Clinical trial NCT04411628
Conditions: COVID-19
Sponsor: Eli Lilly and Company
Start date: 2020-05-28; Completion date: 2020-08-26
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the safety and tolerability of LY3819253 when it is given by injection into a vein to participants hospitalized with COVID-19. Blood tests will be done to check how much LY3819253 is in the bloodstream and how long the body takes to eliminate it. Participation could last about 8 weeks and may include up to 15 visits in the hospital or the home.

Detailed description:

Arms: arm 1: Participants received single doses of 700 milligrams (mg), 2800 mg or 7000 mg LY3819253 administered as intravenous infusion. arm 2: Participants received single dose of Placebo as intravenous infusion.
Interventions: intervention 1: LY3819253 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV. intervention 2: Administered IV.

Protocol documents:
Prot_000.pdf: 
Protocol (b): J2W-MC-PYAA
A Randomized, Placebo-Controlled, Double-Blind, Sponsor Unblinded, Single Ascending 
Dose, Phase 1 First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of Intravenous LY3819253 in Participants Hospitalized for 
COVID-19
NCT04411628   
Approval Date: 09-Jun-2020


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
1
Title Page
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 LY3819253, 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.
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind, Sponsor Unblinded, Single 
Ascending Dose, Phase 1 First in Human Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous 
LY3819253 in Participants Hospitalized for COVID-19
Protocol Number: J2W-MC-PYAA
Amendment Number: (b)
Compound: LY3819253
Study Phase: 1
Short Title: A randomized, placebo-controlled, Phase 1 study to evaluate LY3819253 in 
participants hospitalized for COVID-19
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Number(s)
IND: 150440
Approval Date:
Protocol Electronically Signed and Approved by Lilly on 09 May 2020
Protocol Amendment (a) Electronically Signed and Approved by Lilly on 01 June 2020.
Protocol Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 09-Jun-2020 GMT


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
2
Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Approval Date
Original Protocol
09 May 2020
Amendment (a)
01 June 2020
Amendment (b)
Overall Rationale for the Amendment:
This amendment addresses the United States Food and Drug Administration (FDA) feedback and 
clinical site feedback.   
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Added text for Cohort 4 
randomization
Providing information for all 4 cohorts.
1.3 Schedule of 
Activities
Added clarification to laboratory 
tests and sample collection that 
documentation of hospital-based 
laboratory results are acceptable
Clarification for sites that hospital blood draws 
and results may be used for this study instead of 
duplicating blood draws.  
1.3 Schedule of 
Activities
Updated comment for the SARS-
Cov-2 viral infection 
determination
Expanded the time of initial positive determination 
to 14 days prior to randomization
1.3 Schedule of 
Activities
Pharmacodynamic sample 
instructions updated to include 
mid-turbinate method
Per site feedback
4.2. Scientific Rationale 
for Study Design
Added text for Cohort 4
Per FDA feedback.  Clarification as to why the 
study may expand to include the optional Cohort 
4.
5.1. Inclusion Criteria
Updated Criterion #4
Changed 72 hours to 14 days per site feedback.
5.2. Exclusion Criteria
Updated Criterion #21
Further clarification on timing of measurement
5.2. Exclusion Criteria
Updated Criterion #24
Clarification that chronic kidney disease is 
allowed based on the opinion of the investigator, 
but acute kidney disease is not allowed.
8.6. Pharmacodynamics
Added text to allow mid-
turbinate swab method.  
Per site feedback
9.5. Interim Analyses
Added text for Cohort 4 and 
further clarification on safety 
monitoring
In response to FDA feedback.
10.2. Appendix 2
Removed nasopharyngeal 
specific text for the 
pharmacodynamic sample
Nasopharyngeal or mid-turbinate swabs are now 
allowed
10.8. Appendix 8
Updated the contents to only 
contain the baseline severity 
categorization
For ease of use.
Throughout the 
protocol
Minor editorial and formatting 
changes
Minor, therefore not described


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................10
1.3.
Schedule of Activities (SoA) ......................................................................................11
2.
Introduction..............................................................................................................17
2.1.
Study Rationale ..........................................................................................................17
2.2.
Background ................................................................................................................17
2.3.
Benefit/Risk Assessment ............................................................................................18
3.
Objectives and Endpoints.........................................................................................19
4.
Study Design .............................................................................................................20
4.1.
Overall Design............................................................................................................20
4.1.1.
Single-Ascending Dose Design...................................................................................20
4.2.
Scientific Rationale for Study Design .........................................................................21
4.3.
Justification for Dose..................................................................................................22
4.4.
End of Study Definition..............................................................................................22
5.
Study Population ......................................................................................................23
5.1.
Inclusion Criteria........................................................................................................23
5.2.
Exclusion Criteria.......................................................................................................23
5.3.
Lifestyle Considerations .............................................................................................25
5.4.
Screen Failures...........................................................................................................25
6.
Study Intervention....................................................................................................26
6.1.
Study Intervention(s) Administered ............................................................................26
6.1.1.
Special Treatment Considerations...............................................................................27
6.2.
Preparation/Handling/Storage/Accountability.............................................................29
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................29
6.4.
Study Intervention Compliance...................................................................................30
6.5.
Concomitant Therapy .................................................................................................30
6.6.
Dose Modification......................................................................................................31
6.6.1.
Dose Escalation Criteria .............................................................................................31
6.6.2.
Temporary Stopping Criteria ......................................................................................31
6.7.
Intervention after the End of the Study........................................................................32
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................33
7.1.
Discontinuation of Study Intervention ........................................................................33
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................33
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................33
7.3.
Lost to Follow up .......................................................................................................34
8.
Study Assessments and Procedures .........................................................................35
8.1.
Efficacy Assessments .................................................................................................35
8.2.
Safety Assessments ....................................................................................................35
8.2.1.
Physical Examinations................................................................................................35
8.2.2.
Vital Signs..................................................................................................................35


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
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8.2.3.
Electrocardiograms.....................................................................................................36
8.2.4.
Clinical Laboratory Assessments ................................................................................36
8.2.5.
Hospitalization events.................................................................................................36
8.2.6.
Procedures of Special Interest.....................................................................................36
8.2.7.
Respiratory Support....................................................................................................37
8.3.
Adverse Events and Serious Adverse Events ..............................................................37
8.3.1.
Time Period and Frequency for Collecting AE and SAE
Information.................................................................................................................37
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................37
8.3.3.
Follow-up of AEs and SAEs.......................................................................................38
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................38
8.3.5.
Pregnancy...................................................................................................................38
8.3.6.
Hypersensitivity Reactions .........................................................................................38
8.3.7.
Infusion-related Reactions ..........................................................................................39
8.3.8.
Product Complaints ....................................................................................................39
8.4.
Treatment of Overdose ...............................................................................................40
8.5.
Pharmacokinetics........................................................................................................40
8.5.1.
Bioanalytical ..............................................................................................................40
8.6.
Pharmacodynamics.....................................................................................................41
8.7.
Genetics .....................................................................................................................41
8.8.
Biomarkers.................................................................................................................41
8.9.
Immunogenicity..........................................................................................................41
8.10.
Health Economics.......................................................................................................42
9.
Statistical Considerations.........................................................................................43
9.1.
Statistical Hypotheses.................................................................................................43
9.2.
Sample Size Determination.........................................................................................43
9.3.
Populations for Analyses ............................................................................................43
9.4.
Statistical Analyses.....................................................................................................44
9.4.1.
General Considerations...............................................................................................44
9.4.2.
Safety Analyses ..........................................................................................................44
9.4.3.
Pharmacokinetic and Pharmacodynamic Analyses......................................................45
9.4.4.
Exploratory Endpoints................................................................................................45
9.4.5.
Immunogenicity..........................................................................................................46
9.5.
Interim Analyses.........................................................................................................46
9.6.
Data Monitoring Committee (DMC)...........................................................................46
10.
Supporting Documentation and Operational Considerations ................................47
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................47
10.1.1.
Regulatory and Ethical Considerations........................................................................47
10.1.2.
Financial Disclosure ...................................................................................................47
10.1.3.
Informed Consent Process ..........................................................................................47
10.1.4.
Data Protection...........................................................................................................48
10.1.5.
Committees Structure .................................................................................................48
10.1.6.
Dissemination of Clinical Study Data .........................................................................49
10.1.7.
Data Quality Assurance ..............................................................................................49
10.1.8.
Source Documents......................................................................................................50


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
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10.1.9.
Study and Site Start and Closure.................................................................................50
10.1.10. Publication Policy.......................................................................................................51
10.1.11. Investigator Information .............................................................................................51
10.1.12. Long-Term Sample Retention.....................................................................................52
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................53
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................56
10.3.1.
Definition of AE.........................................................................................................56
10.3.2.
Definition of SAE.......................................................................................................57
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................58
10.3.4.
Reporting of SAEs......................................................................................................60
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................61
10.5.
Appendix 5: Genetics .................................................................................................65
10.6.
Appendix 6: Recommended Laboratory Testing for 
Hypersensitivity Events..............................................................................................66
10.7.
Appendix 7:  Nasopharyngeal Swab Instructions ........................................................68
10.8.
Appendix 8: FDA Guidance for Industry - Baseline Severity 
Categorization for COVID-19.....................................................................................69
10.9.
Appendix 9: Abbreviations and Definitions ................................................................71
10.10.
Protocol Amendment History .....................................................................................73
11.
References.................................................................................................................77


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind, Sponsor Unblinded, Single 
Ascending Dose, Phase 1 First in Human Study to Evaluate the Safety, Tolerability,
Pharmacokinetics and Pharmacodynamics of Intravenous LY3819253 in Participants 
Hospitalized for COVID-19
Rationale:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the 
pandemic spread of coronavirus disease 2019 (COVID-19), which in critical cases results in 
progressive pulmonary failure, complications with acute respiratory distress syndrome (ARDS),
and can result in death.  There is an urgent need for effective therapeutics to modify disease 
outcomes.
LY3819253 is a neutralizing IgG1 monoclonal antibody (mAb) to the spike protein of SARS-
CoV-2.  It is designed to block viral attachment and entry into human cells, and to neutralize the
virus, potentially treating even established COVID-19 by providing a specific potent, 
neutralizing antibody to SARS-CoV-2.
Study J2W-MC-PYAA (PYAA) aims to investigate the safety, tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) of LY3819253 following a single dose of LY3819253
administered to participants hospitalized for COVID-19.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Characterize the safety and tolerability of 
LY3819253 after intravenous infusion 

Safety assessments such as adverse events 
and serious adverse events
Secondary
Characterize the pharmacokinetics of 
LY3819253 after intravenous infusion

LY3819253 mean concentration on Day 29
Characterize the pharmacodynamics of 
LY3819253 after intravenous infusion

Change from baseline in SARS-CoV-2 viral 
load (Days 7, 11, 15 and 22)

SARS-CoV-2 viral load AUC

Time to SARS-CoV-2 clearance


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
8
Overall Design:
Study PYAA is a Phase 1, double-blind, sponsor unblinded, randomized, placebo-controlled, 
single ascending dose study in participants hospitalized for Covid-19. 
Double-blind Treatment and Assessment Period
This is the general sequence of events during the treatment and assessment period:

Participants are randomized to LY3819253 or placebo

Site completes baseline procedures and sample collection

Participants begin a single IV infusion of study intervention, and

Site completes all safety monitoring and post-infusion sample collection.
Discharge from hospital
If hospital discharge…
Then…
Occurs prior to Day 29
participants will be asked to complete the remaining 
study assessments at the timepoints indicated in the 
SoA.  
NOTE: Strategies to manage infection risks and reduce 
the burden of return visits should be considered by 
sites, such as home visits.
Occurs on the same day as a study assessment visit
hospital discharge assessments do not need to be 
repeated if the study assessments occurred within 8 
hours of discharge and there has been no change in 
clinical status.
Does not occur at or prior to day 29
assessments will continue to occur weekly up to Day 
60 or until hospital discharge, whichever is sooner.
Post-treatment follow-up
Post-treatment follow-up assessments will be conducted at Day 60. Strategies to manage 
infection risks and reduce the burden of return visits should be considered by sites, such as home 
visits.
Disclosure Statement: This is a first in human, sequential, single ascending dose study with up 
to 4 cohorts that is participant and investigator blinded.
Number of Participants:
Cohorts 1 – 3:  Approximately 24 total participants.
Optional Cohort 4:  up to 100 total participants. 
Intervention Groups and Duration: Single-Ascending Dose Design
The study will comprise up to 4 dose cohorts.  
Cohorts 1-3 will comprise at least 8 participants: 

6 randomized to LY3819253 and 

2 randomized to placebo.  


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
9
Sentinel dosing will be utilized in any dose cohort that represents a dose increase from the 
preceding cohort.  When sentinel dosing, the first 2 participants in each cohort will be 
randomized 1:1 to LY3819253 and placebo. 
Safety and tolerability will be reviewed for sentinel participants up to 24 hours after dosing.  The 
investigator and the Lilly sponsor team are responsible for determining if safety and tolerability 
is acceptable to continue with dosing subsequent participants. 
Subsequent participants will be randomized to the remaining treatment allocations, 5 to 
LY3819253 and 1 to placebo.  
The decision to dose the next cohort will be made when all participants from the previous cohort 
have been dosed and safety data is assessed for at least 4 days after the IV infusion by the 
investigator(s), Lilly sponsor team, and an independent safety assessment committee (ISAC).
The investigator, Lilly sponsor team and ISAC are responsible for determining any dose 
decisions.  The investigator(s) will remain blinded and the Lilly sponsor team and ISAC will be 
unblinded during these reviews.  All available data from previous cohorts will be reviewed.  
Available PK and PD (virology) data may also be used to guide dose adjustment. 
If temporary stopping criteria are met, dosing will be temporarily stopped, and no further 
participants will be dosed until a full safety review of the study has taken place.  The ISAC will 
be engaged for the full safety review with the sponsor and investigator.  
For the optional Cohort 4, up to 100 participants may be randomized in an approximate 1:1 ratio 
to receive either LY3819253 or placebo.  
Data Monitoring Committee: No
This study will not have a data monitoring committee.  There will be an ISAC.


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
10
1.2.
Schema
Abbreviations:  LY = Lilly study intervention
Figure 1.
Sequential single ascending dose schema of study J2W-MC-PYAA
Cohort 1 – dose level 1
Cohort 2 – dose level 2
= Sentinel subjects (1LY, 1placebo)
= 4-day evaluation of all safety data in each cohort before next cohort and dose escalation
= Remainder of 29-day assessment period
= Remaining participants are randomized and receive LY or placebo in the cohort
Cohort 3 – dose level 3
Cohort 4 – optional – dose level will not exceed dose level 3


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
11
1.3.
Schedule of Activities (SoA)
Assessments obtained previously as part of routine clinical care may be used as the baseline assessment as long as they were done no
more than 48 hours before randomization.
Study 
J2W-MC-PYAA
Screening
Double-blind treatment and assessments
Discharge 
from 
hospital or 
ED
Follow-up if 
inpatient in
hospital 
after Day 29
Post-
treatment 
follow-up
visit
Study Day
1
2
3
4
7
11
15
22
29
Every 7 days 
until 
discharge or 
Day 60
60
Visit window 
(± number of days)
-2
2
2
2
2
2
2
4
Procedures
Comments
Informed Consent
X
Inclusion and 
exclusion criteria 
review
X
Demographics
X
Including age, gender, race, ethnicity
Preexisting conditions 
and medical history
X
Obtained from interview or available 
information, and including timing of 
exposure and onset of symptoms suggestive 
of SARS-CoV-2 infection
Prior treatments of 
special interest within 
the last 2 weeks
X
NSAIDs, antivirals, antibiotics, 
antimalarials, corticosteroids, cytokine-
directed therapy or other investigational 
treatments.
Tobacco use
X
Includes e-cigarettes.
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events (AEs)
X
X
X
X
X
X
X
X
X
X
X
X
X
Any events that occur after signing the 
informed consent are considered AEs as 
defined in Section 10.3.


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
12
Study 
J2W-MC-PYAA
Screening
Double-blind treatment and assessments
Discharge 
from 
hospital or 
ED
Follow-up if 
inpatient in
hospital 
after Day 29
Post-
treatment 
follow-up
visit
Study Day
1
2
3
4
7
11
15
22
29
Every 7 days 
until 
discharge or 
Day 60
60
Visit window 
(± number of days)
-2
2
2
2
2
2
2
4
Physical Evaluation or Clinical Assessments
Physical examination
X
Documentation of hospital-based exam is 
acceptable.
Symptom-directed 
physical exam
X
X
X
X
X
X
X
X
X
X
X
Documentation of hospital-based exam is 
acceptable.
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Documentation of hospital-based exam is 
acceptable.
Includes: temperature, pulse rate, BP, 
respiratory rate, SpO2, and where 
applicable FiO2. 
Day 1 timing: 

immediately before the infusion, 

every 15 minutes during the infusion, 
as possible

every 30 minutes for 2 hours after 
infusion and

every 1 hour for the next 4 hours after 
infusion.  
Automation may be used.
All other study days: once daily.
Single 12-lead ECG 
(local)
X
Documentation of hospital-based exam 
within 72 hours prior to dosing is 
acceptable.


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
13
Study 
J2W-MC-PYAA
Screening
Double-blind treatment and assessments
Discharge 
from 
hospital or 
ED
Follow-up if 
inpatient in
hospital 
after Day 29
Post-
treatment 
follow-up
visit
Study Day
1
2
3
4
7
11
15
22
29
Every 7 days 
until 
discharge or 
Day 60
60
Visit window 
(± number of days)
-2
2
2
2
2
2
2
4
Chest x-ray (local)
X
Day 1: enter interpretation of most recent 
chest CT scan or x-ray in CRF if done.  No 
new imaging is required.
Hospitalization events
X
X
X
X
X
X
X
X
X
X
X
Includes:

hospitalized

ICU admittance, and 

discharge
Clinical status and 
concomitant 
procedures of special 
interest
X
X
X
X
X
X
X
X
X
X
X
X
Includes: 
Limitation on activities due to COVID-19
and requirements for:

Ongoing hospital medical care

Supplemental oxygen

Non-invasive ventilation or high flow 
oxygen device

Mechanical ventilation

ECMO

Additional organ support (e.g. 
pressors, renal replacement), or

Consciousness status (ACVPU).
Clinical symptoms
X
X
X
X
X
X
X
X
X
X
X
X
Including presence of fever, cough, 
shortness of breath at rest or on exertion
Laboratory Tests and Sample Collection
Hematology
X
X
X
X
X
X
X
X
X
X
Documentation of hospital-based laboratory 
results are acceptable.
Local laboratory


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
14
Study 
J2W-MC-PYAA
Screening
Double-blind treatment and assessments
Discharge 
from 
hospital or 
ED
Follow-up if 
inpatient in
hospital 
after Day 29
Post-
treatment 
follow-up
visit
Study Day
1
2
3
4
7
11
15
22
29
Every 7 days 
until 
discharge or 
Day 60
60
Visit window 
(± number of days)
-2
2
2
2
2
2
2
4
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
Documentation of hospital-based laboratory 
results are acceptable.
Local laboratory
eGFR
X
Local calculation using CKD-EPI
Lactate 
dehydrogenase (LDH)
X
X
X
X
X
X
X
X
X
Documentation of hospital-based laboratory 
results are acceptable.
Local laboratory
C-reactive protein 
X
X
X
X
X
X
X
X
X
Ferritin
X
X
X
X
X
X
X
X
X
D-dimer
X
X
X
X
X
X
X
X
X
Procalcitonin
X
X
X
X
X
X
X
X
X
Troponin
X
X
X
X
X
X
X
X
X
SARS-Cov-2 viral 
infection 
determination
X
Date and time of initial positive laboratory 
test was reported for COVID-19 infection 
≤14 days prior to randomization
Local laboratory
Serum pregnancy
X
Only for WOCBP (Section 10.4 Appendix 
4) Local laboratory
Urine pregnancy 
X
Only for WOCBP (Section 10.4 Appendix 
4) Local laboratory
Pharmacokinetic (PK) 
sample
X
X
X
X
X
X
X
Day 1: before the infusion and anytime just 
prior to the end of infusion.
All other scheduled samples may be taken 
at any time during that scheduled day.  
Lilly-designated laboratory


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
15
Study 
J2W-MC-PYAA
Screening
Double-blind treatment and assessments
Discharge 
from 
hospital or 
ED
Follow-up if 
inpatient in
hospital 
after Day 29
Post-
treatment 
follow-up
visit
Study Day
1
2
3
4
7
11
15
22
29
Every 7 days 
until 
discharge or 
Day 60
60
Visit window 
(± number of days)
-2
2
2
2
2
2
2
4
Immunogenicity 
(ADA) sample
X
X
X
X
X
X
Day 1:  before the infusion. 
All other scheduled and unscheduled 
immunogenicity samples should be 
collected with a time-matched PK sample.
Lilly-designated laboratory
Pharmacodynamic 
sample 
X
X
X
X
X
X
X
X
X
SARS-Cov-2 swab 
Methods include nasopharygeal (preferred) 
or mid-turbinate.
The same method of sample collection 
must be used per participant for the 
duration of the study.  Switching methods 
is not allowed.
Day 1:  before the infusion.
Lilly-designated laboratory
Exploratory 
biomarker samples
X
X
X
X
X
X
X
X
X
Day 1: before the infusion
Lilly-designated laboratory
Pharmacogenetics 
sample
X
Lilly-designated laboratory
Randomization and Dosing
Randomization
X
Administer study 
intervention 
(IV infusion)
X
Abbreviations:  ACVPU = alert, consciousness, verbal, pain, unresponsive scale; ADA = anti-drug antibody; BP = blood pressure; CKD-EPI = Chronic Kidney Disease 
Epidemiology Collaboration equation; CRP = C-reactive protein; ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; ED = early discontinuation; FiO2 = 


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fraction of inspired oxygen in the air; ICU = intensive care unit; IV = intravenous; NSAIDS = non-steroidal anti-inflammatory drugs; SARS-Cov-2 = severe acute respiratory 
syndrome coronavirus 2; SpO2 = saturation of peripheral oxygen; WOCBP = women of child-bearing potential.  


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2.
Introduction
The efficient community spread of SARS-CoV-2 has resulted in the current pandemic of COVID-19, 
which in severe and critical cases results in progressive pulmonary infection, complicated by 
respiratory failure, with a high prevalence of acute respiratory distress syndrome.  Although several 
therapies have been explored in severe COVID-19, none have improved survival, including 
antivirals, glucocorticoids, and immunoglobulins (Liu et al 2020).
The SARS-CoV-2 gains entry to cells through binding of the spike (S) protein to ACE2 receptors 
on cells (Hoffmann 2020).  Eli Lilly and Company has a partnership with AbCellera Biologics 
Inc. (AbCellera; Vancouver, Canada) to develop neutralizing IgG1 monoclonal antibodies 
(mAbs) to the Spike (S) protein of SARS-CoV-2 as a potential treatment for COVID-19.  
Candidate antibody gene sequences have been selected from a recently recovered COVID-19 
United States patient’s serum using AbCellera’s core platform screening technologies. 
LY3819253 is a neutralizing IgG1 monoclonal antibody (mAb) to the spike protein of SARS-
CoV-2.  It is designed to block viral attachment and entry into human cells, and to neutralize the 
virus, potentially treating even established COVID-19 by providing a specific potent, 
neutralizing antibody to SARS-CoV-2.   The blocking of viral entry into respiratory cells and 
viral replication, and viral neutralization is expected to mitigate the severity of disease in patients 
in whom ongoing viral spread and replication is the primary driver of COVID-19 
pathophysiology.  The decrease in viral replication may also shorten a patient’s extent and 
duration of viral shedding and transmission, positively impacting public health.  
2.1.
Study Rationale
LY3819253 is a neutralizing IgG1 mAb to the spike protein of SARS-CoV-2.  It is designed to 
block viral attachment and entry into human cells, and to neutralize the virus, potentially treating 
even established COVID-19 by providing a specific potent, neutralizing antibody to SARS-CoV-
2.
Study J2W-MC-PYAA (PYAA) aims to investigate the safety, tolerability, PK, and PD of 
LY3819253 following a single dose administered to participants hospitalized for COVID-19.
The data from this study will inform decisions for the clinical development of LY3819253.
2.2.
Background
The global spread of SARS-CoV-2 has resulted in the current pandemic of COVID-19, which in 
critical cases results in progressive pulmonary failure, complications with ARDS and can result 
in death.
The SARS-CoV-2 gains entry to cells through binding of the spike (S) protein to ACE2 receptors 
on cells (Hoffmann 2020).  By binding to the S protein, LY3819253 is designed to block 
interaction with the ACE2 receptors, interfering with viral attachment and entry into human 
cells, and is also designed to neutralize SARS-CoV-2. These antiviral effects are expected to 
result in a clinically important decrease in viral replication, mitigating the severity of disease in 
patients for whom ongoing viral replication is the primary driver of COVID-19 pathophysiology.  


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Given the current public health emergency and the urgency to discover therapies for COVID-19, 
additional nonclinical efficacy and safety studies will be conducted in parallel with the first 
clinical studies.  Nonclinical data will be shared as it becomes available.
2.3.
Benefit/Risk Assessment
LY3819253 has not been administered to humans.  Nonclinical information for LY3819253 is 
described in the Investigator’s Brochure (IB).  
The potential benefit to humans with COVID-19 disease is considered greater than the likelihood 
of anticipated and unanticipated risk.   
Anticipated risk is considered low and is based on the known mechanism of action for human 
derived neutralizing antibodies in acute viral disease states.  LY3819253 consists of a highly 
specific mAb directed at foreign (non-human) epitope(s) and will be given to infected patients as 
a single dose in a controlled, hospitalized setting.  The complementarity determining regions 
(CDRs) of the mAb were derived from B lymphocytes of a convalescent naturally SARS-CoV-2-
infected patient and, thus, have undergone natural positive and negative selection pressures in 
vivo, unlike humanized antibodies generated in mice.  Therefore, off-target binding and tissue 
cross-reactivity are considered unlikely.  
A theoretical risk is that LY3819253 may cause antibody-dependent enhancement (ADE) of viral 
replication.  This is based on responses observed to some monoclonal antibody therapies used in 
other unrelated viral diseases.  Unlike ADE associated with Dengue and Zika virus infections, 
this phenomenon has not been clearly established for coronaviral infections, such as SARS and 
MERS, and has not been reported to date with SARS-CoV-2.  Additionally, limited experience 
with the use of convalescent serum as a treatment for patients with severe COVID-19 disease has 
not indicated safety concerns (Shen, 2020; Duan, 2020). LY3819253 will be administered to 
patients at sufficiently high dose levels to neutralize SARS-CoV-2 and avoid sub-neutralizing
concentrations in the presence of virus that are typically associated with ADE.  
Additional manageable risks associated with most therapeutic mAbs are the potential for 
infusion-related hypersensitivity and cytokine release reactions.  The single infusion in this study
will be at a controlled rate, the study participants will be monitored in the hospital setting, and 
adjustments in the infusion rate will be made and/or the infusion stopped, if indicated. 
Overall, these risks to patients with COVID-19 disease, for which there is no established 
standard of care treatment, are considered monitorable and manageable in the hospital setting,
and the potential benefit outweighs the risks.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of LY3819253 may be found in the IB. 


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
Characterize the safety and tolerability of 
LY3819253 after intravenous infusion

Safety assessments such as AEs and SAEs
Secondary
Characterize the pharmacokinetics of 
LY3819253 after intravenous infusion

LY3819253 mean concentration on Day 29
Characterize the pharmacodynamics of 
LY3819253 after intravenous infusion

Change from baseline in SARS-CoV-2 viral 
load (Days 7, 11, 15 and 22)

SARS-CoV-2 viral load AUC

Time to SARS-CoV-2 clearance 
Tertiary/Exploratory
Characterize the participant’s clinical status

Duration (days) of hospitalization

Proportion (percentage) of participants 
admitted to ICU

Proportion (percentage) of participants 
requiring mechanical ventilation

Score using the NIAID and WHO ordinal 
scales at pre-specified time points

Proportion (percentage) of participants with at 
least a 2-point improvement on the NIAID 
and WHO ordinal scale or live discharge from 
hospital at pre-specified time points

NEWS2 score at pre-specified time points

Proportion (percentage) of participants with 
any worsening on the NIAID ordinal scale 
from baseline to Day 15
Characterize the pharmacodynamics of 
LY3819253 after intravenous infusion

Proportion of participants that achieve SARS-
CoV-2 clearance (Days 7, 11, 15, 22)
Characterize emergence of viral resistance to 
LY3819253

Comparison from baseline to Day 29
Abbreviations:  AE = adverse event; ICU = intensive care unit; NIAID = National Institute of Allergy and Infectious 
Diseases; NEWS2 = National Early Warning Score; SAE =serious adverse event; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2; WHO = World Health Organization.


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Protocol number J2W-MC-PYAA(b)
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4.
Study Design
4.1.
Overall Design
Study PYAA is a Phase 1, double-blind, sponsor unblinded, randomized, placebo-controlled, 
single-ascending dose study.
Screening
Interested hospitalized participants will sign the appropriate informed consent document(s) prior 
to completion of any procedures. Screening may be performed up to 48 hours prior to dosing.  
Screening and Day 1 may occur on the same day.
Double-blind Treatment and Assessment Period
This is the general sequence of events during the treatment and assessment period:

Participants are randomized to LY3819253 or placebo

Site completes baseline procedures and sample collection

Participants begin a single IV infusion of study intervention, and

Site completes all safety monitoring and post-infusion sample collection.
Discharge from hospital 
Participants discharged from the hospital will complete study procedures outlined in the SoA.  
If hospital discharge…
Then…
Occurs prior to Day 29
participants will be asked to complete the remaining 
study assessments at the timepoints indicated in the 
SoA.  
NOTE: Strategies to manage infection risks and reduce 
the burden of return visits should be considered by 
sites, such as home visits.
Occurs on the same day as a study assessment visit
hospital discharge assessments do not need to be 
repeated if the study assessments occurred within 8 
hours of discharge and there has been no change in 
clinical status.
Does not occur at or prior to day 29
assessments will continue to occur weekly up to Day 
60 or until hospital discharge, whichever is sooner.
Post-treatment follow-up
Post-treatment follow-up assessments will be conducted at Day 60. Strategies to manage 
infection risks and reduce the burden of return visits should be considered by sites, such as home 
visits.
4.1.1.
Single-Ascending Dose Design
The study will comprise up to 4 dose cohorts.  
Planned dosing information is provided in Section 6.1. 
Dose escalation criteria are provided in Section 6.6.1.  


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Temporary stopping criteria are provided in Section 6.6.2
Cohorts 1 - 3 will comprise at least 8 participants: 

6 randomized to LY3819253 and 

2 randomized to placebo. 
Sentinel dosing will be used in any dose cohort that represents a dose increase from the 
preceding cohort. The first 2 participants in each cohort will be randomized 1:1 to LY3819253
and placebo. 
Safety and tolerability will be reviewed for sentinel participants up to 24 hours after dosing.  The 
investigator and the Lilly sponsor team are responsible for determining if safety and tolerability 
is acceptable to continue with dosing subsequent participants. 
Subsequent participants will be randomized to the remaining treatment allocations, 5 to 
LY3819253 and 1 to placebo.  
The decision to dose the next cohort will be made when all participants from the previous cohort 
have been dosed and safety data is assessed for at least 4 days after the IV infusion by the 
investigator(s) and Lilly sponsor team.
Cohort 4 may be initiated, at the discretion of the sponsor team, if more data is needed to inform 
the dose of LY3819253.
4.2.
Scientific Rationale for Study Design
This study is the first investigation of LY3819253 in humans.  The study is designed to explore a 
range of doses that will inform the clinical drug development plan for LY3819253.  
The sequential cohort, single-dose escalation design with safety reviews before each cohort will 
minimize safety risks to participants during dose exploration.  Sentinel dosing is included to 
minimize the risk of any unanticipated acute tolerability or safety concerns in participants 
administered LY3819253.  
The 4-day safety review after dosing is sufficient to monitor for an acute adverse immune 
response to treatment with LY3819253.
The optional, expansion Cohort 4 allows for additional data collection to detect reduction in the 
rate of clinical worsening.
In accordance with FDA recommendation (20 March 2020 Pre-IND Meeting), the population for 
this study are hospitalized patients infected with SARS-CoV-2.  
Participants enrolling to this study will have moderate to severe COVID-19 illness according to 
the Food and Drug Administration (FDA) definitions (FDA resource page [WWW]), but with 
notable exception in the specific eligibility criterion #21 for severe participants.  This exception 
is intended to limit the severity of the participant enrolling to this study to exclude those at 
highest risk of respiratory failure.  Lilly believes the optimal benefit:risk for LY3819253 may be 
found in a participant that does not have impending respiratory failure, as this severity 
of patients with COVID-19 have primary pathology associated with overexuberant 
inflammatory response where LY3819253 is less likely to be effective. Further, adverse events 
in this population could potentially confound our ability to discern safety signals in this study.


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Protocol number J2W-MC-PYAA(b)
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Remote follow-up visits may be conducted to remove the burden of return visits for the hospital and 
clinical trial staff reflecting limited medical resources in the COVID-19 pandemic.
4.3.
Justification for Dose
The dose levels selected for this study are designed to explore a wide exposure-response range 
that potentially encompasses a therapeutic dose, and will provide the safety and tolerability 
underpinnings for the clinical drug development plan for LY3819253. 
Up to 4 cohorts will be enrolled to characterize the dose response of LY3819253 on safety, 
tolerability, PK and PD markers. The first 3 cohorts will explore the efficacious dose range 
(2 doses) and 1 supratherapeutic dose. The planned dose levels for LY3819253 are 700 mg, 
2800 mg and 7000 mg.  
Cohort 4 is optional and may be used to characterize the dose-response relationship for dose 
selection in subsequent studies.  The dose for Cohort 4 may be evaluated at a lower or equal 
level to the maximum investigated dose but will not exceed 7000 mg.
The doses are determined based on these key variables: 

projected human PK of the mAb, including lung tissue distribution   

in vitro binding potency to the viral targets

neutralization of virus cell entry and replication, and 

antibody-viral dynamic modeling and simulation.  
The projected human half-life is expected to be approximately 19 days based on PK/PD 
modeling.  
The starting dose of 700 mg is expected to have a sustained concentration above the in vitro
IC90 of viral cell-entry neutralization for at least 28 days. The maximum dose of 7000 mg is
selected due to uncertainty in model predicted PK concentrations, viral load reduction and 
consideration of infusion volume in participants.  
The dose levels are fixed, not body weight based. Given the planned dose levels, the predicted 
impact of body weight on therapeutic response will be minimal.
4.4.
End of Study Definition
A participant is considered to have completed the study if they have completed all required 
phases of the study including the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last participant.


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Protocol number J2W-MC-PYAA(b)
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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  Due to the criticality of participant health and 
the setting of this research study, verbal interview of a potential participant, their legal 
representative or family member, may be the source for preexisting conditions and medical 
history unless otherwise specified within the eligibility criteria.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Are ≥18 and ≤85 years of age at the time of randomization
Type of Participant and Disease Characteristics
2. In the judgement of the investigator, have moderate or severe COVID-19 illness per the 
FDA resource page (WWW) (Section 10.8, Appendix 8)
3. This criterion was removed
4. Are hospitalized, or in the process of being admitted to hospital, and have an initial 
laboratory determination of current COVID-19 infection ≤14 days of randomization.
Sex
5. Are men or non-pregnant women
Reproductive and Contraceptive agreements and guidance is provided in Section 10.4, 
Appendix 4.  
6. Criterion 6 merged with criterion 5.
Study Procedures
7. Understand and agree to comply with planned study procedures
8. Agree to the collection of nasopharyngeal swabs and venous blood
Informed Consent
9. The participant or legally authorized representative give signed informed consent as 
described in Section 10.1.3, which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. 
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
10. Require invasive mechanical ventilation or anticipated impending need for invasive 
mechanical ventilation 
11. Anticipate transfer to another hospital which is not a study site within 5 days of 
randomization


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Protocol number J2W-MC-PYAA(b)
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12. Have known allergies to any of the components used in the formulation of the 
interventions
13. Have hemodynamic instability requiring use of pressors within 24 hours of 
randomization
14. Were resident in a nursing home or long-term care facility immediately prior to current 
hospitalization
15. Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides 
COVID-19) that in the opinion of the investigator could constitute a risk when taking 
intervention
16. Have any co-morbidity requiring surgery within <7 days, or that is considered life-
threatening within 29 days
17. Have prior history of hepatic impairment, such as 
a.
severe liver cirrhosis Child-Pugh B or worse 
b. cirrhosis with a history of hepatic encephalopathy 
c.
clinically meaningful ascites requiring ongoing treatment with diuretics and/or 
paracentesis, or 
d. history of hepatorenal syndrome.
18. Have any serious concomitant systemic disorder that, in the opinion of the investigator, 
would preclude participation in the study
19. Current diagnosis of active malignancy that, in the opinion of the investigator, could 
constitute a risk when taking investigational product
20. Received convalescent COVID-19 plasma treatment prior to enrollment
Diagnostic assessments
21. Have an SpO2 <88% while breathing room air at rest. If on supplemental oxygen at the 
time of screening, use the last time point of measurement on room air up to 48 hours prior
22. This criterion was removed
23. Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5X upper 
limit of normal (ULN)
24. Have acute kidney disease with an eGFR <30 mL/min/1.73 m2 based on the chronic 
kidney disease epidemiology collaboration equation (CKD-EPI).
Chronic kidney disease is allowable, if judged to be stable for the past 3 months, in the 
opinion of the investigator.
Other Exclusions
25. Are pregnant or breast feeding
26. Are concurrently enrolled in any other type of medical research judged not to be
scientifically or medically compatible with this study
27. Are Lilly employees
28. Are investigator site personnel directly affiliated with this study or their immediate 
families.  


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5.3.
Lifestyle Considerations
Reproductive and Contraceptive guidance is provided in Section 10.4, Appendix 4.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. 
Repeating laboratory tests during the screening period does not constitute rescreening.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Intervention(s) Administered
This is a single dose study.  
Intervention Names
LY3819253
Placebo
Type 
Biologic
Not applicable
Dose Formulation
solution
0.9% Sodium chloride solution
Unit Dose Strength(s)
700 mg/vial
Placebo
Planned Dosage Level(s)
Cohort 1:  700 mg
Cohort 2:  2800 mg
Cohort 3:  7000 mg
Optional Cohort 4 may explore lower or 
equal levels to the max investigated 
dose, but will not exceed 7000 mg.
Not applicable
Route of Administration
IV infusion
IV infusion
Use
experimental
placebo
IMP and NIMP
IMP
IMP
Sourcing
From Lilly
Commercially available 0.9% sodium 
chloride solution will be used as a 
placebo for this study
Packaging and Labeling
Study Intervention will be provided in 
glass vials and will be labeled 
appropriately
Commercially available 0.9% sodium 
chloride solution will be used as a 
placebo for this study
Abbreviations:  IMP = investigational medicinal product; NIMP = non-investigational medicinal product.


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This table describes the infusion volume and rate for the planned LY3819253 doses.  Cohort 4 
instructions will be provided in the pharmacy instructions.  Placebo volume and rate will match 
the LY3819253 dose cohort.
LY3819253 Dose (mg) Volume (mL)
Start Infusion rate x Time
700
50
100 mL/hr x 30 min
2800
75
100 mL/hr x 45 min
7000
100
100 mL/hr x 60 min
The infusion rate may be reduced as deemed necessary if an infusion reaction is observed.  
During the infusion, vital signs will be monitored every 15 minutes as described in the SoA.  
After completion of the infusion, participants will be monitored every 30 minutes for 2 hours and 
then every 1 hour for the next 4 hours. 
The site must have resuscitation equipment, emergency drugs and appropriately training staff 
available during the infusion and for at least 4 hours after the completion of the infusion.
6.1.1.
Special Treatment Considerations
6.1.1.1.
Premedication for Infusions
Premedication for infusions is not planned.  However, if an infusion reaction occurs during 
administration or if the participant has a medical history suggesting a potential benefit from 
premedication, the study investigator(s) should determine the appropriate premedication.
The investigators and sponsor may decide to use premedication for other cohorts if the frequency 
of infusion reactions among participants warrants it.
If minor infusion reactions are observed, but review of the data suggests that dose escalation may 
continue, administration of acetaminophen, 500 mg to 1000 mg, antihistamines and/or other 
appropriately indicated medications may be given prior to the start of infusions for subsequent 
participants. 
The decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator and sponsor and recorded in the study documentation, along with the dose-
escalation decision.  
Any premedications given will be documented as a concomitant therapy.
6.1.1.2.
Management of Infusion Reactions
All participants should be monitored closely, as there is a risk of infusion reaction and 
hypersensitivity (including anaphylaxis) with any biological agent.  
Symptoms and Signs
Symptoms and signs that may occur as part of an infusion reaction include, but are not limited to 
fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash
including urticaria, pruritus, myalgia, and dizziness.  


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Infusion-related reactions severity will be assessed and reported using the Division of Allergy 
and Infectious Diseases (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, version 2.1 (July 2017).
This table describes the severity of reactions according to DAIDS.
Parameter
Mild
Moderate
Severe
Severe and 
Potentially 
Life-threatening
Acute 
Allergic 
Reaction
Localized urticaria 
(wheals) with no 
medical intervention 
indicated
Localized urticaria 
with intervention 
indicated 
OR 
Mild angioedema with 
no intervention 
indicated
Generalized Urticaria 
OR
Angioedema with 
intervention indicated 
OR
Symptoms of mild 
bronchospasm
Acute anaphylaxis 
OR 
Life-threatening 
bronchospasm 
OR
Laryngeal edema
Cytokine 
Release 
Syndromea
Mild signs and 
symptoms 
AND
Therapy, that is, 
antibody infusion 
interruption not 
indicated
Therapy indicated
(that is, antibody 
infusion) interruption 
indicated
AND
Responds promptly to 
symptomatic 
treatment
OR
Prophylactic 
medications indicated 
for ≤24 hours
Prolonged severe 
signs and symptoms 
OR
Recurrence of 
symptoms following 
initial improvement
Life-threatening 
consequences 
(for example, 
requiring pressor or 
ventilator support)
a = A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.
Source:  Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.1 (July 2017).
Site Needs
The clinical site should have necessary equipment and medications for the management of any 
infusion reaction, which may include but is not limited to oxygen, IV fluid, epinephrine, 
acetaminophen and antihistamine.
Management of Infusion Reactions
Investigators should determine the severity of the infusion reaction and manage infusion 
reactions based on standard of care and their clinical judgment.  If an infusion reaction occurs, 
then supportive care should be used in accordance with the signs and symptoms.
If a participant permanently discontinues from study intervention, they should complete adverse 
event (AE) monitoring and other procedures as stated in the SoA.


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6.1.1.3.
In the Event of a Retrospective Positive Sterility Finding from Prepared Study 
Intervention
If a positive sterility finding occurs in the terminally sterile filtered study intervention, the
participants who were dosed from the impacted batch should be contacted immediately and
undergo a full physical examination including, but not limited to, blood pressure, pulse rate and 
body temperature. 
A blood sample should be collected for culture and assayed for inflammatory markers such as 
C-reactive protein and elevations in white blood cell counts.
If the signs and symptoms indicated a participant has a possible infection, they will be clinically 
managed, treated and followed up until resolution. Any adverse events will be recorded as 
appropriate. 
6.2.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention.
To protect blinding, the interventions must be prepared by an unblinded site personnel qualified 
to prepare study intervention who are not involved in any other study-related procedures.  
Instructions for preparation will be provided by the sponsor.
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. 
All study intervention 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 intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the pharmacy manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a blinded study.  
All participants will be centrally randomized to study intervention using an Interactive Web 
Response System (IWRS). Before the study is initiated, the log in information and directions for 
the IWRS will be provided to each site.
This table describes general procedures for unblinding.


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Unblinding (IWRS)

Emergency unblinding for adverse events may be performed through the 
IWRS.  All actions resulting in an unblinding event are recorded and 
reported by the IWRS

In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participants’ intervention assignment 
is warranted

Participant safety must always be the first consideration in making such a 
determination. However, the investigator should make all attempts to 
contact the sponsor in advance of unblinding

If a participant’s intervention assignment is unblinded, the sponsor must be 
notified immediately after breaking the blind even if consultation occurred 
in advance

The date and reason that the blind was broken must be recorded in the 
source documentation and case report form.
Abbreviations:  IWRS = interactive web-response system.
If an investigator, site personnel performing assessments, or participant is unblinded while the 
infusion is ongoing, the participant must be discontinued from the study intervention and the 
infusion stopped. If any amount of study intervention was administered, follow procedures 
according to the SoA as described in Section 7.1.
6.4.
Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision.  The date and time of each dose administered will be recorded in the source 
documents and recorded in the case report form (CRF).  
6.5.
Concomitant Therapy
Prior Treatment for Indication
Any prior therapy, such as antivirals, antibiotics, or antimalarials used as treatment prior to 
signing informed consent should be recorded.
Therapy prior to enrollment with antivirals including lopinavir/ritonavir, remdesivir or other 
therapeutic agents (e.g. corticosteroids) are permitted. 
Convalescent COVID-19 plasma treatment is not allowed prior to enrollment.
Concomitant Therapy
Participants should be treated according to standard of care, even as it evolves, and medications 
may be part of the treatment paradigm. Therefore, remdesivir may be initiated as standard of 
care for participants hospitalized with severe disease (if available through the FDA Emergency 
Use Authorizations) outside of local standard of care per written policies or guidelines.
If the local standard of care per written policies or guidelines (that is, not just an individual 
clinician decision) includes lopinavir/ritonavir, chloroquine, hydroxychloroquine or other 
investigational agents, then initiating these during the study is permitted, but may require 
additional safety monitoring by the site.


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Convalescent COVID-19 plasma treatment is not allowed.
Any medication, investigational agent, or vaccine, including over the counter or prescription 
medicines, vitamins, and/or herbal supplements, or other specific categories of interest that the 
participant is receiving at the time of enrollment or receives during the study must be recorded 
along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency for concomitant therapy of special 
interest
Acetaminophen and corticosteroid use are permitted at any time during the study.
Other concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the sponsor if required.
The sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy.
6.6.
Dose Modification
6.6.1.
Dose Escalation Criteria
By nature of being a Phase 1 sponsor unblinded dose-escalation study, data will be evaluated on 
an ongoing basis until the highest planned dose has been administered.
The decision to dose the next cohort will be made when all participants from the previous cohort 
have been dosed and safety data, including safety laboratory data, AEs and vital signs, are
assessed for at least 4 days after the IV infusion by the investigator(s), Lilly sponsor team and an 
independent safety assessment committee (ISAC).
The investigator, Lilly sponsor team and ISAC are responsible for determining any dose 
decisions.  The investigator(s) will remain blinded and the Lilly sponsor team and ISAC will be 
unblinded during these reviews.  All available data from previous cohorts will be reviewed.  
Available PK and PD data may also be used to guide dose adjustment. 
If temporary stopping criteria are met (Section 6.6.2), dosing will be temporarily stopped and no 
further participants will be dosed until a full safety review of the study has taken place.  The 
ISAC will be engaged for the full safety review with the sponsor and investigator.  
6.6.2.
Temporary Stopping Criteria 
Dosing will be temporarily halted, and no further participants will be dosed until a full safety 
review of the study has taken place if:  

Two or more participants at a given dose level develop severe or severe/potentially life-
threatening acute AEs related to the infusion (see Table in Section 6.1.1.2), during or 
within 2 hour of completion of the infusion, that do not resolve with a reduced infusion 
rate and/or supportive care. 
OR


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
Two or more participants at a given dose level develop severe acute AEs within 4 days of 
dosing which, in the opinion of the investigator, cannot be attributed to the primary 
disease, concomitant medications or extraneous circumstances with a reasonable 
possibility.
This table describes the location of AE-related information in this protocol.
Topic
Location
DAIDS table describing severity of reactions
Section 6.1.1.2
Definition of AEs 
Section 10.3.1
Assessment of Intensity/Severity 
Section 10.3.3
Changes to the planned dosing schedule must be appropriately documented and communicated 
with the study personnel and the IRB/IEC before dosing continues.  
6.7.
Intervention after the End of the Study
No continued access is planned after completion of this study, as additional efficacy would be 
needed to demonstrate continued access criteria.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
These sections describe reasons for a participant’s

permanent or temporary discontinuation of study drug, or

discontinuation (withdrawal) from the study.
Discontinuation of specific sites or of the trial as a whole are handled as part of regulatory, 
ethical, and trial oversight considerations in Section 10.1. Appendix 1.
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If the IV infusion is permanently stopped, the participant will remain in the study 
for follow-up and further evaluations as described in the SoA.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study 

at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons

if the participant becomes pregnant during the study

if 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
See the SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed.  The participant will be permanently 
discontinued both from the study intervention and from the study at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant
withdraws from the study, they may request destruction of any samples taken and not tested, and 
the investigator must document this in the site study records.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue study treatment.  
If the investigator and the sponsor CRP agree it is medically appropriate to continue, the 
investigator must obtain documented approval from the sponsor CRP to allow the inadvertently 
enrolled participant to continue in the study with or without treatment with investigational 
product. 


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Safety follow up is as outlined in 

Section 1.3 (Schedule of Activities), 

Section 8.2 (Safety Assessments), and 

Section 8.3 (Adverse Events and Serious Adverse Events).
7.3.
Lost to Follow up
A participant will be considered lost to follow-up if, after discharge from the hospital, they do
not return for scheduled visits and are unable to be contacted by the study site. Site personnel 
are expected to make diligent attempts to contact participants who fail to return for a scheduled 
visit or were otherwise unable to be followed up by the site.


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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3).
Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
8.1.
Efficacy Assessments
This section is not applicable for this study.
8.2.
Safety Assessments
8.2.1.
Physical Examinations
A complete physical examination will be performed at the screening visit. This examination 
excludes pelvic, rectal, and breast examinations unless clinically indicated.
A symptom-directed physical examination will be performed at other visits, as specified in the 
SoA and as clinically indicated.
Investigators should pay special attention to clinical signs related to COVID-19, to ongoing 
medical conditions and to previous serious illnesses.
8.2.2.
Vital Signs
Vital signs will be measured as specified in the SoA and as clinically indicated.  Vital signs 
include

Body temperature

Blood pressure

Pulse rate

Respiration rate

Saturation of peripheral oxygen, and

Supplemental oxygen flow rate, FiO2 if known, and method of delivery, if applicable.
Additional vital signs may be measured during the study if warranted, as determined by the 
investigator.


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8.2.3.
Electrocardiograms
A single, local, 12-lead electrocardiogram (ECG) will be obtained as outlined in the SoA using 
an ECG machine that automatically calculates the heart rate and measures pulse rate, QRS, QT, 
and corrected QT intervals. Additional ECG readings may occur at investigator discretion.
8.2.4.
Clinical Laboratory Assessments
See Section 10.2, Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
for the timing and frequency.  All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA.
The investigator or appropriate designee must review the laboratory report, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Documentation of the review may be completed according to institution processes or by making 
an entry in the participants’ progress notes (medical record) stating that the laboratory results 
have been reviewed.  
The laboratory reports must be filed with the source documents unless a source document 
agreement or comparable document cites an electronic location that accommodates the expected 
retention duration. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., serious adverse event [SAE] or AE or dose 
modification), then the results must be recorded in the CRF.
Pregnancy Testing
Women of childbearing potential (WOCBP) must undergo pregnancy testing according to the 
SoA.  Participants who are pregnant will be discontinued from the study (Section 7.2). 
8.2.5.
Hospitalization events
The date of hospitalization events will be recorded in the CRF and includes when the participant 
is hospitalized, admitted to the ICU, discharged from the ICU, discharged from the hospital, 
admitted to an extended care facility, discharged to home.
8.2.6.
Procedures of Special Interest
The participants’ clinical status and concurrent procedures of special interest will be recorded in 
the CRF and include limitation on activities due to COVID-19 and requirements for

ongoing hospital medical care

supplemental oxygen

non-invasive ventilation or a high flow oxygen device

mechanical ventilation

ECMO

additional organ support (e.g. pressors, renal replacement), or

consciousness status using alert, consciousness, verbal, pain, unresponsive scale
(ACVPU).


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8.2.7.
Respiratory Support
Once enrolled in the study, participants may be managed with high-flow nasal cannula, 
noninvasive positive pressure ventilation or any other form respiratory support as needed per 
investigator discretion.
8.3.
Adverse Events and Serious Adverse Events
AEs will be reported by the participant or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study.
Discontinuation information is in Section 7.
Detailed AE definitions and procedures are in Section 10.3
AEs and SAEs related to COVID-19 are subject to different reporting requirements detailed in 
Section 10.3.1. 
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the time of signing of the informed consent form (ICF)
until participation in the study has ended.
Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the Adverse Event CRF.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the participant has signed the ICF and has received study 
intervention.  However, if an SAE occurs after signing the ICF, but prior to receiving study 
intervention, it needs to be reported within the SAE reporting timeframe if it is considered 
reasonably possibly related to study procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3, Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.  
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3.


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3.
8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it with the Investigator’s Brochure, and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
Although normal pregnancy is not an adverse event, details of all pregnancies in female 
participants will be collected for 90 days after dosing.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Section 10.4, Appendix 4.
Abnormal pregnancy outcomes, for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy, are considered SAEs.
8.3.6.
Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions.
If such a reaction occurs, additional details describing each symptom should be provided to the 
sponsor in the infusion-related reaction/hypersensitivity CRF. 
If symptoms and/or signs occur during or within 6 hours after infusion of LY3819253 and are 
believed to be hypersensitivity or due to cytokine release, then investigators are encouraged to 
report the event as infusion-related immediate hypersensitivity reaction or cytokine release-
associated infusion reaction, respectively.


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Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving intervention. It is recommended that participants
who experience a systemic hypersensitivity reaction be treated per the local standard of care.  
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Section 10.6, Appendix 6, “Recommended Laboratory Testing for 
Hypersensitivity Events”. Laboratory results are provided to the sponsor via the central 
laboratory. 
In case of skin lesions or rash consistent with vasculitis, efforts should be made to perform the 
following as soon as possible

dermatology consultation

skin biopsy, and

photographs of lesions of interest, including skin biopsy site.
8.3.7. Infusion-related Reactions
As with other mAbs, infusion-related reactions may occur during or following LY3819253
administration. If an infusion-related reaction occurs, additional data describing each symptom 
and sign should be provided to the sponsor in the CRF.  
This table describes the location of infusion-related reaction information in this protocol.
Topic
Location
Special treatment considerations
Section 6.1.1
Premedication for infusions
Section 6.1.1.1
Management of infusion reactions
Section 6.1.1.2
DAIDS table describing severity
Section 6.1.1.2
Symptoms occurring during or after infusion of study intervention may also be defined according 
to AE categories such as acute allergic reaction or cytokine release syndrome (refer to DAIDS).
8.3.8. Product Complaints
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
trial intervention. 
The sponsor collects product complaints on study interventions used in clinical studies in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Participants will be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with the study intervention so that the situation can be assessed.
NOTE: Any AEs or SAEs that are associated with a product complaint will follow the processes 
outlined in Section 8.3.3 and Appendix 10.3 of the protocol.
Time Period for Detecting Product Complaints
Product complaints that result in an adverse event will be detected, documented, and reported to 
the sponsor during all periods of the study in which the study intervention is used.


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If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to the study 
intervention, the investigator will promptly notify the sponsor.
Prompt Reporting of Product Complaints to Sponsor
Product complaints will be reported to the sponsor within 24 hours after the investigator becomes 
aware of the complaint.
The Product Complaint Form will be sent to the sponsor by a method designated by the sponsor.
Follow-up of Product Complaints
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the product complaint.
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator and submitted to the sponsor.
8.4.
Treatment of Overdose
In case of suspected overdose, participants should be monitored for any signs or symptoms of 
adverse reactions or effects, and supportive care should be provided as necessary. 
8.5.
Pharmacokinetics
Venous blood samples will be collected as specified in the SoA for determination of 
concentrations of LY3819253 used to evaluate the PK for LY3819253.  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor.
Instructions for the collection and handling of biological samples will be provided by Lilly. 
Site personnel will record

The date and time (24-hour clock time) of administration (start and end of infusion), and

The date and time (24-hour clock time) of each PK sample.
It is essential that the times are recorded accurately.  
8.5.1.
Bioanalytical
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. Concentrations of LY3819253 will be assayed using a validated 
bioanalytical method.  Analyses of samples collected from placebo-treated subjects are not 
planned.
Sample retention is described in Appendix 1, Section 10.1.12.  Remaining samples used for PK 
may be pooled and used for exploratory metabolism or bioanalytical method experiments as 
deemed appropriate.


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8.6.
Pharmacodynamics
The SARS-CoV-2 viral RNA level and viral clearance will be evaluated by either a 
nasopharyngeal swab or mid-turbinate swab at times specified in the SoA.  The same method of 
sample collection must be used per participant for the duration of the study.  Switching methods 
for a participant is not allowed.  
The nasopharyngeal swab is the preferred method and will be taken from both nostrils.  The 
nasopharyngeal procedure is described in Section 10.7.  
Sample retention is described in Section 10.1.12.  Remaining samples may be used for additional 
exploratory studies to better understand LY3819253 and the disease, which may include 
sequencing and/or culture of the virus for future studies.
8.7.
Genetics
A whole blood sample will be collected for pharmacogenetic analysis where local regulations 
allow.  
See Section 10.2 Clinical Laboratory Tests, and Section 1.3 SoA for sample collection 
information.  
See Section 10.5 for genetic research, custody, and sample retention information.
8.8.
Biomarkers
Blood samples will be collected from all participants for analysis of immune system-related 
markers. Serum, whole blood for cellular and/or epigenetic analysis, and whole blood RNA 
samples for exploratory biomarker research will be collected at the time specified in the SoA 
where local regulations allow. 
Samples will be stored and analysis may be performed on biomarkers thought to play a role in 
immune system related responses to viral infection including, but not limited to, immune 
pathways, cellular composition, serum analytes, or epigenetic biomarkers, to evaluate their 
association with observed clinical responses to LY3819253 and the disease state.  
Samples may be used for research to develop methods, assays, prognostics and/or companion 
diagnostics related to the intervention target (S protein), the COVID-19 disease state, pathways 
associated with disease, and/or the mechanism of action of the study intervention.
Sample retention is described in Section 10.1.12.
8.9.
Immunogenicity 
Visits and times
At the visits and times specified in the SoA, venous blood samples will be collected to determine 
antibody production against LY3819253.  The actual date and time (24-hour clock time) of each 
sample collection will be recorded.
Sample collection, handling, and use
Instructions for the collection and handling of blood samples will be provided by the sponsor.


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Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3819253 at a laboratory approved by the sponsor.  Antibodies may be further characterized 
for their ability to neutralize the activity of LY3819253.  
Sample retention
Sample retention is described in Section 10.1.12.
8.10.
Health Economics
This section is not applicable for this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
This is an exploratory study with a primary objective of assessing safety and tolerability.  Any 
hypothesis tests conducted for treatment comparisons will be exploratory in nature and 
conducted without adjustment for multiplicity.
9.2.
Sample Size Determination
For Cohorts 1 – 3, approximately 24 participants will be randomized to receive one of three dose 
levels of LY3819253 or placebo.  Additional participants may be required to ensure a minimum 
of 8 participants in each cohort complete 7 days of study assessments. Up to a maximum of 3 
additional participants per cohort may be added.
Participant viral loads over time were simulated using a representative PK/PD model to enable a 
Monte Carlo assessment of the power of the trial to detect a 30% treatment difference in mean 
AUC (28 day) of viral load.  This assessment revealed greater than 90% probability of meeting 
the following Bayesian critical success factor:  
Pr ((mean AUCPL – mean AUCLY)/ mean AUCPL > 0.3) > 0.60
PL = placebo, LY = LY3819253  
Additionally, the anticipated 6 participants per treatment provides greater than 80% probability 
(within each treatment arm) of observing safety events of reasonable prevalence (that is, at least 
25%) to support the primary objective of safety assessment.  
For the optional Cohort 4, up to 100 participants may be randomized in an approximate 1:1 ratio 
to receive either LY3819253 or placebo.  The overall numbers of participants randomized to 
LY3819253 and placebo in this study will provide 60% power to detect a reduction in the rate of 
clinical worsening from 22% to 9% (one-sided alpha=0.05).  Clinical worsening is defined as the 
proportion (percentage) of participants with any worsening on the NIAID ordinal scale from 
baseline to Day 15.
A participant is only allowed to receive one IV infusion in one cohort.
9.3.
Populations for Analyses
This table defines the populations for analysis.
Population
Description
Entered
All participants who sign the informed consent form
Safety
All participants randomly assigned and who received study intervention. 
Participants will be analyzed according to the intervention they actually 
received.
Pharmacokinetic 
All randomized participants who received study intervention and have 
evaluable PK sample. Participants will be analyzed according to the 
intervention they actually received.
Pharmacodynamic 
All randomized participants who received study intervention and provided at 
least one post-baseline measure for the relevant endpoint. Participants will be 
analyzed according to the intervention they actually received.


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9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of sponsor or its designee.
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 statistical analysis plan (SAP).  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
The SAP will be finalized prior to the first participant dosed and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints.
9.4.1. General Considerations
This table describes the general statistical methods that may be used in this study.
Method
Analysis 
Descriptive Statistics
number of participants, mean, standard deviation, 
median, minimum, and maximum for continuous 
measures, and frequency counts and percentages for 
categorical measures
Kaplan-Meier curves and summary statistics
Time-to-event analysis
Logistic regression analysis
Treatment comparisons of binary variables with 
treatment in the model.
Nonparametric 
(for example, Mann-Whitney or van Elteren tests)
Treatment comparison of ordinal variables.
Analysis of variance or analysis of covariance
Treatment comparisons of continuous variables 
following appropriate transformations, if necessary
Adjustments for other factors, if any, will be described in the SAP.
9.4.2.
Safety Analyses
Safety analyses will be conducted using the safety population described above. 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of AEs for each treatment will be presented by severity and by association with 
intervention as perceived by the investigator. Adverse events reported prior to randomization
will be distinguished from those reported as new or increased in severity during the study post-
randomization.


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Safety parameters that will be assessed include, but are not limited to, safety laboratory 
parameters, and vital signs. The parameters will be summarized using standard descriptive 
statistics. Additional analysis will be performed if warranted upon review of the data.
9.4.3.
Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetic analyses will be conducted on data from all participants who receive 
intervention and have evaluable PK.
Pharmacokinetic parameter estimates for LY3819253 will be calculated using standard 
noncompartmental methods of analysis.
The primary parameter for analysis will be mean concentration on Day 29.  Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution, may be reported. 
Pharmacodynamic endpoints will be summarized using descriptive methodology.
The SARS-CoV-2 viral dynamics will include evaluation of

Change from baseline in SARS-CoV-2 viral load (Days 7, 11, 15 and 22)

Viral load AUC

Time to SARS-CoV-2 clearance, and

Proportion of participants that achieve SARS-CoV-2 clearance.
Additional PK/PD concentration-response analysis may be performed.  
9.4.4.
Exploratory Endpoints
Exploratory endpoints will be summarized using descriptive methodology and treatment 
comparisons conducted using methods previously described.
Endpoints will include:

Duration (days) of hospitalization

Proportion (percentage) of participants admitted to ICU

Proportion (percentage) of participants requiring mechanical ventilation

Score on the NIAID ordinal scale at pre-specified time points

Score on the WHO ordinal scale at pre-specified time points

Proportion (percentage) of participants with at least a 2-point improvement on the WHO 
ordinal scale or live discharge from hospital, at pre-specified time points

Proportion (percentage) of participants with at least a 2-point improvement on the NIAID 
ordinal scale or live discharge from hospital at pre-specified time points

NEWS2 score at pre-specified time points

Proportion (percentage) of participants with any worsening on the NIAID ordinal scale 
from baseline to Day 15, and

Comparison from baseline to Day 29 for the emergence of viral resistance to LY3819253.
Mortality and categorical changes on the ordinal scale will be analyzed as discrete variables.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for safety, pharmacodynamic, or 


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population PK analysis purposes to avoid issues with post-hoc analyses and incomplete 
disclosures of analyses.
9.4.5.
Immunogenicity
If data from validated immunogenicity assays are available, treatment-emergent anti-drug 
antibodies (TE-ADAs) may be assessed. 
Treatment-emergent ADAs are defined as participants

with a 2-fold (1 dilution) increase in titer than the minimum required dilution if no ADAs 
were detected at baseline (treatment-induced ADA) or 

with a 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected 
at baseline (treatment-boosted ADA).
The frequency and percentage of participants with preexisting ADA and who are TE-ADA 
positive (TE-ADA+) to LY3819253 will be tabulated.  
The distribution of titers and frequency of neutralizing antibodies (if assessed) for the TE-ADA+ 
participants may also be tabulated.
The relationship between the presence of antibodies and PK parameters, PD response or safety to 
LY3819253 may also be assessed. Additional details may be provided in the SAP.
9.5.
Interim Analyses 
Periodic, unblinded reviews of PK, PD and safety data will occur throughout the study in 
addition to the scheduled dose escalation reviews.
If Cohort 4 proceeds, then up to 4 interim analyses may occur.  
Monitoring of unblinded safety data (including AEs, SAEs, and selected laboratory
measurements) will occur throughout the study and will be conducted by the ISAC. Details of 
the unblinded safety reviews, including the frequency and approximate timing, are specified in 
the ISAC charter.
The approximate timing, decision criteria, and statistical methods associated with each possible
modification to the ongoing study will be fully described in the SAP and ISAC Charter and 
finalized prior to the first study unblinding.  
9.6.
Data Monitoring Committee (DMC)
This study will not have a data monitoring committee.  Independent safety assessment committee 
information is in Section 10.1.5 and the ISAC charter.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable International Council for Harmonization (ICH) Good Clinical Practice (GCP) 
Guidelines, and

Applicable laws and regulations.
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC
before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, and

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable local regulations.
Investigator sites are compensated for participation in the study as detailed in the clinical trial
agreement.
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study.
10.1.3.
Informed Consent Process
The investigator or their representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative and answer all questions 
regarding the study.


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Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.
Due to strict respiratory isolation policies, limited access to COVID-19 patient rooms and SARS-
CoV-2 transmissibility via droplet-contaminated paper, verbal consent and alternative methods 
of obtaining consent (for example, by phone) will be allowed if approved by the IRB. 
If a signed paper copy of the ICF is allowed by hospital policy, how it will be obtained and 
stored will need to be determined. Any variation from the standard consent process due to 
isolation and infection control should be sent to the IRB for approval prior to enrollment.
The site should document the process in their regulatory files and demonstrate that the process 
has IRB concurrence or approval.
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent and, if applicable, the individual designated to 
witness a verbal consent, must also sign the ICF.
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative and is kept on file.
10.1.4.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets
or tissue samples that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred.
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The sponsor has processes in place to ensure data protection, information security and data 
integrity.  These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach.
10.1.5.
Committees Structure
The ISAC will consist of a chair external to Lilly and will include at least two other Lilly 
physicians external to the PYAA study team.  The ISAC will be engaged in dosing decisions or 
if any of the stopping criteria are met, and may also conduct periodic reviews of available data to


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make recommendations on study conduct. Details of the ISAC will be provided in the ISAC 
charter.
10.1.6.
Dissemination of Clinical Study Data
A clinical study report will be provided for this study and a summary of study information 
provided on publicly available websites. 
10.1.7.
Data Quality Assurance
Investigator responsibilities
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
Data monitoring and management
The Monitoring Plan includes

monitoring details describing strategy, for example, risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-based 
monitoring 

methods 

responsibilities 

requirements 

handling of noncompliance issues, and 

monitoring techniques.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  The sponsor assumes accountability for actions delegated to other 
individuals (e.g., contract research organizations).
Study monitors will perform ongoing source data verification to confirm that data entered in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents.  
They will also ensure that the safety and rights of participants are being protected, and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records retention and audits
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement (CTA)
unless local regulations or institutional policies require a longer retention period. 


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No records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written notification 
to the sponsor.
The sponsor or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site.  The study may be audited by the sponsor or 
its representatives, and by regulatory agencies at any time.  Investigators will be given notice 
before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Sponsor data 
warehouse.
Data from complaint forms submitted to Sponsor will be encoded and stored in the global 
product complaint management system.
10.1.8.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Current medical 
records must be available.
The definition of what constitutes source data can be found in Section 10.1.7.
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and enough notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator, or

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participants and assure 
appropriate participant therapy and/or follow-up.
10.1.10.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.
10.1.11.
Investigator Information
Physicians with a specialty in infectious disease, critical care, or pulmonary disease may
participate as investigators.


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10.1.12.
Long-Term Sample Retention
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of the 
intervention or after the intervention becomes commercially available.
This table describes the retention period for potential sample types.
Sample Type
Custodian
Retention Period After Last Participant Visit
Pharmacogenetics sample
Sponsor or designee
up to 7 years
Exploratory Biomarker Samples
Sponsor or designee
up to 7 years
Pharmacokinetic (PK) sample
Sponsor or designee
up to 2 years
Pharmacodynamic Samples
Sponsor or designee
up to 7 years
Immunogenicity (ADA) sample
Sponsor or designee
up to 7 years


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10.2.
Appendix 2: Clinical Laboratory Tests
Clinical laboratory tests will be performed according to the SoA.  
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations.
Pregnancy testing will be performed according to the SoA.
Central and local laboratories will be used.  The table below describes when the local or central 
laboratory will be used.
If the local laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be recorded in the CRF.
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5
of the protocol.
Investigators must document their review of the laboratory safety report as described in Section 
8.2.4.
Refer to Section 10.6 for recommended laboratory testing for hypersensitivity events.


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Clinical Laboratory Tests
Comments  
Hematology
Assayed by local laboratory
Hemoglobin
Hematocrit
Erythrocyte count (RBCs - Red Blood Cells)
Mean cell volume 
Mean cell hemoglobin
Leukocytes (WBCs - White Blood Cells) 
Differential
   Neutrophils, segmented
   Lymphocytes
   Monocytes
   Eosinophils
   Basophils
Platelets
Cell Morphology (RBC and WBC)
Clinical Chemistry
Assayed by local laboratory
Sodium
Potassium
Chloride
Bicarbonate
Total bilirubin
Direct bilirubin
Record on Day 1 and if abnormal values occur
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Record on Day 1 and if abnormal values occur
Blood urea nitrogen (BUN)
Creatinine 
Creatine kinase (CK)
Record on Day 1 and if abnormal values occur
Uric acid
Record on Day 1 and if abnormal values occur
Total protein
Albumin
Calcium
Record on Day 1 and if abnormal values occur
Phosphorus
Record on Day 1 and if abnormal values occur
Glucose
Amylase
Record on Day 1 and if abnormal values occur
Lipase
Record on Day 1 and if abnormal values occur
Lactate dehydrogenase (LDH)
Calculations
Completed locally
eGFR 
calculated by CKD-EPI equation
SARS-Cov-2 viral infection determination
Local laboratory


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Clinical Laboratory Tests
Comments  
SARS-Cov-2 Panel
C-Reactive Protein
Ferritin
D-dimer
Procalcitonin 
Troponin 
SARS-Cov-2 viral infection confirmation
Hormones (female)
Assayed by local laboratory.
Serum Pregnancy 
Urine Pregnancy
Pharmacokinetic (PK) Samples  
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Pharmacodynamic Sample
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
   SARS-Cov-2 test
Pharmacogenetics sample
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Exploratory Biomarker Samples
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Serum
   RNA (PAXGene)
Whole Blood (EDTA) 
   Whole Blood (EDTA) Epigenetics
Immunogenicity Samples
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
   Anti-LY3819253 antibodies 
   Anti-LY3819253 antibodies neutralization


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition
An AE is any untoward medical occurrence in a clinical study participant temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical 
study is to establish treatment effect.

The following study-specific clinical events related to COVID-19 are exempt from AE
reporting unless the investigator deems the event to be related to the administration of 
intervention:
o
Hypoxemia due to COVID-19 requiring supplemental oxygen;
o
Hypoxemia due to COVID-19 requiring non-invasive ventilation or high flow 
oxygen devices;
o
Respiratory failure due to COVID-19 requiring invasive mechanical ventilation 
or ECMO


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
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease under study, unless 
judged by the investigator to be more severe than expected for the participant’s 
condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure, such as endoscopy or appendectomy. The condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
Please note:  If an event is not an AE per definition above, then it cannot be an SAE.
An SAE is defined as any AE that:
a.
Results in death
b.
Is immediately life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital
for >”23 hour observation” and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
o
Examples of such events include intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by 
Sponsor or designee. In this case, all participant identifiers, except the participant number, will 
be redacted on the copies of the medical records before submission to Sponsor or designee.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity/Severity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories, which together with serious criteria 
on the AE CRF (“results in death” and “life-threatening”), are aligned with the Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 
2.1 (July 2017).
Mild: Mild symptoms causing no or minimal interference with usual social and functional 
activities, with intervention not indicated.


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Moderate: Moderate symptoms causing greater than minimal interference with usual 
social and functional activities, with intervention indicated.
Severe: Severe symptoms causing inability to perform usual social and functional 
activities, with intervention or hospitalization indicated.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.  
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
The investigator will also consult the investigator’s brochure and/or Product Information, for 
marketed products, in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very 
important that the investigator always assess the causality for every event before the initial 
transmission of the SAE data to Sponsor or designee.
The investigator may change their opinion of causality after consideration of follow-up 
information and send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.


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If a participant dies during participation in the study or during a recognized follow-up period,
the investigator will provide the sponsor or designee with a copy of any post-mortem findings 
including histopathology. 
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to Sponsor or designee within 24 hours of 
receipt of the information.
10.3.4.
Reporting of SAEs
SAE Reporting via Paper CRF
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor.
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames.
Contacts for SAE reporting can be found in site training documents.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Women
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Woman not of Childbearing Potential (WOCBP)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with either
a.
Documented hysterectomy
b. Documented bilateral salpingectomy, or
c.
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Müllerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with:
a.
12 months of amenorrhea for women >55, with no need for FSH
b. 12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and 
no other medical condition such as anorexia nervosa and not taking medications 
during the amenorrhea (e.g. oral contraceptives, hormones, gonadotropin 
releasing hormone, anti-estrogens, selective estrogen receptor modulators 
[SERMs], or chemotherapy that induced amenorrhea)
Participation in the Study
Women of child-bearing potential may participate in this study.
Women of child-bearing potential must test negative for pregnancy prior to initiation of 
treatment as indicated by a negative serum pregnancy test at the screening visit.
Women of child-bearing potential who are completely abstinent or in a same sex relationship, as 
part of their preferred and usual lifestyle, must agree to either remain abstinent or stay in a same 
sex relationship without sexual relationships with males.
All other women of child-bearing potential must agree to use two forms of effective 
contraception, where at least one form is highly effective (less than 1% failure rate), for the 
entirety of the study. 


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Abstinence or contraception must continue for 90 days after the last dose of intervention.
Acceptable Methods of Contraception
Highly effective methods of contraception (less than 1% failure rate) comprise, but are not 
limited to

combination oral contraceptives

implanted contraceptives, or 

intrauterine devices. 
Effective methods of contraception comprise but are not limited to diaphragms with spermicide 
or cervical sponges.  
Not Acceptable Methods of Contraception
Use of male and female condoms as a double barrier method is not considered acceptable due to 
the high failure rate when these barrier methods are combined.
Barrier protection methods without concomitant use of a spermicide are not an effective or 
acceptable method of contraception. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.
Men
Men, regardless of their fertility status, must agree to either remain abstinent (if this is their 
preferred and usual lifestyle) or use condoms as well as one additional highly effective method 
of contraception (less than 1% failure rate) or effective method of contraception with non-
pregnant women of child bearing potential partners for the duration of the study and until their 
plasma concentrations are below the level that could result in a relevant potential exposure to a 
possible fetus, predicted to be 90 days after the last dose.
Men with pregnant partners should use condoms during intercourse for the duration of the study 
and until the end of estimated relevant potential exposure to the fetus, predicted to be 90 days 
after the last dose.
Acceptable Methods of Contraception
Highly effective methods of contraception (less than 1% failure rate) comprise, but are not 
limited to

combination oral contraceptives

implanted contraceptives, or 

intrauterine devices. 
Effective methods of contraception comprise but are not limited to diaphragms with spermicide 
or cervical sponges.  


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Men and their partners may choose to use a double–barrier method of contraception that must 
include use of a spermicide.
Other Guidance
Men should refrain from sperm donation for the duration of the study and until their plasma 
concentrations are below the level that could result in a relevant potential exposure to a possible 
fetus, predicted to be 90 days after the last dose. 
Collection of Pregnancy Information
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive study intervention.
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. Generally, 
the follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported including fetal status (presence or absence of 
anomalies) and indication for the procedure. 
Female Participants who become pregnant
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study.  The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant's 
pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, including 
fetal status (presence or absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring at >20
weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting.


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Any female participant who becomes pregnant while participating in the study will be withdrawn 
from the study and will follow the standard discontinuation process.  


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Protocol number J2W-MC-PYAA(b)
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10.5.
Appendix 5: Genetics
Sample collection information is found in Appendix 2, Section 10.2 (Clinical Laboratory Tests).
Genetic variation may impact a participant’s response to study intervention, susceptibility to, and 
severity and progression of disease. Variable response to study intervention may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease being 
treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected 
for DNA analysis from consenting participants.
DNA samples may be used for research related to SARS-CoV-2 and related diseases. They may 
also be used to develop tests/assays including diagnostic tests related to LY3819253 or SARS-
CoV-2. Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome as appropriate.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to LY3819253 or study interventions of this class to understand study disease or 
related conditions.
The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate 
study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained at a facility selected by the sponsor or its designee while research 
on SARS-CoV-2 continues but no longer than 7 years or other period as per local requirements.


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Protocol number J2W-MC-PYAA(b)
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10.6.
Appendix 6: Recommended Laboratory Testing for Hypersensitivity 
Events.
Laboratory assessments should be performed if the participant experiences generalized urticaria 
or if anaphylaxis is suspected.

Collect sample after the participant has been stabilized, and within 1 to 2 hours of the 
event; however, samples may be obtained as late as 12 hours after the event as analytes 
can remain altered for an extended period of time.  Record the time at which the sample 
was collected.

Obtain a follow-up sample after approximately 4 weeks.


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Protocol number J2W-MC-PYAA(b)
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Clinical Lab Tests for Hypersensitivity Events
Hypersensitivity Tests
Notes
Selected test may be obtained in the event of anaphylaxis or 
systemic allergic/hypersensitivity reactions.
LY3819253 anti-drug 
antibodies 
(immunogenicity/ADA)
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
LY3819253 concentrations 
(PK)
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Tryptase
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Urine N-methylhistamine testing is performed in addition to 
tryptase testing. Collect the first void urine following the event. 
Collect a follow-up urine sample after approximately 4 weeks.
Note: If a tryptase sample is obtained more than 2 hours after the
event (that is, within 2 to 12 hours), or is not obtained because more 
than 12 hours have lapsed since the event, collect a urine sample for 
N-methylhistamine testing. 
N-methylhistamine
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Drug-specific IgE
Will be performed if a validated assay is available.
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Basophil activation test
Will be performed if a validated assay is available.
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
NOTE: The basophil activation test is an in vitro cell based assay 
that only requires a serum sample. It is a surrogate assay for drug 
specific IgE but is not specific for IgE.
Complement (C3, C3a and 
C5a)
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Cytokine panel
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Abbreviations: IgE = immunoglobulin E; PK = pharmacokinetic.


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Protocol number J2W-MC-PYAA(b)
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10.7.
Appendix 7:  Nasopharyngeal Swab Instructions
Personal Protective Equipment for healthcare provider collecting specimen: 
•
N95 or higher-level respirator (or facemask if a respirator is not available), eye 
protection, gloves, and a gown.
Nasopharyngeal swab: 
•
Use only synthetic fiber swabs with plastic or wire shafts. 
•
Have participant blow nose to clear.  Provide tissues for participant in case of sneeze.
•
Insert minitip swab with a flexible shaft (wire or plastic) through the nostril parallel to the 
palate (not upwards) until resistance is encountered or the distance is equivalent to that 
from the ear to the nostril of the participant, indicating contact with the nasopharynx. 
•
Swab should reach depth equal to distance from nostrils to outer opening of the ear. 
•
Gently rub and roll the swab. Leave swab in place for several seconds to absorb 
secretions. 
•
Slowly remove swab while rotating it. 
•
Repeat in other nostril using same swab unless there is an obstruction from a deviated 
septum or other blockage. 
•
Swabs should be placed immediately into a sterile transport tube containing 2-3 mL of 
viral transport medium and stored at 2-8°C for up to 72 hours, then at -70°C or below.


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Protocol number J2W-MC-PYAA(b)
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10.8.
Appendix 8: FDA Guidance for Industry - Baseline Severity 
Categorization for COVID-19.
This appendix contains pages from the COVID-19: Developing Drugs and Biological Products 
for Treatment or Prevention Guidance for Industry by the U.S. Department of Health and 
Human Services, FDA, Center for Drug Evaluation and Research (CDER), and Center for 
Biologics Evaluation and Research (CBER), dated May 2020 (FDA resource page, [WWW]).


CONFIDENTIAL
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10.9.
Appendix 9: Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
ADE
antibody-dependent enhancement
blinding
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
CIOMS
Council for International Organizations of Medical Sciences
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.
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.
ECG
electrocardiogram
EDC
electronic data capture system
enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Informed consent
A process by which a participant 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 participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form.
intervention
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IWRS
interactive web-response system


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NIAID
National Institute of Allergy and Infectious Diseases
NIH
National Institutes of Health
NEWS2
National Early Warning Score
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PK/PD
pharmacokinetics/pharmacodynamics
SAE
serious adverse event
SAP
statistical analysis plan
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. 
WHO
World Health Organization


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10.10.
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment (a): 01 June 2020
Overall Rationale for Amendment (a):
This amendment addresses the United States Food and Drug Administration (FDA) feedback.  
Additional changes were made to address newly available internal or external information.  
Other changes were made for clarity and consistency.  This table describes the changes made for 
Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Title Page
Changed PIND to IND
Per FDA
Synopsis
Changes to secondary objectives 
and endpoints
To match changes in Section 3. 
Synopsis
Updates to general sequence of 
events during double-blind 
treatment and assessment period
To more accurately represent the sequence
Synopsis
Updated Number of Participants 
and Intervention Groups and 
Duration sections.
Based on new internal and external information
Synopsis
Updated when the independent 
safety assessment committee will 
be engaged
Per FDA feedback
Schema
Updates to cohort 4 and sample 
size
Cohort 4 will not have sentinel dosing because the 
dose level will not exceed dose level 3.  Removed 
the sample size information for all cohorts that 
was no longer correct and removed indicator for 
sentinel dosing for Cohort 4. 
1.3 Schedule of 
Activities
Screening visit window update
Correction to align with randomization and dosing
1.3 Schedule of 
Activities
Vital Signs - updated 
comments/instructions
Per FDA feedback
1.3 Schedule of 
Activities
Clinical symptoms - updated 
comments/instructions
For clarity
1.3 Schedule of 
Activities
Pharmacokinetic (PK), 
pharmacodynamic (PD), 
immunogenicity and exploratory 
biomarker samples – updated 
comments/instructions
For clarity
3 Objectives and 
Endpoints
Secondary PK objective 
endpoint changed
More clinically meaningful
3 Objectives and 
Endpoints
Secondary PD objective 
endpoint
Added timepoints for analysis
3 Objectives and 
Endpoints
Moved PD secondary endpoint 
to exploratory
Decision that viral clearance should be exploratory


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Protocol number J2W-MC-PYAA(b)
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Section # and Name
Description of Change
Brief Rationale
3 Objectives and 
Endpoints
Added 2 exploratory objectives
Per FDA feedback
4.1. Overall Design
Updates to general sequence of 
events during double-blind 
treatment and assessment period
To more accurately represent the sequence
4.1.1. Single-ascending 
Dose Design
Updated text for the change with 
Cohort 4
Cohort 4 increase in sample size
4.2. Scientific Rationale 
for Study Design
Added text for Cohort 4
Cohort 4 increase in sample size
4.2. Scientific Rationale 
for Study Design
Updated text for participant 
population
The I/E criteria were updated to provide more 
clarity, and the severity of illness definitions were 
changed to the FDA definitions.
4.3. Justification for 
Dose
Updated projected half-life and 
in vitro IC90
New data available for the updates
5.1 Inclusion Criteria
Increased age limit to 85 years
Based on clinical site feedback
5.1 Inclusion Criteria
Updated disease characteristics 
In order to provide more clarity based on clinical 
site feedback.  Severity definitions were updated 
to those provided by the FDA.
5.1 Inclusion Criteria
Removed criterion describing 
symptoms
Not needed because of the update to the disease 
characteristics
5.1 Inclusion Criteria
Updated criterion for 
hospitalization
Corrected the timing
5.1 Inclusion Criteria
Criterion #6 was merged with 
Criterion 5
Correction 
5.2. Exclusion Criteria
Updated criterion for mechanical 
ventilation to state, “invasive 
mechanical ventilation”
For clarity
5.2. Exclusion Criteria
The timing of SpO2 
measurement while breathing 
room air was changed to occur at 
screening
SpO2 is measured at screening and instructions 
were added for participants on supplemental 
oxygen.
5.2. Exclusion Criteria
Removed respiratory rate 
criterion 
It is covered in the new update to disease 
characteristics in the inclusion criteria
6.1. Study 
Intervention(s) 
Administered
Added information about Cohort 
4.
Instructions for infusion volume and rate will be in 
the pharmacy instructions.
6.1. Study 
Intervention(s) 
Administered
Updated the monitoring 
instructions
Per FDA feedback
6.1.1.2. Management of 
Infusion Reactions
Removed table of specific 
guidelines 
Investigators should determine the severity of the 
infusion reaction and manage the reactions based 
on standard of care and their clinical judgment.
6.5. Concomitant 
Therapy
Updated text about standard of 
care and allowing remdesivir 
during the study
Per FDA feedback


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Protocol number J2W-MC-PYAA(b)
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Section # and Name
Description of Change
Brief Rationale
6.6.1. Dose escalation 
criteria
Updated when the independent 
safety assessment committee 
(ISAC) would be engaged for 
reviews
Per FDA feedback
6.6.2. Temporary 
Stopping Criteria
Removed redundant text
Already stated in Section 6.6.1.
8.2.4. Clinical 
Laboratory 
Assessments
Updated required text
Per Lilly required language
8.3.5. Pregnancy
Updated collection timing to 90 
days
New data available for the update
8.3.7. Infusion-related 
Reactions
Updated table
Removed link to table that was removed in Section 
6.1.1.2.
8.9. Immunogenicity
Removed “predose”
Refer to SoA for sample times
8.6. Pharmacodynamics
Updated text to clarify how the 
samples may be used
Per FDA feedback
9.2. Sample Size 
Determination
Updated sample size information 
Based on new internal and external information
9.2. Sample Size 
Determination
Corrected Bayesian critical 
success factor equation
correction
9.4.1. General 
Considerations
Updated table
corrections
9.4.1. General 
Considerations
updated one sentence and 
removed another
corrections
9.4.2. Safety analyses
Removed listings
Parameters will not be listed, only summarized
9.4.4. Exploratory 
Endpoints
Addition of exploratory endpoint
Per Section 3. Objectives and Endpoints
9.4.3. Pharmacokinetic 
and Pharmacodynamic 
Analyses
Updated PK and PD analyses
To match endpoints in Section 3.
9.4.4. Exploratory 
Endpoints
Updated exploratory endpoints
To match table in Section 3.
10.1.5. Committees 
Structure
Updated when the Independent 
Safety Assessment Committee 
(ISAC) will be engaged
Per FDA feedback
10.1.12. Long-term 
sample Retention
Updated sample retention times
Per internal Lilly decision
10.2. Appendix 2: 
Clinical Laboratory 
Tests
Updates to text
For clarity
10.4. Appendix 4: 
Contraceptive Guidance 
and Collection of 
Pregnancy Information
Updated collection timing to 90 
days
New data available for the update
10.5. Appendix 5: 
Genetics
Updated sample retention time
Per internal Lilly decision
10.8. Appendix 8
Added an appendix to contain 
FDA resource page
The COVID-19 severity criteria from this resource 
page will be used for inclusion criteria purposes


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Protocol number J2W-MC-PYAA(b)
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Section # and Name
Description of Change
Brief Rationale
Section 11 References
Added FDA reference
For inclusion criteria
Throughout the 
protocol
Minor editorial and formatting 
changes
Minor, therefore not described


CONFIDENTIAL
Protocol number J2W-MC-PYAA(b)
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11.
References
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events. National Institute of Allergy and Infectious Diseases. National Institutes of Health. US 
Department of Health and Human Services. Corrected version 2.1. July 2017. Available at: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed: 14 April 
2020.
Duan K, Liu B, Li, C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, 
Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, 
Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, 
Gong Q, Zhang W, Zheng, X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, 
Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. 
PNAS. 2020. Available at: https://doi.org/10.1073/pnas.2004168117.
FDA resource page. COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention Guidance for Industry. Food and Drug Administration web site. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-
developing-drugs-and-biological-products-treatment-or-prevention. Accessed 26 May 2020.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrier T, Erichsen S, Schiergens TS, 
Herrler G, Wu NH, Nitsche A, Müller M, Drosten C, Pöhlmann, S. SARS-Cov-2 Cell Entry 
Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. 
Cell. 2020;181:1-10. DOI:10.1016/j.cell.2020.02.052.
Liu Y, Sun W, Li J, Chen L, Wang Y, Zhang L, Yu L. Clinical features and progression of acute 
respiratory distress syndrome in coronavirus disease 2019. medRxiv. Posted 27 February
2020. preprint DOI: https://doi.org/10.1101/2020.02.17.20024166. 
National Institutes for Health (NIH) resource page. Management of Persons with COVID-19.  
NIH web site. Available at:
https://covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/. Accessed: 08 
May 2020.
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, SXing L, Wei J, Xiao 
H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, 
Liu D, Zhang Z, Liu Y, Liu Lei. Treatment of 5 Critically Ill Patients with COVID-19 With 
Convalescent Plasma. JAMA. Published online 27March2020. DOI:10.1001/jama.2020.4783.

SAP_001.pdf: 
Statistical Analysis Plan: J2W-MC-PYAA
A Randomized, Placebo-Controlled, Double-Blind, Sponsor Unblinded, Single Ascending 
Dose, Phase 1 First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of Intravenous LY3819253 in Participants Hospitalized for 
COVID-19
NCT04411628   
Approval Date: 04-Jun-2020


Final, 04 June 2020
             Page 1 of 22
STATISTICAL ANALYSIS PLAN
A Randomized, Placebo-Controlled, Double-Blind, Sponsor Unblinded, Single Ascending 
Dose, Phase 1 First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of Intravenous LY3819253 in Participants Hospitalized for 
COVID-19
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 04-June-2020
Study Drug: LY3819253
Sponsor Reference: J2W-MC-PYAA
Covance CRU Study: 1001215-8440133
Clinical Phase I
Approval Date: 04-Jun-2020 GMT


Final, 04 June 2020
             Page 2 of 22
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary Objective..........................................................................................................6
4.2
Secondary Objectives ....................................................................................................6
4.3
Exploratory Objective....................................................................................................6
5.
STUDY ENDPOINTS .........................................................................................................7
5.1
Primary Endpoint ..........................................................................................................7
5.2
Secondary Endpoints.....................................................................................................7
5.3
Exploratory Endpoints...................................................................................................7
6.
STUDY DESIGN.................................................................................................................7
7.
TREATMENTS...................................................................................................................9
8.
SAMPLE SIZE JUSTIFICATION .......................................................................................9
9.
DEFINITION OF ANALYSIS POPULATIONS..................................................................9
10. STATISTICAL METHODOLOGY ...................................................................................10
10.1 General........................................................................................................................10
10.2 Demographics and Participant Disposition...................................................................10
10.3 Pharmacokinetic Assessment.......................................................................................11
10.3.1
Pharmacokinetic Analysis...................................................................................11
10.3.2
Pharmacokinetic Statistical Methodology ...........................................................15
10.4 Pharmacodynamic Assessment ....................................................................................15
10.4.1
Pharmacodynamic Analysis................................................................................15
10.4.2
Pharmacodynamic Statistical Methodology ........................................................16
10.5 Efficacy Assessments ..................................................................................................18
10.5.1
Hospitalization and clinical events, clinical status, and 
environmental risk factors ..................................................................................18
10.6 Safety and Tolerability Assessments............................................................................19
10.6.1
Adverse events ...................................................................................................19
10.6.2
Medical history, pre-existing conditions, and prior medication ...........................20
10.6.3
Concomitant medication.....................................................................................20
10.6.4
Chest x-ray.........................................................................................................20
10.6.5
Clinical laboratory parameters............................................................................20
10.6.6
Vital signs ..........................................................................................................20
10.6.7
Immunogenicity Assessments.............................................................................20
10.6.8
Hypersensitivity reactions...................................................................................21
10.6.9
Infusion-related Reactions ..................................................................................21


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
10.6.10 Other assessments...............................................................................................21
10.6.11 Safety and Tolerability Statistical Methodology..................................................21
11. INTERIM ANALYSES .....................................................................................................21
12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............21
13. REFERENCES ..................................................................................................................21
14. DATA PRESENTATION ..................................................................................................22
14.1 Derived Parameters .....................................................................................................22
14.2 Missing Data ...............................................................................................................22
14.3 Insufficient Data for Presentation ................................................................................22


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ADA
Anti-drug antibody
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-∞)
AUC from time 0 to infinity
AUC(0-D29)
AUC from Day 1 to Day 29
AUC(0-tlast)
AUC from time 0 to the time of the last quantifiable concentration
CI
Confidence interval
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CSR
Clinical Study Report
CT
Cycle time
CV
Coefficient of variation
DAIDS
Division of Allergy and Infectious Diseases
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
ICU
Intensive care unit
ISAC
Independent safety assessment committee
IV
Intravenous
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
NEWS2
National Early Warning Score
NIAID
National Institute of Allergy and Infectious Diseases
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2


Final, 04 June 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
SD
Standard deviation 
SoA
Schedule of assessments
SpO2
Saturation of peripheral oxygen
TE ADA
Treatment-emergent ADAs
TE ADA+
Positive treatment-emergent ADAs
TFLs
Tables, Figures, and Listings
Tmax
Time to reach Cmax
WHO
World Health Organization


Final, 04 June 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
09 May 2020) and Protocol Amendment (a) (final version dated 01 June 2020).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical, PK, and PD analyses of 
data. In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Eli Lilly and Company. A limited amount of information 
concerning this study (e.g., objectives, study design) is given to help the reader’s interpretation. 
When the SAP and TFL shells are agreed upon and finalized, they will serve as the template for 
this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective
The primary objective of this study is to characterize the safety and tolerability of LY3819253 
after intravenous (IV) infusion.
4.2
Secondary Objectives
The secondary objectives of this study are:

To characterize the PK of LY3819253 after IV infusion.

To characterize the PD of LY3819253 after IV infusion.
4.3
Exploratory Objective
The exploratory objectives of this study are:

To characterize the participant’s clinical status.


Final, 04 June 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA

Characterize the pharmacodynamics of LY3819253 after intravenous infusion.

Characterize emergence of viral resistance to LY3819253.
5. STUDY ENDPOINTS
5.1
Primary Endpoint

Safety assessments such as adverse events (AEs) and serious AEs (SAEs).
5.2
Secondary Endpoints

LY3819253 mean concentration on Day 29.

Change from baseline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
viral load (Days 7, 11, 15, and 22).

SARS-CoV-2 viral load area under the concentration versus time curve (AUC).

Time to SARS-CoV-2 clearance.
5.3
Exploratory Endpoints

Duration (days) of hospitalization.

Proportion (percentage) of participants admitted to intensive care unit (ICU).

Proportion (percentage) of participants requiring mechanical ventilation.

Score using the National Institute of Allergy and Infectious Diseases (NIAID) and World 
Health Organization (WHO) ordinal scale or live discharge from hospital at pre-specified 
time points.

National Early Warning Score (NEWS2) score at pre-specified time points.

Proportion (percentage) of participants with at least a 2-point improvement on the NIAID
and WHO ordinal scale or live discharge from hospital at pre-specified time points.

NEWS2 score at pre-specified time points.

Proportion (percentage) of participants with any worsening on the NIAID ordinal scale 
from baseline to Day 15.

Proportion of participants that achieve SARS-CoV-2 clearance (Days 7, 11, 15, 22).

Emergence of viral resistance to LY3819253 from baseline to Day 29.
6. STUDY DESIGN
Study PYAA is a Phase 1, double-blind, sponsor unblinded, randomized, placebo-controlled,
single-ascending dose study in participants hospitalized for COVID-19.
The study will comprise up to 4 dose cohorts. Cohorts 1-3 will compromise at least 8 
participants:


 
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 6 randomized to LY3819253 and 
 2 randomized to placebo. 
Sentinel dosing will be used in any dose cohort that represents a dose increase from the 
preceding cohort. The first 2 participants in each cohort will be randomized 1:1 to LY3819253 
and placebo. 
Safety and tolerability will be reviewed for sentinel participants up to 24 hours after dosing. The 
investigator and the Lilly sponsor team are responsible for determining if safety and tolerability 
is acceptable to continue with dosing subsequent participants. Subsequent participants will be 
randomized to the remaining treatment allocations, 5 to LY3819253 and 1 to placebo. 
The decision to dose the next cohort will be made when all participants from the previous cohort 
have been dosed and safety data is assessed for at least 4 days after the IV infusion by the 
investigator(s) and Lilly sponsor team in consultation with an independent safety assessment 
committee (ISAC). 
Cohort 4 may be initiated, at the discretion of the sponsor team, if more data is needed to inform 
the dose of LY3819253. 
Figure 1 - Sequential single ascending dose schema of study J2W-MC-PYAA 


 
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7. TREATMENTS 
The following is a list of the study treatment abbreviations that will be used in the TFLs. 
Cohort 
Study Treatment Name* 
Treatment order in TFL 
All 
Pooled placebo IV 
1 
1 
700 mg LY3819253 IV 
2 
2 
2800 mg LY3819253 IV 
3 
3 
7000 mg LY3819253 IV 
4 
4 (optional) 
TBD mg LY3819253 IV 
5 
Abbreviations: IV = intravenous; TBD = to be determined. 
* Planned doses presented - the actual dose administered will be displayed in the TFLs. 
8. SAMPLE SIZE JUSTIFICATION 
For Cohorts 1-3, approximately 24 participants will be randomized to receive one of three dose 
levels of LY3819253 or placebo. Additional participants may be required to ensure a minimum 
of 8 participants in each cohort complete 7 days of study assessments. Up to a maximum of 3 
additional participants per cohort may be added. 
Participant viral loads over time were simulated using a representative PK/PD model to enable a 
Monte Carlo assessment of the power of the trial to detect a 30% treatment difference in mean 
AUC (28 day) of viral load. This assessment revealed greater than 90% probability of meeting 
the following Bayesian critical success factor: 
Pr ((mean AUCPL – mean AUCLY)/ mean AUCPL > 0.3) > 0.60 
PL = placebo, LY = LY3819253 
Additionally, the anticipated 6 participants per treatment provides greater than 80% probability 
(within each treatment arm) of observing safety events of reasonable prevalence (that is, at least 
25%) to support the primary objective of safety assessment.  
For the optional Cohort 4, up to 100 participants may be randomized in an approximate 1:1 ratio 
to receive either LY3819253 or placebo.  The overall numbers of participants randomized to 
LY3819253 and placebo in this study will provide 60% power to detect a reduction in the rate of 
clinical worsening from 22% to 9% (one-sided alpha=0.05).  Clinical worsening is defined as the 
proportion (percentage) of participants with any worsening on the NIAID ordinal scale from 
baseline to Day 15.  
A participant is only allowed to receive one IV infusion in one cohort. 
9. DEFINITION OF ANALYSIS POPULATIONS 
The “Entered” population will consist of all participants who sign the informed consent form. 


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The “Safety” population will consist of all participants randomly assigned and who received 
study intervention (either placebo or LY3819253). Participants will be analyzed according to the 
intervention they actually received.
The “Pharmacokinetic” population will consist of all randomized participants who received 
study intervention (LY3819253) and have at least one evaluable PK sample. Participants will be 
analyzed according to the intervention they actually received.
The “Pharmacodynamic” population will consist of all randomized participants who received 
study intervention (either placebo or LY3819253) and provided at least one post-baseline 
measure for the relevant endpoint. Participants will be analyzed according to the intervention 
they actually received.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations.
10.
STATISTICAL METHODOLOGY
10.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and maximum observed 
drug concentration [Cmax]) the geometric mean and geometric coefficient of variation (CV%) 
will also be presented. For categorical and ordinal data, frequency count and percentages will be 
presented. Data listings will be provided for all participants up to the point of withdrawal, with 
any participants excluded from the relevant population highlighted. Summary statistics and 
statistical analyses will generally only be performed for participants included in the relevant 
analysis population. For the calculation of summary statistics and statistical analysis, unrounded 
data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
10.2
Demographics and Participant Disposition
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
ethnicity, country of enrolment, site ID, body weight, height, body mass index and saturation of 
peripheral oxygen (SpO2) will be summarized and listed. All other demographic variables will 
be listed only. Additional clinic meaningful parameters may be added if deemed necessary.


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10.3
Pharmacokinetic Assessment
10.3.1
Pharmacokinetic Analysis
PK analysis will be the responsibility of the Eli Lilly PK/PD group prior to database lock.  
PK parameter estimates for LY3819253 will be calculated using standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be geometric mean of concentration on Day 29. Other 
noncompartmental parameters, such as half-life, AUC from time 0 to infinity (AUC[0-∞]), AUC 
from time 0 to Day 29 (AUC[0-D29]), Cmax, clearance, and volume of distribution may be 
reported.
Additional population PK model-based analyses may be performed.
Noncompartmental methods applied with a validated software program (Phoenix WinNonlin 
Version 8.1 or later) to the serum concentrations of LY3819253 will be used to determine the 
following PK parameters, when possible: 
Parameter
Unitsa
Definition
AUC(0-D29)
µg.h/mL
Area under the concentration versus time curve from time zero to 
time t, where t is Day 29
AUC(0-tlast)
µg.h/mL
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
µg.h/mL
Area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
%
Percentage of AUC(0-∞) extrapolated
tlast
Time of the last observed drug concentration
Cmax
µg/mL
Maximum observed drug concentration
CD29
µg/mL
Observed drug concentration on Day 29
tmax
h
Time of maximum observed drug concentration
t½
h
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL
L/h
Total body clearance of drug calculated 
Vz
L
Volume of distribution during the terminal phase
Vss
L
Volume of distribution at steady state 
a Units of source LY3819253 serum concentration data will be ng/mL, to one decimal place.
Additional PK parameters may be calculated, as appropriate.  
The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the final study report.


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Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and time of maximum observed drug concentration (tmax) will be reported from 
observed values. If Cmax occurs at more than one time point, tmax will be assigned to the 
first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive serum concentrations above the lower limit of quantification, with at least 
one of these concentrations following Cmax.

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal log-
linear portion of the concentration-time curve. The start of the terminal elimination phase 
for each participant will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in serum
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on predicted last quantifiable drug concentration will be reported 
(except in bioequivalence and bioavailability studies, where only the observed parameters 
will be reported).
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantification (BQL).  Serum concentrations reported as BQL will be set to a value of 
zero when all of the following conditions are met:


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o
The compound is non-endogenous.
o
The samples are from the initial dose period for a patient or from a 
subsequent dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.


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Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.


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Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
10.3.2
Pharmacokinetic Statistical Methodology
All PK parameters will be summarized by treatment using descriptive statistics.
The PK parameter estimates will be evaluated to delineate dose proportionality. Log-transformed 
Cmax, and AUC(0-∞) of LY3819253 will be evaluated using a power model (where log-dose acts 
as an explanatory variable) to estimate ratios of dose-normalized geometric means and 
corresponding 90% confidence intervals. Results of the dose proportionality analysis will be 
plotted.
The estimated ratio of dose-normalized geometric means of PK parameters between the highest 
and lowest doses will be used to assess dose proportionality.
Example SAS code for the analysis:
proc mixed data=pk;
model log_pk = log_dose / alpha=0.1 cl solution residual ddfm=kr2;
estimate '700 mg' intercept 1 log_dose 2.87506126 / alpha=0.1 cl; /*Log of 700 */
estimate '2800 mg' intercept 1 log_dose 3.44715803 / alpha=0.1 cl; /*Log of 2800 */
estimate '7000 mg' intercept 1 log_dose 3.84509804 / alpha=0.1 cl; /*Log of 7000 */
estimate '2800 mg - 250 mg'    log_dose 0.97003679 / alpha=0.1 cl; /*Difference in
log values of 7000 and 700 */
ods output solutionf=est;
ods output estimates=estims;
run;
10.4
Pharmacodynamic Assessment
10.4.1
Pharmacodynamic Analysis
The PD endpoints for this study are: 

Change from baseline in SARS-CoV-2 viral load (Days 7, 11, 15 and 22)

Viral load AUC (Day 1 to 29)

Proportion of participants that achieve SARS-CoV-2 clearance (Days 7, 11, 15, 22)

Time to SARS-CoV-2 clearance

Viral resistance to LY3819253 (from baseline to Day 29)
Viral clearance is defined as two consecutive negative SARS-CoV-2 values from the 
nasopharyngeal swabs. When deriving clearance, any missing data from the nasopharyngeal 
swabs will be set to positive. Time to SARS-CoV-2 clearance is defined as the earliest timepoint 
of the two.
If these two negative values are followed by a subsequent positive value, this measurement will 
be flagged and considered for evaluation of viral mutation or resistance.


 
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10.4.2 Pharmacodynamic Statistical Methodology 
SARS-CoV-2 viral load 
SARS-CoV-2 viral load will be measured using the cycle time (CT) from a polymerase chain 
reaction (PCR) assay. Higher CT values indicate a lower viral load. 
SARS-CoV-2 viral load, including changes from baseline, will be summarized and plotted by 
treatment, and listed. Baseline is defined as the Day 1 predose assessment. Overlaying individual 
profiles of SARS-CoV-2 viral load data will also be presented graphically over time.   
Changes from baseline in SARS-CoV-2 viral load data will be statistically analyzed using a 
mixed model for repeated measures (MMRM). The model will contain baseline as a covariate, 
treatment, day and treatment-by-day interaction as fixed effects, and subject as a random effect. 
The unstructured covariance matrix will be selected initially; if this analysis fails to converge 
another covariance structure will be selected based on AIC and BIC values. The least square 
(LS) means and treatment differences (LY3819253 minus pooled placebo at each dose level) will 
be calculated and presented with their corresponding 90% confidence intervals (CIs). All 
available data will be used in the analysis.  
An example of the SAS code that will be used is as follows: 
proc mixed data=xxx; 
class trtmnt subject day; 
model chg = base trtmnt day trtmnt*day / alpha=0.1 cl ddfm=kr2; 
repeated day / subject=subject type=un; 
lsmeans trtmnt*day / alpha=0.1 cl pdiff ; 
ods output lsmeans=lsm01  diffs=diff01; 
run; 
where chg is the change from baseline, base is the baseline in SARS-CoV-2 viral load data, day 
is the study day, and trtmnt is the treatment used in the comparison. 
A Bayesian linear mixed effect model will be fitted to evaluate the critical success factor by Lilly 
statistics group with the model listed below: 
            ݕ௜௝௞ൌߤ൅ߙൈܾܽݏ݁൅ߙ௜൅ߚ௞൅ሺߙߚሻ௜௞൅ߝ௜௝൅ߝ௜௝௞ 
   Where ݕ௜௝௞: the change from baseline for treatment i, subject j at day k 
              µ:  a constant common to all observations 
              α: a fixed coefficient on the covariate baseline viral load 
              αi: a parameter corresponding to treatment i 
             βk: a parameter corresponding to day k 


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             (αβ)ik: an interaction parameter corresponding to treatment i and day k
              εij, εijk: random error for between and within subject variability
        prior  µ, α, αi, βk, (αβ)ik ~ N(0, 100)
                  εij ~ N(0, σ1),  εijk ~ N(0, σ2)
                 σ1, σ2 ~ uniform(0, 100) or igamma(0.01,0.01)
           the posterior of the following quantity will be assessed:
                      pr(ΔanyLYdose – Δplacebo<-0.3)>0.6 at Day 7, 11, 15, and 22 in log base 10 scale.
SARS-CoV-2 viral load AUC
The AUC from Day 1 predose to Day 29 (AUC[0-D29]) will be calculated according to the 
linear trapezoidal rule using the measured SARS-CoV-2 viral load-time values above the lower 
limit of quantification. No imputations of missing data will be conducted. No AUC(0-D29)
values will be calculated when Day 1 predose and/or Day 29 values are missing, or if there are 
more than 3 values missing in the profile.
The AUC(0-D29) will be summarized and plotted by treatment and listed.
Additionally, AUC(0-D29) data will be statistically analyzed using a linear model. The model 
will contain treatment as a fixed effect and baseline viral load as a covariate. The least square 
(LS) means and treatment differences (LY3819253 minus pooled placebo at each dose level) will 
be calculated and presented with their corresponding 90% confidence intervals (CIs). All 
available data will be used in the analysis.
An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
class trtmnt;
model AUC = base trtmnt / alpha=0.1 cl ddfm=kr2;
lsmeans trtmnt / alpha=0.1 cl pdiff;
ods output lsmeans=lsm01;
ods output diffs=diff01;
run;
where AUC is the AUC(0-D29) data, trtmnt is the treatment used in the comparison, and base is 
the baseline viral load.
Similar Bayesian model listed in Section 10.4.2 by removing the day, interaction, and within 
subject error term will be applied for AUC measure analysis.


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SARS-CoV-2 clearance
The proportion of patients that achieve SARS-CoV-2 clearance will be summarized by treatment 
in frequency tables, and listed.
In addition, the number of patients that achieve SARS-Cov-2 clearance will be analyzed using a 
Chi-square test to compare LY3819253 versus pooled placebo at each dose level, if there are 
sufficient data available.
An example of the SAS code that will be used is as follows:
proc freq data=xxx;
weight count;
table trtmnt*clear / chisq all;
run;
where trtmnt is the treatment used in the comparison, clear is the SAR-CoV-2 clearance (yes/no), 
and count is the corresponding number of patients.
Additional analyses on viral clearance, such as logistic regression with treatment as a fixed 
effect, may be conducted as deemed appropriate and where sufficient data are available.
Time to SARS-CoV-2 clearance
The time to SARS-CoV-2 clearance will be summarized by treatment, and listed.
In addition, a graphical presentation of the clearance times will be provided using a 
Kaplan-Meier plot.
Viral Resistance to LY3819253
Participant who show signs of viral resistance will be summarized in frequency tables by 
treatment and listed.
PK/PD Modeling 
Additional PK/PD exposure-response modeling of viral dynamics may be conducted. These 
analyses will be the responsibility of Eli Lilly PK/PD group. 
10.5
Efficacy Assessments
10.5.1
Hospitalization and clinical events, clinical status, and environmental risk factors
All hospitalization events, procedures of special interest, and environmental risk factors will be 
listed.
The following data will be summarized by treatment using descriptive statistics:

Duration of hospitalization (in days);


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
Score on the NIAID ordinal scale at pre-specified time points;

Score on the WHO ordinal scale at pre-specified time points;

NEWS2 score at pre-specified time points.
The following data will be summarized by treatment using frequency tables:

Proportion (percentage) of participants admitted to ICU;

Proportion (percentage) of participants requiring mechanical ventilation;

Proportion (percentage) of participants with at least a 2 point improvement on the NIAID
scale or live discharge from hospital from baseline at any time during the study;

Proportion (percentage) of participants with at least a 2-point improvement on the WHO 
ordinal scale or live discharge from hospital from baseline at any time during the study;

Proportion (percentage) of participants with any worsening on the NIAID ordinal scale
from baseline to Day 15;

Proportion (percentage) of participants with at least a 2-point worsening on the NIAID 
ordinal scale from baseline at any time during the study;

Consciousness level score assessed by NEWS2;

Severity of pre specified clinical events (fever, cough, and shortness of breath).
10.6
Safety and Tolerability Assessments
10.6.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the participant has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing, and that does not worsen postdose. 
A treatment-emergent AE is defined as an AE which occurs postdose or which is present prior to 
dosing and becomes more severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of participants 
experiencing an AE and the percentage of participants experiencing an AE) of 
treatment-emergent AEs will be summarized by treatment, Medical Dictionary for Regulatory 
Activities (MedDRA) version 23.0 system organ class and preferred term. The summary and 
frequency AE tables will be presented for all causalities and those considered related to the study 
drug by the investigator. Any serious AEs will be listed. 
The severity of infusion reactions will be graded using the table for assessing acute allergic 
reactions and events of cytokine release syndrome in protocol Section 6.1.1.2.; all other AEs will 
be graded for severity using the definitions of mild, moderate and severe provided in protocol 
Section 10.3.3. from the Division of Allergy and Infectious Diseases (DAIDS) Table for Grading 
the Severity of Adult and Pediatric Adverse Events, version 2.1 (July 2017).
Discontinuations of study intervention and/or of study due to AEs will be listed.


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10.6.2
Medical history, pre-existing conditions, and prior medication
All medical history, pre-existing conditions and prior medication data will be listed.
10.6.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version Global B3 
202003 / WHODD MAR20B3). Concomitant medication will be listed.
10.6.4
Chest x-ray
All chest x-ray data will be listed.
10.6.5
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment
together with changes from baseline, and listed. Baseline is defined as the Day 1 predose 
assessment. Additionally, clinical chemistry and hematology data outside the reference ranges 
will be listed and flagged on individual participant data listings.
All SARS-CoV-2 panel parameters (C-reactive protein, ferritin, D-dimer, procalcitonin, and 
troponin) will be summarised separately, together with changes from baseline, and listed. 
Baseline is defined as the Day 1 predose assessment. Additionally, SARS-CoV-2 panel data 
outside the reference ranges will be listed and flagged on individual participant data listings.
10.6.6
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment. 
Values for individual participants will be listed.
10.6.7
Immunogenicity Assessments
The frequency and percentage of participants with pre-existing antidrug antibody (ADA) and 
with treatment-emergent ADAs (TE ADA) to LY3819253 may be evaluated only if the data 
from validated immunogenicity assays available. 
For participants who are ADA negative at baseline, TE ADAs are defined as those with a titer 
2-fold (1 dilution) greater than the minimum required dilution of the assay. For participants who 
are ADA positive at baseline, TE ADAs are defined as those with a 4-fold (2 dilution) increase in 
titer compared to baseline. The frequency and percentage of participants with cross-reactive and 
neutralizing antibodies, if measured, may also be tabulated for participants with TE ADA.
The relationship between the presence of antibodies and PK parameters, PD response or safety to 
LY3819253 may also be assessed only if are the data available. These analyses will be the 
responsibility of Eli Lilly PK/PD group.  


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
10.6.8 Hypersensitivity reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to
assess the participant’s medical history, alternative causes, and symptoms.
These data will be listed.
10.6.9
Infusion-related Reactions
Infusion-related reaction data will be listed and summarized by treatment and premedication 
used for infusion (if applicable) in frequency tables.
10.6.10 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
10.6.11 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
11.
INTERIM ANALYSES
No interim analyses are planned. Periodic, unblinded reviews of PK, PD and safety data will
occur throughout the study in addition to the scheduled dose escalation reviews. 
Analyses to support these data review will be the responsibility of Eli Lilly and Company Stats 
and PK/PD group. 
12.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
13.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1, July 2017. Division of AIDS, National Institute of Allergy 
and Infectious Diseases, National Institutes of Health, US Department of Health and Human 
Services.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8440133
Sponsor Reference J2W-MC-PYAA
14.
DATA PRESENTATION
14.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
14.2
Missing Data
Missing data will not be displayed in listings.
14.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.”


Leo Document ID = 783bdba3-b98f-46ec-9c44-68bdf516cc0f
Approver: 
Approval Date & Time: 04-Jun-2020 13:05:50 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Jun-2020 14:59:04 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Jun-2020 15:35:04 GMT
Signature meaning: Approved
PPD
PPD
PPD