of HA synthesis. We hypothesize that 
neutralization of IL-13 will protect from acute and chronic pulmonary damage by blocking acute HA synthesis 
and inflammation downstream of IL-13. 
 
Clinical Experience: We have conducted a phase IIa randomized double-blind placebo-controlled trial to assess 
the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating 
respiratory failure and death in those hospitalized with COVID-19 (HSR 210184, enrollment completed/closed 
November 2021). Through this trial we found that dupilumab was safe for use in this population and that there 
was a reduced 60-day mortality in those who received dupilumab plus standard of care regimens versus placebo 
plus standard of care regimens4. These findings implicate dupilumab as a promising and novel treatment for those 
hospitalized with COVID-19. Given this, along with our pre clinical data showing IL-13 influence on pulmonary 
injury, we plan to determine differences in post recovery pulmonary function between those who were 
randomized to the dupilumab arm versus placebo during acute COVID-19 infection in the HSR 210184 study 
cohort 1 year after enrollment.  
 
 
Primary Objective:  
• 
Determine the difference in post recovery pulmonary function between those randomized to 
dupilumab arm versus placebo for acute moderate to severe COVID-19.  
 
Primary Endpoint:   
• 
Proportion of patients with abnormal diffusing capacity for carbon monoxide (DLCO) and/or 6 
minute walk testing 1 year after acute COVID-19 infection.  
 
Secondary Objectives:  
• 
Evaluate the immunologic and biologic end points of inhibition of type 2 inflammation post recovery 
from COVID-19 in the dupilumab arm compared to placebo.  
• 
Evaluate imaging abnormalities post recovery from COVID-19 in the dupilumab arm compared to 
placebo. 
• 
Evaluate long haul symptom incidence post COVID-19 recovery in the dupilumab arm compared to 

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placebo.  
 
Secondary Endpoints: 
• 
Proportion of patients with new systemic, respiratory, musculoskeletal, neuropsychiatric and/or 
cardiac symptoms post COVID-19 consistent with long haul syndrome (fatigue, poor concentration, 
daily activity restriction, chronic malaiase, asthenia, dyspnea, persistent cough, pleurisy, sleep 
abnormalities, chronic headache, olfactory impairments, gustatory impairments, brain fog, memory 
defects, depression, anxiety, dizziness, myalgias, joint pain, chest pain, palpitations5): 1 year after 
HSR 210184 enrollment  
• 
Proportion of patients with reduce neurocognitive function: 1 year after HSR 210184 enrollment 
• 
Proportion of abnormal predicted forced expiratory volume (FEV1), forced vital capacity (FVC) 
and/or total lung capacity (TLC): 1 year after HSR 210184 enrollment 
• 
Proportion of patients with new oxygen requirnment after COVID-19 hospitalization: 1 year after 
initial enrollment 
• 
Proportion of patients with greater than 3% oxygen desaturation during 6 minute walk testing: 1 year 
after HSR 210184 enrollment 
• 
Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, Arg1, 
Hyaluronan, soluble ST21: 1 year after HSR 210184 enrollment 
• 
Differences in high resolution computed tomography (HRCT) chest scan appearance post recovery: 1 
year after HSR 210184 enrollment 
 
Study Design: As an extension to the randomized double-blind placebo-controlled trial assessing dupilumab for 
treatment of those hospitalized with acute moderate to severe COVID-19, this is a follow up assessment of this 
study cohort post recovery from COVID-19 for evaluation of pulmonary function testing (PFT), pulmonary 
imaging, immune biomarkers and symptoms. All data will be collected at a single follow up visit 1 year after 
initial enrollment in the parent study HSR 210184 .  
 
Study Population:  
Inclusion Criteria: 
• 
Subjects that were enrolled in study protocol HSR 210184 per inclusion criteria below: 
• 
Male or female 18 years of age or older at the time of enrollment.  
• 
Patients hospitalized with a positive RT-PCR for SARS-CoV-2 within the last 14 days, with illness 
duration within the last 14 days, and evidence of moderate to severe COVID-19 infection as defined 
by NIH COVID-19 Severity Categorization (8): 
-Moderate illness: Individuals who show evidence of lower respiratory disease during 
clinical assessment or imaging and who have saturation of oxygen SpO2≥ 94% on room 
air at sea level.  
-Severe illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial 
partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, 
respiratory frequency >30 breaths/min, or lung infiltrates >50%. 
• 
Patient and/or legally authorized representative is willing and able to provide written informed 
consent and comply with all protocol requirements. 
• 
Patients with hematologic malignancies or solid tumors are eligible. 
• 
Patients with autoimmune disorders are eligible. 
• 
Patients with immunodeficiency and organ or stem cell transplant recipients are eligible. 
• 
Patients with acute or chronic renal injury/failure are eligible. 
• 
Patients with neutropenia/lymphopenia are eligible. 
 
1Plasma cytokines will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels, 
and individual Simplex or ELISA kits.  

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• 
Patients with elevated liver function tests are eligible. 
• 
Women who are not taking contraception are eligible. 
• 
Patients who are currently or have recently received steroids and/or remdesivir are eligible.  
• 
Patient agrees to not participate in another clinical trial for the treatment of COVID-19 through end 
of study period.  
 
Exclusion Criteria: 
• 
Subjects enrolled in study protocol HSR 210184 no longer alive, able or willing to complete follow up visit 
at 1 year after enrollment.  
• 
Any woman who is currently pregnant, or who could be pregnant due to menses history/positive pregnancy 
test 
 
Assessment and Data Acquisition (1 year after HSR 210184 enrollment):  
1. Pulmonary function testing: diffusing capacity for carbon monoxide (DLCO), 6 minute walk testing 
(6MWT), predicted forced expiratory volume (FEV1), predicted forced vital capacity (FVC) and 
predicted total lung capacity (TLC) 
2. High resolution computed tomography (HRCT) imaging of chest  
3. Symptom assessment via questionnaire: fatigue, poor concentration, daily activity restriction, chronic 
malaiase, asthenia, dyspnea, persistent cough, pleurisy, sleep abnormalities, chronic headache, olfactory 
impairmenets, gustatory impairments, brain fog, memory defects, depression, anxiety, dizziness, 
myalgias, joint pain, chest pain, palpitations 
4. Neurocognitive testing via questionaire 
5. Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, Arg1, 
Hyaluronan, soluble ST22 
 
Immune Evaluations: Immune evaluations will be performed to assess the extent to which dupilumab 
administration influences immune markers post recovery from their COVID-19 hospitalization. IL-4, IL-13, 
TARC (CCL17), YKL40, eotaxin 3 (CCL26), Arg1, Hyaluronan, soluble ST2 and levels of other Th1/Th2 
serum cytokines will be measured 1 year after HSR 210184 enrollment.  
  
 
 
 
2Plasma cytokines will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels, 
and individual Simplex or ELISA kits.  

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List of Abbreviations  
ADR 
 
Adverse Drug Reaction 
ADE  
 
Antibody-mediated enhancement of infection 
BP 
 
Blood pressure 
CT 
 
Computed Tomography 
DAIDS 
 
Common Terminology Criteria for Adverse Events 
DBP 
 
Diastolic Blood Pressure 
DLT 
 
Dose limiting Toxicity 
DSMB  
 
Data and Safety Monitoring Board 
ECG/EKG Electrocardiogram 
EUA  
 
Emergency Use Authorization 
FDA  
 
Food and Drug Administration 
GCP  
 
Good Clinical Practice 
IB 
 
Investigator’s Brochure 
ICF  
 
Informed Consent (Informed Consent Form) 
ICH  
 
International Conference on Harmonization 
ICU  
 
Intensive Care Unit 
IEs 
 
Immune Evaluations 
IEC 
 
Independent ethics committee 
IL 
 
Interleukin  
IND 
 
Investigational New Drug Application 
IRB  
 
Institutional review board 
LOS 
 
Length of Stay  
LVEF  
Left Ventricular Ejection Fraction 
MERS   
Middle East Respiratory Syndrome  
NA 
 
Nuclear antibody  
NP  
 
Nasopharyngeal  
OP  
 
Oropharyngeal 
OS  
 
Overall Survival 
PBMC  
Peripheral Blood Mononuclear Cells  
PI 
 
Principal Investigator 
Pts 
 
Patients 
RT-PCR  
Reverse Transcriptase Real-Time Polymerase chain reaction 
PFT 
 
Pulmonary Function Testing 
 
 
PK  
 
Pharmacokinetic 
SAE  
 
Serious adverse event 
SARS   
Severe Acute Respiratory Syndrome 
SARS-CoV-2    Severe Acute Respiratory Syndrome Coronavirus 2 
SBP 
 
Systolic Blood Pressure 
SOC 
 
Standard of Care 
UP  
 
Unanticipated Problem 
UPnonAE  
Unanticipated Problem that is not an Adverse Event 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 SUMMARY .........................................................................................................................................................2 
List of Abbreviations ................................................................................................................................................5 
2.0 OBJECTIVES .....................................................................................................................................................8 
2.1 Primary Objective ...........................................................................................................................................8 
2.2 Secondary Objectives......................................................................................................................................8 
2.3 Study Design ....................................................................................................................................................8 
3.0 BACKGROUND AND SIGNIFICANCE .........................................................................................................8 
3.1 Background and Scientific Rationale ............................................................................................................8 
3.2 Experience with the use of dupilumab in COVID-19 ..................................................................................9 
4.0 ELIGIBILITY.....................................................................................................................................................9 
4.1 Inclusion Criteria ............................................................................................................................................9 
4.2 Exclusion Criteria ...........................................................................................................................................9 
5.0 STUDY TIMELINE ...........................................................................................................................................9 
5.1 Known potential benefits ................................................................................................................................9 
5.2 Known potential risks .....................................................................................................................................9 
1. PFT: Dizziness, coughing, shortness of breath and/or provocation of asthma attack with deep 
inhalation during testing. ........................................................................................................... 10 
2. HRCT scan: radiation exposure, harm to unborn children. ...................................................... 10 
6.0 STATISTICAL CONSIDERATIONS ............................................................................................................10 
7.0 CLINICAL EFFICACY AND IMMUNE MEASURES ...............................................................................10 
7.1 Clinical Efficacy ............................................................................................................................................10 
7.2 Immune Evaluations .....................................................................................................................................11 
8.0 REGISTRATION AND REQUIRED DATA .................................................................................................11 
8.1 Protocol Registration ....................................................................................................................................11 
8.2 Evaluations and Assessments .......................................................................................................................11 
8.3 Immune Evaluations .....................................................................................................................................11 
8.4 Subject Status Definitions ............................................................................................................................11 
9.0 RISKS AND BENEFITS ..................................................................................................................................11 
9.1 Potential Benefits of Follow up with Patient ..............................................................................................12 
9.2 Potential risks ................................................................................................................................................12 
9.3 Alternatives ....................................................................................................................................................12 
10.0 ADVERSE EVENTS AND SAFETY EVALUATION ................................................................................12 
10.1 Adverse Event (AE) ....................................................................................................................................12 
10.2 Serious Adverse Event (SAE) ....................................................................................................................12 
10.3 Unexpected Adverse event: (UAE) ............................................................................................................12 
10.4 Unanticipated Problem (UP) ......................................................................................................................13 

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10.5 Protocol Deviation .......................................................................................................................................13 
10.6 Reporting Interval ......................................................................................................................................13 
10.7 Investigator’s Assessment of Adverse Events ...........................................................................................13 
10.8 Assessment of Severity ................................................................................................................................13 
10.9 Assessment of Association ..........................................................................................................................13 
11.0 REPORTING ADVERSE EVENTS AND PROTOCOL DEVIATIONS .................................................14 
12.0 SAFETY OVERSIGHT .................................................................................................................................16 
12.1 Study monitoring ........................................................................................................................................16 
13.0 STOPPING DECISION RULES ...................................................................................................................16 
14.0 STUDY MANAGEMENT .............................................................................................................................17 
14.1 Institutional Review Board (IRB) Approval ............................................................................................17 
14.2 Informed Consent .......................................................................................................................................17 
14.3 Adherence to the Protocol ..........................................................................................................................17 
14.3.1 Emergency Modifications .............................................................................................. 17 
14.3.2 Other Protocol Deviations/Violations .............................................................................. 18 
14.4 Obligations of Investigators .......................................................................................................................18 
15.0 DATA HANDLING AND RECORDKEEPING..........................................................................................18 
15.1 Data Collection and Management Responsibilities ..................................................................................18 
15.2 Study Records Retention ............................................................................................................................19 
15.3 Publication and Data Sharing Policy ........................................................................................................19 
15.4 Conflict of Interest Policy ...........................................................................................................................19 
16.0 REFERENCES ...............................................................................................................................................19 
 
 

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2.0 OBJECTIVES 
 
2.1 Primary Objective 
• 
Determine the difference in post recovery pulmonary function between those randomized to 
dupilumab arm versus placebo for acute moderate to severe COVID-19.  
 
2.2 Secondary Objectives  
• 
Evaluate the immunologic and biologic end points of inhibition of type 2 inflammation post recovery 
from COVID-19 in the dupilumab arm compared to placebo.  
• 
Evaluate imaging abnormalities post recovery from COVID-19 in the dupilumab arm compared to 
placebo. 
• 
Evaluate long haul symptom incidence post COVID-19 recovery in the dupilumab arm compared to 
placebo.  
 
2.3 Study Design  
As an extension to the randomized double-blind placebo-controlled trial assessing dupilumab for treatment of 
those hospitalized with acute moderate to severe COVID-19, this is a follow up assessment of this study cohort 
post recovery from COVID-19 for evaluation of pulmonary function testing (PFT), pulmonary imaging, immune 
biomarkers and symptoms. All data will be collected at a single follow up visit 1 year after initial enrollment. 
 
3.0 BACKGROUND AND SIGNIFICANCE 
 
3.1 Background and Scientific Rationale  
We have discovered that COVID-19 patients with high plasma interleukin (IL)-13 levels have a significantly greater 
risk of needing mechanical ventilation1. IL-13, which signals through the receptor IL-4Rα along with the closely 
related cytokine IL-4, is involved in eosinophilic inflammation, mucous secretion, goblet cell metaplasia and 
fibrosis, and has been regularly implicated in airway hyperresponsiveness and atopic disease7. We additionally 
found that neutralization of IL-13 in K18-hACE2 C57Bl/6J mice protected the animals from severe infection with 
SARS-CoV-2, as evidenced by reduced clinical score, weight loss and mortality1. The association of IL-13 along 
with other effectors of type 2 immunity with respiratory failure from COVID-19 has also been demonstrated in 
other observation studies8. These findings established mechanistic and biologic plausibility for IL-13 as a driver of 
pulmonary injury in COVID-19. 
RNA-seq analysis of whole lung tissue taken from infected mice who underwent IL-13 neutralization revealed the 
most downregulated gene to be Has1, which encodes a synthase responsible for hyaluronan (HA) production, a 
polysaccharide apart of the extracellular matrix that has previously been implicated in other inflammatory 
pulmonary diseases1,3. This was mechanistically further supported by an increase in HA deposition in human and 
mouse lung with SARS-CoV-2 infection. Additionally, neutralization of the HA receptor, CD44, led to improved 
survival1. As HA has been proposed previously in asthma as a potential culprit in airway remodeling, this led to the 
hypothesis that HA, as a downstream effector of IL-13, may be involved in pulmonary dysfunction post recovery 
from COVID-199. 
We tested our hypothesis that IL-13 leads to post-recovery pulmonary dysfunction in COVID-19 in a pilot cohort 
of 55 patients from the UVA Post-COVID-19 clinic who were hospitalized for severe to critical COVID-19 (79% 
requiring mechanical ventilation). Pulmonary function tests (PFTs) were measured from 1-8 months post recovery, 
focusing on DLCO (diffusing capacity for carbon monoxide) and 6MWT (six-minute walk test) as prior data in 
ARDS and COVID-19 implicated these in post recovery pulmonary abnormalities. We discovered that patients with 
high IL-13 during admission were almost 2.4 times as likely to have an abnormal 6MWT or abnormal DLCO post 
recovery from COVID-19 when adjusting for race/ethnicity, body mass index, smoking status and days from 
symptom onset (DFSO) to acute sample collection. Although it is fully recognized that this represents a preliminary 
exploratory analysis, especially given the small sample size and biomarker heterogeneity in acute disease, this initial 

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evidence of acute type 2 immune impact on post recovery pulmonary function is an exciting finding and, at the very 
least, warranting of further investigation. 
 
3.2 Experience with the use of dupilumab in COVID-19   
Dupilumab, an anti-interleukin-4 receptor-α monoclonal antibody, leading to blockage of IL-4 and IL-13 
signaling, has been FDA approved for treatment of moderate to severe atopic dermatitis since 201710. It has been 
successfully shown to reduce disease severity in not only those with atopic dermatitis but in other allergic diseases 
where Th2 cytokines have been implicated, including asthma and chronic rhinosinusitis11. Original clinical trials 
noted excellent safety profiles in addition to favorability in its use when considering the negative impacts of long 
term steroid use in these patients11. 
We have previously conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety 
and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory 
failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days, with 
collection of clinical outcomes, adverse events and immunologic biomarkers at multiple time points throughout 
the study period. Through this trial we found that dupilumab was safe to use for this indication, that there was 
reduced 60-day mortality in those who received dupilumab compared to placebo and that there was a trend toward 
reduction in ICU admission in the dupilumab group, all of which implicated dupilumab as a promising treatment 
for those hospitalized with moderate to severe COVID-194. 
 
4.0 ELIGIBILITY 
 
4.1 Inclusion Criteria  
• 
Subjects that were enrolled in study protocol HSR 210184.  
 
4.2 Exclusion Criteria 
• 
Subjects enrolled in study protocol HSR 210184 no longer alive, able or willing to complete follow up visit 
at 1 year after enrollment.  
• 
Any woman who is currently pregnant, or who could be pregnant due to menses history/pregnancy test 
 
5.0 STUDY TIMELINE 
 
Telephone call to discuss follow up visit on Day 365 ± 90 days after enrollment for HSR 210184:  
1. Discuss and consent for follow up visit and procedures 
2. Schedule follow up visit  
 
Follow Up Visit on Day 365 ± 90 days after enrollment for HSR 210184 to discuss participation in 220171:  
1. Urine pregnancy test at the time of consenting to rule out participation 
2. Blood for immune evaluation of cytokine levels (1 light green top, 3 mL/draw)  
3. CT chest imaging (non-contrast) 
4. Pulmonary function testing (spirometry, lung volumes, diffusing capacity for carbon monoxide 
(DLCO), 6 minute walk testing (6MWT)) 
5. Symptom screen (fatigue, poor concentration, daily activity restriction, chronic malaiase, asthenia, dyspnea, 
persistent cough, pleurisy, sleep abnormalities, chronic headache, olfactory impairmenets, gustatory 
impairments, brain fog, memory defects, depression, anxiety, dizziness, myalgias, joint pain, chest pain, 
palpitations5) 
6. Neurocognitive testing via questionnaire  
 
5.1 Known potential benefits 
Subject recovery from COVID-19 will be assessed by a Pulmonary and Critical Care attending at follow up visit. 
Subjects will be provided with recommendations based on any abnormalities found. 

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5.2 Known potential risks 
1. PFT: Dizziness, coughing, shortness of breath and/or provocation of asthma attack with deep inhalation 
during testing. 
2. HRCT scan: radiation exposure, harm to unborn children.  
3. Phlebotomy: local discomfort, bruising and/or hematoma, bleeding, fainting, infection. Total blood draw 
not to exceed 5mL.  
 
6.0 STATISTICAL CONSIDERATIONS 
 
6.1 Statistical analysis 
All subjects who received one dose of study drug will be included in the safety analysis. Each primary and 
secondary efficacy outcome measure will be analyzed for the intent-to-treat (ITT) and evaluable population. The 
intent-to-treat principle is that participants will be analyzed in the groups to which they were randomized, 
regardless of whether they received the randomized study medication.  
Data will be summarized as frequency with percentage for categorical clinical variables, and as mean ± standard 
deviation or median with interquartile range for continuous variables. The difference between dupilumab and 
placebo arms will be tested with Chi-square for categorical measures (e.g., the primary endpoint) and two-sample 
t-test or Wilcoxon rank sum test for continuous measures (e.g., biomarkers). Due to the relatively small sample 
size in the study, the adjusted treatment effect of dupilumab will be estimated exploratively in generalized linear 
regression for the primary and secondary outcomes to account for the potential impact of patient characteristics 
(e.g., age, sex, race and co-morbidities) and baseline biomarker measures. Data transformation will be considered 
for the outcomes with skewed distribution. The difference in the biomarker measures at the follow-up visit and 
their changes from baseline between dupilumab and placebo groups will also be assessed. Since this is intended to 
be an early stage, proof of concept study for which the primary goal is to inform future trials rather than to 
perform formal hypothesis testing, no multiplicity adjustment is planned.  
 
6.2 Sample Size justification 
Under the protocol HSR 210184, we conducted a randomized double-blind placebo-controlled trial assessing the 
safety and efficacy of dupilumab for treating hospitalized patients with acute moderate to severe COVID-19, 
which was designed as an early stage (Phase IIa) and proof of concept study. A total of 40 patients were enrolled 
from June 23, 2021 through November 180 11, 2021 in the Phase IIa study, and 7 of them died by Day 60. The 
sample size of 40 in the original Phase II study were determined largely based on the feasibility with a primary 
goal to collection reliable data and obtain sufficient evidence for future trials. The current proposed study is an 
extension of the original Phase IIa study under the HSR 210184, to assess the post recovery of remaining 33 
patients from COVID-19 with respect to pulmonary function testing (PFT), pulmonary imaging, immune 
biomarkers and symptoms at one-year follow-up. All data will be collected at a single visit, 1 year (i.e., 365 ± 90 
days) after initial enrollment in the remaining 33 parents from the study HSR 210184. Formal sample size 
estimation and power analysis is not performed due to the pilot nature of this proposed follow-up study. 
 
7.0 CLINICAL EFFICACY AND IMMUNE MEASURES 
 
7.1 Clinical Efficacy  
• 
Proportion of patients with abnormal diffusing capacity for carbon monoxide (DLCO) and/or 6 
minute walk testing 1 year after acute COVID-19 infection 
• 
Proportion of patients with new systemic, respiratory, musculoskeletal, neuropsychiatric and/or 
cardiac symptoms post COVID-19 consistent with long haul syndrome (fatigue, poor concentration, 
daily activity restriction, chronic malaiase, asthenia, dyspnea, persistent cough, pleurisy, sleep 
abnormalities, chronic headache, olfactory impairments, gustatory impairments, brain fog, memory 
defects, depression, anxiety, dizziness, myalgias, joint pain, chest pain, palpitations5): 1 year after 
HSR 210184 enrollment  

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• 
Proportion of patients with reduce neurocognitive function: 1 year after HSR 210184 enrollment 
• 
Proportion of abnormal predicted forced expiratory volume (FEV1), forced vital capacity (FVC) 
and/or total lung capacity (TLC): 1 year after HSR 210184 enrollment 
• 
Proportion of patients with new oxygen requirnment after COVID-19 hospitalization: 1 year after 
initial enrollment 
• 
Proportion of patients with greater than 3% oxygen desaturation during 6 minute walk testing: 1 year 
after HSR 210184 enrollment 
• 
Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, Arg1, 
Hyaluronan, soluble ST23: 1 year after HSR 210184 enrollment 
• 
Differences in high resolution computed tomography (HRCT) chest scan appearance post recovery: 1 
year after HSR 210184 enrollment 
 
7.2 Immune Evaluations 
Plasma cytokines including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, Arg 1, Hyaluronan, soluble 
ST2 will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels, and 
individual Simplex or ELISA kits (1 light green top with approximately 2 mL of anti-coagulated blood will be 
allotted for cytokine assessment). 
 
8.0 REGISTRATION AND REQUIRED DATA 
8.1 Protocol Registration 
Subject must have been enrolled in HSR 210184. Subjects who are consented to the study must be registered in 
the Clinical Trials Office. All subjects who have signed an informed consent should have demographics and 
date of signed informed consent entered into the database.  
8.2 Evaluations and Assessments 
All evaluations and assessments should be completed as described in Study Timeline. Any assessments not 
described in detail below should be done according to standard of care practices.  
 
8.3 Immune Evaluations 
Plasma cytokines including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, Arg 1, Hyaluronan, soluble 
ST2 will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels, and 
individual Simplex or ELISA kits (1 light green top with approximately 2 mL of anti-coagulated blood will be 
allotted for cytokine assessment). 
 
8.4 Subject Status Definitions 
• 
Enrolled: All subjects who sign an informed re-consent will be considered enrolled on the study. All 
subjects consented on the study must be entered into Clinical Trials Office Database. 
• 
Note: The IRB defines any individual that has signed an informed consent as an enrollment in this study 
and so screen failures should be reported to the IRB with enrollment numbers. 
• 
On-Study: A subject is considered on-study on the date when the study team has confirmed the subject 
has met all of the inclusion and none of the exclusion criteria,  
• 
On Follow-up: A subject is considered on follow-up on the date that they have met any of the criteria in 
section 4.0. 
• 
Off-Study: A subject is considered off-study if they are removed from the study for any of the reasons 
listed in section 4.0  
9.0 RISKS AND BENEFITS 
 
3Plasma cytokines will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels, 
and individual Simplex or ELISA kits.  

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12
 
9.1 Potential Benefits of Follow up with Patient  
Subject recovery from COVID-19 is assessed by a Pulmonary and Critical Care attending working in clinic that day 
and are provided with recommendations based on any abnormalities found.   
    
9.2 Potential risks 
1. Risks of PFTs: Dizziness, coughing, shortness of breath and/or provocation of asthma attack with deep 
inhalation during testing. 
2. Risks of HRCT scan: radiation exposure, harm to unborn children 
3. Risks of phlebotomy: local discomfort, bruising and/or hematoma, bleeding, fainting, infection. 
4. Total blood draws will not exceed 5 mL 
 
9.3 Alternatives 
Follow up as needed with primary care physician.  
 
10.0 ADVERSE EVENTS AND SAFETY EVALUATION  
Adverse events will be evaluated and scored using Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events Version 2.1 (DAIDS v2.1). 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf ) 
 
10.1 Adverse Event (AE)  
An adverse event will be considered any undesirable sign, symptom, medical, or psychological condition even if 
the event is not considered to be related to the investigational drug/intervention. Medical condition/diseases present 
before starting the investigational drug/intervention will be considered adverse events only if they worsen after 
starting study treatment/intervention.  An adverse event is also any undesirable and unintended effect of research 
occurring in human subjects as a result of the collection of identifiable private information under the research.  
Adverse events also include any problems associated with the use of an investigational drug that adversely affects 
the rights, safety or welfare of subjects. 
 
10.2 Serious Adverse Event (SAE) 
An adverse event (AE) is considered a serious adverse event (SAE) if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or  
• 
a congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the 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. 
 
10.3 Unexpected Adverse event: (UAE)  
The PI will be responsible for determining whether an 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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10.4 Unanticipated Problem (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UPs) (may include a data 
breach) involving risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given the research procedures that are described in 
the protocol-related documents, such as the Institutional Review Board (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. 
 
10.5 Protocol Deviation 
A protocol deviation is defined as any change, deviation, or departure from the study design or procedures of a 
research project that is NOT approved by the institution’s IRB prior to its initiation or implementation, OR 
deviation from standard operating procedures, Good Clinical Practices (GCPs), federal, state or local regulations. 
Protocol violations may or may not be under the control of the study team or UVA staff. These protocol violations 
may be major or minor violations. 
 
10.6 Reporting Interval 
All AEs and SAEs will be documented from the first administration of study product and for the following 60 days 
or until un-enrollment from the study, whichever comes sooner. All AEs and SAEs will be followed until resolution 
even if this extends beyond the study-reporting period. Resolution of an adverse event is defined as the return to 
pre-treatment status or stabilization of the condition with the expectation that it will remain chronic.  
 
10.7 Investigator’s Assessment of Adverse Events  
The determination of seriousness, severity, and causality will be made by an on-site investigator who is qualified 
(licensed) to diagnose adverse event information, provide a medical evaluation of adverse events, and classify 
adverse events based upon medical judgment. This includes but is not limited to physicians, physician assistants, 
and nurse practitioners. The study PI will review events that occur at the time of occurrence.  
 
10.8 Assessment of Severity 
For 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.  
• 
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”. 
 
10.9 Assessment of Association 
All 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.  
• 
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, 

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occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals.  
 
• 
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.  
 
• 
Possibly 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).  
• 
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. 
 
. 
11.0 REPORTING ADVERSE EVENTS AND PROTOCOL DEVIATIONS 
All AEs meeting DAIDS grade 3 severity or above including local and systemic reactions not meeting the criteria 
for SAEs will be captured. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and authority to 
make a diagnosis), and time of resolution/stabilization of the event. All AEs meeting DAIDS grade 3 severity or 
above occurring while on study must be documented appropriately regardless of relationship. All AEs meeting 
DAIDS grade 3 severity or above will be followed to adequate resolution. 
 
Any medical condition (including a laboratory abnormality) that is present at the time that the participant is 
screened will be considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration 
of each episode. 
 
AEs meeting DAIDS grade 3 severity or above must be recorded into the case report forms and will be reported 
per the following guidelines (Error! Reference source not found.2). 
 
It is the responsibility of the principal investigator to use continuous vigilance to prevent, identify and report 
protocol deviations. Major protocol deviations must be reported to the UVA IRB-HSR per the following 
guidelines (Table 2).  Minor deviations do not need to be reported to the UVA IRB-HSR.  All deviations must be 
addressed in study source documents.  
 
Table 2 
 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 

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Any internal event 
resulting in death that is 
deemed DEFINITELY 
related to (caused by) 
study participation 
 
IRB-HSR 
Within 24 
hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, 
Unexpected adverse event  
All adverse events deemed to 
be related to the drug meeting 
DAIDS severity grade 3 and 
above will be reported. 
 
 
IRB-HSR 
Within 7 
calendar days 
from the time 
the study team 
received 
knowledge of 
the event. 
 
Unanticipated Problems 
that are not adverse events 
or protocol deviations  
This might include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 
calendar days 
from the time 
the study team 
received 
knowledge of 
the event.  
Unanticipated Problem report 
form.  
Unanticipated Problem Report 
Form 
 
 
Protocol 
Deviations/Noncompliance 
 
  
IRB-HSR 
 
 
Within 7 
calendar days 
from the time 
the study team 
received 
knowledge of 
the event.  
 
Protocol Deviation, 
Noncompliance and Protocol 
Exception Reporting Form 
Protocol Deviation Protocol 
Exception Reporting Form 
  
 
 
Data Breach  
The UVa 
Corporate 
Compliance and 
Privacy Office 
 
 
 
ITC:  if breach 
involves  
electronic data  
 
 
 
 
Police if breach 
includes items that 
are stolen: 
 
As soon as 
possible and no 
later than 24 
hours from the 
time the 
incident is 
identified. 
 
As soon as 
possible and no 
later than 24 
hours from the 
time the 
incident is 
identified. 
 
IMMEDIATEL
Y.  
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
https://security.virginia.edu/report
-information-security-incident 
 
 
 
 
 
 
 
 

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16
Stolen on UVA 
Grounds 
 
OR  
 
Stolen off UVa 
Grounds- contact 
police department 
of jurisdiction of 
last known 
location of PHI 
 
UVa Police-Phone- (434) 924-
7166 
 
12.0 SAFETY OVERSIGHT 
 
12.1 Study monitoring  
The study team will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion according to institutional policies.  
Any study under the purview of the University of Virginia IRB-HSR is subject to review of files at the University 
of Virginia. Studies are chosen for Post-approval Monitoring either a) at random or b) requested by a study team 
member or any member of the IRB-HSR.   
The purpose of Post-approval Monitoring audits is to ensure that documentation of clinical research studies is of 
the highest quality, verify protocol adherence, and ensure that all Federal and local rules concerning clinical 
research are being fulfilled.  Post-approval monitoring is done by staff within the office of the Vice President for 
Research (VPR) in accordance with their Standard Operating Procedures. The conduct of an on-site review may 
include but is not limited to: 
• 
requests for progress reports from investigators, 
• 
examinations of research records, including signed informed consent documents, protocol modifications, 
and unexpected, serious, and/or related adverse experience reports, 
• 
contacts with research subjects, or 
• 
observation of the consent process and/or research procedures. Examples of when observation of the 
consent process could occur are: 
• 
Full board IRB determines during review of a project that a conflict of interest exists such that the 
informed consent process should be observed by a neutral party; 
• 
IRB is made aware of a complaint or concern with regard to the informed consent process; or 
• 
IRB determines as a result of the monitoring process that the consent process is insufficient and 
education/training is required for conduct of consent. 
 
13.0 STOPPING DECISION RULES 
 
The study enrollment will be stopped and reviewed by the PI if any of the following specific events occur or, if in 
the judgement of the study physician, subject safety is at risk of being compromised during the visit: 
• 
Death due to study procedure 
• 
Occurrence of a life threatening allergic/hypersensitivity reaction (analphylaxis), manifested by 
bronchospasm with or without urticaria or angioedema requiring hemodynamic support with pressor 
medications or mechanical ventilation due to any of the study procedures performed (pulmonary function 
testing, blood collection) 
• 
One subject with a grade 4 or persistent grade 3 (≥72 hours) associated with study procedures 

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• 
Two subjects with persistent Grade 3 (≥ 72 hours) or higher lab toxicity for the same parameter associated 
with study procedures 
• 
An overall pattern of symptomatic, clinical, or laboratory events that the study investigators consider 
associated with study product and that may appear minor in terms of individual events but that collectively 
may represent a serious potential concern for safety. 
• 
Any other event(s) which is considered to be a serious adverse event in the good clinical judgment of the 
attending physician team.  This will be appropriately documented. 
 
 
14.0 STUDY MANAGEMENT 
 
14.1 Institutional Review Board (IRB) Approval 
It is expected that the IRB will have the proper representation and function in accordance with federally mandated 
regulations.  The IRB should approve the consent form and protocol. 
 
14.2 Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Consent forms will be Institutional Review Board 
(IRB)-approved and the participant will be asked to read and review the document. A member of the study team 
will explain the research study to the participant and answer any questions that may arise. A verbal explanation 
will be provided in terms suited to the participant’s 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 family or surrogates or think about it prior to agreeing to participate. If the 
participant is deemed incapable of making their own medical decisions, a surrogate decision maker or legally 
authorized representative will be provided with the study information as detailed above and may consent to 
enrollment on behalf of the participant. The participant (or surrogate decision maker) will sign the informed 
consent document prior to any procedures being done specifically for the study. Both paper-based and 
electronic/e-consent approaches will be utilized as appropriate. 
 
Results from procedures completed prior to consent for standard of care purposes may be used for research 
purposes.  
 
Participants must be informed that participation is voluntary and that they may withdraw from the study at any 
time, without prejudice. A copy of the informed consent document will be given to the participants for their 
records.  
 
The informed consent process will be conducted and documented in the source document (including the date), and 
the form signed, before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 
14.3 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the study subject 
requires alternative treatment, the study shall be conducted exactly as described in the approved protocol.   
 
14.3.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB-HSR approval/favorable opinion.   
For any such emergency modification implemented, a UVA IRB modification form must be completed by 
study personnel within five (5) business days of making the change. 

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14.3.2 Other Protocol Deviations/Violations 
Protocol Deviations: A protocol deviation is any unplanned variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the value of the data 
collected  
• 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
Study personnel will record the deviation, and report to any sponsor or data and safety monitoring 
committee in accordance with their policies.  Deviations should be summarized and reported to the IRB at 
the time of continuing review. 
 
Protocol Violations: An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, or 
University policies. 
 
Violations should be reported by study personnel to the IRB within one (1) week of the investigator 
becoming aware of the event (refer to Table 2 in section 13 – Reporting Adverse Events and Protocol 
Deviations). 
 
14.4 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 21 
of the Code of Federal Regulations, all applicable local regulatory laws and regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the treatment of all study subjects.  
The Principal Investigator must assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. It is the responsibility of the Principal Investigator to ensure that all study 
site personnel are aware that the study protocol and all data generated is confidential and should not be disclosed to 
third parties (with the exception of local and national regulatory bodies which require access for oversight purposes).  
The Principal Investigator will be responsible for assuring that all the required data will be collected and entered 
onto the Case Report Forms. Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of data. At the completion of the 
study, all case report forms will be reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
15.0 DATA HANDLING AND RECORDKEEPING 
 
15.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff under the supervision of the Principal Investigator. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into RedCap electronic database.  Clinical data will be entered directly 
from the source documents. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   

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15.2 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing application in 
an International Conference on Harmonisation (ICH) region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study intervention. These documents should be retained for a longer period, however, 
if required by local regulations. No records will be destroyed without the written consent of the IND sponsor, if 
applicable. It is the responsibility of the IND sponsor to inform the study team when these documents no longer 
need to be retained. Record retention will be in accord with 21 CFR 312.62 and HIPAA regulations. 
 
15.3 Publication and Data Sharing Policy 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts 
that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, 
this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.   
 
15.4 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by industry, is critical.  Therefore, 
any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any 
aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest 
will be required to have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial.  The study leadership in conjunction with the institution has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
16.0 REFERENCES 
1.  
Donlan AN, Sutherland TE, Marie C, et al. IL-13 is a driver of COVID-19 severity. JCI Insight. 
2021;6(15). doi:10.1172/jci.insight.150107 
2.  
Gour N, Wills-Karp M. IL-4 and IL-13 signaling in allergic airway disease. Cytokine. 2015;75(1):68-78. 
doi:10.1016/j.cyto.2015.05.014 
3.  
Lennon FE, Singleton PA. Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology. Am 
J Physiol - Lung Cell Mol Physiol. 2011;301(2). doi:10.1152/ajplung.00071.2010 
4.  
Sasson J, Donlan AN, Ma JZ, et al. Safety and Efficacy of Dupilumab for the Treatment of Hospitalized 
Patients with Moderate to Severe COVID 19: A Phase IIa Trial. Unpublished. Published online 2022. 
doi:https://doi.org/10.1101/2022.03.30.22273194 
5.  
Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23(2):194-202. 
doi:10.1038/s41590-021-01104-y 
6.  
National Institutes of Health (NIH). Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. 
2020;2019:130. https://covid19treatmentguidelines.nih.gov 
7.  
Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425-456. 
doi:10.1146/annurev.immunol.21.120601.141142 
8.  
Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-
19. Nature. 2020;584(7821):463-469. doi:10.1038/s41586-020-2588-y 
9.  
Liang J, Jiang D, Jung Y, et al. Role of hyaluronan and hyaluronan-binding proteins in human asthma. J 
Allergy Clin Immunol. 2011;128(2):403-411.e3. doi:10.1016/j.jaci.2011.04.006 
10.  
Food and Drug Administration (FDA). Dupixent package insert. Published online 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761055s014lbl.pdf 
11.  
Thibodeaux Q, Smith MP, Ly K, Beck K, Liao W, Bhutani T. A review of dupilumab in the treatment of 

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atopic diseases. Hum Vaccines Immunother. 2019;15(9):2129-2139. doi:10.1080/21645515.2019.1582403 
 
APPENDIX: 
NIAID 8-POINT ORDINAL SCALE FOR CLINICAL IMPROVEMENT  
• 
The ordinal scale is an assessment of the clinical status at the first assessment of a given 
study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-
invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring 
supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring 
ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring 
supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, 
limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no 
limitations on activities. 
 
NIH SEVERITY CATEGORIZATION 
• 
Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-CoV-2 using a 
virologic test (i.e., a nucleic acid amplification test or an antigen test) but who have no symptoms that are 
consistent with COVID-19. 
• 
Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, 
cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but 
who do not have shortness of breath, dyspnea, or abnormal chest imaging. 
• 
Moderate Illness: Individuals who show evidence of lower respiratory disease during clinical assessment or 
imaging and who have saturation of oxygen (SpO2) ≥94% on room air at sea level. 
• 
Severe Illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial pressure 
of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, 
or lung infiltrates >50%. 
• 
Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.