Conditions: COVID-19
Keywords: Anti-Inflammatory Agents
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, superiority phase IIa trial to assess the safety and efficacy of dupilumab use in hospitalized patients with moderate to severe COVID-19 infection. Subsequently, we conducted a 1 year follow up study to investigate the occurrence of Post COVID conditions (PCC) in our study population through assessment of pulmonary function, symptoms, neurocognition and immune biomarkers to observe for any treatment group differences.

Detailed description:
A total of 40 eligible subject were enrolled and randomized in a 1:1 ratio to receive either dupilumab or placebo, stratifying on the disease severity measured by the required oxygen ≤ 15L or \> 15L by nasal cannula. Both arms received standard of care management per current National Institutes of Health (NIH) COVID-19 treatment guideline in addition to their randomized treatments. Patients were then followed prospectively for up to 360 days after enrollment.

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, subjects were followed up at 1 year for evaluation of pulmonary function testing (PFT), pulmonary imaging, immune biomarkers, neurocognition and symptoms.

Arms:
arm 1: Dupilimab: 600 mg, given as two 300 mg subcutaneous injections on day 0/1. If participants are still hospitalized a second and third dose (300 mg) will be given on days 14 and 28. arm 2: Normal saline will be given as two one mL subcutaneous injections on day 0/1. If participants are still hospitalized a second and third dose (1 mL) will be given on days 14 and 28.

Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a loading dose of dupilumab (600 mg, given as two 300 mg subcutaneous injections) on day 0/1. If participants are still hospitalized a second and third dose (300 mg) will be given on days 14 and 28. intervention 2: Normal Saline.

Protocol document:
SAP_002.pdf: 
Statistical analysis plan (SAP) for the Dupilumab Study 
Version 6 
March 29, 2022 
 
1.0 Introduction 
1.1 Study objectives: The primary objective is to determine the efficacy of dupilumab use plus 
standard of care management in patients hospitalized with moderate to severe COVID-19 
infection compared to placebo plus standard of care management assessed by the proportion 
of patients alive and free of invasive mechanical ventilation at 28 days. The secondary 
objectives are to: (1) evaluate the safety of Dupilumab use in terms of eosinophilia in patients 
hospitalized with moderate to severe COVID-19 infection, (2) compare clinical outcomes on 
Dupilumab versus placebo across a range of secondary clinical safety and efficacy domains, 
and (3) evaluate the immunologic and biologic end points of inhibition of type 2 
inflammation. 
 
1.2 Study design: This is a randomized, double-blind, placebo-controlled, superiority phase 
IIa trial to assess the safety and efficacy of dupilumab use in hospitalized patients with 
moderate to severe COVID-19 infection. A total of 40 eligible subject will be enrolled 
and randomized in a 1:1 ratio to receive either dupilumab or placebo, stratifying on the 
disease severity measured by the required oxygen ≤ 15L or > 15L by nasal cannula. Both 
arms will receive standard of care management per current National Institutes of Health 
(NIH) COVID-19 treatment guidelines (https://covid19treatmentguidelines.nih.gov/) in 
addition to their randomized treatments. Patients will be followed prospectively for up to 
60 days after enrollment. 
 
1.3 Database Sources: Completed forms and electronic data will be entered into the data 
management system in the REDCap platform. Only authorized individuals shall have access 
to electronic CRFs. 
 
1.4 Randomization:  
 
In this randomized, double-blind, placebo-controlled Phase IIa trial, a total of 40 eligible 
subjects will be enrolled and randomized in a 1:1 ratio to receive either dupilumab or 
placebo, stratifying on the disease severity, which is measured by the required oxygen ≤ 
15L or > 15L by nasal cannula. Both arms will receive standard of care management per 
current National Institutes of Health (NIH) COVID-19 treatment guidelines 
(https://covid19treatmentguidelines.nih.gov/) in addition to their randomized treatments.  
Since this is a small trial, simple randomization procedure may result by chance in the 
compositions of the study arms being markedly different with respect to factors that may 
affect the outcome measures in the trial, or markedly unequal numbers of participants may 
be recruited to each arm. Further, disease severity measured by the required oxygen ≤ 15L 
or > 15L by nasal cannula may impact on the outcomes differentially. Thus, to ensure the 


balance of treatment allocation in disease severity, the blocked randomization with block 
size of 4 will be performed, stratifying based on disease severity: patients who are on 15L 
or less of oxygen by nasal cannula (severity group A) and those requiring more than 15L 
of oxygen by nasal cannula including any noninvasive ventilation measures (severity group 
B). Thus, separate randomization lists will be generated for mild and severe patients, using 
the Proc Plan procedure in SAS, and the complete randomization lists will be sent to UVa 
Pharmacy only to ensure the blindness for others. 
 
Example list for mild disease group: 
Disease 
Severity 
Order 
Treatment 
Arm 
Subject 
Initial 
 
SubjectID 
Date of 
Randomization 
Randomized 
By 
Mild 
101 
A 
  
 
  
 
Mild 
102 
A 
  
 
  
 
Mild 
103 
B 
  
 
  
 
Mild 
104 
B 
  
 
  
 
Mild 
105 
B 
  
 
  
 
Mild 
106 
A 
  
 
  
 
Mild 
107 
A 
  
 
  
 
Mild 
108 
B 
  
 
  
 
 
 
1.5 Study population:  
Adult patients (18 years of age or older) who are 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 (see the Appendix of study protocol): 
− 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%. 
 
Inclusion Criteria  
• 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. 
• 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 
• Patients who do not require inpatient admission for COVID-19 infection. 
• Patients who require invasive mechanical ventilation at time of enrollment.  
• A pre-existing condition or use of a medication that, in the opinion of the site investigator, 
may place the individual at a substantially increased risk due to study participation. 
• Pregnancy or breast feeding (lactating women who agree to discard breast milk from day 1 
until two weeks after the last study product is given are not excluded). 
• Allergy to Dupilumab or its excipients. 
• Current acute parasitic helminth infection or history of chronic parasitic infection. 
• History of ocular scleritis, uveitis, keratitis or recent (<6 months) eye injury (chemical or 
traumatic), infection or vascular occlusion. 
• Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, 
or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-
live (inactivated) vaccinations is allowed for all subjects. 
 
2.0 Outcomes 
2.1 Primary outcome: The primary efficacy endpoint of this double-blind, placebo-controlled 
phase IIa trial is a binary indicator for whether a patient would be alive and free of invasive 
mechanical ventilation at 28 days. The outcome will be summarized as the proportion of 
patients alive and free of invasive mechanical ventilation at 28 days in those receiving 
dupilumab in addition to standard of care (treatment arm) compared to those receiving solely 
standard of care management (placebo arm). 
 
2.2 Secondary outcomes:  
2.2.1 Eosinophilia as the safety outcome: The safety endpoint of this study is a binary 
indicator for whether a patient would have eosinophilia, which is defined as an 
absolute eosinophil count > 0.6 k/µl at ≥ 1 measurement throughout the study period. 
The outcome will be summarized as the proportion of patients with eosinophilia for 
treatment arm and placebo arm respectively. Complete blood counts with differentials 


and complete metabolic panels will be measured on Day 0, 2, 5, 7, 14, 28 and 60. Day 
7, 28 and 60 optional, although recommended, if patient discharged within the time 
frame. 
 
2.2.2 Other secondary safety and efficacy outcomes: 
• Cumulative incidence (defined as number of new events divided by the total 
number of individuals in the population at risk for the time interval) of grade 3 
and 4 adverse events, serious adverse events or death including: injection site 
reactions, eye/eyelid inflammation, conjunctivitis, oropharyngeal pain, 
insomnia, tooth ache, gastritis, arthralgia, bacterial pneumonia, herpes viral 
infection, hypereosinophilic syndrome, hypersensitivity reaction. 
• Prevalence of B.1.1.7 and B.1.351 and other SARS-CoV-2 lineages in study 
cohort: Day 0. 
• Plasma total Immunoglobulin E (IgE) levels: Day 0 and 14. 
• Plasma inflammatory markers (C-reactive protein and ferritin): Day 0, 7 and 14. 
Day 7 optional if patient discharged. 
• Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), 
IL-13, IL-4, Arg1, Hyaluronan, soluble ST2: Day 0, 2, 5, 7, 14, and 28. Day 7 
and 28 optional if patient discharged. 
• Change in PaO2/SaO2 to FiO2 ratio: Day 0, 2, 5, 7 (if patient remains inpatient 
throughout) 
• All-cause mortality rate at 28 days. 
• Hospital length of stay (LOS) 
• ICU LOS 
• Proportion of patients alive and free of invasive respiratory failure at 28 days. 
• Proportion of patients alive and free of invasive mechanical ventilation at 60 
days. 
• Proportion of patients alive and free of invasive mechanical ventilation at 90 
days. 
• Proportion of patients alive and free of invasive mechanical ventilation at 120 
days. 
• Proportion of patients alive and free of invasive mechanical ventilation at 150 
days. 
• Proportion of patients alive and free of invasive mechanical ventilation at 180 
days. 
• Proportion of patients alive and free of invasive mechanical ventilation at 270 
days.  
• Proportion of patients alive and free of invasive mechanical ventilation at 360 
days. 
• National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal 
scale (see Appendix): Day 0, 2, 5, 7, 14, 28, 60, 180 and 360. 
• Need for vasopressors 
• Need for renal replacement therapy 
• Need for extracorporeal membrane oxygenation (ECMO) 
 


3.0 General considerations 
3.1 Analysis populations: 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. 
Another analysis population of interest is the as-treated population. The as-treated 
population will consist of only participants who were inducted onto study medication, 
even one dose of drug. Safety outcome will be primarily analyzed for the as-treated 
population.  
 
Major differences in the results for the ITT and as-treated populations, if any, will be 
further explored. While there is every intention to be complete in describing the analyses 
to be performed, it is not possible to anticipate every contingency, and some adjustments 
may be required to meet constraints posed by the structure of the data. Constraints such 
as non-linearity, non-normality, etc. may lead to different but more appropriate 
approaches to analysis. 
 
3.2 Testing of Distribution assumptions: Empirical distributions of all variables will be 
visually inspected to detect outliers. The underlying proposed statistical methods for each 
analysis will be examined, primarily through inspection of graphical displays, 
standardized residuals, or influence diagnostics. Where appropriate and/or necessary, 
transformations will be utilized for continuous measures such as biomarker data, or 
categorized biomarkers will be analyzed. 
 
3.3 Interim analysis: there is no formal scheduled interim analysis with respect to the 
primary efficacy outcome and thus the sample size estimation would not be altered. 
However, analysis for some selected biomarkers will be performed after the 14th day of 
the 20th patient enrolled. Particularly, the proportion and rate of change of C- reactive 
protein and ferritin levels will be calculated from day 0 and day 14 time points to 
determine efficacy trends between the two treatment groups. Additionally, percentage of 
eosinophilia will be calculated between the two groups to determine safety trend. Data 
will be analyzed by a third party and remain blinded to the study investigators. We expect 
greater changes in C-reactive protein and ferritin for patients receiving Dupilumab than 
those receiving placebo and no significant differences in eosinophilia between the two 
groups. 
 
3.4 Software: All analyses will be performed utilizing SAS® version 9.4. All statistical tests 
will be conducted at the 5% Type I error rate (two-sided). When multiple tests are 
conducted, the chance of finding a significant difference in one of the tests, when in fact 
no difference exists, is greater than the stated Type I error rate. The investigators are 
aware of the multiple testing issues and will interpret results with caution and use 
confidence intervals where possible. 
 
4.0 Analysis of demographic and baseline data:  
The demographic variables for this study include age, gender, race, ethnicity, and BMI, etc. The 
baseline clinical characteristics include disease severity, symptoms, comorbid conditions, days 


from COVID-19 symptom onset, and baseline blood lab results, etc.  
 
Descriptive statistics for baseline and demographic variables will be presented for patients 
randomized to each of the treatment arms and overall. Descriptive statistics will include N, 
mean, standard deviation, median, 25th and 75th percentiles, minimum and maximum for 
continuous variables and proportions and percentages for categorical variables. In general, 
randomization is expected to produce balance at baseline between the two arms of the trial, 
formal statistical comparisons of treatment groups with respect to baseline characteristics will 
not be necessary. However, since this is a relatively small study, the differences in baseline 
characteristics between the treatment arms will be evaluated exploratorily for better 
understanding the study population. The updated CONSORT statement no longer recommends 
formal testing of statistical significance of differences between baseline characteristics. 
 
5.0 Efficacy analyses:  
5.1 General analysis strategy:  The difference between dupilumab and placebo arms in outcome 
measures will be primarily analyzed under ITT principle, regardless of patient’s use of rescue 
medications, protocol violations, or investigational product discontinuation. The difference 
will be tested initially with Chi-square for categorical measures (e.g., the primary efficacy 
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 the 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). Data transformation will be 
considered for the outcomes with skewed distribution such as hospital length of stay (LOS) 
and ICU LOS. The trajectory of each immune biomarker over the follow-up time points will 
be plotted to characterize the change of immune responses over time, and difference in 
biomarker (or transformed biomarker to improve normal distribution, if necessary) 
trajectories between the two study arms will be assessed in the mixed effects model.  
 
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. In addition, machine learning methods such as random forests 
algorithm will be applied to fully evaluate the treatment effect and predictability of 
dupilumab and other important predictors on the outcomes non-parametrically. 
5.2 Primary efficacy outcome 
The primary efficacy endpoint of this study is a binary indicator for whether a patient would 
be alive and free of invasive mechanical ventilation at 28 days. The outcome will be 
summarized as the proportion of patients alive and free of invasive mechanical ventilation at 
28 days and the difference in the proportions between the two study arms will be evaluated 
with Chi-square test. The odds ratio of being alive and free of invasive mechanical 
ventilation at 28 days for Dupilumab vs. placebo and its 95% confidence interval (CI) will be 
estimated in logistic regression, adjusting for potential baseline characteristics if necessary. 
5.3 Secondary outcomes 
5.3.1 Eosinophilia as the safety outcome: Eosinophilia is a binary indicator for a patient 


to have an absolute eosinophil count > 0.6 k/µl at ≥ 1 measurement based on the 
blood counts with differentials and complete metabolic panels on Day 0, 2, 5, 7, 14, 
28 and 60 (Data on Day 7, 28 and 60 would be optional). The outcome will be 
summarized as the proportion of patients with eosinophilia and the difference in the 
proportions between the two study arms will be evaluated with Chi-square test. The 
odds ratio of having eosinophilia for Dupilumab vs. placebo and its 95% CI will also 
be estimated in logistic regression, with adjustment for other covariates. 
 
5.3.2 Other secondary safety and efficacy outcomes: 
• Cumulative incidence rate of adverse events (injection site reactions, eye/eyelid 
inflammation, conjunctivitis, oropharyngeal pain, insomnia, tooth ache, gastritis, 
arthralgia, bacterial pneumonia, herpes viral infection, hypereosinophilic 
syndrome, hypersensitivity reaction, other grade 3 or 4 adverse events, serious 
adverse events or death) is defined as number of adverse events divided by the 
total number of individuals in the population at risk for the time interval. The rate 
ratio of adverse events for Dupilumab vs. placebo and its 95% CI will be analyzed 
in Poisson regression, in which the follow-up time interval will be considered as 
the offset. Adjusted analysis for other covariates will be performed, as necessary. 
Mortality at 60 days will be analyzed as the time to event response. Survival 
probabilities will be estimated by the Kaplan-Meier method, and the difference in 
the mortality risk between the two treatment groups will be evaluated by the log-
rank test and further in Cox regression, adjusting for the baseline covariates. For 
the analysis of mortality over the first year, additional adjustment for dynamic 
mechanical ventilation effect will be considered by including being on ventilation 
as a time-vary covariate in the Cox regression. 
• Plasma total Immunoglobulin E (IgE) levels on Day 0 and 14 will be considered 
as continuous responses, and difference between treatment arms will be evaluated 
by t-test or Wilcoxon test initially, and adjusted difference and its 95% CI will be 
estimated from linear regression. Further, changes of IgE from Day 0 to Day 14 
will also be explored and the difference between the two study arms will be 
analyzed similarly. 
• Plasma inflammatory markers (C-reactive protein and ferritin) on Day 0, 7 and 14 
(Day 7 would be optional if patient discharged) will be analyzed as longitudinal 
responses in the linear mixed effects model with Dupilumab treatment as a fixed 
effect. Since this is a randomized study, significant effect of treatment on 
intercept is not expected. Thus, the longitudinal analysis will focus on the slope 
difference between the treatment arms via interaction of treatment and time in the 
model. Since there are only 3 measures for each subject, only random slopes will 
be specified as a prior. Model fitting indices will be examined carefully to ensure 
the validity of estimated parameters.  If Day 7 data won’t be available for all 
patients, these biomarkers between Day 0 to Day 14 will be analyzed as the IgE 
above. 
• Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), 
IL-13, IL-4, Arg 1, Hyaluronan, soluble ST2 on Day 0, 2, 5, 7, 14, and 28 (Day 7 
and 28 optional if patient discharged) will be analyzed as longitudinal responses 


in the linear mixed effects model with Dupilumab treatment as a fixed effect, and 
with appropriate transformation of biomarkers if necessary. The trajectories of 
these biomarkers will be carefully evaluated, and the slope difference between the 
treatment arms will be evaluated by the interaction of treatment and time. 
Additional curvature in trajectories will also be explored and captured whenever 
possible in the linear mixed effects model.  
• Change in PaO2/SaO2 to FiO2 ratio on Day 0, 2, 5, 7 (if patient remains inpatient 
throughout) will be analyzed as longitudinal responses in the linear mixed effects 
model, similar methods to that for inflammatory biomarkers and cytokine 
biomarkers as described above. 
• All-cause mortality at 28 days will be analyzed as the binary response, using the 
same methods as that for the primary efficacy outcome and eosinophilia. 
• Hospital length of stay (LOS) and ICU LOS between treatment arms will be 
analyzed as continuous measures using t-test or Wilcoxon test initially, and 
adjusted difference and its 95% CI will be estimated from linear regression. Since 
the distributions of hospital LOS and ICU LOS are often skewed, the log-
transformed LOS data will be considered in the analyses. 
• The response of being alive and free respiratory failure at 28 days is a binary 
response and will be analyzed using the same methods as that for the primary 
efficacy outcome. 
• The response of being alive and free invasive mechanical ventilation at 60 days is 
a binary response and will be analyzed using the same methods as that for the 
primary efficacy outcome. 
• National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal 
scale on Day 0, 2, 5, 7, 14, 28, 60, 180 and 360 will be considered as longitudinal 
data. The distributions of the data will be examined visually first and further 
collapsing will be considered. Collapsed data will be analyzed in the generalized 
linear mixed effect model or multinomial logistic regression with the generalized 
estimating equation approach. 
• Proportion of patients alive and free of invasive mechanical ventilation at 60, 90, 
120, 150, 180, 270 and 360 days  will be estimated from the Kapan-Meier 
survival for the time to mechanical ventilation-free survival over the first year. 
The difference in these proportions between the two treatment groups will be 
evaluated by the log-rank test and further in Cox regression adjusting for the 
baseline covariates. For the analysis of mortality over the first year, additional 
adjustment for dynamic mechanical ventilation effect will be considered by 
including being on ventilation as a time-vary covariate in the Cox regression.  
• Need for vasopressors is a binary response and will be analyzed using the same 
methods as for the primary efficacy outcome. 
• Need for renal replacement therapy is a binary response and will be analyzed 
using the same methods as for the primary efficacy outcome. 
• Need for extracorporeal membrane oxygenation (ECMO) is a binary response and 
will be analyzed using the same methods as for the primary efficacy outcome. 


 
6.0 Other safety analyses: 
Analysis of adverse event (AE) data will primarily be descriptive based on 
CTCAE coding of events. The proportion of subjects experiencing a severe 
AE and the proportion experiencing a Grade 3 or higher will be recorded. 
AE will be compared to published data. 
7.0 Sample size estimation and power analysis:  
This trial is intended to be an early stage and proof of concept study with the primary 
goal to collect reliable data and obtain sufficient evidence for future trials. Thus, the 
emphasis of the study is an exploratory estimation of effect size and incidence of adverse 
events in terms of eosinophilia; it is not considered as a pivotal trial for efficacy at this 
time. Therefore, a larger significance level (one-sided alpha=0.1), and the sample size is 
pre-selected based on the feasibility. Given the current decline trend in the incidence of 
COVID-19 positive cases, we anticipate to enroll 40 patients realistically into this 
randomized clinical trial, which shall be sufficient for us to collect reliable and 
interpretable data for proof of concept to inform future trials. The COVID-19 
hospitalization data from our University of Virginia Health System between March 2020 
and April 6, 2021 showed that 79.5% of COVID-19 inpatients were alive and free of 
mechanical ventilation at 28 days under the usual care. With 40 patients that are deemed 
to be feasible, we would expect Dupilumab to improve a margin of 17.7% in the 
proportion of patients alive and free of mechanical ventilation at 28 days. That is, it is 
anticipated that 97.2% of patients being alive and free of ventilation at 28 days in the 
Dupilumab arm. The power analysis is conducted using the one-sided Score test 
(Farrington & Manning) with 75% power and 10% type I error. 
 
8.0 Missing data 
Since patients in this study will be closely followed for mortality and status on mechanical 
ventilation, the primary outcome of being alive and free of ventilation is likely captured. 
Dropout from the study will be carefully evaluated for its potential informativeness. A 
sensitivity analysis will be performed to examine the impact on the proportion and its 
confidence limits. In particular for the primary endpoint, individuals who withdraw will be 
considered events if their statuses on day 28 are unknown.  
 
Other outcome variables (clinical conditions and laboratory biomarkers) will have missing 
data due to dropout from treatment and/or from study participation, or due to missed 
outpatient visits if patients have been discharged from the hospital. The generalized linear 
model, or mixed effects model frameworks that will be used for analyses, works with what 
data are gathered, and assumes missing data are missing at random. For selected secondary 
outcome analyses, sensitivity analyses will be considered to examine the stability of 
estimated treatment effects in the face of departures from the assumption of missing at 
random. 
 
 
 

Prot_003.pdf: 
Version date: 2-2-22 
1 
Title: 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 
 
Short Title: Safety and Efficacy of Dupilumab for Treatment of Hospitalized COVID-19 Patients 
 
Phase of Study: Phase IIa 
IND Number: 154664 
 
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 
Scott Heysell, MD, MPH (ID) 
Jeffrey Sturek, MD, PhD (P&CCM) 
Patrick Jackson, MD (ID) 
 
BIOSTATISTICS  
Jennie Z. Ma, PhD 
University of Virginia 
Department of Public Health Sciences 
Po Box 800717 
Charlottesville, VA 22908 
jzm4h@virginia.edu 
 
Uma Nayak, PhD 


Version date: 2-2-22 
2 
University of Virginia 
Center of Public Health Genomics 
Po Box 800717 
Charlottesville, VA 22908 
un8x@virginia.edu 
 
 
 
 
 


Version date: 2-2-22 
3 
1.0 SUMMARY 
 
Background: It has been widely recognized that severe disease from SARS-CoV-2 infection has been attributed 
to a substantial dysregulation of the immune system leading to significant respiratory compromise, end organ 
damage and death (1). Central to this immune response are certain cytokines, specifically those that activate the 
Type 2 (Th2) pathway of inflammation, which have been associated with severe disease in COVID-19 (2,3). 
Interleukin-13 (IL-13) has been identified as a key driver in respiratory compromise leading to ventilation in 
patients with COVID-19 and, when neutralized in mice, has shown reduced disease severity. Dupilumab, an 
inhibitor of IL-13 and IL-4 used currently in treatment of atopic disease, has also been associated with reduced 
disease severity when observing outcomes of those diagnosed with COVID-19 who are concomitantly prescribed 
dupilumab (2). This therefore raises the possibility of successful use of dupilumab for treatment of COVID-19 
infection and moreover provides an avenue for more targeted anti-inflammatory therapy in these patients. 
 
Clinical Experience: 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 
2017. 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 rhinosinusitis (4). 
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 patients (5,6).  
Dupilumab therapy for asthma is associated with eosinophilia, with the highest incidence at 16-20 weeks after the 
initiation of therapy, and in approximately 4% of patients, of which only 0.3% were symptomatic (7). Preliminary 
analysis of COVID-19 hospitalization data at our institution showed an increase in eosinophil counts in patients 
throughout their admission. Although an overall favorable drug safety profile, the association of eosinophilia with 
dupilumab use in addition to its association with severe COVID-19 infection raises concern for an additive effect 
with both exposures and potential subsequent clinical repercussions. It is therefore important that safety is also 
evaluated in addition to clinical efficacy of dupilumab use in those hospitalized with COVID-19 in this 
randomized, double-blind, placebo-controlled, superiority phase IIa trial. 
 
 
Primary Objective:  
• 
Determine the efficacy of dupilumab use plus standard of care management in patients hospitalized with 
moderate to severe COVID-19 infection compared to placebo plus standard of care management assessed 
by the proportion of patients alive and free of invasive mechanical ventilation at 28 days.  
 
Primary Endpoint:   
• 
Proportion of patients alive and free of invasive mechanical ventilation at 28 days. 
 
Secondary Objectives:  
• 
Evaluate the safety of dupilumab use in patients hospitalized with moderate to severe COVID-19 
infection.  
• 
Evaluate clinical endpoints of dupilumab use in patients with COVID-19. 
• 
Evaluate the immunologic and biologic end points of inhibition of type 2 inflammation. 
 
Secondary Endpoints: 
• 
Percentage of patients with eosinophilia (defined as an absolute eosinophil count > 0.6 k/µl at 
≥ 1 measurement throughout the study period) in those receiving dupilumab in addition to 
standard of care compared to those who receive standard of care management plus placebo. 
Complete blood counts with differentials and complete metabolic panels will be measured on 
Day 0, 2, 5, 7, 14, 28 and 60. Day 7, 28 and 60 optional, although recommended, if patient 


Version date: 2-2-22 
4 
discharged within the time frame1.  
• 
Cumulative incidence (defined as number of new events divided by the total number of 
individuals in the population at risk for the time interval) of adverse events: injection site 
reactions, eye/eyelid inflammation, conjunctivitis, oropharyngeal pain, insomnia, tooth ache, 
gastritis, arthralgia, bacterial pneumonia, herpes viral infection, hypereosinophilic syndrome, 
hypersensitivity reaction. 
• 
Prevalence of B.1.1.7 and B.1.351 and other SARS-CoV-2 lineages in study cohort: Day 0. 
• 
Plasma total Immunoglobulin E (IgE) levels2: Day 0 and 14. 
• 
Plasma inflammatory markers (C-reactive protein and ferritin)3: Day 0, 7 and 14. Day 7 optional 
if patient discharged1. 
• 
Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, 
Arg1, Hyaluronan, soluble ST24: Day 0, 2, 5, 7, 14, and 28. Day 7 and 28 optional if patient 
discharged1. 
• 
Change in PaO2/SaO2 to FiO2 ratio: Day 0, 2, 5, 7 (if patient remains inpatient throughout) 
• 
All-cause mortality rate at 28 days. 
• 
Hospital length of stay (LOS) 
• 
ICU LOS 
• 
Proportion of patients alive and free of invasive respiratory failure at 28 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 60 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 90 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 120 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 150 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 180 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 270 days.  
• 
Proportion of patients alive and free of invasive mechanical ventilation at 360 days. 
• 
National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale (see 
Appendix): Day 0, 2, 5, 7, 14, 28, 60, 180 and 360. 
• 
Need for vasopressors 
• 
Need for renal replacement therapy 
• 
Need for extracorporeal membrane oxygenation (ECMO) 
 
Study Design: This is a randomized, double-blind, placebo-controlled, superiority phase IIa trial to assess the safety 
and efficacy of dupilumab use in hospitalized patients with moderate to severe COVID-19 infection. A total of 40 
eligible subject will be enrolled and randomized in a 1:1 ratio to receive either dupilumab or placebo, stratifying on 
the disease severity measured by the required oxygen ≤ 15L or > 15L by nasal cannula. Both arms will receive 
standard of care management per current National Institutes of Health (NIH) COVID-19 treatment guidelines (8) 
in addition to their randomized treatments. Patients will be followed prospectively for up to 360 days after 
enrollment. 
 
Study Population:   
 
 
1 Patient will be required to have mandatory in person follow up 14 days after initial dupilumab dose. Therefore, if patient 
inpatient through day 14 thus receiving 2nd dupilumab dose, will be required to follow up 14 days after (same for day 28 
injection).  
2Total IgE levels will be analyzed through UVAMC clinical lab. 
3C-reactive protein and ferritin levels will be analyzed through UVAMC clinical lab. 
4Plasma 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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Inclusion Criteria for Enrollment 
• 
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. 
• 
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 
• 
Patients who do not require inpatient admission for COVID-19 infection. 
• 
Patients who require invasive mechanical ventilation at time of enrollment.  
• 
A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the 
individual at a substantially increased risk due to study participation. 
• 
Pregnancy or breast feeding (lactating women who agree to discard breast milk from day 1 until two weeks 
after the last study product is given are not excluded). 
• 
Allergy to Dupilumab or its excipients. 
• 
Current acute parasitic helminth infection or history of chronic parasitic infection. 
• 
History of ocular scleritis, uveitis, keratitis or recent (<6 months) eye injury (chemical or traumatic), 
infection or vascular occlusion. 
• 
Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to 
receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations 
is allowed for all subjects. 
 
Assessment and Data Acquisition: 
1. Baseline: Age, sex, symptoms, pertinent comorbidities and medical history, days from symptom onset to 
initiation of dupilumab treatment, NIAID 8 point ordinal scale, type of admission to the floor or ICU, 
physical exam, chest xray, chest CT, vital signs including temperature, blood pressure, heart rate, 
respiratory rate, oxygen saturation, oxygen requirement 
2. Safety and efficacy: Day 0 (baseline), 2, 5, 7, 14, 28 and day 60. Safety labs and cytokine data may not be 
obtained if patient has since been discharged and chooses not to follow up in person on optional follow up 
time points as previously discussed5.  
 
5Patient will be required to have mandatory in person follow up 14 days after initial dupilumab dose. Therefore, if patient 
inpatient through day 14 thus receiving 2nd dupilumab dose, will be required to follow up 14 days after (same for day 28 
injection). 


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6 
3. Complete blood count with differential and complete metabolic panel: Day 0, 2, 5, 7, 14, 28 and 60. Day 7, 
28 and 60 are optional if patient discharged in this time frame5.  
4. Day 0 viral sample collected for SARS-CoV-2 PCR as above will be held for sequencing to determine 
prevalence of SARS-CoV-2 B.1.1.7 and B.1.351 lineages in study cohort.  
5. Plasma total IgE levels6: Day 0 and 14. 
6. Plasma inflammatory markers (C-reactive protein and ferritin)7: Day 0, 7 and 14. Day 7 optional if patient 
since discharged. 
7. Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, Arg1, 
Hyaluronan, soluble ST28: Day 0, 2, 5, 7, 14, and 28. Day 7 and 28 optional if patient since discharged5. 
8. Change in PaO2/SaO2 to FiO2 ratio: Day 0, 2, 5, 7 (if remains inpatient throughout). 
9. NIAID 8-point ordinal scale (see Appendix): Day 0, 2, 5, 7, 14, 28, 60, 180 and 360. 
10. Outcome measures: O2 requirement (PaO2/FiO2 ratio or SpO2/FiO2), supplemental oxygen strategy (nasal 
cannula, high flow nasal cannula, noninvasive ventilation, intubation and invasive mechanical ventilation, 
rescue ventilation i.e. neuromuscular blocking agents, prone positioning, ECMO), vasopressors, renal 
support, ICU LOS, hospital LOS, all-cause mortality at 28 days, proportion of patients alive and free of 
respiratory failure at 28 days, and proportion of patients alive and free of mechanical ventilation at 28, 60, 
90, 120, 150, 180, 270 and 360 days.  
 
Drug: Subjects will receive a loading dose of dupilumab (600 mg, given as two 300 mg subcutaneous injections) 
on day 0. This dosing regimen was selected to be equivalent to regimen used in the LIBERY ASTHMA VENTURE 
phase 3 clinical trial and per recommendations for patients with asthma in the dupilumab Food and Drug 
Administration (FDA) package insert (9,10).  Given the suspected longevity of IL-13 elevation in severe COVID-
19 disease (documented by Lucas et al.) out to day 25 of illness, additional single doses of 300 mg will be given at 
14 days and 28 days (dose spacing as recommended for atopic disease) if the patient remains hospitalized and 
receiving active care by these days (i.e. NIAID 8 point ordinal scale of 4 and above) (3,9). 
 
Immune Evaluations: Immune evaluations will be performed to assess the extent to which dupilumab 
administration influences the immune response in COVID-19 disease. Total serum IgE levels will be measured at 
day 0 and day 14. 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 0, 2, 5, 7, 14, and 28 days after dupilumab injection. 
Plasma inflammatory markers will be measured at 0, 7 and 14 days after dupilumab injection. Day 7 and 28 optional 
to patient if has been discharged in time frame5.  
 
 
 
 
 
 
6Total IgE levels will be analyzed through UVAMC clinical lab. 
7C-reactive protein and ferritin levels will be analyzed through UVAMC clinical lab. 
8Plasma cytokines will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels 
and individual Simplex or ELISA kits. 


Version date: 2-2-22 
7 
List of Abbreviations  
ADR 
 
Adverse Drug Reaction 
ADE  
 
Antibody-mediated enhancement of infection 
BP 
 
Blood pressure 
CIP 
 
Convalescent Immune Plasma 
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 
HBV  
 
Hepatitis B virus 
HCV  
 
Hepatitis C virus 
HIV 
 
Human immunodeficiency virus 
HTLV  
 
Human T-cell lymphotropic virus 
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 
IFN-γ   
Interferon-gamma 
IND 
 
Investigational New Drug Application 
IRB  
 
Institutional review board 
ISBT   
International Society of Blood Transfusion 
LOS 
 
Length of Stay  
LVEF  
Left Ventricular Ejection Fraction 
MAS 
 
Macrophage Activation Syndrome 
MNC  
Mononuclear Cells 
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 
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 
TACO   
Transfusion-associated circulatory overload 
T. cruzi  
Trypanosoma cruzi 
TRALI  
Transfusion-related acute lung injury 
UP  
 
Unanticipated Problem 
UPnonAE  
Unanticipated Problem that is not an Adverse Event 


Version date: 2-2-22 
8 
Table of Contents 
1.0 SUMMARY .........................................................................................................................................................3 
Inclusion Criteria for Enrollment .......................................................................................................................5 
Exclusion Criteria .................................................................................................................................................5 
List of Abbreviations ................................................................................................................................................7 
2.1 Primary Objective .........................................................................................................................................11 
2.2 Secondary Objectives....................................................................................................................................11 
2.3 Study Design ..................................................................................................................................................11 
3.0 BACKGROUND AND SIGNIFICANCE .......................................................................................................11 
3.1 Background and Scientific Rationale ..........................................................................................................11 
3.2 Experience with the use of dupilumab in allergic disease .........................................................................12 
4.0 ELIGIBILITY...................................................................................................................................................13 
4.1 Inclusion Criteria for Enrollment ...............................................................................................................13 
4.2 Exclusion Criteria .........................................................................................................................................13 
5.0 TREATMENT PLAN ......................................................................................................................................14 
5.1 Treatment Summary ....................................................................................................................................14 
5.2 Study drug administration ...........................................................................................................................14 
5.2.1 Concomitant medications will be documented on the Case Report Form (CRF) ............................... 14 
5.2.2 Acceptable Concomitant Medications .............................................................................. 15 
5.2.3 Prohibited Concomitant Medications ................................................................................ 15 
5.2.5 Enrollment, Screen Failures, and Study Completion ....................................................... 15 
5.4 Concomitant medications will be documented on the CRF .......................... Error! Bookmark not defined. 
5.5 Known potential benefits ..............................................................................................................................17 
5.6 Known potential risks ...................................................................................................................................17 
5.6.1 Conjunctivitis......................................................................................................................... 17 
5.6.2 Skin infection ......................................................................................................................... 17 
5.6.4 Hypersensitivity reaction ........................................................................................................ 18 
6.0 PREPARATION AND ADMINISTRATION OF DUPILUMAB ................................................................18 
7.0 STATISTICAL CONSIDERATIONS ............................................................................................................20 
7.1 Statistical Analyses and Power Calculation ...................................................................................................20 
7.2 Expected accrual rate, accrual duration, and study duration ..................................................................20 
7.3 Analysis of AE data .......................................................................................................................................21 
7.3 Endpoints .......................................................................................................................................................21 
7.3.1 
Primary Endpoints.............................................................................................................. 21 
8.0 EFFICACY, VIROLOGY AND IMMUNE MEASURES ............................................................................22 
8.1 Clinical Efficacy ............................................................................................................................................22 
8.2 Virologic measures ........................................................................................................................................23 


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9 
8.3 Immune Evaluations .....................................................................................................................................23 
9.0 REGISTRATION AND REQUIRED DATA .................................................................................................23 
9.1 Pre-Study .......................................................................................................................................................23 
9.2 Protocol Registration ....................................................................................................................................23 
9.3 Evaluations and Assessments .......................................................................................................................23 
9.4 Medical History/Physical Examination .......................................................................................................23 
9.5 Vital Signs ......................................................................................................................................................24 
9.6 Laboratory Parameters ................................................................................................................................24 
9.7 Laboratory and Clinical Data Review ........................................................................................................24 
9.8 Immune Evaluations .....................................................................................................................................24 
9.9 Subject Status Definitions ............................................................................................................................24 
10.0 RISKS AND BENEFITS ................................................................................................................................24 
10.1 Potential Benefits of Treatment for the Patient .......................................................................................24 
10.3 Potential benefits of clinical monitoring and virologic testing ................................................................24 
10.4 Potential risks ..............................................................................................................................................25 
10.5 Alternatives ..................................................................................................................................................25 
11.0 ADVERSE EVENTS AND SAFETY EVALUATION ................................................................................25 
11.1 Adverse Event (AE) ....................................................................................................................................25 
11.2 Serious Adverse Event (SAE) ....................................................................................................................25 
11.3 Unexpected Adverse event: (UAE) ............................................................................................................25 
11.4 Unanticipated Problem (UP) ......................................................................................................................26 
11.5 Protocol Deviation .......................................................................................................................................26 
11.6 Reporting Interval ......................................................................................................................................26 
11.7 Investigator’s Assessment of Adverse Events ...........................................................................................26 
11.8 Assessment of Severity ................................................................................................................................26 
11.9 Assessment of Association ..........................................................................................................................26 
12.0 REPORTING ADVERSE EVENTS AND PROTOCOL DEVIATIONS .................................................27 
13.0 SAFETY OVERSIGHT .................................................................................................................................29 
13.1 Independent Medical Monitor ...................................................................................................................29 
13.2 Study monitoring ........................................................................................................................................29 
14.0 STOPPING DECISION RULES ...................................................................................................................30 
14.1 Study stopping decision rules .....................................................................................................................30 
14.2 Study Drug Stopping Rules Within a Single Subject ...............................................................................30 
15.0 STUDY MANAGEMENT .............................................................................................................................31 
15.1 Institutional Review Board (IRB) Approval ............................................................................................31 
15.2 Informed Consent .......................................................................................................................................31 


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10
15.3 Adherence to the Protocol ..........................................................................................................................31 
15.3.1 Emergency Modifications ....................................................................................................... 31 
15.3.2 Other Protocol Deviations/Violations ....................................................................................... 32 
15.4 Obligations of Investigators .......................................................................................................................32 
16.0 DATA HANDLING AND RECORDKEEPING..........................................................................................32 
16.1 Data Collection and Management Responsibilities ..................................................................................32 
16.2 Study Records Retention ............................................................................................................................33 
16.3 Publication and Data Sharing Policy ........................................................................................................33 
16.4 Conflict of Interest Policy ...........................................................................................................................33 
17.0 REFERENCES ...............................................................................................................................................33 
 
 


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2.0 OBJECTIVES 
 
2.1 Primary Objective 
• 
Determine the efficacy of dupilumab use plus standard of care management in patients hospitalized with 
moderate to severe COVID-19 infection compared to placebo plus standard of care management assessed 
by the proportion of patients alive and free of invasive mechanical ventilation at 28 days.  
 
2.2 Secondary Objectives  
• 
Evaluate the safety of dupilumab use in patients hospitalized with moderate to severe COVID-19 
infection. 
• 
Evaluate clinical endpoints of dupilumab use in patients with COVID-19. 
• 
Evaluate the immunologic and biologic end points of inhibition of type 2 inflammation. 
 
2.3 Study Design  
This is a randomized, double-blind, placebo-controlled, superiority phase IIa trial to assess the safety and efficacy 
of dupilumab use in hospitalized patients with moderate to severe COVID-19 infection. A total of 40 eligible 
subjects will be enrolled and randomized in a 1:1 ratio to receive either dupilumab or placebo, stratifying on the 
disease severity measured by the required oxygen ≤ 15L or > 15L by nasal cannula. Both arms will receive 
standard of care management per current National Institutes of Health (NIH) COVID-19 treatment guidelines (8) 
in addition to their randomized treatments. Patients will be followed prospectively for up to 360 days after 
enrollment. 
 
3.0 BACKGROUND AND SIGNIFICANCE 
 
3.1 Background and Scientific Rationale  
It has been widely recognized that severe disease from SARS-CoV-2 infection has been attributed to a substantial 
dysregulation of the immune system leading to significant respiratory compromise, end organ damage and death 
(1). This has been further exemplified through finding a reduction in mortality of COVID-19 patients requiring 
oxygen with use of dexamethasone when compared to patients not receiving steroids (11). Central to this 
inflammatory process are cytokines, including interleukin-6 (IL-6), which have led to clinical trials investigating 
their blockade in severe COVID-19 infection (12). However, due to the significant heterogeneity of cytokine 
elevations seen in SARS-CoV-2 infection, it has been difficult to identify specific targets for intervention that are 
associated with and can provide clinical benefit for patients with COVID-19 (12–14). Nevertheless some studies 
have implicated type 2 (Th2) cytokines in severe disease (3). 
 
Elevated interleukin-13 (IL-13), a Th2 cytokine, has been shown to be a central component of the immune 
response leading to ventilation in patients with SARS-CoV-2 infection. This was validated in two separate patient 
cohorts from University of Virginia and Virginia Commonwealth University Medical Center, and is consistent 
with findings of Lucas et al. in demonstrating an association of IL-13 with severe COVID-19 disease (2,3). 
Furthermore, Lucas et al. show increasing levels of IL-13 through the course of disease, with elevations out to day 
25 of illness (3). IL-13 is known to be involved in eosinophilic inflammation, mucous secretion, goblet cell 
metaplasia and fibrosis, and has been regularly implicated in airway hyperresponsiveness and atopic disease (15). 
Inhibition of IL-13 in a K18- hACE2 transgenic mouse model led to improved clinical scores and reduced weight 
loss when infected with SARS-CoV-2. RNAseq analysis of mice infected with SARS-CoV-2 further found 
elevations in type 2 associated genes (2). Hyaluronan, a pulmonary glycosaminoglycan whose low molecular 
weight form is proinflammatory and implicated in numerous other lung pathologies, was identified as a driver of 
pulmonary disease in COVID-19 patients and, additionally, as a downstream effector of IL-13 (2,16). 
 
This has led to consideration of dupilumab, an anti-interleukoin-4 receptor-α monoclonal antibody which blocks 
signaling by both IL-4 and IL-13, as a treatment for moderate to severe COVID-19 infection. In a large 


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12
retrospective analysis of an international cohort of 350,004 patients with COVID-19, those on dupilumab prior to 
infection with SARS-CoV-2 were shown to have a lower risk of ventilation and death when matched to with 
patients of similar comorbidities (2). 
 
Dupilumab has been FDA approved for treatment of moderate to severe atopic dermatitis since 2017. 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 rhinosinusitis (4). Original clinical trials 
noted limited adverse events in addition to its favorability in use for treatment of atopic patients as a steroid 
sparing regimen (5,6). Overall, dupilumab’s excellent safety profile, its demonstrated ability in reduce other Th2 
pathologic processes and its targeted approach to therapy which limits harmful effects of steroid use makes it an 
exciting prospective candidate for successful treatment of COVID-19 infection.   
 
3.2 Experience with the use of dupilumab in allergic disease   
Dupilumab was first FDA approved in the United States for treatment of moderate to severe atopic dermatitis in 
adults uncontrolled with topical medications. In 2018, it was approved in patients with moderated to severe 
asthma aged 12 years or older with eosinophilic phenotypes or with oral steroid dependent asthma (4). In 2019, 
the FDA approved its use in adults with nasal polyps accompanied by chronic rhinosinusitis (17). Its use in atopic 
dermatitis was extended to children aged 6-11 years old in 2020 for those with moderate to severe disease not 
adequately controlled with topical prescription therapies (18). Studies of dupilumab use in these patients 
demonstrates its ability to reduce Th2 associated biomarkers in addition to reduction in expression of genes 
involved in Th2 inflammation including IL-13 (4,19). Dupilumab is supplied as a single-dose pre filled syringe of 
either 300 mg per 2mL solution or 200 mg per 1.14 mL solution, which are administered subcutaneously. For 
atopic dermatitis, a 600 mg initial dose followed by maintenance dose of 300 mg injected every other week is 
recommended (4). A peak mean concentration of drug is reached within one week of initial dosing. Although 
trough concentrations were noted to be lower in adult patients with higher body weights, no dose adjustments are 
recommended. In addition, while there have not been any studies on the pharmacokinetics of dupilumab in 
hepatic or renal impairment, no dose adjustments are recommended in these patients (4).  
 
Adverse events (AEs) identified through clinical trials with dupilumab in atopic dermatitis include eczema 
herpeticum and herpes zoster although these have not been consistently validated in subsequent meta-analysis 
studies (4). Dupilumab has additionally been found to result in a lower risk of skin infections which is suspected 
to be due to its normalization of the skin barrier (4,9). Prescribing information additionally lists conjunctivitis as 
an AE with dupilumab use in those with atopic dermatitis, although this increased risk was not seen in asthma and 
chronic sinusitis trials. Conjunctivitis episodes are listed as mild to moderate in severity with rare need for drug 
discontinuation (4). Additional prescribing information for dupilumab lists additional AEs as hypersensitivity 
reactions and cardiovascular events (9). Although no trials to date have been devoted to dupilumab use in 
pregnancy, there are trials ongoing in this patient population (20).  
 
Clinical trials in asthma patients revealed similar rates of AEs across study groups. Common AEs from these 
trials included injection site reactions, nasopharyngitis, nausea, conjunctivitis, headache, upper respiratory tract 
infections, bronchitis, and sinusitis. Transient eosinophilia (>500 cells/ µL) was noted in both phase 2 and phase 3 
asthma clinical trials (4). In the LIBERTY ASTHMA VENTURE phase 3 international, randomized, double-
blind, placebo-controlled trial enrolling 210 asthma patients found asymptomatic eosinophilia in 14% of 
dupilumab treated patients compared to 1% of placebo patients. Per the trial authors, eosinophilia was of no 
clinical consequence in these patients (10). In LIBERTY ASTHMA QUEST phase 3 randomized, double-blind- 
placebo-controlled, parallel group enrolling 1,902 asthma patients, eosinophilia was seen in 4.1% of the 
dupilumab treated patients compared to 0.6% of the placebo treated patients, with 1.2% of dupilumab-treated with 
eosinophil counts of greater than 3,000 cells/µL. Eosinophilia in this trial resulted in eight patients to be 
discontinued from the trial (7 in the dupilumab group and 1 in the control group) (7). In a multicenter 
retrospective cohort enrolling 214 patients with atopic dermatitis found higher rates of eosinophilia than in the 
clinical trials, reporting 57% had eosinophilia out of 177 patients who had at least 1 eosinophil count measured 


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with 29.8% with hypereosinophilia (>1500 cells/ µL) and a maximum count of 7800 cells/µL. A total of five of 
these patients discontinued the drug due to persistent hypereosinophilia (21). 
 
4.0 ELIGIBILITY 
 
4.1 Inclusion Criteria for Enrollment 
• 
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. 
• 
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.  
 
4.2 Exclusion Criteria 
• 
Patients who do not require inpatient admission for COVID-19 infection. 
• 
Patients who require invasive mechanical ventilation at time of enrollment.  
• 
A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the 
individual at a substantially increased risk due to study participation. 
• 
Pregnancy or breast feeding (lactating women who agree to discard breast milk from day 1 until two weeks 
after the last study product is given are not excluded). 
• 
Allergy to Dupilumab or its excipients. 
• 
Received any of the following in the two weeks prior to screening as treatment of COVID-19: 
• 
small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, etc.); 
• 
monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-
IL-6 [or sarilumab], etc.); 
• 
monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19; 
• 
Any other immunomodulatory (other than steroids) medications within 5 half-lives or 30 days 
prior to randomization. 
• 
 
• 
Current acute parasitic helminth infection or history of chronic parasitic infection. 
• 
History of ocular scleritis, uveitis, keratitis or recent (<6 months) eye injury (chemical or traumatic), 
infection or vascular occlusion. 


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14
• 
Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to 
receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations 
is allowed for all subjects. 
 
4.3 Strategies to Maintain Diversity of Enrollment 
Subjects will be enrolled at the University of Virginia Medical Center, a tertiary care center with over 600 beds 
and a large catchment area including areas in Tennessee, West Virginia and North Carolina. UVA Health provides 
services to a wide variety of patients including racial and ethnic minorities, which have been disproportionately 
affected by COVID-19. Each patient admitted to UVA hospital for management of COVID-19 infection will be 
assessed for possible enrollment. If eligibility criteria are met, patients will be approached with special care taken 
to provide clear language and open communication about trial goals and design, particularly when discussing with 
minority populations. Every effort will be made to encourage patient trust and maintain study transparency.  
 
5.0 TREATMENT PLAN 
5.1 Treatment Summary 
This is a randomized, double-blind, placebo-controlled phase IIa trial to assess the safety of dupilumab use in 
hospitalized patients with moderate to severe COVID-19 infection. A total of 40 eligible subjects will be enrolled 
and randomized to receive either dupilumab or placebo at 1:1 ratio. The randomization will be stratified based on 
disease severity: patients who are on 15L or less of oxygen by nasal cannula (severity group A) and those 
requiring more than 15L of oxygen by nasal cannula including any noninvasive ventilation measures (severity 
group B). Both arms will receive standard of care management per current National Institutes of Health (NIH) 
COVID-19 Treatment Guidelines (8) in addition to their randomized treatments. Patients will be followed 
prospectively for up to 360 days after enrollment. We will document adverse events related to respiratory or 
clinical status with injection of dupilumab and adverse events duringthe first 60 days of the study period: injection 
site reactions, eye/eyelid inflammation, conjunctivitis, oropharyngeal pain, insomnia, tooth ache, gastritis, 
arthralgia, bacterial pneumonia, herpes viral infection, hypereosinophilic syndrome, hypersensitivity reaction. 
Immune testing will be performed to sequentially profile the immune responses of the patients after they receive 
dupilumab. Patients ≥ 18 years of age, 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 will 
be enrolled in the study. Subjects will receive a loading dose of dupilumab (600 mg, given as two 300 mg 
subcutaneous injections) on day 0. This dosing regimen was selected to be equivalent to regimen used in the 
LIBERY ASTHMA VENTURE phase 3 clinical trial and per recommendations for patients with asthma in the 
dupilumab Food and Drug Administration (FDA) package insert (9,10).  Given the suspected longevity of IL-13 
elevation in severe COVID-19 disease out to day 25 of illness, additional single doses of 300 mg will be given at 
14 days and 28 days (dose spacing as recommended for atopic disease) only if the patient remains hospitalized 
and receiving active care by these days (i.e. NIAID 8 point ordinal scale of 4 and above) (3,9). 
 
5.2 Study drug administration 
• 
Subcutaneous administration will be done in the hospital. 
• 
If an AE develops directly after injection, management will occur per investigator and clinical care team 
discretion (i.e. if perceived as allergic reaction, will treat with epinephrine, steroids, diphenhydramine as 
dictated per guidelines for anaphylaxis). 
• 
Subjects will be removed from the trial if anaphylaxis or other severe, life threatening AE occurs and is 
deemed to have developed due to first or any subsequent dupilumab injections.  
 
5.3 Concomitant medications  
Concomitant medications will be documented on the Case Report Form (CRF).  Concomitant medications will 
be assessed from 7 days prior to enrollment to Day 60 for all medications with the exceptions listed in the bullets 
below. All medications, except biologics and corticosteroids, can be recorded once regardless of the number of 


Version date: 2-2-22 
15
times it was given during the time period. For example, vasopressors should be recorded when first dose given (as 
the start date) and the last dose given (as the end date) during the period of assessment. 
  
The following medications will not be recorded in the concomitant medications list: 
• 
All topical medications: ointments, creams, and lotions; 
• 
All intranasal medications: nasal decongestants, nasal allergy medications, nasal steroids, and nasal saline 
drops/sprays; 
• 
All ophthalmic medications: ophthalmic allergy medication, ophthalmic medications for infection, and 
ophthalmic medications for eye dryness (e.g., saline eye drops); 
• 
Antiseptic mouth wash, lozenges; 
• 
Cough medication: mucolytics, cough suppressants, and expectorates; 
• 
GI medications: H2 blockers, proton pump inhibitors, GI stimulants, prokinetics, laxatives, stool softeners, 
antacids, anti-diarrheal and anti-nausea medications; 
• 
Symptomatic care medications: antipyretics, antihistamines, decongestants, and NSAIDs; 
• 
Mineral or herbal supplements, dietary supplements, iron/ferrous sulfate, magnesium, calcium, electrolyte 
replacement; 
• 
Albumin infusions; 
• 
Melatonin; 
• 
Nicotine patch, lozenge, gum, or nasal spray, or other product to treat tobacco dependence; 
• 
Dyes: contrast media, iodine – based dye, barium sulfate, and diatrizoate sodium. 
 
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at the 
discretion of the investigator. This includes antimicrobial therapies, steroids, insulin, acetaminophen, ibuprofen, 
anticoagulants, and any other therapies that are considered standard of care, are recommended in the National 
Institutes of Health (NIH) COVID-19 Treatment Guidelines, and are not listed in the exclusion criteria. 
Overlapping toxicities of dupilumab with standard of care treatment including off-label use of other drugs will be 
monitored. 
 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving medications or vaccinations that are specified in the exclusion criteria 
during study period. 
 
5.4 Subject Removal 
Subjects will not receive any further study treatments if life threatening or severe AEs are deemed to have 
developed due to first or any subsequent injections of dupilumab.  Discontinuation of study drug will not mean 
withdrawal from the study.  All remaining study procedures should be completed as indicated by protocol. 
 
Subjects are free to withdraw from participation in the study at any time upon request without prejudice. 
 
5.5 Enrollment, Screen Failures, and Study Completion 
Patients are considered enrolled from time consented to participate until designated as a screen failure, or have 
revoked consent and have been withdrawn from the study, or have completed the study. A screen failure is a 
patient who signed informed consent, but then was determined to be ineligible or withdraws from the study prior 
to any study interventions. Subjects are considered to have completed the study when they are followed through 
day 360 or death occurred prior to day 360.   
 
5.6 Study Timeline 


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16
 
Day 0 Baseline:  
A. Subject informed consent (obtained before performing study related activities)’ 
B. Baseline Screening: 
1. Medical history as it pertains to inclusion/exclusion criteria 
2. Demographics (age) 
3. Determination of RT-PCR for SARS-CoV-2 within the last 14 days, with illness duration within the 
last 14 days 
 
DAY 0 Baseline Enrollment, Randomization and Administration:  
1. Additional demographics (sex, ethnicity, race), height and weight 
2. COVID-19 onset of symptoms, source of contagion (if known) and symptom screen (fevers, cough, 
shortness of breath, diarrhea, anosmia) 
3. Assessment of clinical status (8-point ordinal scale) 
4. Medical history and medication use 
5. Physical examination 
6. COVID-19 testing (RT-PCR) from nasopharyngeal or throat if not already obtained on admission 
7. CBC with differential, comprehensive metabolic panel, C-reactive protein and ferritin 
8. Blood for immune evaluation of cytokine levels (1 light green top, 2 mL/draw)  
9. Randomization and dupilumab administration: subcutaneous injection into the upper arm, thigh or 
lower abdomen, avoiding areas within 2 inches of navel, avoiding areas where skin is damaged or 
tender. 
 
 Day 1-6 (data collected through electronic medical record and/or documentation per primary team) 
1. Vital signs daily (including supplemental oxygen requirements) 
2. COVID-19 symptom screen (fevers, cough, shortness of breath)  
3. Assessment of clinical status (8-point ordinal scale) 
4. New medical conditions, AE evaluation 
5. PaO2/SaO2 to FiO2 ratio at days 0, 2, 5, 7 days (if patient remains hospitalized). 
 
Days 0, 2, 5, 7 (± 1 day), 14 (± 2 days), 28 (± 2 days), 60 (± 7 days):  
1. Complete blood count with differential (lavender top tube, ~3mL) and comprehensive metabolic 
panel (light green top tube, ~2mL) on days 0, 2, 5, 7, 14, 28 and 60 days. Day 7, 28 and 60 labs are 
optional if patient has been discharged in the time frame9. 
2. SARS-CoV-2 PCR from oropharyngeal or nasopharyngeal swabs: Day 0 (if not already obtained 
on admission). 
3. Day 0 viral sample collected for SARS-CoV-2 PCR as above will be held for sequencing to 
determine prevalence of SARS-CoV-2 B.1.1.7 and B.1.351 lineage in study cohort.  
4. Blood for immune evaluation of cytokines including TARC (CCL17), YKL40, eotaxin 3 (CCL26), 
IL-13, IL-4, Arg 1, Hyaluronan, soluble ST210: before dupilumab administration (day 0) and 2, 5, 
7, 14, and 28 days after dupilumab administration (light green top tube, ~2mL). Day 7 and 28 are 
optional if patient has been discharged9. 
5. Blood for total IgE levels11: Day 0 and 14 (gold top tube, ~2mL). 
 
9Patient will be required to have mandatory in person follow up 14 days after initial dupilumab dose. Therefore, if patient 
inpatient through day 14 thus receiving 2nd dupilumab dose, will be required to follow up 14 days after (same for day 28 
injection). 
10Plasma cytokines will be measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth 28 Factor Panels, 
and individual Simplex or ELISA kits. 
11Total IgE levels will be analyzed through UVAMC clinical lab. 


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17
6. Blood for inflammatory markers (C-reactive protein and ferritin)12: Day 0, 7 and 14 (light green 
top tube as CMP above). Day 7 labs are optional if patient has been discharged13. 
7. Physical examination: Day 28 (optional in person attendance, otherwise will be done via telephone 
call without exam)13. 
8. Vital signs, assessment of clinical status (8-point ordinal scale – see Appendix), symptom screen, 
concomitant medications and AE evaluation: Day 0, 2, 5, 7, 14, 28 and 60. Mandatory in person 
assessment at day 14 if previously discharged, otherwise optional in person attendance with 
information obtained via telephone call if preferred13.  
9. Status of alive and free of mechanical ventilation and proportion of patients alive and free of 
respiratory failure at Day 28 and proportion of patients alive and free of invasive mechanical 
ventilation at day 60 derived from the 8-point ordinal scale clinical status. 
 
Days 180 (±90 days) and 360 (±30 days) (via telephone call): 
1. Patient status on day 90, 120, 150, 180, 270 and 360 as it pertains to end points of alive and free of 
mechanical ventilation at days 90, 120, 150, 180, 27, 360. This will be assessed via telephone call 
from study team on days 180 and 360.  
2. 8 point ordinal score assessment on day 180 and 360 assessed via telephone call.   
 
5.7 Known potential benefits 
This trial is being conducted to test efficacy and ensure safety of dupilumab use in patients hospitalized with 
moderate to severe COVID-19. If successful, a key potential benefit to dupilumab use in those with clinical disease 
of COVID-19 is prevention of disease progression than current standard of care for hospitalized patients with 
COVID-19. Given its favorable safety profile, promising previous observation studies coupled with the high 
mortality of COVID-19, particularly in elderly and vulnerable persons, suggests that the benefits of its use outweigh 
the risks. However, for all cases where dupilumab administration is considered, a risk-benefit assessment must be 
conducted to assess individual variables. 
 
5.8 Known potential risks 
5.8.1 Conjunctivitis 
Prescribing information for dupilumab lists conjunctivitis as an AE with use in those with atopic 
dermatitis, although this increased risk was not seen in asthma and chronic sinusitis trials (4). A meta-
analysis done with clinical trials for use of dupilumab in atopic dermatitis found a reported conjunctivitis 
rate of 8% in those treated with dupilumab compared to 3.6% receiving placebo (18). Another meta-
analysis comparing twenty-two unique studies involving dupilumab use in atopic dermatitis reported a 
pooled proportion of 26.1% in those receiving dupilumab. In most studies, details of conjunctivitis 
episodes were not described in detail but were considered treatable without discontinuation of dupilumab 
therapy (19). Regardless, given the high occurrence of ocular disease in these patients, and in some 
circumstance’s severe disease, we will exclude patients with history of certain ocular diseases as listed in 
our exclusion criteria. Occurrence of ocular symptoms will be assessed and managed per the investigator 
team with consultation of Ophthalmology depending on clinical severity.  
 
5.8.2 Herpes Reactivation 
Prescribing information for dupilumab lists herpes infection and eczema herpeticum as an AE with 
dupilumab use (4). Initial clinical trials for dupilumab use in atopic dermatitis reported herpes infection in 
6.1% of participants treated with dupilumab and 5.2% in those treated with placebo (18). Subsequent 
meta-analysis of dupilumab clinical trials in atopic dermatitis found no association between dupilumab 
 
12C-reactive protein and ferritin levels will be analyzed through UVAMC clinical lab. 
13Patient will be required to have mandatory in person follow up 14 days after initial dupilumab dose. Therefore, if patient 
inpatient through day 14 thus receiving 2nd dupilumab dose, will be required to follow up 14 days after (same for day 28 
injection). 


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18
and herpes infections, with a decrease odds of eczema herpeticum. They additionally found no association 
between dupilumab and overall infection risk (20). Another meta-analysis comparing twenty-two unique 
studies involving dupilumab use in atopic dermatitis found a pooled proportion of 5.8% of herpes simplex 
virus (19). Given this, any concern for herpes infection will be assessed and managed per investigator 
team. Severe manifestation of herpes virus including ocular herpes infection or herpes eczema herpeticum 
will involve prompt consultation of appropriate subspecialty teams and initiation of treatment therapies as 
needed.  
 
5.8.3 Injection site reaction 
The most common adverse reaction found with dupilumab use in initial trials was injection site reactions, 
which according to a meta-analysis of clinical trials for use in atopic dermatitis, occurred in 13.2% of 
those receiving dupilumab compared to 6.5% in those receiving placebo (18). Bothersome injection site 
reactions will be assessed and managed with appropriate symptomatic therapies.  
 
5.8.4 Hypersensitivity reaction 
Hypersensitivity reaction is listed as a potential AE of dupilumab use. There have been case reports of 
patients developing these reactions with their second dose of dupilumab (21). Response to initial and 
second injection of dupilumab will be monitored closely with vital sign assessments. Any concern for 
acute hypersensitivity reaction will involve prompt assessment from the investigator or primary team and, 
if warranted, treatment with appropriate therapies (i.e. epinephrine, steroids, diphenhydramine etc.). 
 
5.8.5 Hypereosinophilic Syndrome 
Hypereosinophilia (HE) is defined as an eosinophil count  >1.5 k/µl on peripheral laboratory 
measurement and/or pathologic evaluation via tissue staining with evidence of: eosinophils exceeding 
20% of all nucleated cells in a bone marrow section and/or pathologist opinion of extensive eosinophil 
tissue infiltration and/or marked deposition of eosinophil granules. Hypereosinophilic syndrome (HES) is 
defined as meeting criteria for HE plus organ damage and/or dysfunction attributable to HE, and 
exclusion of other disorders as a major reason for organ damage (22). While eosinophilia and HE were 
reported in dupilumab clinical trials in asthma patients as previously discussed, most of these instances 
were considered asymptomatic with no subsequent clinical consequences. In the phase 2b trial assessing 
efficacy and safety of dupilumab use in 300 asthma patients with a baseline blood eosinophil count >0.3 
k/µl, one subject discontinued study treatment due to HES, which was noted to resolve with subsequent 
steroid treatment (5). Patients will be monitored via lab work for eosinophilia, hypereosinophilia and HES 
as laid out in the treatment plan with frequent assessments of symptoms. Subjects will be discontinued 
from study treatment and managed with appropriate therapies (i.e. high dose glucocorticoids etc.) with 
any evidence of or concern for HES as deemed by the investigator team.  
 
6.0 PREPARATION AND ADMINISTRATION OF DUPILUMAB 
Dupilumab and placebo (normal saline) will be maintained in prefilled syringes as prepared by the investigational 
pharmacy at the University of Virginia. Dupilumab will be sourced commercially and repackaged into syringes 
that are identical to the placebo to maintain blinding. Per package insert, dupilumab is stored refrigerated at 36°F 
to 46°F in original carton to protect from light. If necessary pre-filled syringes can be kept at room temperature 
up to 77°F for a maximum of 14 days. Pre filled syringes should not be exposed to heat or direct sunlight (9).  
Subcutaneous injection will occur in the hospital in the upper arm, thigh or lower abdomen (avoiding areas within 
2 inches of navel) and avoiding areas where skin is damaged or tender. If an AE develops directly after injection, 
management will occur per investigator and clinical care team discretion (i.e. if perceived as allergic reaction, 
will treat with epinephrine, steroids, diphenhydramine as dictated per guidelines for anaphylaxis). Subjects should 
be removed from the trial if life threatening or severe AEs are deemed to have developed due to first or any 
subsequent dupilumab injections.  
 


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19
Table I: 
Schedule  
Scre
en 
Baselin
e 
Randomiz./ 
Admin. 
Follow-up 
Day (d) 
0d 
0d 
0d 
2±1d 
5±1d 
7±1d 
14±2d 
28±2d 
60±7d 
180±90d   360±30d 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographic 
and Medical 
history 
x 
X 
 
 
 
 
 
 
 
 
 
COVID-19 
symptom 
screen 
 
x 
 
 
 
 
 
 
 
 
 
SARS-CoV-
2  
RT-PCR7,9  
x 
 
 
 
 
 
x 
 
 
 
 
Drug 
administratio
n1 
 
 
X 
 
 
 
X1 
X1 
 
 
 
Study Procedures 
Vital 
signs2,3,4 
 
X 
X2 
x 
x 
X5,6 
X5 
X5,6 
 
 
 
Physical 
exam4 
 
x5 
 
 
 
 
 
x5,6 
 
 
 
Symptom 
screen3,4 
 
x 
 
x 
x 
X5 
X5 
X5 
X5 
 
 
Concomitant 
medications3,
4 
 
x 
 
x 
x 
X5 
X5 
X5 
X5 
 
 
Assessment 
with 8-point 
ordinal 
scale3,4 
 
x 
 
x 
x 
X5 
X5 
X5 
X5 
X5 
X5 
Adverse 
event 
monitoring3,4 
 
 
x 
x 
x 
X 
x5 
X5 
X5 
 
 
Study Labs 
Blood for 
total IgE 
levels7 
 
x 
 
 
 
 
x 
 
 
 
 
Blood for 
cytokine 
testing8  
 
x 
 
x 
x 
X6 
x 
X6 
 
 
 
SARS-CoV-
2 NP or OP 
PCR9 
 
x 
 
 
 
 
 
 
 
 
 
Blood for 
inflammatory 
markers7,10 
 
x 
 
 
 
X6 
x 
 
 
 
 


Version date: 2-2-22 
20
1Drug to be administered on subsequent days if remains hospitalized and undergoing active medical therapy (i.e. at least 
ordinal score 4). 
2Vital signs will be performed pre-administration. 
3Done daily through hospitalization by primary team or until patient is discharged from the hospital, whichever comes first.  
4Data to be collected through electronic medical record and/or documentation per primary team unless otherwise stated. 
5Data to be collected via team investigators directly via in person (mandatory on day 14) or via telephone (day 7, 28, 60, 180 
and 360). 
6Optional lab work/in person assessment unless patient had remained inpatient through day 14 or day 28 and thus received 
subsequent dupilumab injections on those days then will be required to have a 14 day follow up after the last injection 
received. 
7To be analyzed through UVAMC clinical lab.  
8Cytokine analysis to be done using MILLIPLEX SARS-CoV-2 MAP Human Cytokine/Chemokine/Growth Factor Panels, 
and individual Simplex or ELISA kits. 
9Sample collected for SARS-CoV-2 PCR will be held for sequencing to determine prevalence of SARS-CoV-2 B.1.1.7 lineage 
in study cohort. If SARS-CoV-2 NP PCR not previously collected during current admission, will be collected for sequencing 
prior to treatment administration. 
10Includes serum CRP and ferritin. 
 
7.0 STATISTICAL CONSIDERATIONS 
 
7.1 Randomization and Stratification 
The double-blind, placebo-controlled, randomized clinical trial aims to evaluate the safety and efficacy of 
dupilumab in hospitalized patients with COVID-19 positive. Patients will be enrolled and randomized to either 
dupilumab or placebo and followed prospectively for 360 days post enrollment. The primary outcome is the 
proportion of patients alive and free of invasive mechanical ventilation at 28 days. The study will also evaluate the 
incidence of other serious adverse reactions as the secondary outcome. This study will use an automated central 
randomization procedure to allocate patients in a 1:1 ratio to each of the two treatment groups. The randomization 
will be stratified based on disease severity: patients who are on 15L or less of oxygen by nasal cannula (severity 
group A) and those requiring more than 15L of oxygen by nasal cannula including any noninvasive ventilation 
measures (severity group B). 
 
7.2 Sample Size Justification and Power Analysis 
This trial is intended to be an early stage and proof of concept study with the primary goal to collect reliable data 
and obtain sufficient evidence for future trials. Thus the emphasis of the study is an exploratory estimation of 
effect size and incidence of adverse events in terms of eosinophilia; it is not considered as a pivotal trial for 
efficacy at this time. Therefore, a larger significance level (one-sided alpha=0.1) is used and the sample size is 
pre-selected based on the feasibility. Given the current decline trend in the incidence of COVID-19 positive cases, 
we anticipate to enroll 40 patients realistically into this randomized clinical trial, which shall be sufficient for us 
to collect reliable and interpretable data for proof of concept to inform future trials. The COVID-19 
hospitalization data from our University of Virginia Health System between March 2020 and April 6, 2021 
showed that 79.5% of COVID-19 inpatients were alive and free of mechanical ventilation at 28 days under the 
usual care. With 40 patients that are deemed to be feasible, we would expect Dupilumab to improve a margin of 
17.7% in the proportion of patients alive and free of mechanical ventilation at 28 days. That is, it is anticipated 
that 97.2% of patients being alive and free of ventilation at 28 days in the Dupilumab arm. The power analysis is 
conducted using the one-sided Score test (Farrington & Manning) with 75% power and 10% type I error.   
 
7.3 Expected accrual rate, accrual duration, and study duration 
Our anticipated accrual rate is about 5-6 patients per month. Thus, it should take approximately 12-14 months to 
accrue the 40 patients needed for the trial. Allowing for 360 days of follow-up to obtain the primary endpoints on 
CBC with 
differential 
and CMP7 
 
x 
 
x 
x 
X6 
x 
X6 
X6 
 
 


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21
the last patient enrolled and 3 months to assemble, analyze and interpret the data the total study duration is projected 
to be at most 18 months. 
 
7.4 Analysis of AE data 
Analysis of AE data will primarily be descriptive based on DAIDS coding of events. The proportion of subjects 
experiencing an SAE and the proportion experiencing a Grade 3 or higher will be recorded. AE will be compared 
to published data. 
 
7.5 Endpoints  
7.5.1 Primary Endpoint: 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 28 days. 
 
7.5.2 Secondary Endpoints: 
• 
Percentage of patients with eosinophilia (defined as an absolute eosinophil count > 0.6 k/µl at 
≥ 1 measurement throughout the study period) in those receiving dupilumab in addition to 
standard of care compared to those who receive standard of care management plus placebo. 
Complete blood counts with differentials and complete metabolic panels will be measured on 
Day 0, 2, 5, 7, 14, 28 and 60. Day 7, 28 and 60 optional, although recommended, if patient 
discharged within the time frame14.  
• 
Cumulative incidence (defined as number of new events divided by the total number of 
individuals in the population at risk for the time interval) of adverse events: injection site 
reactions, eye/eyelid inflammation, conjunctivitis, oropharyngeal pain, insomnia, tooth ache, 
gastritis, arthralgia, bacterial pneumonia, herpes viral infection, hypereosinophilic syndrome, 
hypersensitivity reaction. 
• 
Prevalence of B.1.1.7 and B.1.351 and other SARS-CoV-2 lineages in study cohort: Day 0. 
• 
Plasma total Immunoglobulin E (IgE) levels15: Day 0 and 14. 
• 
Plasma inflammatory markers (C-reactive protein and ferritin)16: Day 0, 7 and 14. Day 7 optional 
if patient discharged1. 
• 
Plasma cytokine levels including TARC (CCL17), YKL40, eotaxin 3 (CCL26), IL-13, IL-4, 
Arg1, Hyaluronan, soluble ST217: Day 0, 2, 5, 7, 14, and 28. Day 7 and 28 optional if patient 
discharged1. 
• 
Change in PaO2/SaO2 to FiO2 ratio: Day 0, 2, 5, 7 (if patient remains inpatient throughout) 
• 
All-cause mortality rate at 28 days. 
• 
Hospital length of stay (LOS) 
• 
ICU LOS 
• 
Proportion of patients alive and free of invasive respiratory failure at 28 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 60 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 90 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 120 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 150 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 180 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 270 days.  
 
14 Patient will be required to have mandatory in person follow up 14 days after initial dupilumab dose. Therefore, if patient 
inpatient through day 14 thus receiving 2nd dupilumab dose, will be required to follow up 14 days after (same for day 28 
injection).  
15Total IgE levels will be analyzed through UVAMC clinical lab. 
16C-reactive protein and ferritin levels will be analyzed through UVAMC clinical lab. 
17Plasma 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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22
• 
Proportion of patients alive and free of invasive mechanical ventilation at 360 days. 
• 
National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale (see 
Appendix): Day 0, 2, 5, 7, 14, 28, 60, 180 and 360. 
• 
Need for vasopressors 
• 
Need for renal replacement therapy 
• 
Need for extracorporeal membrane oxygenation (ECMO) 
 
7.6 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. Another analysis population of interest is 
the as-treated population. The as-treated population will consist of only participants who were inducted onto study 
medication, even one dose of drug. Safety outcome will be primarily analyzed for the as-treated population. 
Summary statistics for each endpoint will be provided for each relevant comparison group including the results of 
statistical tests. All subjects who have a result for the baseline and a follow-up and who have received at least one 
dose of study drug will be included for the analysis of efficacy.   
 
After the 14th day of the 20th patient enrolled, the proportion and rate of change of C- reactive protein and ferritin 
levels will be calculated from day 0 and day 14 time points to determine efficacy trends between the two 
treatment groups. Additionally, percentage of eosinophilia will be calculated between the two groups to determine 
safety trend. We expect greater changes in C- reactive protein and ferritin for patients receiving Dupilumab than 
those receiving placebo and no significant differences in eosinophilia between the two groups. Data will be 
analyzed by a third party and remain blinded to the study investigators. 
   
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 efficacy endpoint) and 
two-sample t-test or Wilcoxon rank sum test for continuous measures (e.g., age or 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). Data transformation will be considered 
for the outcomes with skewed distribution such as hospital length of stay (LOS) and ICU LOS. The trajectory of 
each immune biomarker over the follow-up time points will be plotted to characterize the change of immune 
responses over time, and difference in biomarker (or transformed biomarker to improve normal distribution, if 
necessary) trajectories between the two study arms will be assessed in the mixed effects model.  
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. In addition, machine 
learning methods such as random forests algorithm will be applied to fully evaluate the treatment effect and 
predictability of dupilumab and other important predictors on the outcomes non-parametrically. 
 
8.0 EFFICACY, VIROLOGY AND IMMUNE MEASURES 
 
8.1 Clinical Efficacy  
• 
Proportion of patients alive and free of invasive respiratory failure at 28 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 28 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 60 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 90 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 120 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 150 days. 


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23
• 
Proportion of patients alive and free of invasive mechanical ventilation at 180 days. 
• 
Proportion of patients alive and free of invasive mechanical ventilation at 270 days.  
• 
Proportion of patients alive and free of invasive mechanical ventilation at 360 days. 
• 
Change in PaO2/SaO2 to FiO2 ratio at days 0, 2, 5 and 7 days (if remains hospitalized). 
• 
All-cause mortality rate at 28 days. 
• 
Hospital length of stay (LOS) 
• 
ICU LOS 
• 
National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale: Day 0, 2, 
5, 7, 14, 28, 60, 180 and 360. 
• 
Need for vasopressors 
• 
Need for renal replacement therapy 
• 
Need for extracorporeal membrane oxygenation (ECMO) 
 
8.2 Virologic measures  
1. Day 0 OP or NP swabs obtained for assessment of SARS-CoV-2 RNA positivity as above will be held 
for sequencing to determine prevalence of B.1.1.7 and B.1.351 and other SARS-CoV-2 
lineages in study population. 
 
8.3 Immune Evaluations 
Immune evaluations (IEs) will be conducted as delineated in Table 1. Blood draws will occur at each time point. 
Inflammatory markers, CBC, CMP and IgE levels will be obtained through UVAMC clinical lab. 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 at each time point). 
 
9.0 REGISTRATION AND REQUIRED DATA 
 
9.1 Pre-Study  
All patients on-study will be evaluated prior to initiation of therapy.  Baseline studies will be completed prior to 
on-study. 
9.2 Protocol Registration 
Subject must meet all eligibility requirements listed in Section 4.0 prior to enrollment. 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.  
9.3 Evaluations and Assessments 
All evaluations and assessments should be completed as described in Table 1. Any assessments not 
described in detail below should be done according to standard of care practices.  
9.4 Medical History/Physical Examination 
A complete medical history and physical examination will be obtained prior to dupilumab injection. 
The medical history includes clinically significant diseases and all medications (with the exception of medications 
listed in section 5.3). A physical examination will be performed prior to dupilumab injection for baseline 
conditions. Physical examinations will include the following body systems: general appearance (including 
height and body weight), skin, neck, HEENT (head, ears, eyes, nose and throat), heart (auscultation of heart 
sounds), lungs (auscultation of lung fields), abdomen palpation and auscultation of bowel sounds, lymph 
nodes and extremities. 


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9.5 Vital Signs 
Vital signs including respiratory rate, pulse rate, systolic blood pressure [SBP], and diastolic blood 
pressure [DBP] and body temperature, and supplemental oxygen requirements will be recorded at time points 
listed in Table 1.   
9.6 Laboratory Parameters 
Blood samples for clinical labs will be obtained as described in the Time and Events table for 
adverse event determination and clinical decision making. 
9.7 Laboratory and Clinical Data Review 
The Investigator, or designee, must review all laboratory values and report any clinically significant change 
compared to the baseline sample as an AE. When reporting such AEs the Investigator will use the appropriate 
clinical term, rather than the laboratory test result (e.g. anemia versus low hemoglobin). 
 
9.8 Immune Evaluations 
Immune evaluations (IEs) will be conducted as delineated in Table 1. Blood draws will occur at each time point. 
Inflammatory markers, CBC, CMP and IgE levels will be obtained through UVAMC clinical lab. 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 tube containing approximately 2 milliliters of anti-coagulated blood will 
be allotted for cytokine assessment at each time point). 
 
9.9 Subject Status Definitions 
• 
Enrolled: All subjects who sign an informed consent will be considered enrolled on the study. All subjects 
consented on the study must be entered into Clinical Trials Office Database. 
• 
Screen Failure: A subject who is withdrawn or discontinues from study screening prior to being on study 
is considered a screen failure. Screen failures are not considered a study accrual and will be replaced. 
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, and the treating physician/surgeon or study 
PI has signed off on the confirmation. 
• 
On-Treatment: A subject is considered on-treatment on the date that they receive the first study treatment. 
A subject who is withdrawn or discontinues from the study after receiving at least 1 infusion is considered 
a discontinuation and will not be replaced. 
• 
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 or if they have completed all study assessments through follow-up. 
 
10.0 RISKS AND BENEFITS 
 
10.1 Potential Benefits of Treatment for the Patient 
The benefits of anti-inflammatory therapy with dupilumab in patients with respiratory symptoms consistent with 
pneumonia due to COVID 19 infection at high risk for requiring ICU admission are not known. It is anticipated that 
treatment will decrease the time to recovery, risk of disease progression, decrease ICU admissions and decrease 
aggressive respiratory support including possible mechanical ventilation and other ICU support. 
 
10.3 Potential benefits of clinical monitoring and virologic testing 
Subjects enrolled in the study may reduce their chances of disease progression. 
    


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10.4 Potential risks 
1. Risks of dupilumab: injection site reactions, eye/eyelid inflammation, conjunctivitis, oropharyngeal pain, 
insomnia, toothache, gastritis, arthralgia, bacterial pneumonia, herpes viral infection, eosinophilia, hyper 
eosinophilic syndrome, hypersensitivity reaction. 
2. Risks of phlebotomy: local discomfort, bruising and/or hematoma, bleeding, fainting, infection. 
3. Total blood draws will not exceed 500 mL 
4. Risks of oropharyngeal and throat swab: local discomfort, vomiting 
 
10.5 Alternatives 
The alternative to participation in this study is routine care. 
 
11.0 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 ) 
 
11.1 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. 
 
11.2 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. 
 
11.3 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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11.4 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. 
 
11.5 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. 
 
11.6 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.  
 
11.7 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. 
 
11.8 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”. 
 
11.9 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. 
 
. 
12.0 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 
 
 
 
 
 
 
 
 


Version date: 2-2-22 
29
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 
UVA PI HELD IND 
Life-threatening and/or 
fatal unexpected events 
related or possibly 
related to the use of the 
investigational agent. 
FDA 
Within 7 
calendar days 
of the study 
team learning 
of the event 
Form FDA 3500A (MedWatch) 
or narrative 
Serious, unexpected 
and related or possibly 
related adverse events 
FDA 
Within 15 
calendar days 
after the study 
team receives 
knowledge of 
the event 
Form FDA 3500A (MedWatch) 
or narrative 
Adverse events meeting 
DAIDS severity grade 3 
and above 
FDA 
Annually 
IND annual report 
 
 
13.0 SAFETY OVERSIGHT 
 
13.1 Independent Medical Monitor 
An independent medical monitor will provide additional safety oversight for this study.  The medical monitor will 
report to the principal investigator and IND sponsor. They will review the following: 
• 
All adverse events 
• 
Audit results 
• 
Application of study designed stopping/decision rules 
• 
Whether the study accrual pattern warrants continuation/action 
• 
Protocol violations 
 
The medical monitor will review the information listed above every two months (or more frequently if needed 
based on rate of accrual or safety issues) for aggregate review of data.  Issues of immediate concern by the 
medical monitor will be brought to the attention of the Principal Investigator/IND sponsor (and if appropriate to 
the IRB) and a formal response from the IND-sponsor is requested.   
 
13.2 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. A safety review and analysis will be 
conducted after the 10th and 40th participant is enrolled.  


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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. 
 
14.0 STOPPING DECISION RULES 
 
14.1 Study stopping decision rules 
The study enrollment and further dosing will be stopped and an ad hoc independent medical monitor review will be 
performed if any of the following specific events occur or, if in the judgment of the study physician, subject safety 
is at risk of being compromised: 
1. Death within one hour of dupilumab administration 
2. Occurrence of a life-threatening allergic/hypersensitivity reaction (anaphylaxis), manifested by 
bronchospasm with or without urticaria or angioedema requiring hemodynamic support with pressor 
medications or mechanical ventilation 
3. One subject with a grade 4 or persistent grade 3 (≥72 hours) associated with study product. 
4. Two subjects with persistent Grade 3 (≥ 72 hours) or higher lab toxicity for the same parameter associated 
with study product. 
5. An overall pattern of symptomatic, clinical, or laboratory events that the medical monitor, ISM, or SMC 
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. 
6. 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. 
 
Upon completion of this review and receipt of the advice of the independent medical monitor, the PI will determine 
if study entry or study dosing should be interrupted or if study entry and study dosing may continue according to 
the protocol. 
 
14.2 Study Drug Stopping Rules Within a Single Subject 
Injection of study drug (i.e., patient will not receive any further dupilumab injections if they remain in the hospital 
during pre-specified time periods) will be halted if any of the following manifestations of anaphylaxis develop and 
will not be restarted: 
1. Skin or mucous membrane manifestations: hives, pruritus, flushing, swollen lips, tongue or uvula 
2. Respiratory compromise: dyspnea, wheezing, stridor, hypoxemia 


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3. A decrease in systolic blood pressure to < 90 mmHg or >30% decrease from baseline or a diastolic drop of 
>30% from baseline. 
4. Tachycardia with an increase in resting heart rate to > 130bpm; or bradycardia <40 that is associated with 
dizziness, nausea or feeling faint. 
5. Any other symptom or sign which in the good clinical judgment of the study clinician or supervising 
physician warrants halting the infusion.  For example, the rapid onset of gastrointestinal symptoms, such 
as nausea, vomiting, diarrhea, and cramps, for instance, may be manifestations of anaphylaxis and may 
warrant an immediate halt prior to meeting full SAE criteria. 
 
15.0 STUDY MANAGEMENT 
 
15.1 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. 
 
15.2 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 (i.e., mechanically ventilated, or otherwise 
incapacitated), 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.  
 
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. 
 
15.3 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.   
 
15.3.1 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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15.3.2 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). 
 
15.4 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. 
 
16.0 DATA HANDLING AND RECORDKEEPING 
 
16.1 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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16.2 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. 
 
16.3 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.   
 
16.4 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. 
 
17.0 REFERENCES 
 
1.  
Pedersen SF, Ho YC. SARS-CoV-2: A storm is raging. J Clin Invest. 2020;130(5):2202–5.  
2.  
Donlan AN, Sutherland TE, Marie C, Preissner S, Bradley T, Carpenter RM, et al. IL-13 is a driver of 
COVID-19 severity. Unpublished. 2020;  
3.  
Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, et al. Longitudinal analyses reveal 
immunological misfiring in severe COVID-19. Nature. 2020;584(7821):463–9.  
4.  
Thibodeaux Q, Smith MP, Ly K, Beck K, Liao W, Bhutani T. A review of dupilumab in the treatment of 
atopic diseases. Hum Vaccines Immunother [Internet]. 2019;15(9):2129–39. Available from: 
https://doi.org/10.1080/21645515.2019.1582403 
5.  
Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in 
adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus 
a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging 
trial. Lancet [Internet]. 2016;388(10039):31–44. Available from: http://dx.doi.org/10.1016/S0140-
6736(16)30307-5 
6.  
Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, et al. Long-term 
management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical 
corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, 
phase 3 trial. Lancet. 2017;389(10086):2287–303.  


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7.  
Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in 
Moderate-to-Severe Uncontrolled Asthma. N Engl J Med [Internet]. 2018 Jun 28;378(26):2486–96. 
Available from: http://www.nejm.org/doi/10.1056/NEJMoa1804092 
8.  
NIH. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Disponible en: 
https://covid19treatmentguidelines.nih.gov/. Nih. 2020;2019:130.  
9.  
Food and Drug Administration (FDA). Dupixent package insert. 2020; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761055s014lbl.pdf 
10.  
Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in 
Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475–85.  
11.  
Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. N Engl J Med. 2020;1–11.  
12.  
Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in nonventilated patients 
hospitalized with Covid-19 pneumonia. medRxiv [Internet]. 2020;(650):2020.10.21.20210203. Available 
from: https://doi.org/10.1101/2020.10.21.20210203 
13.  
Nienhold R, Ciani Y, Koelzer VH, Tzankov A, Haslbauer JD, Menter T, et al. Two distinct 
immunopathological profiles in autopsy lungs of COVID-19. Nat Commun [Internet]. 2020;11(1):1–13. 
Available from: http://dx.doi.org/10.1038/s41467-020-18854-2 
14.  
Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory 
cytokine signature predicts COVID-19 severity and survival. Nat Med [Internet]. 2020;26(10):1636–43. 
Available from: http://dx.doi.org/10.1038/s41591-020-1051-9 
15.  
Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–56.  
16.  
Lennon FE, Singleton PA. Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology. Am 
J Physiol - Lung Cell Mol Physiol. 2011;301(2).  
17.  
Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab 
in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY 
NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group 
phase 3 trials. Lancet [Internet]. 2019;394(10209):1638–50. Available from: 
http://dx.doi.org/10.1016/S0140-6736(19)31881-1 
18.  
Simpson EL, Paller AS, Siegfried EC, Boguniewicz M, Sher L, Gooderham MJ, et al. Efficacy and Safety 
of Dupilumab in Adolescents with Uncontrolled Moderate to Severe Atopic Dermatitis: A Phase 3 
Randomized Clinical Trial. JAMA Dermatology. 2020;156(1):44–56.  
19.  
Guttman-Yassky E, Bissonnette R, Ungar B, Suárez-Fariñas M, Ardeleanu M, Esaki H, et al. Dupilumab 
progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy 
Clin Immunol. 2019;143(1):155–72.  
20.  
Regeneron Pharmaceuticals. Dupilumab and Pregnancy Outcomes: A Retrospective Cohort Sutdy Using 
Administrative Health Care Databases (Dupi PODS) [Internet]. Available from: 
https://clinicaltrials.gov/ct2/show/record/NCT03936335 
21.  
Faiz S, Giovannelli J, Podevin C, Jachiet M, Bouaziz J-D, Reguiai Z, et al. Effectiveness and safety of 
dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. J Am Acad 
Dermatol [Internet]. 2019 Jul;81(1):143–51. Available from: 
https://linkinghub.elsevier.com/retrieve/pii/S0190962219303457 
22.  
Valent P, Klion AD, Horny H-P, Roufosse F, Gotlib J, Weller PF, et al. Contemporary consensus proposal 


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35
on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol 
[Internet]. 2012 Sep;130(3):607-612.e9. Available from: 
https://linkinghub.elsevier.com/retrieve/pii/S009167491200348X 
 
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. 
FDA EXAMPLE OF BASELINE SEVERITY CATEGORIZATION  
SARS-CoV-2 infection without symptoms 
• Positive testing by virologic test (i.e., a nucleic acid amplification test of an antigen test) • No symptoms  
Mild COVID-19  
• Positive testing by virologic test (i.e., a nucleic acid amplification test of an antigen test)  
• Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, malaise, headache, 
muscle pain, nausea, vomiting, diarrhea, and loss of taste or smell, without shortness of breath or dyspnea  
• No clinical signs indicative of Moderate, Severe, or Critical Severity  
Moderate COVID-19  
• Positive testing by virologic test (i.e., a nucleic acid amplification test of an antigen test) • Symptoms of 
moderate illness with COVID-19, which could include any symptom of mild illness or shortness of breath with 
exertion  
• Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥ 20 breaths per minute, 
heart rate ≥ 90 beats per minute; with saturation of oxygen (SpO2) > 93% on room air at sea level  
• No clinical signs indicative of Severe or Critical Illness Severity  


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36
Severe COVID-19  
• Positive testing by standard RT-PCR assay or an equivalent test 
• Symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of 
moderate illness or shortness of breath at rest, or respiratory distress  
• Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥ 30 per minute, 
heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300  
• No criteria for Critical Severity  
Critical COVID-19  
• Positive testing by standard RT-PCR assay or an equivalent test 
 
Respiratory failure defined based on resource utilization requiring at least one of the following:  
• 
Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg or 
requiring vasopressors)  
• 
Endotracheal intubation and mechanical ventilation, oxygen delivered by high- flow nasal cannula 
(heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction 
of delivered oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or clinical diagnosis of 
respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able 
to be administered in setting of resource limitation)  
• 
Multi-organ dysfunction/failure  
 

Prot_004.pdf: 
Version date: 06/15/2022 
1 
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 


Version date: 06/15/2022 
2 
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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3 
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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4 
• 
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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5 
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 
 
 
 
 
 
 
 
 


Version date: 06/15/2022 
6 
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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8 
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 


Version date: 06/15/2022 
9 
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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10
 
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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14
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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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 
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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.