Clinical trial NCT04342897
Conditions: COVID-19 Pneumonia
Keywords: Corona Virus Disease 19 (COVID-19) 2019 Novel Coronavirus (2019 n-COV) Severe Acute Respiratory Syndrome (SARS) Pulmonary Disease SARS-CoV-2
Sponsor: Eli Lilly and Company
Start date: 2020-04-20; Completion date: 2020-10-12
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind, placebo-controlled, clinical trial of LY3127804 in participants who are hospitalized with pneumonia and presumed or confirmed COVID-19.

Detailed description:

Arms: arm 1: Participants received 20 milligrams (mg) per kilogram (kg) of LY3127804 as an intravenous (IV) infusion on Days 1 and 15. arm 2: Participants received 20 mg/kg of Placebo as an IV infusion on Days 1 and 15.
Interventions: intervention 1: LY3127804 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol: I7W-MC-UDAA(c)
A Randomized, Double-blind, Placebo-controlled, Clinical Trial of LY3127804 in Patients who are 
Hospitalized with Pneumonia and Presumed or Confirmed COVID-19 
NCT04342897
Approval Date: 11-June-2020


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Approval Date: 11-June-2020 GMT
Protocol I7W-MC-UDAA(c)
A Randomized, Double-blind, Placebo-controlled, Clinical 
Trial of LY3127804 in Patients who are Hospitalized with 
Pneumonia and Presumed or Confirmed COVID-19
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators. It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3127804, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities: This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3127804
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 08 April 2020.
Amendment (a) Electronically Signed and Approved by Lilly: 16 April 2020.
Amendment (b) Electronically Signed and Approved by Lilly: 18 May 2020.
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below.


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Table of Contents
Section
Page
Protocol I7W-MC-UDAA(c) A Randomized, Double-blind, Placebo-
controlled, Clinical Trial of LY3127804 in Patients who are 
Hospitalized with Pneumonia and Presumed or Confirmed COVID-
19........................................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................15
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Patients.......................................................................................................18
5.3.
End of Study Definition ...............................................................................................18
5.4.
Scientific Rationale for Study Design...........................................................................18
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................21
6.1.
Inclusion Criteria..........................................................................................................21
6.2.
Exclusion Criteria ........................................................................................................21
6.3.
Lifestyle Restrictions....................................................................................................22
6.4.
Screen Failures.............................................................................................................23
7.
Treatments........................................................................................................................24
7.1.
Treatments Administered .............................................................................................24
7.1.1.
Packaging and Labelling ......................................................................................24
7.2.
Method of Treatment Assignment ................................................................................24
7.2.1.
Selection and Timing of Doses.............................................................................25
7.3.
Blinding .......................................................................................................................25
7.4.
Dosage Modification....................................................................................................25
7.5.
Preparation/Handling/Storage/Accountability...............................................................25
7.6.
Treatment Compliance .................................................................................................26
7.7.
Concomitant Therapy...................................................................................................26
7.8.
Treatment after the End of the Study............................................................................26


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8.
Discontinuation Criteria ....................................................................................................27
8.1.
Discontinuation from Study Treatment.........................................................................27
8.2.
Discontinuation from the Study....................................................................................27
8.3.
Lost to Follow-Up........................................................................................................27
9.
Study Assessments and Procedures ...................................................................................29
9.1.
Efficacy Assessments...................................................................................................29
9.1.1.
Primary Efficacy Assessments .............................................................................29
9.1.2.
Secondary Efficacy Assessments..........................................................................29
9.1.2.1.
NIAID Ordinal Assessment ............................................................................29
9.1.2.2.
Survival Without the Need for Mechanical Ventilation...................................29
9.1.2.3.
28-day Mortality.............................................................................................30
9.1.2.4.
Length of hospital stay....................................................................................30
9.1.3.
Exploratory Efficacy Analysis..............................................................................30
9.1.3.1.
Pulmonary Function .......................................................................................30
9.1.4.
Appropriateness of Assessments ..........................................................................30
9.2.
Adverse Events ............................................................................................................30
9.2.1.
Serious Adverse Events........................................................................................31
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................32
9.2.2.
Infusion-Related Reactions ..................................................................................33
9.2.3.
Complaint Handling.............................................................................................35
9.2.4.
Adverse Events of Special Interest – Secondary Infections...................................35
9.3.
Treatment of Overdose.................................................................................................35
9.4.
Safety...........................................................................................................................35
9.4.1.
Electrocardiograms ..............................................................................................35
9.4.2.
Vital Signs ...........................................................................................................35
9.4.3.
Laboratory Tests ..................................................................................................36
9.4.4.
Immunogenicity Assessments ..............................................................................36
9.4.5.
Safety Monitoring ................................................................................................36
9.5.
Pharmacokinetics .........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................36
9.7.
Pharmacogenomics/Genetics........................................................................................37
9.8.
Health Economics ........................................................................................................37
10.
Statistical Considerations ..................................................................................................38
10.1. Sample Size Determination ..........................................................................................38
10.2. Populations for Analyses..............................................................................................38
10.3. Statistical Analyses ......................................................................................................38
10.3.1.
General Statistical Considerations ........................................................................38
10.3.2.
Patient Comparability...........................................................................................39


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10.3.2.1.
Patient Disposition..........................................................................................39
10.3.2.2.
Patient Characteristics ....................................................................................39
10.3.2.3.
Concomitant Therapy .....................................................................................39
10.3.3.
Efficacy Analyses ................................................................................................39
10.3.3.1.
Primary Analyses ...........................................................................................39
10.3.3.2.
Secondary Analyses........................................................................................39
10.3.3.3.
Exploratory Analyses .....................................................................................40
10.3.4.
Safety Analyses....................................................................................................40
10.3.5.
Other Analyses.....................................................................................................40
10.3.5.1.
Subgroup Analyses.........................................................................................40
10.3.6.
Interim Analyses..................................................................................................40
11.
References ........................................................................................................................42
12.
Appendices .......................................................................................................................45


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List of Tables
Table
Page
Table 2-1.
Schedule of Activities....................................................................................12
Table 7-1.
Treatment Regimens......................................................................................24
Table 9-1.
NCI-CTCAE 5.0 Infusion-Related Reactions.................................................33


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List of Figures
Figure
Page
Figure 5-1.
Illustration of study design for Clinical Protocol I7W-MC-UDAA.................18
Figure 5-2.
Simulations for several dose levels (in mg/kg, givenIV Q2W)
compared to the median Ang2 levels reported in patients with 
pneumonia.....................................................................................................20


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................46
Appendix 2.
Clinical Laboratory Tests...............................................................................49
Appendix 3.
Study Governance Considerations..................................................................50
Appendix 4.
Sampling Summary .......................................................................................53
Appendix 5.
Protocol Amendment I7W-MC-UDAA(c) Summary .....................................54


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1. Synopsis
Title of Study:
A randomized, double-blind, placebo-controlled, clinical trial of LY3127804 in patients who are 
hospitalized with pneumonia and presumed or confirmed COVID-19.
Rationale:
The SARS-CoV 2 virus (Severe Acute Respiratory Syndrome Corona Virus) has resulted in the 
pandemic spread of coronavirus disease 2019 (COVID-19), which in severe cases results in 
progressive pulmonary failure with a high prevalence of acute respiratory distress syndrome 
(ARDS). In the early experience, approximately 15% of COVID-19 cases are classified as severe 
with pulmonary symptomology and require hospitalization. Reports on the prevalence of 
progression to ARDS vary, but conservatively estimates suggest that 25% of hospitalized 
patients will develop ARDS with a case fatality rate (CFR) of 50% in the first 30 days for those 
who develop ARDS. (Wang et al 2020, Liu et al 2019, Guan et al 2020, Huang et al 2020). 
Although a number of therapies have been explored in severe COVID-19 patients, none to date 
have been shown to improve survival (including antivirals, glucocorticoids, and 
immunoglobulins; Liu et al 2019). 
ARDS is characterized by loss of integrity of capillary endothelium (endothelial tight junctions) 
with extravasation of protein rich fluid and white blood cells (WBC) into the alveolar 
interstitium. This is associated with inflammation, activation of resident tissue macrophages and 
immune activation with patchy alveolar infiltrates evident on x-ray and with pulmonary edema 
and death from progressive respiratory failure (Thompson et al. 2017). Angiopoietin 2 (Ang2) 
levels in plasma are strongly correlated with increased ARDS risk in several human studies 
(Gutbier et al. 2018, Qi et al 2016, van der Heijden et al 2008, Parikh et al 2006). Importantly, 
Parikh et al. showed that Ang2 alone is able to replicate the pathological features of progressive 
lung failure observed in patients, namely the loss of tight junctions in the pulmonary epithelium, 
vascular hyperpermeability, and pulmonary congestion. In addition, RNAi Knockdown or anti-
Ang2 antibody treatment improves survival and pulmonary function in experimental models of 
ARDS (Lomas-Neira et al. 2016, Steihl et al. 2014). 
LY3127804 is an anti-Ang2 monoclonal antibody (mAb) that has been evaluated in both 
monotherapy and combined with ramucirumab in a Phase 1 clinical study of patients with 
advanced solid tumors (NCT02597036). The study results indicated LY3127804 has an 
acceptable safety profile with dose linear PK and evidence of target engagement (Ang 2) both as 
a single agent and in combination across the range of doses (4 mg/kg to 27 mg/kg). Study 
Protocol I7W-MC-UDAA (UDAA) will test whether LY3127804 can reduce the high proportion 
of patients who progress with pulmonary insufficiency, as assessed by ventilator free days, after 
being admitted to the hospital with a pneumonia and presumed or confirmed COVID-19 patient.


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Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To evaluate ventilator free days during treatment 
with LY3127804

Number of days from Day 1 to Day 28 on which a 
patient breathes without assistance, if the period of 
unassisted breathing lasted at least 24 consecutive 
hours and the patient did not die within 28 days
from first dose of study drug
Secondary

To evaluate clinical status of patients during
treatment with LY3127804

NIAID ordinal assessment (see Section 9.1.2.1 for 
definition)

To evaluate survival without the need for 
IMV/ECMO in patients treated with LY3127804

Proportion of patients who are alive and 
respiratory failure free (i.e. never having required 
mechanical ventilatory support) by Day 28

To evaluate mortality rate during treatment with 
LY3127804

Death within 28 days from first dose of study drug

To evaluate reduction in hospital stay during 
treatment with LY3127804

Length of hospitalization

To evaluate safety of LY3127804

AEs and SAEs
Abbreviations: AE = adverse event; ECMO = extracorporeal membrane oxygenation; IMV= intermittent mandatory 
ventilation; NIAID = National Institute of Allergy and Infectious Diseases; SAE = serious adverse event; SpO2 = 
oxygen saturation
Summary of Study Design:
Study I7W-MC-UDAA (UDAA) is a multicenter, randomized, double-blind, parallel, placebo-
controlled study in patients who are hospitalized for pneumonia and presumed or confirmed 
COVID-19.
Treatment Arms and Duration:
LY3127804 20 mg/kg or placebo administered intravenously (IV) on Days 1 and 15. If patients 
are discharged from the hospital prior to day 15, they will not receive a second dose and will 
undergo Completion or Hospital Discharge visit procedures.
Number of Patients:
Approximately 210 patients will be enrolled so that 200 patients complete the study, for an 
estimated total of 100 evaluable patients per treatment group. A sample size of 100 in each group 
will have 81% power to detect a difference between the placebo group and the LY3127804 
group using a Wilcoxon rank-sum test with a 0.05 one-sided significance level.


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Statistical Analysis:
The Wilcoxon rank-sum analysis of the primary endpoint, days free of mechanical ventilation 
within 28 days among survivors, will use a scoring scheme where a higher score is a better 
patient outcome. We will assign a score of -1 to patients who die before 28 days. For those 
patients who survive to Day 28 the score will be equal to the number of ventilator free days
(VFDs) calculated according to the above definition. The statistical method for this endpoint will 
be based on the van Elteren test adjusting for the randomization stratification factors. 
Randomization will be stratified by age group (<65 years and ≥65 years), sex and site.
Secondary efficacy analyses will assess secondary endpoints as well as analyses of relevant 
subgroups.
Safety analyses will include assessments of adverse events, vital signs, electrocardiograms and 
laboratory parameters.
An independent Data Monitoring Committee will be used to monitor unblinded safety data.


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2. Schedule of Activities


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Table 2-1.
Schedule of Activities
S a
Treatment
Completion
or Hospital 
Discharge or ED b,c
Follow-
Up Phone 
Visit 1 d
Follow-
Up Phone 
Visit 2 d
Study Day
≤1
1
2 
7
15
16
21
28 (or the day 
discharged from 
hospital or ED)
42 d
60
Window Period (days)
-
-
±2
-
-
±2
±1
±2
±2
Eligibility review
X
Informed consent
X
Demographics
X
Medical history e
X
Height
X
Weight
X
X
Physical examination 
(directed unless otherwise 
noted)
X
(complete)
X
X
X
X
X
(complete)
Vital signs f
X
Every day from Day 1 to 27 
Predose and postdose on Days 1 and 15 
X
Hematology and clinical 
chemistry
X (pre-dose)g
X
X
X 
(pre-dose)
X
X
X
COVID-19 panelh
X (pre-dose)
X
X
X
X
X
Influenza/RSV/respiratory 
viral paneli
X
Thyroid function test (TSH 
and FT4)
X (pre-dose)
X
Pregnancy Testj
X
(serum / 
urine)
X
(urine)
12-Lead ECGk
X (pre-and 
post-dose)l
X
(pre-and 
post-dose)
X


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Abbreviations: ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; ED = early discontinuation; fT4 = free thyroxine; FU = follow-up; 
h = hours; ICF = informed consent form; IMV = intermittent mandatory ventilation; NIAID = National Institute of Allergy and Infectious Diseases; PK = 
pharmacokinetic; S = Screening; SO2 = oxygen saturation; TSH = thyroid stimulating hormone.
a
Any procedure done as a standard of care 1 calendar day prior to ICF may be used as the screening procedure. Screening and Day 1 may occur on the same 
day.
b Patients who are discharged from the hospital will complete the Completion or Hospital Discharge visit procedures 
c
Patients who discontinue the study prior to study completion will complete the ED visit procedures.
d Follow-up phone visit 1 should be conducted at 14 days after completion or hospital discharge or early discontinuation, or 28 days after the first dose of study 
drug, whichever occurs later. Follow-up phone visit 2 should be conducted at 60 days after first dose of study drug.
e
Ensure the onset of illness symptoms are captured, examples include fever, coughing, extreme fatigue, headache, myalgia.
f
Includes respiration rate, heart rate, temperature, and blood pressure. Vital signs need to be recorded once at approximately the same time each day. Post dose 
vital signs on Days 1 and 15 should be collected at the end of infusion and at approximately 1 hr after end of infusion. 
g If procedures were performed within 1 calendar day prior to infusion as part of standard of care and prior to ICF, that may be used as the sample collection on 
Day 1.
h Data should be collected from local COVID19 panel laboratory pre-dose within 1 calendar day ≤Day 1, between 24 and 48 hr postdose on Day 2, and Day 16; 
and at any time on Days 7, 21, and 28 (or discharge or ED). Collection on Days 16 and 21 to be performed only if a Day 15 dose of study treatment was 
administered (Appendix 2).
S a
Treatment
Completion
or Hospital 
Discharge or ED b,c
Follow-
Up Phone 
Visit 1 d
Follow-
Up Phone 
Visit 2 d
Study Day
≤1
1
2 
7
15
16
21
28 (or the day 
discharged from 
hospital or ED)
42 d
60
Window Period (days)
-
-
±2
-
-
±2
±1
±2
±2
Randomizationm
Within 24 
hours of 
screening
Study drug administrationn
Within 8 hours 
of 
randomization
X
SpO2, O2 flow rateo
X
Every day from Day 1 to 27 
X
NIAID ordinal assessmentp
X
Every day from Day 1 to 27 
X
X
X
Adverse event monitoringq
Every day from Day 1 to 27 
X
X
X
Supportive pulmonary carer
Every day from Day 1 to 27 
X
Concomitant medicationss
Every day from Day 1 to 27 
X


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i
Viral testing is only performed for patients who have undetermined or negative COVID-19 test(s). Viral testing is per the institution’s testing guidelines.
j
For pregnancy test, only for women of child-bearing potential.
k Single 12-lead ECGs will be obtained in the supine position at all indicated timepoints. On Days 1 and 15, ECGs will be collected pre-dose and at the end of
infusion.
l
Pre-dose ECG to be collected within 1 calendar day of study drug administration. Post-dose ECG to be collected within 1 hour of study drug administration.
m The time from screening to randomization is provided as a guidance and may be modified based on clinical needs.
n The exact start and end time study drug infusion will be recorded. The time from randomization to study drug administration is provided as a guidance and 
may be modified based on clinical needs.
o Range of the average lowest value of the SpO2 and highest value of O2 flow rate administered and method of delivery should be recorded.
p NIAID ordinal scale is provided in Section 9.1.2.1. If IMV/ECMO is initiated or withdrawn, the date and reason for initiation and withdrawal of care (clinical 
deterioration, lack of clinical response, resource limitation, or other medical decision) should be captured.
q Any secondary infection in addition to Severe Acute Respiratory Syndrome Corona Virus (SARS-CoV-2) is an Adverse Event of Special Interest (See 
Section 9.2.4) and the site of infection, the culture source, and the pathogen(s) identified should be captured. Anti-infective therapy initiated (including anti-
bacterial and anti-fungal agents) should be captured under Concomitant Medications.
r
Supportive pulmonary care provided should be recorded as specified in the data capture documents. Specifically, proning should be recorded for any 
treatment day on which the time of maintaining a patient in a prone position is at least 8 hours.
s
Concomitant medications captured should include unapproved (“off-label”) medication (for example, chloroquine, hydroxychloroquine, and IL-6 
antagonists). 


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3. Introduction
3.1.
Study Rationale
The SARS-CoV 2 virus (Severe Acute Respiratory Syndrome Corona Virus) has resulted in the 
pandemic spread of coronavirus disease 2019 (COVID-19), which in severe cases results in 
progressive pulmonary failure with a high prevalence of acute respiratory distress syndrome 
(ARDS). In the early experience, approximately 15% of COVID-19 cases are classified as severe 
with pulmonary symptomology and require hospitalization. Reports on the prevalence of 
progression to ARDS vary, but it is conservatively estimated that 25% of hospitalized patients 
will develop ARDS with a case fatality rate (CFR) of 50% in the first 30 days for those who 
develop ARDS (Wang et al 2020, Liu et al 2019, Guan et al 2020, Huang et al 2020). Although a 
number of therapies have been explored in severe COVID-19, none to date have been shown to 
improve survival (including antivirals, glucocorticoids, and immunoglobulins; Liu et al 2019). 
3.2.
Background
ARDS is characterized by loss of integrity of capillary endothelium (endothelial tight junctions) 
with extravasation of protein rich fluid and white blood cells (WBC) into the alveolar 
interstitium. This is associated with inflammation, activation of resident tissue macrophages and 
immune activation with patchy alveolar infiltrates evident on x-ray and with pulmonary edema 
and death from progressive respiratory failure (Thompson et al. 2017). Angiopoietin 2 (Ang2) 
levels in plasma are strongly correlated with increased ARDS risk in several human studies 
(Gutbier et al. 2018, Qi et al 2016, van der Heijden et al 2008, Parikh et al 2006). Importantly, 
Parikh et al. showed that Ang2 alone is able to replicate the pathological features of progressive 
lung failure observed in patients, namely the loss of tight junctions in the pulmonary epithelium, 
vascular hyperpermeability, and pulmonary congestion. In addition, RNAi Knockdown or anti-
Ang2 antibody treatment improves survival and pulmonary function in experimental models of 
ARDS (Lomas-Neira et al. 2016, Steihl et al. 2014). 
LY3127804 is an anti-Ang2 monoclonal antibody (mAb) that has been evaluated in both 
monotherapy and combined with ramucirumab in a Phase 1 clinical study of patients with 
advanced solid tumors (NCT02597036). The study results indicated LY3127804 has an
acceptable safety profile with dose linear pharmacokinetics (PK) and evidence of target 
engagement (Ang2) both as a single agent and in combination across the range of doses (4 mg/kg 
to 27 mg/kg). 
The intent of this study is to test whether LY3127804 can reduce the high proportion of patients
who progress with pulmonary insufficiency, as assessed by ventilator free days (VFDs), after 
being admitted to the hospital with a pneumonia and presumed or confirmed COVID-19.
3.3.
Benefit/Risk Assessment
The potential benefit of LY3127804 has been described in Section 3.2. Based on the nonclinical 
safety data and clinical data reported so far, LY3127804 initial clinical data have shown it to 
have an acceptable safety profile at the dose selected for this study. Given the lack of any 
available therapy that has shown to be effective in preventing progressive pulmonary failure and 


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progression to ARDS in patients with viral induced pneumonia, there currently exists an acute 
need for such treatment to address the immense unmet medical need resulting from large 
numbers of patients presenting with COVID-19, some of which will progress to ARDS with 
unacceptably high mortality. Given the acceptable safety profile of LY3127804 and the dire 
prognosis for patients progressing to ARDS secondary to SARS-CoV-2 infection, the potential 
benefit of LY3127804 outweighs the potential risk.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3127804 are to be found in the 
Investigator’s Brochure (IB).


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4.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate ventilator free days during treatment 
with LY3127804

Number of days from Day 1 to Day 28 on which a 
patient breathes without assistance, if the period of 
unassisted breathing lasted at least 24 consecutive 
hours and the patient did not die within 28 days 
from first dose of study drug
Secondary

To evaluate clinical status of patients during 
treatment with LY3127804

NIAID ordinal assessment (see Section 9.1.2.1 for 
definition)

To evaluate survival without the need for 
IMV/ECMO in patients treated with LY3127804

Proportion of patients who are alive and 
respiratory failure free (i.e. never having required 
mechanical ventilatory support) by Day 28

To evaluate mortality rate during treatment with 
LY3127804

Death within 28 days from first dose of study drug

To evaluate reduction in hospital stay during 
treatment with LY3127804

Length of hospitalization

To evaluate safety of LY3127804

AEs and SAEs
Exploratory

To evaluate pulmonary function of patients during 
treatment with LY3127804

SpO2, O2 flow rate
Abbreviations: AE = adverse event; ECMO = extracorporeal membrane oxygenation; IMV= intermittent mandatory 
ventilation; NIAID = National Institute of Allergy and Infectious Diseases; SAE = serious adverse event; SpO2 = 
oxygen saturation


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5. Study Design
5.1.
Overall Design
Study I7W-MC-UDAA is a multicenter, randomized, double-blind, parallel, placebo-controlled 
Phase 2 study in patients who are hospitalized with pneumonia and presumed or confirmed 
COVID-19.
Study governance considerations are described in detail in Appendix 3.
Figure 5-1 illustrates the study design.
Figure 5-1.
Illustration of study design for Clinical Protocol I7W-MC-UDAA.
5.2.
Number of Patients
Approximately 210 patients will be enrolled so that200 patients complete the study, for an 
estimated total of 100 evaluable patients per treatment group.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patients.
5.4.
Scientific Rationale for Study Design
Approximately 25% of patients who are hospitalized with COVID-19 are admitted to the 
intensive care unit (ICU) and develop ARDS; half of patients with COVID-19-associated ARDS 
die within 30 days (Liu et al 2019). ARDS is characterized by loss of capillary endothelial 
integrity with increased permeability across endothelial tight junctions, permitting extravasation 
of protein rich fluid and WBCs into the alveolar interstitium, which (along with activation of 
resident macrophages) results in immune activation with inflammation, pulmonary edema and 
ultimately death from progressive pulmonary failure (Yadav et al. 2017). Many previous clinical 
trials have failed to improve outcomes when treatment was initiated after ARDS onset (Fuller et
al. 2015, Matthay et al. 2011, Rice et al. 2011, Unknown Authors 2002, Abraham et al. 1999,
Bernard et al. 1997, Zeiher et al. 2004, Liu et al, 2008, Unknown Authors 2000, Davidson et al.
2006, McAuley et al. 2014); resulting in the National Heart, Lung, and Blood Institute (NHLBI) 
to recommend that future therapies target prevention of ARDS (Spragg et al. 2010). Ang2 acts 
directly on endothelial cells to promote permeability across the microvascular barrier, vascular 
leakage, and WBC infiltration (Augustin et al. 2009, Zeiher et al. 2013, Fiedler and Augustin


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2006, Fiedler et al. 2006, David et al. 2012), which all occur in the early stages of ARDS 
development. The present Study UDAA is designed to evaluate LY3127804 for the prevention of
progression of respiratory distress to ARDS in hospitalized patients with confirmed or suspected 
COVID-19, that are presenting with pneumonia.
Patients who are discharged from the hospital will complete study procedures for a Completion 
or Hospital Discharge visit (see Section 2). Those patients will not return to the site for 
evaluation, study procedures, or additional study drug administration. However, patients will be 
contacted for vital status, including the NIAID ordinal assessment; first phone visit at 14 days 
after completion or hospital discharge or early discontinuation, or 28 days after the first dose of 
study drug, whichever occurs later; second phone visit at 60 days after the first dose of study 
drug. This strategy was chosen to remove the burden of return visits for the hospital and clinical 
trial staff reflecting limited medical resources in the COVID-19 pandemic and to minimize 
exposure risk to patients and their caregivers.
5.5.
Justification for Dose
In a previous study conducted in advanced cancer patients (I7W-MC-JQBA; JQBA), the 
maximum tolerated dose of LY3127804 was not reached at doses up to 27 mg/kg given IV once 
every 14 days (Q2W) and the recommended Phase 2 dose was 20 mg/kg IV Q2W. In JQBA, 
LY3127804 had an acceptable safety profile. The PK of LY3127804 was linear in the 
4-27 mg/kg Q2W dose range. However, due to significantly reduced Ang2 clearance associated 
with binding to LY3127804, pharmacodynamic (PD; total Ang2 in plasma) did not show a 
dose-dependency, and a PK/PD model could not be derived to explain the relationship of 
LY3127804 dose or concentrations to Ang2 plasma concentrations. Therefore, the LY3127804
concentration at which the target would be optimally saturated could not be estimated. 
In lieu of a PK/PD model, PK simulations were performed to evaluate the potential benefit of 
using different doses and compared to median Ang2 concentrations observed in patients with 
pneumonia/ARDS in the literature (Gutbier et al. 2018, Calfee et al. 2015).
Figure 5-2 shows simulations for several LY3127804 doses compared to the median Ang2 levels 
in patients with pneumonia reported in Gutbier et al. 2018.


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LY3127804
Figure 5-2.
Simulations for several dose levels (in mg/kg, given IV Q2W)
compared to the median Ang2 levels reported in patients with 
pneumonia.
Based on Study JQBA data and PK simulations based on the JQBA data, median LY3127804 
plasma concentrations after two 20 mg/kg doses (~1200 – 2200 nM) are expected to exceed 
median circulating Ang2 concentrations on a molar basis by >15-fold in patients with 
pneumonia. In addition, each LY3127804 molecule can bind to two Ang2 molecules, effectively 
doubling the effective LY3127804 exposure available for target binding.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening, unless specified otherwise:
1. Must be admitted to the hospital
2. Confirmed pneumonia with:
a.
Presence of signs and symptoms of respiratory disease (ie, cough, 
tachypnea, and/or shortness of breath) 
and at least one of the following
b. Infiltrates on chest imaging
c.
oxygen saturation (SpO2) of ≤95% on room air
3.
With presumed or confirmed COVID-19 
4. Are at least 18 years of age at the time of randomization.
5. Are able and willing to give signed informed consent (legally authorized 
representative can provide informed consent if needed).
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening, until specified otherwise:
1. Have ARDS and/or require immediate intermittent mandatory ventilation (IMV).
2. In the opinion of the investigator, is moribund irrespective of the provision of 
treatments.
3. Any concurrent serious medical condition (e.g.  patients with estimated 
glomerular filtration rate [eGFR] <15 mL/min/1.73m2 or on dialysis, preexisting 
lung disease requiring O2 at rest, a body mass index [BMI] that precludes 
techniques such as proning) or concomitant medication that in the opinion of the 
investigator that would preclude participation in the study.
4. Have received treatment with a drug predominantly targeting Ang2 activity (e.g., 
tyrosine kinase inhibitors and/or antibody treatment) within the past month or 5 
half-lives, whichever is longer.
5. Have a known sensitivity to mAbs or other therapeutic proteins, to agents of 
similar biologic composition as LY3127804, or to any products used in the 
formulation of LY3127804 (refer to the IB for LY3127804 for details) or are 
incompatible with the treatment of LY3127804.


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6. Have a known history or show evidence of human immunodeficiency virus (HIV) 
and/or hepatitis A, B or C 
7. Exclusion Criterion [7] has been deleted.
8. Have a significant bleeding disorder or active vasculitis or had a Grade ≥3 
bleeding episode within 12 weeks prior to receiving treatment
9. Have experienced any arterial thromboembolic event, including myocardial 
infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, 
within 6 months prior to receiving treatment
10. Have experienced any Grade 3 or 4 venous thromboembolic event that is
considered by the investigator to be life-threatening or that is symptomatic and 
not adequately treated by anticoagulation therapy within 6 months prior to
receiving treatment. Patients with chronic portal vein thrombosis who are
asymptomatic and not considered to need anticoagulation therapy are eligible.
11. Have chronic congestive heart failure (New York Heart Association class ≥3) or 
uncontrolled cardiac dysrhythmia
12. Have a serious nonhealing: (a) wound, (b) peptic ulcer, or (c) bone fracture,
within 28 days prior to receiving first dose of study drug
13. Have undergone major surgery within 28 days prior to randomization or central 
venous access device placement for another pre-existing condition within 7 days 
prior to receiving first dose of study drug
14. Have liver cirrhosis with a Child-Pugh class B or worse or cirrhosis (any degree) 
and a history of hepatic encephalopathy or clinically meaningful ascites resulting 
from cirrhosis. Clinically meaningful ascites is defined as ascites resulting from 
cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
15. Have a history of hypertensive crisis or hypertensive encephalopathy or current 
poorly controlled hypertension (systolic BP ≥160 mm Hg and/or diastolic BP 
≥95 mm Hg) despite standard medical management.
16. Are concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
17. Female patients who are pregnant and/or lactating.
18. Are investigator site personnel directly affiliated with this study and/or their 
immediate families. Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
19. Are Lilly employees or are employees of any third-party involved in the study 
who require exclusion of their employees.
6.3.
Lifestyle Restrictions
Study patients must be instructed not to donate blood or blood products during the study and for 
8 weeks following the last dose of study drug.


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The following patients must agree to use medically approved contraceptive methods during the 
study and for 90 days post the last dose of study drug:

Male patients with female partners of child-bearing potential

Female patients of childbearing potential who have a fertile male sexual partner 
Medically approved contraceptives include the following:

Hormonal contraceptives (oral, transdermal patches, vaginal or injectable), 

Intrauterine device with or without hormones, 

Condom (‘barrier’ method), 

Diaphragm or cervical cap (‘barrier’ method),

Sexual abstinence
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of LY3127804 20 mg/kg administered intravenously once 
every two weeks to placebo. The investigator may withhold the second dose (refer to 
Section 8.1). Table 7-1 shows the treatment regimens.
Table 7-1.
Treatment Regimens
Regimen
Dose
Day 1
Dose
Day 15
LY3127804
20 mg/kg
20 mg/kg
Placebo
Matching placebo
Matching placebo
Note:  Patents weighing 150 kg and above will receive a maximum LY3127804 dose of 3000 mg. Please see the 
Pharmacy Manual for further instructions.
LY3127804 will be administered as a slow IV infusion over at least 90 (±15) minutes. Infusion 
duration may be increased or stopped as deemed necessary based on the institutional standard of 
care. If an infusion reaction is observed, the patient should be treated according to instructions in
Section 9.2.2. Resuscitation equipment and emergency drugs must be available at all times when the 
patient is being infused. Patients should be observed for at least 60 minutes after completion of the 
infusion. The actual start and stop time of infusion will be recorded.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product infusion and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law.
7.1.1. Packaging and Labelling
The drug product will be manufactured, tested, packaged, and labeled in accordance with all 
applicable Good Manufacturing Practice (GMP) requirements and country’s regulatory 
requirements. A certificate of analysis confirming the materials are released for human use in 
clinical trials will be supplied. LY3127804 drug products are for investigational use only and are 
to be used only within the context of this study.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be stratified by age group (<65 years and ≥65 
years), sex, and site, and then, on Day 1, randomly assigned in a 1:1 ratio within each stratum to 
receive either LY3127804 or placebo. Treatment assignment will be determined by a computer 
generated randomization sequence using an interactive web response system (IWRS).


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7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same times on each day. The actual time of 
all dose administrations will be recorded in the patient’s electronic case report form (eCRF).
7.3.
Blinding
This is a double-blind study; patients, investigator, and site personnel performing trial related 
activities or with the ability to influence study outcomes will be blinded with respect to 
LY3127804 and placebo treatment. To preserve the blinding, all sponsor personnel involved in 
study conduct will remain blinded to treatment while the study is ongoing, except for individuals
(or designee) from Global Patient Safety (GPS) to manage individual serious adverse events and 
safety reporting. This individual from the GPS team is not involved in day-to-day activities of 
study conduct. Site staff who are responsible for drug preparation will not be blinded; laboratory 
personnel will also not be blinded.
After the reporting database is locked for statistical analysis of the double-blind treatment phase, 
a limited number of sponsor personnel will be unblinded to complete the study report. However, 
any sponsor personnel continuing with the management and oversight of the study will remain 
blinded to patients’ treatment assignments.
Emergency unblinding may be performed through the IWRS. This option may be used only if the 
patient’s well-being requires knowledge of the patient’s treatment assignment. All unblinding 
events will be recorded and reported by the IWRS.
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a patient’s treatment assignment is warranted for medical management of the 
event. The patient’s safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, it is the responsibility of 
the Investigator to promptly document the decision and rationale and notify sponsor as soon as 
possible.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study. In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a sponsor medical 
representative for the patient to continue in the study. During the study, emergency unblinding 
should occur only by accessing the IWRS.
This is a double-blind study.
Upon completion of the study, all codes must be returned to the sponsor or its designee.
7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:


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
confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only patients enrolled in the study may receive study treatment and 
only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
Detailed instructions for the preparation and handling of LY3127804 and placebo will be 
provided to the unblinded site pharmacy personnel by the Sponsor.
LY3127804 for Injection vials are to be stored in refrigerated condition (2ºC to 8ºC).
7.6.
Treatment Compliance
All study drug doses will be administered at study site.
7.7.
Concomitant Therapy
All concomitant therapies that are part of routine care are allowed and can be used during the 
study. If indicated, anticoagulation therapies, including full-dose anticoagulation therapies, are
allowed.
All concomitant therapies must be recorded in the eCRF.
Concomitant medications captured should include unapproved (“off-label”) medication, such as, 
for example, convalescent antibodies, remdesivir, chloroquine, hydroxychloroquine, and IL-6 
antagonists.
7.8.
Treatment after the End of the Study
Study drug will not be made available after conclusion of the study to patients.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of study drug:

Patient Decision

the patient requests to discontinue study drug.

Investigator Decision

The investigator may discontinue treatment after the first dose, if in the 
judgement of the investigator the benefit/risk assessment for LY3127804 
does not support administration of a second dose.

Grade 3 or higher infusion-related reaction per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0 (refer to Section 9.2.2)

Grade 2 and greater bleeding events associated with study treatment.
Patients discontinuing from the study drug prematurely for any reason should complete adverse 
event and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

patient consent withdrawal
Patients discontinuing from the study prematurely for any reason should complete adverse event 
and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly is unable to be contacted by 
the study site. Site personnel are expected to make diligent attempts to contact patients for the 
follow-up phone visit.


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Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product. Public sources may be searched for vital status information. If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed per local site procedures.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
Ventilator free days will be defined as the number of days from Day 1 to Day 28 on which a 
patient does not require a ventilator (IMV), if the period of breathing without a ventilator (IMV) 
lasted at least 24 consecutive hours and the patient did not die within 28 days from first dose of 
study drug; if the patient died within 28 days, then this end point will be set equal to -1.
9.1.2. Secondary Efficacy Assessments
9.1.2.1.
NIAID Ordinal Assessment
The NIAID will be assessed daily and defined as the lowest score achieved for that day
[NCT04280705].
1- Death
2- Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO)
3- Hospitalized, on non-invasive ventilation or high flow oxygen devices
4- Hospitalized, requiring supplemental oxygen
5- Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care 
(COVID-19 related or otherwise)
6- Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care
7- Not hospitalized, limitation on activities and/or requiring home oxygen
8- Not hospitalized, no limitations on activities. 
9.1.2.2.
Survival Without the Need for Mechanical Ventilation
Proportion of patients who are alive and respiratory failure free (i.e., never having required 
mechanical ventilatory support; i.e. IMV/ECMO) will be calculated at Day 28.


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9.1.2.3.
28-day Mortality
Mortality will be defined as 28-day all-cause mortality, defined as 672 hours from the time of 
randomization. All patients will be classified as either “alive at Study Day 28” or, if dead, “dead 
at Study Day 28.”
9.1.2.4.
Length of hospital stay
Length of hospital stay will be defined as the number of days hospitalized for at least 1 hour 
duration.
9.1.3. Exploratory Efficacy Analysis
9.1.3.1.
Pulmonary Function
Pulmonary function will be assessed daily as the range of the average lowest value for SpO2 and 
the highest value of O2 flow rate for that day.
9.1.4. Appropriateness of Assessments
All assessments are widely used and generally regarded as reliable, accurate, and relevant.
9.2.
Adverse Events
A clinical trial AE is any untoward medical event associated with the use of a drug or drug 
delivery system in humans, whether or not it is considered related to that drug or drug delivery 
system.
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report and electrocardiogram 
(ECG).
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the study drug before completing 
the study. The patient should be followed until the event resolves, stabilizes with appropriate 
diagnostic evaluation, or is reasonably explained. The frequency of follow-up evaluations of the 
AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via electronic 
data capture (EDC) the occurrence and nature of each patient’s pre-existing conditions, including 
clinically significant signs and symptoms of the disease under treatment in the study. In addition, 
site personnel will record via eCRF any change in the condition(s) and any new conditions as 


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AEs. Investigators should record their assessment of the potential relatedness of each AE to 
protocol procedure or investigational product via EDC.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, and pathologies.
A “reasonable possibility” means that there potentially is a cause and effect relationship between 
the investigational product, study device, and/or study procedure and the AE.
The investigator will use AE follow-up forms to record additional details regarding AEs related 
to injection sites and hypersensitivity events.
If a patient’s study drug is discontinued as a result of an AE, study site personnel must report this 
to the sponsor or its designee via EDC, clarifying if possible the circumstances leading to 
discontinuation of treatment.
9.2.1. Serious Adverse Events
Study-specific clinical outcomes of progressive pulmonary failure in hospitalized patients with 
presumed or confirmed COVID-19 are exempt from all serious adverse event reporting unless 
the investigator deems the event to be related to the administration of study drug. Monitoring by 
the DMC will include continuous assessment of a potential imbalance in aggregate events 
between the treatment and control groups (please refer to Section 9.4.5).
The following events will be considered clinical outcomes and not reported as SAEs:
• 
Death related to progressive pulmonary failure and/or ARDS, that is, related to severe 
ARDS or a sequela of ARDS based on the interpretation of the investigator.
• 
Cardiovascular events: cardiac failure.
• 
Respiratory events: pneumonia, hemoptysis, decreased PaO2/FiO2, mechanical 
ventilation/ECMO, hypoxia, hypoxemia, ARDS, acute lung injury, or respiratory failure.
• 
Systemic inflammatory response syndrome related criteria: tachypnea, hypopnea,
leukocytosis, leukopenia, hypothermia, hyperthermia, tachycardia, or bradycardia.
• 
Secondary infections
An SAE is any AE from this study that results in one of the following outcomes and is not 
classified as a clinical outcome of COVID-19 using the definitions shown in Section 9.2.:

death that is not related to COVID-19 or a sequela of COVID-19 or death that is 
considered by the investigator to be related to study drug

prolonged inpatient hospitalization or re-hospitalization life-threatening experience (that 
is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect


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
important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.
The study site personnel must alert the sponsor, or its designee, of any SAE as soon as 
practically possible but no later than 24 hours.
Additionally, study site personnel must alert the sponsor, or its designee, of any SAE within 
24 hours of Investigator awareness of the event via a sponsor-approved method. If alerts are 
issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms. This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the case report form or EDC after signing informed consent, 
SAE reporting to the Sponsor begins after the patient has signed informed consent and has 
received the study drug. However, if an SAE occurs after signing informed consent, but prior to 
receiving the study drug, AND is considered Reasonably Possibly Related to a study procedure 
then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued from and/or completed the study (the patient disposition EDC has been completed).
However, if the Investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the Investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to the study drug) does not meet the definition of an 
adverse event. However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
The designated medical monitor of the Sponsor will monitor safety data throughout the course of 
the study. The Sponsor and/or its designee will review SAEs within appropriate timeframes to 
meet reporting obligations imposed by regulatory authorities. All serious and unexpected AEs 
for this study will be reported to regulatory authorities in accordance with local laws, directives, 
and regulations.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the 
identification, recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.


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9.2.2. Infusion-Related Reactions
As with other mAbs, infusion-related reactions may occur during or following LY3127804
administration. Infusion-related reactions will be defined according to the NCI-CTCAE 5.0 
definition of infusion-related reactions (refer to “General disorders and administration site 
conditions” in NCI-CTCAE 5.0), as detailed below.
Symptoms occurring during or after infusion of study drug(s) may also be defined according to
AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome (refer to
“Immune System Disorders” in NCI-CTCAE 5.0). If symptoms occur during or after infusion of
LY3127804, investigators are encouraged to use the AE term “infusion-related reaction” and any
additional terms (including those not listed here) that best describe the event. Those described
above should be graded as shown in Table 9-1.
Table 9-1.
NCI-CTCAE 5.0 Infusion-Related Reactions
Adverse 
Event
Grade
1
2
3
4
5
Infusion-
related 
reaction
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated
Therapy or infusion 
interruption indicated 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hr
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacologic or biologic substances.
Allergic 
reaction
Systemic 
intervention not 
indicated 
Systemic intervention 
not indicated
Systemic intervention 
not indicated
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
—
—
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-
related 
edema/angioedema; 
hypotension
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and 
histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with 
breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death.
Cytokine-
Fever with or 
Fever with or without 
Fever with or without 
Fever with or 
Death


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Adverse 
Event
Grade
1
2
3
4
5
release 
syndrome
without 
constitutional 
symptoms
constitutional 
symptoms
constitutional 
symptoms
without 
constitutional 
symptoms
Definition: A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia 
caused by the release of cytokine.
Abbreviations: hr = hours; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug.
Consistent with usual medical practice, selected parenteral medications may be used for Grade 2
allergic/hypersensitivity reaction as detailed below. The Lilly CRP/study team must be
contacted immediately.
The following are treatment guidelines for infusion-related reactions:
Grade 1

Slow the infusion rate by 50% (by doubling the infusion time).

Monitor the patient for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV
(or equivalent); additional premedication may be administered at the investigator’s
discretion.
Grade 2

Stop the infusion.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), acetaminophen
650 mg orally for fever, and oxygen.

Resume the infusion at 50% of the prior rate (by doubling the infusion time) once the
infusion-related reaction has resolved or decreased to Grade 1; the infusion duration
should not exceed 4 hours.

Monitor for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV
(or equivalent); additional premedication may be administered at the investigator’s
discretion.
For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 8 to 10 mg IV (or
equivalent).
Grade 3

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone 8 
to 10 mg IV (or equivalent), bronchodilators for bronchospasm, and other
medications/treatment as medically indicated.
Patients who have a Grade 3 infusion-related reaction will not receive further treatment with 
LY3127804 but will continue to be followed per protocol.


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Grade 4

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone 8 
to 10 mg IV (or equivalent), and other medications/treatment as medically indicated.

Give epinephrine or bronchodilators as indicated.
Patients who have a Grade 4 infusion-related reaction will not receive further treatment with 
LY3127804 but will continue to be followed in the study.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study patients, monitor quality, and to facilitate 
process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed.
9.2.4. Adverse Events of Special Interest – Secondary Infections
Adverse events of special interest for this study including infections in addition to SARS-CoV-2, 
inclusive of all sites and pathogens. Site of infection, source of culture (e.g. BAL, tracheal 
aspirate, sputum, blood, urine) and pathogen(s) identified (including fungal and bacterial 
pathogens) should be recorded.
9.3.
Treatment of Overdose
There is no antidote to LY3127804. In case of overdose, use supportive measures. 
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational treatment should be reported to Lilly or its 
designee as an AE via EDC.
9.4.2. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).
The sponsor recognizes that vital sign assessments will be performed more frequently than 
indicated in the Schedule of Events, with continuous monitoring in the ICU and every 2 to 4 
hours in non-ICU settings. The time points specified in the protocol are collection times used for 
data analysis purposes only. The vital sign schedule in the protocol is not intended to interfere 
with standard of care practices in a given hospital unit. In all cases, institutional standard of care 
with respect to monitoring of patients is allowed and encouraged.


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Any clinically significant findings from vital sign measurements that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via EDC.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via EDC.
9.4.4. Immunogenicity Assessments
Results from Clinical Study JQBA are consistent with a low risk for the development of 
significant levels of anti-drug antibodies. The proposed treatment will include one or two doses 
of LY3127804, making the mounting of a significant specific immune response to LY3127804 
unlikely. Additionally, the collection of multiple blood draws presents significant challenges and 
an additional risk of infection to site personnel and is deemed unfeasible. There will be no 
assessment of immunogenicity as part of Study UDAA.
9.4.5. Safety Monitoring
The study will have a Data Monitoring Committee (DMC) consisting of at least 2 physicians and 
one statistician, all experienced clinical trialists and external to the sponsor. The role of the DMC 
is to advise the sponsor regarding conduct of the study. Only the DMC is authorized to evaluate 
unblinded data. Study sites will receive unblinded results ONLY if they need to know for the 
safety of their patients. Unblinding details are specified in the unblinding plan section of the 
statistical analysis plan (SAP) or a separate unblinding plan document.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC can conduct additional analyses of the safety data.
All deaths and SAE reports will be reviewed in a blinded manner by Lilly during the clinical 
trial. These reports will be reviewed to assure completeness and accuracy but will not be 
unblinded to Lilly during the clinical trial. If a death or clinical AE is deemed serious, 
unexpected, and possibly related to investigational product, one individual (or designee) in Lilly 
Global Patient Safety will be unblinded for regulatory reporting and safety monitoring purposes.
These measures will preserve the integrity of the data collected during this trial and minimize 
any potential for bias while providing for appropriate safety monitoring.
9.5.
Pharmacokinetics
Samples for pharmacokinetic analysis will not be collected in this study.
9.6.
Pharmacodynamics
Samples for pharmacodynamic analysis will not be collected in this study.


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9.7.
Pharmacogenomics/Genetics
Samples for pharmacogenomics or genetics will not be collected in this study.
9.8.
Health Economics
Not applicable.


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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 210 patients may be enrolled in a 1:1 ratio to LY3127804 or placebo (105 per 
treatment group) in order that 200 patients complete the study. A sample size of 100 in each 
group will have 81% power to detect a difference between the placebo group and the 
LY3127804 group using a Wilcoxon rank-sum test with a 0.05 one-sided significance level. This 
powering is based on the following assumptions: IMV rate of 25% and mortality rate of 12.5% in 
the placebo group, 50% improvement in IMV rate and mortality rate for the LY3127804 group
relative to placebo, and a mean difference (LY3127804 minus placebo) of 3.0 ventilator-free 
days where patients who die are assigned a value of -1.
Randomization will be stratified by age group (<65 years and ≥65 years), sex, and site.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled Set
All patients who sign informed consent
Efficacy Analysis Set
All randomized patients who take at least 1 dose of double-blind study 
treatment. Patients will be included in the treatment group they were 
randomized.
Safety Analysis Set
All randomized patients who take at least 1 dose of double-blind study 
treatment. Patients will be analyzed according to the treatment they actually 
received.
10.3. Statistical Analyses
10.3.1.
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. A detailed 
statistical analysis plan (SAP) describing the statistical methodologies will be developed.
Efficacy analyses will be conducted on the Efficacy Analysis Set; safety analyses will be 
conducted on the Safety Analysis Set.
Descriptive statistics will include the number of patients, mean, standard deviation, median, 
minimum, and maximum for continuous measures, and frequency counts and percentages for 
categorical measures.
Investigators with fewer than 2 randomized patients per treatment group will be pooled for 
statistical analysis purposes. Sensitivity analyses accounting for missing data will be described in 
the SAP.
Unless otherwise noted, treatment comparisons of discrete variables will be made using logistic 
regression analysis with treatment and randomization stratification variables in the model. The 
percentages, difference in percentages, and 95% confidence interval (CI) of the difference in 
percentages will be reported.


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Unless otherwise noted, treatment comparisons of continuous variables will be made using a 
restricted maximum likelihood-based mixed-effects model of repeated measures (MMRM). The 
model will include treatment, age group, and site, and, if applicable, study day and treatment-by-
study day interaction as fixed categorical effects. Additional details on the MMRM analyses will 
be described in the SAP.
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.05, unless otherwise 
stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR). Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
10.3.2.
Patient Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study. Reasons for 
discontinuation will be summarized by treatment group.
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be described. No statistical comparisons between 
treatment groups will be made.
10.3.2.3. Concomitant Therapy
Concomitant medications will be summarized for patients who enter each treatment period and 
will be presented by anatomical therapeutic chemical drug classes using the latest version of the 
WHO drug dictionary.
10.3.3.
Efficacy Analyses
10.3.3.1. Primary Analyses
The Wilcoxon rank-sum analysis of the primary endpoint, death at day 28 and days free of 
mechanical ventilation within 28 days among survivors (VFDsurv), will use a scoring scheme 
with patients from the Efficacy Analysis Set who do better getting a higher score. We will assign 
a VFDsurv score of -1 to patients who die before 28 days. For those patients who survive to day 
28 the VFDsurv score will be equal to the number of VFDs calculated according to the above 
definition. If a patient is discharged from the hospital before day 28, and if the patient is still 
alive at day 28, they will be credited with ventilator free days from the time of discharge until 
day 28. The statistical method for this endpoint will be based on the van Elteren test adjusting for 
the randomization stratification factors (age group, sex, and site). 
10.3.3.2. Secondary Analyses
Secondary end points will be described and compared between treatment groups. The NIAID 
ordinal scale and length of hospitalization will be analyzed with the Wilcoxon rank-sum test.


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Mortality, survival without respiratory failure, and categorical changes on the NIAID ordinal 
scale will be analyzed as discrete variables.
10.3.3.3. Exploratory Analyses
Pulmonary function will be analyzed via MMRM analysis.
10.3.4.
Safety Analyses
Safety will be assessed by evaluating all reported AEs and changes in laboratory analytes, ECGs, 
and vital signs (including body weight) in the Safety Analysis Set and summarized by treatment 
group.
Duration of exposure to therapy will be calculated for each patient.
AEs will be coded according to the Medical Dictionary for Regulatory Activities and 
summarized by system organ class, preferred term, severity, and relationship to investigational 
product. A TEAE is defined as an event that first occurred or worsened in severity after baseline. 
In the analysis of TEAEs, all preexisting conditions recorded before the first dose of study drug
will be used as baseline. For each event classification term, the number of patients experiencing 
a TEAE with that classification term will be tabulated. Treatment-related TEAEs are defined as 
events that are indicated by the investigator on the eCRF to be related to treatment. If a patient
reports the occurrence of a particular event more than once, the most severe of those events will 
be included in the summary tables of TEAEs, and the most severe of the most related of those 
events will be included in the summary tables of treatment-related events.
Additional safety parameters include laboratory test results, ECGs, and vital-sign measurements. 
The baseline for computing the change in safety data is the last value collected before the first 
dose of study drug. The parameters will be listed and summarized with standard descriptive 
statistics. Change from baseline will also be summarized.
10.3.5.
Other Analyses
10.3.5.1. Subgroup Analyses
Subgroup analyses of the primary analysis will be conducted on relevant subgroups, including 
patients who are confirmed SARS-CoV-2 positive, age group, and sex.
10.3.6.
Interim Analyses
An interim analysis may be conducted to assess efficacy results. The interim efficacy results may 
be used for internal decision-making to trigger planning activities associated with the 
investigational product and/or to assess futility. No adjustment of Type I error will be performed
as the study will not be stopped for efficacy, and no modification of Study UDAA is expected
based on these interim results, other than possibly stopping the study for futility. The assessment 
would be conducted by a sponsor assessment committee with a limited number of preidentified 
team members who do not have direct site contact or data entry/validation responsibilities. 
Unblinding details will be specified in the unblinding plan section of the SAP or in a separate 


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unblinding plan document. Information that may unblind the study during the analyses will not 
be reported to study sites or to the blinded study team until the study has been unblinded.
An independent DMC will review unblinded safety data on an ongoing basis (Section 9.4.5). 
Details are specified in the DMC Charter.
Ongoing monitoring of safety data (including AEs, SAEs, and selected laboratory 
measurements) will continue throughout the study by the sponsor using blinded data.


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11.
References
[NCT02597036] ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine 
(US). Identifier NCT02597036, A Study of LY3127804 With Ramucirumab in Participants 
With Advanced Solid Tumors; 2019 Nov 19 [cited 2020 Apr 08]; Available from: 
https://clinicaltrials.gov/ct2/show/NCT02597036
[NCT04280705] ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine 
(US). Identifier NCT04280705, Adaptive COVID-19 Treatment Trial (ACTT); 2020 Apr 06 
[cited 2020 Apr 08]; Available from: https://clinicaltrials.gov/ct2/show/NCT04280705
Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute 
respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical 
trial. TLC C-53 ARDS Study Group. Crit Care Med. 1999;27(8):1478–1485.
Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and 
homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10(3):165–177.
Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and 
procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest. 1997;112(1):164–172.
Calfee CS, Janz DR, Bernard GR, et al. Distinct molecular phenotypes of direct vs indirect 
ARDS in single-center and multicenter studies. Chest. 2015;147(6):1539-48.
David S, Mukherjee A, Ghosh CC, et al. Angiopoietin-2 may contribute to multiple organ 
dysfunction and death in sepsis. Crit Care Med. 2012;40(11):3034–3041.
Davidson WJ, Dorscheid D, Spragg R, Schulzer M, Mak E, Ayas NT. Exogenous pulmonary 
surfactant for the treatment of adult patients with acute respiratory distress syndrome: results 
of a meta-analysis. Crit Care. 2006;10(2):R41.
Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends 
Immunol. 2006;27(12):552-8.
Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-
alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12(2):235–239.
Fuller BM, Mohr NM, Skurpky L, Flower S, Kollef MH, Carpenter CR. The Use of Inhaled 
Prostaglandins in Patients With ARDS: A Systematic Review and Meta-Analysis. Chest.
2015;147(6):1510-22.
Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. NEJM. 
2020. DOI: 10.1056/NEJMoa2002032.
Gutbier B, Neuhau A, Reppe K, et al. Prognostic and pathogenic role of angiopoietin-1 and -2 in 
pneumonia. Am J Respir Crit Care Med. 2018;198(2):220-31.
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet. 2020;395:497-506.
Liu KD, Levitt J, Zhuo H, et al. Randomized clinical trial of activated protein C for the treatment 
of acute lung injury. Am J Respir Crit Care Med. 2008;178(6):618–623.


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Liu Y, Sun W, Li J, et al. Clinical features and progression of acute respiratory distress syndrome 
in coronavirus disease 2019. medRxiv. Preprint available at: 
https://doi.org/10.1101/2020.02.17.20024166 
Lomas-Neira JL, Heffernan DS, Ayala A, Monaghan SF. Blockade of endothelial growth factor, 
angiopoietin-2, reduces indices of ARDS and mortality in mice resulting from the dual-insults 
of hemorrhagic shock and sepsis. Shock. 2016;45(2):157-65.
Matthay MA, Brower RG, et al. Randomized, placebo-controlled clinical trial of an aerosolized 
β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 
2011;184(5):561-568.
McAuley DF, Laffey JG, O'Kane CM, et al. Simvastatin in the acute respiratory distress 
syndrome [published correction appears in N Engl J Med. 2016 Nov 17;375(20):2010]. N Engl 
J Med. 2014;371(18):1695–1703.
Parikh SM, Mammoto T, Schultz A, Yuan H-T, Christiani D, Karumanchi SA, et al. Excess 
Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans. 
PLoS Med. 2006;3(3):e46.
Qi Z, Li Z, Hao D, et al. Association between angiopoietin-2 and enterovirus 71 induced 
pulmonary edema. The Indian Journal of Pediatrics. 2016;83:391-6.
Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, 
and antioxidant supplementation in acute lung injury [published correction appears in JAMA. 
2012 Feb 8;307(6):563]. JAMA. 2011;306(14):1574–1581.
Spragg RG, Bernard GR, Checkley W, et al. Beyond mortality: future clinical research in acute 
lung injury. Am J Respir Crit Care Med. 2010;181(10):1121–1127.
Steihl T, Thamm K, Kaufmann, J, et al. Lung-targeted RNA interference against angiopoietin-2 
ameliorates multiple organ dysfunction and death in sepsis. Critical Care Medicine. 
2014;42(10):e654-62.
Thompson BT, Chamber RC, Liu KD. Acute respiratory distress syndrome. NEJM. 
2019;377:562-572.
Unknown Authors. Ketoconazole for early treatment of acute lung injury and acute respiratory 
distress syndrome: a randomized controlled trial. The ARDS Network [published correction 
appears in JAMA 2000 Nov 15;284(19):2450] [published correction appears in JAMA 2001 
Oct 3;286(13):1578] [published correction appears in JAMA 2200 Nov 22-29;284(20):2597]. 
JAMA. 2000;283(15):1995–2002.
Unknown Authors. Randomized, placebo-controlled trial of lisofylline for early treatment of 
acute lung injury and acute respiratory distress syndrome. Crit Care Med. 2002;30(1):1–6.
van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, et alAngiopoietin-2, permeability 
oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. 
Thorax. 2008;63:903-909.
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel 
coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020. Doi: 
:10.1001/jama.2020.1585.


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Yadav H, Thompson BT, Gajic O. Is acute respiratory distress syndrome a preventable disease? 
Am J Respir Crit Care Med. 2017;195(6):725–736.
Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: 
results of the STRIVE study. Crit Care Med. 2004;32(8):1695–1702.
Ziegler T, Horstkotte J, Schwab C, et al. Angiopoietin 2 mediates microvascular and 
hemodynamic alterations in sepsis [published online ahead of print, 2013 Jul 1]. J Clin Invest. 
2013;123(8):3436–3445.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
Ang2
angiopoietin 2
ARDS
Acute respiratory distress syndrome
AST
aspartate aminotransferase
Blinding
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CFR
case fatality rate
COVID-19
coronavirus disease
CI
confidence interval
CRP
clinical research physician: Individual responsible for the medical conduct of the study.
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
DMC
data monitoring committee
ECG
electrocardiogram
ECMO
extracorporeal membrane oxygenation
eCRF
electronic case report form
ED
early discontinuation
EDC
electronic data capture


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enroll
The act of assigning a patient to a treatment. Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
fT4
free thyroxine
FU
follow-up
GCP
good clinical practice
GPS
Global Patient Safety
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IMV
intermittent mandatory ventilation
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form.
IV
intravenous
IWRS
interactive web-response system
mAb
monoclonal antibody
MMRM
mixed-effects model of repeated measures
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NIAID
National Institute of Allergy and Infectious Diseases
PK/PD
pharmacokinetics/pharmacodynamics
QTc
corrected QT interval
Q2W
every two weeks
SAE
serious adverse event
SAP
statistical analysis plan


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Screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SpO2
oxygen saturation
SUSARs
suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TSH
thyroid stimulating hormone
VFD
ventilator free days
VFDsurv
ventilator free days among survivors
WBC
white blood cell


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)a
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose (random)
Albumin
COVID-19 Panel
Creatine kinase (CK)
D-dimer
Total protein
Cardiac troponin (I or T)
LDH
Pregnancy Test (females only)
C-reactive protein
Procalcitonin
Thyroid Function Test
Ferritin
Free thyroxine (fT4)
IL-6
Thyroid stimulating hormone (TSH)
BNP
Influenza/RSV/Respiratory Viral Panelb
Abbreviations: BNP = brain natriuretic peptide; IL-6 = interleukin 6; LDH = lactate dehydrogenase; RBC = red 
blood cells; RSV = respiratory syncytial virus; WBC = white blood cells.
a
For purposes of this study, if AST is not routinely reported when ALT is normal, then AST is not required.
b Viral testing is only performed for patients who have undetermined or negative COVID-19 test(s). Viral testing 
is per the institution’s testing guidelines.


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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

ensuring that informed consent is given by each patient or legal 
representative. This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the patient or the patient’s legal 
representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the patient was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients. Individual 
investigators may have additional local requirements or processes.
Investigator(s) will be responsible for patient recruitment through local requirements or 
processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s). Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s). All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).


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The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study

informed consent form 

other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in pulmonology and/or intensive care and/or other identified critical 
care staff will participate as investigators in this clinical trial.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures.

review study data remotely where possible 


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LY3127804

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or electronic mail

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. This may be virtual as current sites are not allowing monitors on site to reduce 
the risk of COVID-19 contamination.
The investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An EDC system will be used in this study. The site maintains a separate source for the data 
entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study UDAA is described in clinical trial agreement.


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Appendix 4.
Sampling Summary
This table summarizes the approximate number of samples [venipunctures, blood draws from 
lines, urine] and volumes for all sampling [screening, standard of care laboratory,] and tests 
during the study. Fewer samples may actually be taken, but this will not require a protocol 
amendment.
Protocol I7W-MC-UDAA Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample
Maximum 
Number Samples
Maximum 
Total Amount
Hematology and Chemistry 
(most are stand of care 
samples)a
Blood
3-6 mL
7
21-42 mL
Pregnancy Test (blood or 
urine)
Blood/
urine
3 mL blood or urine 
sample
2
6 mL blood or 
urine sample
Thyroid Function Test and
Covid Panel (Appendix 2)
Blood
8.5 mL
3
25.5 mL
a
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor.


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Appendix 5.
Protocol Amendment I7W-MC-UDAA(c)
Summary
Protocol I7W-MC-UDAA has been amended; the new version is indicated as amendment (c) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section
Changes made
Rationale for the change
6.1 Inclusion Criteria
Removed time frame for admission to the 
hospital and increased SpO2 to 95%
Feedback from sites regarding
baseline SpO2 in admitted patients;
to allow including moderately ill 
patients
6.2 Exclusion Criteria
Exclusion criteria revised to

remove ineligibility of patients 
with DNI orders

not exclude patients with active 
malignancies or patients with 
postorgan transplant

delete BMI criteria as long as 
proning is possible

remove ineligibility of patients 
anticipated to receive or 
receiving anticoagulants

clarify “active” vasculitis

replace “symptomatic” with 
“chronic” congestive heart 
failure and clarify wording
Following evolving feedback from 
clinical sites and FDA to include 
patients who have the greatest need
to be enrolled in the study. 
7.1 Treatments Administered
Added a footnote to the table to reflect a 
maximum dose of 3000 mg
For consistency with existing 
instructions in the Pharmacy 
manual
7.7 Concomitant Therapy
Amended to include

anticoagulation therapies at any 
time during the study

convalescent antibodies, and

remdesivir
Following evolving feedback from 
clinical sites and FDA 
8.1 Discontinuation from Study 
Treatment
Added discontinuation for bleeding 
events
Per FDA feedback
10.3.6 Interim Analysis
Added the potential for a futility analysis
Per FDA feedback


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Revised Protocol Sections
Note: Deletions have been identified by strikethroughs or grayed out for figures. Additions 
have been identified by the use of underscore.
6. Study Population
6.1 Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening, unless specified otherwise:
1. Must be admitted to the hospital for less than 48 hours
2. Confirmed pneumonia with:
a.
Presence of signs and symptoms of respiratory disease (ie, cough, 
tachypnea, and/or shortness of breath) 
and at least one of the following
b. Infiltrates on chest imaging
3. oxygen saturation (SpO2) of ≤953% on room air
6.2. Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening, until specified otherwise:
1. Have ARDS and/or require immediate intermittent mandatory ventilation 
(IMV)or are ineligible for IMV due to a pre-existing medical condition, including 
those with DNI orders.
3. Any concurrent serious medical condition (e.g. active malignancies on 
chemotherapy, post organ transplant, patients with estimated glomerular filtration 
rate [eGFR] <15 mL/min/1.73m2 or on dialysis, preexisting lung disease requiring 
O2 at rest, body mass index [BMI] ≥40 kg/m2that precludes techniques such as 
proning) or concomitant medication that in the opinion of the investigator that 
would preclude participation in the study.
7. Exclusion Criterion [7] has been deleted. At the time of study drug administration, 
anticipated to be requiring full-dose (therapeutic) anticoagulation with warfarin 
and/or other anticoagulants
Patients receiving prophylactic, low-dose anticoagulation therapy are eligible 
provided that they are on low-molecular-weight heparin or oral Factor Xa 
inhibitors or it is medically appropriate at the investigator’s judgment that patients 
switch to low-molecular-weight heparin or oral Factor Xa inhibitors before 
initiation of study therapy


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8. Have a significant bleeding disorder or active vasculitis or had a Grade ≥3 
bleeding episode within 12 weeks prior to receiving treatment
11. Have chronicsymptomatic congestive heart failure (New York Heart Association 
class ≥3) or symptomatic or poorly uncontrolled cardiac dysarrhythmia
7.1. Treatments Administered
Table 7-1.
Treatment Regimens
Regimen
Dose
Day 1
Dose
Day 15
LY3127804
20 mg/kg
20 mg/kg
Placebo
Matching placebo
Matching placebo
Note:  Patents weighing 150 kg and above will receive a maximum LY3127804 dose of 3000 mg.  Please see the 
Pharmacy Manual for further instructions.
7.7. Concomitant Therapy
All concomitant therapies that are part of routine care are allowed and can be used during the 
study. If indicated, after completion of study drug administration, anticoagulation therapies, 
including full-dose anticoagulation therapies, are allowed.
All concomitant therapies must be recorded in the eCRF.
Concomitant medications captured should include unapproved (“off-label”) medication, such as, 
for example, convalescent antibodies, remdesivir, chloroquine, hydroxychloroquine, and IL-6 
antagonists.
8.1. Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of study drug:

Patient Decision

the patient requests to discontinue study drug.

Investigator Decision

The investigator may discontinue treatment after the first dose, if in the 
judgement of the investigator the benefit/risk assessment for LY3127804 
does not support administration of a second dose.

Grade 3 or higher infusion-related reaction per National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0 (refer to Section 9.2.2).


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LY3127804

Grade 2 and greater bleeding events associated with study treatment.
10.3.6. Interim Analysis
An interim analysis may be conducted to assess efficacy results. The interim efficacy results may 
be used for internal decision-making to trigger planning activities associated with the 
investigational product and/or to assess futility. No adjustment of Type I error will be performed 
as the study will not be stopped for efficacy, and no modification of Study UDAA is 
expectedwill be based on these interim results, other than possibly stopping the study for futility.
The assessment would be conducted by a sponsor assessment committee with a limited number 
of preidentified team members who do not have direct site contact or data entry/validation 
responsibilities. Unblinding details will be specified in the unblinding plan section of the SAP or 
in a separate unblinding plan document. Information that may unblind the study during the 
analyses will not be reported to study sites or to the blinded study team until the study has been 
unblinded.


PPD

SAP_001.pdf: 
Statistical Analysis Plan (V3): I7W-MC-UDAA(c)
A Randomized, Double-blind, Placebo-controlled, Clinical Trial of LY3127804 in Patients who are 
Hospitalized with Pneumonia and Presumed or Confirmed COVID-19 
NCT04342897
Approval Date: 09-Feb-2021


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Statistical Analysis Plan:  
  
A Randomized, Double-blind, Placebo-controlled, Clinical Trial of  
LY3127804 in Patients who are Hospitalized with Pneumonia and 
Presumed or Confirmed COVID-19  
  
I7W-MC-UDAA  
  
  
Eli Lilly and Company  
Indianapolis, Indiana USA 46285  
  
  
  
 
 


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LY3127804  
  
Table of Contents  
  
  
  
Page  
1.  Revision History ..........................................................................................................................3 
2.  Study Objectives ..........................................................................................................................4 
2.1  Primary Objective ...................................................................................................................4 
2.2  Secondary Objectives ..............................................................................................................4 
3.  Study Design ................................................................................................................................4 
3.1  Summary of Study Design ......................................................................................................4 
3.2  Determination of Sample Size ................................................................................................5 
3.3  Method of Assignment to Treatment ......................................................................................5 
4.  A Priori Statistical Methods .........................................................................................................5 
4.1  General Considerations ...........................................................................................................5 
4.2  Analysis Populations ............................................................................................................7 
4.3  Handling of Dropouts or Missing Data ...................................................................................7 
4.3.1  NIAID Ordinal Scale ........................................................................................................7 
4.3.2  Non-Responder Imputation (NRI) ....................................................................................7 
4.3.3  Missing Data Imputation for Adverse Event, Concomitant  ............................................7 
Medication Dates, and Laboratory Values ...............................................................................7 
4.4  Handling of Deaths in Efficacy Analyses ...............................................................................8 
4.5  Multicenter Studies .................................................................................................................8 
4.6  Multiple Comparisons/Multiplicity .........................................................................................8 
4.7  Patient Disposition ..................................................................................................................9 
4.8  Patient Characteristics .............................................................................................................9 
4.9  Medical History .......................................................................................................................9 
4.10 Treatment Compliance ...........................................................................................................9 
4.11 Concomitant Therapy .............................................................................................................9 
4.12 Efficacy Analyses.................................................................................................................10 
4.12.1  Primary Outcome and Methodology .............................................................................10 
4.12.2  Additional Analyses of the Primary Outcome ..............................................................10 
4.12.3  Secondary Efficacy Analyses .......................................................................................10 


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4.12.3.1  Alive and Respiratory Failure Free Complete Response ........................................10 
4.12.3.2  NIAID Ordinal Assessment ....................................................................................10 
4.12.3.3  28-day Mortality ......................................................................................................12 
4.12.3.4  Length of Hospital Stay ..........................................................................................12 
4.12.4  Other Efficacy Analyses ...............................................................................................12 
4.12.4.1  Pulmonary Function ................................................................................................13 
4.12.4.2  Supportive Care .......................................................................................................14 
4.13 Safey Analyses .....................................................................................................................14 
4.13.1  Extent of Exposure ........................................................................................................15 
4.13.2  Adverse Events .............................................................................................................15 
4.13.3  Clinical Laboratory Evaluation .....................................................................................16 
4.13.4  Vital Signs .....................................................................................................................17 
4.13.5  Electrocardiograms .......................................................................................................17 
4.14 Subgroup Analyses ..............................................................................................................17 
4.15 Protocol Violations ..............................................................................................................18 
4.16 Interim Analyses and Data Monitoring ................................................................................18 
4.16.1  Interim Analysis ............................................................................................................18 
4.17 Clinical Trial Registry Analyses ..........................................................................................18 
5.  List of TLFs ...............................................................................................................................20 
5.1  List of Tables .........................................................................................................................20 
5.2  List of Data Listings ..............................................................................................................21 
5.3  List of Figures .......................................................................................................................22 
 
  
1. Revision History  
SAP Version 1.0 approved on May 8, 2020 prior to unblinding.    
SAP Version 2.0 prepared after the decision of study discontinuation due to futility.  
SAP Version 3.0 released before database lock/unblinding.  
 


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LY3127804  
2. Study Objectives  
2.1  
Primary Objective  
The primary objective is to evaluate ventilator free days during treatment with LY3127804. This 
is defined as the number of days from Day 1 to Day 28 on which a patient breathes without 
assistance, if the period of unassisted breathing lasted at least 24 consecutive hours and the 
patient did not die within 28 days from first dose of study drug. If the patient died within 28 
days, then this end point will be set equal to -1.   
2.2  
Secondary Objectives  
Objectives  
Endpoints  
•  To evaluate clinical status of patients 
during treatment with LY3127804  
•  
NIAID ordinal assessment   
•  To evaluate survival without the need for  
IMV/ECMO  
•  
Complete response is the proportion of 
patients who are alive and respiratory 
failure free (i.e. never having required 
mechanical ventilatory support) by Day 
28  
•  To evaluate mortality rate during 
treatment with  
LY3127804  
•  
Death within 28 days from first dose of 
study drug  
•  To evaluate reduction in hospital stay 
during treatment with LY3127804  
•  
Length of hospitalization  
•  To evaluate safety of LY3127804  
•  
AEs and SAEs  
Abbreviations: AE = adverse event; NIAID = National Institute of Allergy and Infectious Diseases; SAE = serious 
adverse event; SpO2 = oxygen saturation   
   
3. Study Design   
3.1  
Summary of Study Design  
Study I7W-MC-UDAA is a multicenter, randomized, double-blind, parallel, placebo-controlled 
Phase 2 study in patients who are hospitalized with a pneumonia and presumed or confirmed 
COVID-19.  
 
 
 
 


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Figure 1.0. Illustration of study design for Clinical Protocol I7W-MC-UDAA.  
  
3.2  
Determination of Sample Size  
Approximately 210 patients may be enrolled in a 1:1 ratio to LY3127804 or placebo (105 per 
treatment group) in order that 200 patients complete the study. A sample size of 100 in each 
group will have 81% power to detect a difference between the placebo group and the  
LY3127804 group using a Wilcoxon rank-sum test with a 0.05 one-sided significance level. This 
powering is based on the following assumptions: intermittent mandatory ventilation (IMV) rate 
of 25% and mortality rate of 12.5% in the placebo group, 50% improvement in IMV rate and 
mortality rate for the LY3127804 group relative to placebo, and a mean difference (LY3127804 
minus placebo) of 3.0 ventilator-free days where patients who die are assigned a value of -1.  
3.3  
Method of Assignment to Treatment  
Patients who meet all criteria for enrollment will be stratified by age group (<65 years and ≥65 
years), sex, and site, and then, on Day 1, randomly assigned in a 1:1 ratio within each stratum to 
receive either LY3127804 or placebo. Treatment assignment will be determined by a computer 
generated randomization sequence using an interactive web response system (IWRS).  
4. A Priori Statistical Methods  
4.1  
General Considerations  
Efficacy analyses will be conducted on the Efficacy Analysis Set; safety analyses will be 
conducted on the Safety Analysis Set. Analyses to be conducted on both the Efficacy set and the 
Safety set will not be replicated if the two Analysis sets are the same.  
Descriptive statistics will include the number of subjects, mean, standard deviation, median, 
minimum, and maximum for continuous measures, and frequency counts and percentages for 
categorical measures. The minimum and maximum will be reported to the same number of 
decimal places as the raw data recorded in the database. The mean and median will be reported 
to one more decimal place than the raw data recorded in the database. The SD will be reported to 
two more decimal places than the raw data recorded in the database. Percentages will be 
presented to one decimal place. Percentages will not be presented for zero counts. Percentages 
will be calculated using n (the number of observations with non-missing values) as the 
denominator. In general, the maximum number of decimal places reported shall be four for any 
summary statistic.  


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Change from baseline will be calculated as the visit value of interest minus the baseline value. If 
all baseline values are missing for a particular variable, then the change from baseline and 
percent change (or percent improvement) from baseline will not be calculated.  
All confidence intervals (CIs) and statistical tests will be two-sided unless otherwise specified. P-
values which are greater than or equal to 0.001, and less than or equal to 0.999, will be presented 
to three decimal places. All other p-values which are less than 0.001 will be presented as ‘ 
<0.001’, while p-values greater than 0.999 will be presented as ‘>0.999’. CIs will be presented to 
one more decimal place than the raw data.  
Unless otherwise noted, treatment comparisons of dichotomous variables will be made using  
Chi-square test. The proportions, difference in proportions, and 90% Wald confidence interval 
(CI) of the difference in proportions will be reported. Stratification is ignored in the analysis of 
dichotomous variables.  
Unless otherwise noted, treatment comparisons of quantitative variables will be made using a 
restricted maximum likelihood-based mixed-effects model of repeated measures (MMRM). The 
model will include treatment, age group, sex, and site as fixed categorical effects, and, if 
applicable, study day as a continuous effect and treatment-by-study day interaction. The 
covariance structure to model the within-patient errors will be unstructured. If the available data 
cannot support the covariance structure (e.g., due to missing values), other structures will be 
attempted. If the unstructured covariance matrix results in a lack of convergence, the 
heterogeneous Toeplitz (TOEPH) covariance structure, followed by the heterogeneous 
autoregressive [ARH(1)] covariance structure, followed by the compound symmetry structure 
will be used. The first structure to yield convergence will be used for inference. The 
NewtonRaphson with ridging optimization technique will be used to aid with convergence. The  
Kenward-Roger approximation (KR2) will be used to estimate the denominator degrees of 
freedom and adjust standard errors. Type III tests based on the LS means will be used for the 
statistical comparison; the 90% CI will also be reported.   
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.05, unless otherwise 
stated. No adjustments for multiple comparisons will be made.  
All computations for statistical analyses will be performed using SAS® software, Version 9.4 or 
later. All SAS programs used in the production of statistical summary outputs will be validated 
with independent programming prior to finalization. In addition, all program outputs will be 
independently reviewed. The validation process will be used to confirm that all data 
manipulations and calculations were accurately done. Upon completion of validation and quality 
review procedures, all documentation will be collected and filed by the project statisticians.   
When implementing parametric methods of analysis, the distribution of analysis variables will be 
examined to determine if model assumptions are satisfied. Transformations or nonparametric 
methods of analysis may be added as sensitivity analyses if warranted. Whenever alternative 
methods of analysis are required, the description of the new method along with the rationale for 
its use will be documented in the Clinical Study Report (CSR).   


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Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Additional exploratory analyses of the 
data will be conducted as deemed appropriate.  
4.2  
Analysis Populations  
Population   
Description   
Enrolled Set   
All patients who sign informed consent  
Efficacy Analysis Set  
  
  
All randomized patients who take at least 1 dose of double-blind 
study treatment.  Patients will be included in the treatment group 
to which they were randomized.  
Safety Analysis Set  
All randomized patients who take at least 1 dose of double-blind 
study treatment.  Patients will be analyzed according to the 
treatment they actually received.  
If any of the above population definitions result in the same set of patients, then analyses will not 
be replicated for each population.  
4.3  
Handling of Dropouts or Missing Data  
4.3.1 NIAID Ordinal Scale  
Missing values for NIAID ordinal scale during Days 1-28 will be imputed as the worse of the 
two values recorded before and after the missing value(s), including values after Day 28. If the 
patient has been discharged, then the imputed value will be, at worst, “7- Not hospitalized, 
limitation on activities and/or requiring home oxygen.” If there is no recorded value after the 
missing value, then the missing value will not be imputed.  
4.3.2 Non-Responder Imputation (NRI)  
For categorical efficacy endpoints, non-responder imputation (NRI) will be used when the 
response status cannot be determined. Patients whose survival status cannot be determined at day 
28 will be non-responders in the analyses of Complete Response.  
4.3.3 Missing Data Imputation for Adverse Event, Concomitant  
Medication Dates, and Laboratory Values  
If a medication date or AE date is completely or partially missing, the following imputation rules 
should be utilized in the analysis unless otherwise stated:  
• 
For the start date:  
o If year, month, and day are missing then use the patient's first treatment date.  
o If either month or month and day are missing, then use the same month and day as 
treatment start. 
o If only day is missing, impute as day of treatment start. 
• 
For the start time: o Impute as 23:59.  


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• 
For the end date:  
o If year, month, and day are missing then use the patient's last visit date. o If either 
month or month and day are missing then use December 31.  
o o If only day is missing then use the last day of the month.  
o The imputed date will not be beyond the patient’s last visit date.  
The incomplete dates will be imputed only if it is deemed necessary in calculation/determination 
for analysis purpose. If there is any doubt for the start and end date/times for AEs, the event will 
be flagged as treatment-emergent. For medications, the medication will be flagged as 
concomitant.  
For determining treatment-emergent status, missing severity in the baseline period will be 
considered “mild” and missing severity in the post-baseline period will be considered “severe”. 
When reporting TEAEs by severity or causality, “missing” severity or causality will be 
considered its own category.  
Laboratory parameters will be summarized based on the available data at each time point and no 
imputation is proposed in this document.  
4.4  
Handling of Deaths in Efficacy Analyses  
For the endpoint that does not contain mortality as a component, such as length of hospital stay 
during Days 1 to 28, they will be assumed in the hospital for 29 days. The median length in such 
case will be more appropriated to be reported.  
Other efficacy endpoints will handle death via similar imputation: patients who die will be 
assumed to have experienced the worst outcome. These analyses include percentage of patients 
discharged from hospital at Day 28, percentage of patients who ever received each of the various 
types of supportive care, and length of the various types of supportive care.  
4.5  
Multicenter Studies  
While study center will be included as a covariate for some analyses, differences between study 
centers will not be a feature of the statistical analyses for this study. Baseline variables and 
demographics will be described by site.  
ALL sites that have one or no patient in either treatment group will be pooled together as a single 
site. If there is only one site with one or no patient in either treatment group, it will be pooled 
with the next smallest site. If more than one sites with the same number of patients as the next 
smallest site, the one with the patient who enrolled the study last will be chosen for pooling.  
4.6  
Multiple Comparisons/Multiplicity  
There are no planned adjustments for multiple efficacy endpoints or analyses.  


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4.7  
Patient Disposition  
The disposition of all enrolled patients will be summarized. The disposition of all randomized 
patients will be presented by level of stratification factors in randomization, by treatment group 
and overall. In addition, the reason for study discontinuation will be tabulated using the list of 
reasons provided in the eCRF. The disposition of randomized patients will be analyzed for the 
Efficacy population and the Safety population.  
4.8  
Patient Characteristics  
Patient’s baseline age, sex, race, height, body weight, body mass index, other baseline efficacy 
measures including NIAID ordinal assessment, FiO2, respiratory rate, disease history, and 
preexisting conditions will be summarized using descriptive statistics by treatment arm, overall, 
and by study site (unpooled). These summaries will be based on both the Efficacy population and 
the Safety population. Patients who are missing measurements of the baseline variable being 
analyzed will not be included in the summary for that variable.   
Patient height and weight will be collected prior to randomization. Both variables will be 
reported in metric units (height in cm and weight in kg) and will be summarized as continuous 
variables along with Body Mass Index (in kg/m2).  
No statistical testing will be performed for comparisons of baseline characteristics.  
4.9  
Medical History  
Medical history will be coded according to MedDRA. The number of subjects reporting medical 
history events will be summarized by treatment and overall, by system organ class, and preferred 
term. The summary will present the SOC in alphabetical order; while PTs within the SOC will be 
presented in order of overall decreasing frequency of occurrence overall.  
4.10 Treatment Compliance  
As all study drug doses will be administered at study site, treatment compliance per se will not be 
reported.  
4.11 Concomitant Therapy  
Concomitant medications will be defined as medications taken on or after the date of the first 
dose of study treatment. This includes all medications initially taken prior to the date of first dose 
of study treatment but with a stop date that is either missing or after the date of first dose of study 
treatment. Those medications where the stop date is documented as prior to the date of first dose 
of study treatment will be classified as prior medications. The prior medications will not be 
included in any summary reports.  
Concomitant medications will be summarized and will be presented by anatomical therapeutic 
chemical drug classes (ATC level 4) using the latest version of the WHO drug dictionary.  


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4.12 Efficacy Analyses  
4.12.1  
Primary Outcome and Methodology  
The primary outcome variable will be defined as follows:  
o For patients who survive through day 28, the value is the number of days free of 
mechanical ventilation.  
o For patients who do not survive through day 28, the value is set to -1.  
If a patient is discharged from the hospital before day 28, and if the patient is still alive at day 28, 
then days between hospital discharge and Day 28 will be considered ventilator free. A table 
listing the counts of patients with each number of ventilator free days, including patients with -1 
values due to death, will be presented by treatment group. The statistical method for this 
endpoint will be based on the Wilcoxon rank-sum test using the van Elteren test adjusting for the 
randomization stratification factors (age group, sex, and site).  
4.12.2  
Additional Analyses of the Primary Outcome  
The number of ventilator free days among survivors will also be reported.  
4.12.3  
Secondary Efficacy Analyses  
Secondary end points will be described and compared between treatment groups.   
4.12.3.1 Alive and Respiratory Failure Free Complete Response  
Complete Response is defined as being alive and never requiring mechanical ventilator support 
(at any point while on trial) through day 28.  
The rates of complete response and non-response will be summarized by treatment group and by 
the stratification factors. See section 4.1 for details on the methods to be used to test the 
differences between LY3127804 and placebo.  
Ninety percent confidence interval for the difference in proportions (LY3127804 – placebo) will 
be reported.   
Patients for whom complete response status cannot be determined will be considered non-
responders. See section 4.3.2 for details on NRI.  
4.12.3.2 NIAID Ordinal Assessment  
The NIAID will be assessed daily and defined as the lowest score achieved for that day.  
The scoring is based on the clinical status of the patient as described below.  
NIAID Score  
Description  
1  
Death  


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2  
Hospitalized, on invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO)  
3  
Hospitalized, on non-invasive ventilation or high flow oxygen devices  
4  
Hospitalized, requiring supplemental oxygen  
5  
Hospitalized, not requiring supplemental oxygen - requiring ongoing 
medical care (COVID-19 related or otherwise)  
6  
Hospitalized, not requiring supplemental oxygen - no longer requires 
ongoing medical care  
7  
Not hospitalized, limitation on activities and/or requiring home oxygen  
8  
Not hospitalized, no limitations on activities  
  
The lowest value from Day 1 through Day 28 for a patient on the NIAID ordinal scale will be 
analyzed using the van Elteren test adjusting for the randomization stratification factors. The 
number need to treat (NNT) to prevent one patient from progressing to level 2 or 1 will be 
calculated. Mean values will be calculated and differences in treatment effect estimates at Days 
7, 14 and 28 will be analyzed. Mean value by treatment group will be plotted over time.  
Time to the first 2-point improvement on the NIAID scale will be analyzed between treatment 
groups. The time for subjects who did not achieve 2-point improvement will be censored at day 
28 and stratification will be ignored in this analysis. A Kaplan-Meier plot with log-rank test will 
be used to compare treatment groups.  
The stacked bar plot(s) representing the proportion of subjects in each score by treatment arm 
over time will be generated with stratification ignored. An example of such plot is as follows. 
The details of the score will be included in the footnote of the plot.  
In addition to the stacked bar plot based on the original NIAID scores, another stacked bar plot 
that lumps NIAID scores into four categories will be generated. The four new categories are:  
a. Death (NIAID score = 1),  
b. IMV/ECMO (NIAID score = 2),  
c. Requiring O2 or medical care (NIAID scores = 3, 4, 5), and  
d. Not requiring O2 nor medical care (NIAID scores = 6, 7, 8).  
  
 
 
 


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Figure 2.0 Example of a Stacked Bar Plot: 
  
4.12.3.3 28-day Mortality  
Mortality will be defined as 28-day all-cause mortality, defined as 672 hours from the time of 
randomization. All patients will be classified as either “alive at Study Day 28” or, if dead, “dead 
at Study Day 28.”  Patients whose mortality status cannot be determined will be classified as 
“dead at Study Day 28.” The difference between treatment groups will be analyzed.  
The 60-day mortality will be analyzed in a similar fashion.  
4.12.3.4 Length of Hospital Stay  
Length of hospital stay will be defined as the number of days hospitalized for at least 1 hour 
duration.   
The length of hospitalization will be analyzed with the Wilcoxon rank-sum test using the van  
Elteren test adjusting for the randomization stratification factors and will be evaluated through 
Day 28. The summary will include the median length of hospital stay for the patients who died 
before Day 28.  
Hospital discharge rates at Day 28 will be reported and compared between treatment groups.  
4.12.4  
Other Efficacy Analyses  
Other efficacy endpoints will be described and compared between treatment groups.   


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4.12.4.1 Pulmonary Function  
Pulmonary function will be reported daily as the range of average lowest value for SpO2 and the 
highest value of oxygen flow-rate; the FiO2 will be derived for non-closed systems. The midpoint 
of the range of average lowest SpO2 and derived FiO2 and respiratory rate for each day will be 
analyzed via MMRM and plotted over time by treatment group. Mean values will be calculated 
and differences in treatment effect estimates at Days 7, 14 and 28 will be analyzed.   
If any subject has multiple FiO2 records in a day, the maximum of the records of the day will be 
taken in the analysis; if a subject has multiple respiratory rate records in a day, the mean of the 
records of the day will be used in the analysis.  
However, FiO2 will only be available for analysis when the patients used the following devices 
during the study:   
• 
Ventilator (FiO2 is given directly in the CRF),  
• 
Nasal Cannula (FiO2 will be calculated using the table listed below),  
• 
Venturi Mask (FiO2 will be calculated using the table listed below).    
FiO2 (Fraction of Inspired Oxygen) information (from louisville.edu, for reference only):  
For all supplemental oxygen delivery devices, the patient is not just breathing the direct oxygen, 
but rather is breathing a combination of room air plus the oxygen from the supplemental device. 
Different devices deliver to the patient more or less of a % of what is coming in from the tank.   
Fraction of Inspired Oxygen (FiO2) for a nasal canula and a Venturi mask are given in the tables 
below. For other oxygen delivery systems, such as masks, tents, there is more oxygen that 
"blows by" or is lost, therefore higher flow rate setting on the oxygen tank are needed to achieve 
the same FiO2. A tracheostomy would require different calculations as well.  
Example: with a nasal cannula, we assume that the fraction of oxygen that is inspired (above the 
normal atmospheric level or 20%) increases by 4% for every additional liter of oxygen flow 
administered.  
 
 


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For a Nasal Cannula:  
  
  
For a Venturi Mask:  
Oxygen tank FLOW RATE in liters / min  
FiO2 – Fraction of Inspired Oxygen Value  
0 (no oxygen, just room air)  
.20  
4 L / min  
.26  
6 L / min  
.31  
8 L / min  
.375  
12 L / min  
.447  
  
4.12.4.2 Supportive Care  
The following types of supportive care will be analyzed: ECMO, IMV, ECMO or IMV, 
noninvasive ventilation, and/or high-flow oxygen, any of the previous 4 types of care, proning, 
tracheostomy, COVID-19 convalescent plasma, and remdesivir use. The percent of patients who 
ever receive each of these and the number of days each of these is given, during Days 1-28, will 
be analyzed between treatment groups.  
4.13 Safety Analyses  
All safety evaluations will be based upon the Safety Analysis Set.  
Safety will be assessed by evaluating all reported AEs and changes in laboratory analytes, ECGs, 
and vital signs (including body weight) in the Safety Analysis Set and summarized by treatment 
group.  


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The baseline for computing the change in safety data is the last value collected before the first 
dose of study drug. The parameters will be listed and summarized with standard descriptive 
statistics. Change from baseline will also be summarized.  
4.13.1  
Extent of Exposure  
Exposure to therapy will be calculated for each subject as the number of complete infusions 
delivered.  
4.13.2  
Adverse Events  
Summaries of AEs will include the number of patients with at least one AE for each treatment 
group. When reporting by system organ class (SOC) and preferred term (PT), the reports will 
present the SOC in alphabetical order; while PTs within the SOC will be presented in order of 
overall decreasing frequency of occurrence overall. A patient with multiple AEs (different PTs) 
coded to the same SOC will be counted only once for that SOC, but will be counted each time 
for different PTs within that SOC. A patient with separate events of the same PT (different 
start/stop dates) will be counted only once in the frequency tables for that PT.   
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline. The MedDRA Lowest Level Term (LLT) will be used in the 
treatment-emergent computation. The maximum severity for each LLT during the screening 
period will be used as baseline. The treatment period will be included as post-baseline for the 
analysis.   
AEs will be coded according to the Medical Dictionary for Regulatory Activities and 
summarized by system organ class, preferred term, severity, and relationship to investigational 
product. For each event classification term, the number of subjects experiencing a TEAE with 
that classification term will be tabulated.   
In an overview table, the number and percentage of patients who experienced a TEAE, serious 
adverse event, adverse event related to study drug, died due to an adverse event, or discontinued 
from the study due to an adverse event will be summarized by treatment. TEAEs will be reported 
separately for Days 1-28 while in the hospital and for the post-hospitalization follow-up period.  
Treatment-Emergent Adverse Events  
Treatment-emergent adverse events (TEAE) include all adverse events that emerge or worsen 
after taking the first dose of study drug. TEAEs will be summarized for each treatment group by 
SOC and PT, and by PT in order of decreasing frequency of preferred term.  
  
Serious Adverse Events  
Treatment-Emergent SAEs will be summarized for each treatment arm by SOC and PT. These 
reports will also include the total number of SAE for each SOC and PT.  
  
Treatment-Emergent Adverse Events Resulting in Death  
If there are any TEAEs that result in death, a listing of all deaths will be provided. In addition, a 
summary table may also be created by PT in order of decreasing frequency of preferred term.  
  


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Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation  
TEAEs for which the action taken with medication is ‘Drug Withdrawal’ will be identified as 
TEAEs that lead to study drug discontinuation. The TEAEs that lead to study drug 
discontinuation will be summarized for each treatment group by SOC and PT for the Safety 
population.   
  
Treatment-Related Treatment-Emergent Adverse Events  
Every AE will be assessed by the investigator for its relationship to the randomly assigned study 
medication. The subset of TEAEs considered by the investigator as either possibly, probably, or 
definitely related to study treatment will be summarized as drug-related TEAEs by SOC and PT.  
  
Treatment-Emergent Adverse Events by Maximal Severity  
Every AE will be graded by the CTCAE criteria, so for each patient the greatest severity 
observed can be obtained by comparing the severity of all of a patient’s TEAEs that share the 
same SOC or PT. A table of TEAEs by maximal severity will be prepared for each treatment arm 
by SOC and PT.  
 
4.13.3  
Clinical Laboratory Evaluation  
Blood samples for hematology and clinical chemistry will be collected. Profiles for the 
hematology, clinical chemistry will be summarized, and patients with values outside the normal 
range during the on-treatment period during the study will be summarized.  
  
Change from baseline for each of the hematology, clinical chemistry will be derived for each of 
the post-dose time points using the pre-dose measurement as the baseline. Descriptive statistics 
for the measurement at baseline and the measurement and change from baseline at each postdose 
time point will be tabulated.  
  
Laboratory results recorded as "< x" or "≤ x" will be imputed as x; results recorded as "> x" or "≥ 
x" will be imputed as x and a footnote will be added to indicate the number of patients and visits 
that were above the limit.  
  
Each laboratory parameter will be classified as low, normal or high relative to the central 
laboratory’s normal range. For each treatment group shift tables will be generated from the 
predose category to the category post-dose for each laboratory parameter. The shift tables will 
present the number (percent) of patients who started in a category (low, normal, high) at baseline 
and ended in a category at each scheduled visit before the end of the study. A missing category 
will be included for both pre-dose and post-dose, so that all patients in the Safety population will   
  
  
be represented in the table. The missing category includes the cases where the normal range is 
partially or completely missing, the unit of measurement is missing, and/or the laboratory result 
itself is missing. The percentages will be calculated using number of patients in the Safety 
population who have measurements at pre-dose and post-dose.  
  


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Shift tables comparing pre-dose to the other time points in the study may be generated if 
warranted after data review.  
 
4.13.4  
Vital Signs   
Extreme vital signs will be determined using the following criteria:  
• 
Heart rate either < 50 bpm or > 100 bpm,  
• 
Systolic blood pressure either ≤ 90 mmHg or ≥ 160 mmHg,   
• 
Diastolic blood pressure either ≤ 50 mmHg or ≥ 100 mmHg.  
  
The number (percent) of patients having extreme vital signs will be tabulated by treatment group 
at each scheduled visit. The percentage will be calculated using the number of patients in the 
Safety population with data at each visit as the denominator. The number (percent) of patients 
having extreme vital signs post-baseline (including unscheduled assessments) will be calculated.  
  
Change from baseline statistics will also be defined for the measurements of blood pressure, 
heart rate and temperature using the pre-dose values as baseline. Descriptive statistics for the 
measurement of temperature will also be provided by treatment group.  
  
All patients who have an extreme vital sign value will be documented in a by-patient listing. The 
listing will include all of the vital sign measurements from the study for the patient, and the 
extreme values will be flagged.  
4.13.5  
Electrocardiograms  
  
The number (percent) of patients who had an abnormal ("Abnormal, CS" or "Abnormal, NCS") 
ECG at any time while on-treatment will be tabulated by treatment group. All on-treatment 
ECGs, including unscheduled assessments, will be considered.  
4.14 Subgroup Analyses  
The primary end point will be analyzed for the following subgroups:  
o Patients who are confirmed SARS-CoV-2 positive and otherwise o age group < 65 and ≥ 
65 o sex o BMI < 30 and ≥ 30 o Patients that receive one dose and two doses of study 
drug o Patients who reach NIAID ordinal scale score = 2 within day 4 and those who do 
not o Patients with baseline NIAID ordinal scale score of 3, and those with baseline 
score of 4 or 5  
o Patients who received remdesivir and those who do not.  
For endpoints which do not consider mortality, subgroup analyses of survivors only may be 
conducted if appropriate.  


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4.15 Protocol Violations  
A list of major protocol violations that could potentially impact the analysis of the study will be 
determined during the conduct of the study by study team members who are blinded to study 
treatment being received. These will be presented in a listing.  
4.16 Interim Analyses and Data Monitoring  
An independent DMC will review unblinded safety data on an ongoing basis (Protocol Section  
9.4.5). These will consist of the following:  
o Listing of individual SAEs o Table of SAEs by treatment group o Table of TEAEs by 
treatment group o Table of NIAID ordinal scale assessment – worst value per patient by 
treatment group o Table of demographics by treatment group  
o Table of Baseline disease characteristics by treatment group  
If the DMC requests and the sponsor agrees to conducting a futility analysis, the conditional 
power for the primary efficacy analysis will be assessed via simulations, using the data collected 
so far to predict the remaining data to be collected.  
Ongoing monitoring of safety data (including AEs, SAEs, and selected laboratory measurements) 
will continue throughout the study by the sponsor using blinded data.  
4.16.1  
Interim Analysis  
After approximately 100 randomized patients have 28 day data available, an analysis was 
conducted to assess study futility. An unblinded snapshot of the eCRF database was used for this 
interim analysis. In addition to the safety data regularly provided to the DMC for their review, 
efficacy data consisting of ventilation status, hospital discharge, and mortality during days 1-28 
as well as the calculation of ventilator free days (VFD) were provided for evaluation.  
The conditional power for the primary efficacy analysis was calculated by the DMC Statistician, 
using the data collected as of the interim analysis to predict the data to be collected after the 
interim analysis. If this conditional power is less than 10%, then the DMC should recommend 
that the study be stopped: no new patients should be randomized, and no new doses of study drug 
given, but ongoing patients should be allowed to complete other protocol procedures and be 
followed to collect their full data.  
4.17 Clinical Trial Registry Analyses  
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.    
Analyses provided for the CTR requirements include the following:  
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term.  
• 
An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
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• 
An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:  
o The number of participants at risk of an event 
o The number of participants who experienced each event term  
o The number of events experienced.  
• 
Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).  
AE reporting is consistent with other document disclosures for example, the CSR, manuscripts, 
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5. List of TLFs  
The numbering of the TLFs will be left for the medical writers to assign. The sequential numbers 
are provided below just for clarity. These numbers should be excluded from the TLFs.    
5.1  
List of Tables  
  
Title  
1  
Demographics and Baseline Characteristics (Safety Population)  
2  
Demographics and Baseline Characteristics by Site (Safety Population)  
3  
Analysis Populations   
4  
Patient Disposition by Treatment Group and Overall  
5  
Drug Exposure (Safety Population)  
6  
Concomitant Medications By Drug Class And Name (Safety Population)  
7  
Medical History (Safety Population)  
8  
Overview of Adverse Events (Safety Population)  
9  
Number and Percentage of Subjects with Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (Safety Population)  
10  
Number and Percentage of Subjects with Study Drug Related Treatment Emergent 
Adverse Events by System Organ Class and Preferred Term (Safety Population)  
11  
Number and Percentage of Subjects with Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Maximal Severity (Safety Population)  
12  
Serious Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Population)  
13  
Treatment Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term (Safety Population)  
14  
Treatment Emergent Adverse Events that Result in Death by System Organ Class and 
Preferred Term (Safety Population)  
15  
Hematology Lab Results by Study Day and Change from Baseline (Safety Population)  
16  
Chemistry Lab Results by Study Day and Change From Baseline (Safety Population)  
17  
Hematology Shift from Baseline (Safety Population)  
18  
Chemistry Labs Shift from Baseline (Safety Population)  
19  
Subjects with Abnormal Hematology Results (Safety Population)  
20  
Subjects with Abnormal Chemistry Results (Safety Population)  
21  
Pregnancy Status (Safety Population)  
22  
Vital Signs and Change from Baseline by Study Day (Safety Population)  
23  
Subjects with Extreme Vital Signs (Safety Population)  


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24  
Number and Percentage of Subjects with Abnormal ECGs (Safety Population)  
25  
COVID-19, Influenza, RSV, and Respiratory Viral Panels (Safety Population)  
26  
(Primary Objective) Ventilator Free Days (Efficacy Population)  
27  
Ventilator Free Days by SARS-Cov-2 Status (Efficacy Population)  
28  
Ventilator Free Days by Age Group (Efficacy Population)  
29  
Ventilator Free Days by Sex (Efficacy Population)  
30  
Ventilator Free Days by BMI Group (Efficacy Population)  
31  
Ventilator Free Days by Number Of Doses (Efficacy Population)  
32  
Ventilator Free Days by NIAID = 2 within Day 4 (Efficacy Population)  
33  
Ventilator Free Days by NIAID = 3 vs. NIAID = 4 or 5 (Efficacy Population)  
34  
Ventilator Free Days by Remdesivir Use (Efficacy Population)  
35  
(Secondary Objective) Alive and Respiratory Failure Free Complete Response 
(Efficacy Population)  
36  
(Secondary Objective) NIAID Ordinal Assessments (Efficacy Population)   
37  
(Secondary Objective) Time to 2-Point Improvement on NIAID (Efficacy Population)  
38  
(Secondary Objective) Mortality Rate within 28 Days from Randomization (Efficacy 
Population)  
39  
(Secondary Objective) Mortality Rate within 60 Days from Randomization (Efficacy 
Population)  
40  
(Secondary Objective) Length of Hospitalization Stay (Efficacy Population)  
41  
(Secondary Objective) Hospital Discharge Rate at Day 28 (Efficacy Population)  
42  
(Other Objective) Pulmonary Function by Study Day (Efficacy Population)  
43  
(Other Objective) Supportive Pulmonary Care (Efficacy Population)  
  
5.2  
List of Data Listings  
  
Title  
1  
Analysis Populations (including exclusion reason from efficacy population)  
2  
Protocol Deviations  
3  
Demographics and Baseline   
4  
Patient Disposition   
5  
Drug Exposure   
6  
Concomitant Medications by Drug Class and Name   
7  
Medical History  


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8  
Adverse Events  
9  
Serious TEAEs  
10  All Deaths  
11  Related TEAEs  
12  Hematology Lab Results  
13  Abnormal Hematology Lab Results  
14  Chemistry Lab Results  
15  Abnormal Chemistry Lab Results  
16  Pregnancy Test Results  
17  Vital Signs   
18  Extreme Vital Signs  
19  ECGs  
20  Abnormal ECGs  
21  Physical Exams  
22  COVID-19, Influenza, RSV, and Respiratory Viral Panels  
23  Thyroid Panels  
24  Ventilator Free Days  
25  Mortality and Respiratory Failure Status  
26  NIAID Ordinal Assessments     
27  Pulmonary Function  
28  Hospitalizations   
29  Supportive Pulmonary Care  
  
5.3  
List of Figures  
  
Title  
1  
NIAID Mean Score over Time by Treatment Group   
2  
NIAID Category over Time by Treatment Group (Stacked Bar Plot)  
3  
NIAID Category over Time by Treatment Group (Stacked Bar Plot) where Categories 
3-5 are Combined and 6-8 are Combined  
4  
Time to 2-Point Improvement on NIAID (Kaplan-Meier Plot)  
5  
Pulmonary Function over Time by Treatment Group