A Randomized, Double-blind, Placebo-Controlled, Phase 2/3 Study to Evaluate the Efficacy and Safety of LY3819253 and LY3832479 in Participants With Mild to Moderate COVID-19 Illness
Phase: PHASE2
Conditions: COVID-19
Sponsor: Eli Lilly and Company

 
  
 J2W-MC-PYAB Addendum (4.2)  
 
 
A Randomized, Double-blind, Placebo-Controlled, Phase 2/3 Study to Evaluate the Efficacy and 
Safety of LY3819253 and LY3832479 in Participants with Mild to Moderate COVID-19 Illness 
 
NCT04427501 
 
Approval Date: 01-Jul-2022 
 
 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
Page 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 bamlanivimab (LY3819253), etesevimab (LY3832479), and bebtelovimab (LY3853113), 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, Double-blind, Placebo-Controlled, Phase 2/3 Study to Evaluate the Efficacy and 
Safety of LY3819253 and LY3832479 in Participants with Mild to Moderate COVID-19 Illness 
Protocol Number: J2W-MC-PYAB 
Addendum Number: 4.2 
Addendum Statement:  This addendum is to be performed in addition to all procedures required 
by protocol J2W-MC-PYAB or any subsequent amendments to that protocol.  Participants 
enrolled in this addendum will follow the specified sections in this addendum in place of the 
corresponding sections in the main PYAB protocol.  
Compound(s): bebtelovimab (LY3853113) 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number(s) 
IND:  150440  
Document ID: VV-CLIN-068441 
Approval Date: Protocol Addendum (4.2) Electronically Signed and Approved by Lilly on date 
provided below.  
 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
Page 2 
 
Table of Contents 
 
Protocol Addendum Summary of Changes Table .........................................................................4 
1. 
Rationale for Addendum ......................................................................................................5 
2. 
Protocol Additions .................................................................................................................7 
2.1. 
Section 1.2. Schema ...........................................................................................................7 
2.2. 
Section 1.3. Schedule of Activities.....................................................................................8 
2.2.1. Section 1.3.4. Treatment arm 23 ........................................................................................8 
2.3. 
Section 3.0. Objective and Endpoints...............................................................................19 
2.4. 
Section 4.0. Study Design ................................................................................................20 
2.4.1. Section 4.1.1. Design Outline ...........................................................................................20 
2.5. 
Section 4.2. Scientific Rationale for Study Design ..........................................................20 
2.6. 
Section 4.3. Justification for Dose ....................................................................................21 
2.7. 
Section 5.0. Study Population ..........................................................................................23 
2.7.1. Section 5.1. Inclusion Criteria ..........................................................................................23 
2.7.2. Section 5.2. Exclusion Criteria .........................................................................................24 
2.8. 
Sectionn 6.1 Study Intervention(s) Administered ............................................................25 
2.9. 
Section 8.1. Efficacy Assessments ...................................................................................26 
2.9.1. Section 8.1.2. Symptom Assessment for Pediatric Participants .......................................26 
2.10. Section 9.0. Statistical Considerations .............................................................................26 
2.10.1. 
Section 9.1. Statistical Hypotheses ..........................................................................26 
2.10.2. 
Section 9.2. Sample Size Determination ..................................................................26 
2.10.3. 
Section 9.3. Populations for Analyses .....................................................................28 
2.10.4. 
Section 9.4. Statistical Analyses ..............................................................................28 
2.10.4.1. 
Section 9.4.1. General Considerations .....................................................................28 
2.10.4.2. 
Section 9.4.2. Primary Endpoint ..............................................................................29 
2.10.4.3. 
Section 9.4.3. Secondary Endpoints .........................................................................29 
2.10.4.4. 
Section 9.4.3.4. Pharmacokinetic and Pharmacodynamic 
Analyses ...........................................................................................................................29 
2.10.5. 
Section 9.5. Interim Analyses ..................................................................................29 
2.10.6. 
Section 9.6 Assessment Committee (AC) ................................................................29 
2.11. Section 10.1.11. Investigator Information ........................................................................30 
2.12. Section 10.6. Appendix 6: Recommended Laboratory Testing for 
Hypersensitivity Events ....................................................................................................31 
2.13. Section 10.7. Appendix 7: Liver Safety Suggested Actions and 
Follow-up Assessments ....................................................................................................32 
2.14. Section 10.10. Appendix 10: Blood Collection Restrictions and 
Guidance for Pediatric Participants ..................................................................................35 
3. 
References ............................................................................................................................37 

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J2W-MC-PYAB (4.2) 
 
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4. 
Supporting Documentation ....................................................................................................39 
4.1. 
Protocol Addendum Revision History..............................................................................39 
 
 
 

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J2W-MC-PYAB (4.2) 
 
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Protocol Addendum Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Version 4.1 
29-Apr-2022 
Original Protocol Addendum 
14-Apr-2022 
Revision 4.2 
Overall Rationale for the Revision: 
The purpose of this revision is to add the collection of body weight for participants at each of the 
visits where pharmacokinetic (PK) samples are collected: Day 1, Day 5, Day 11, Day 29, ED and 
Day 60 (in addition to Day 0). This is in order to deliver on the primary objective of assessing 
pharmacokinetics in the pediatric pharmacokinetic population.  This is supported by the 
following: 
- 
PK of bebtelovimab is impacted by bodyweight. This is known from the adult PK 
modeling. 
- 
The weight of newborns/infants changes significantly following their first few 
weeks/months from birth. 
- 
The visits in which PK are collected span approximately 2 months (to Day 60). Because 
this is an extended time period, the impact of weight changes on PK needs to be 
captured.   
- 
Therefore, to accurately describe the PK of bebtelovimab in pediatrics down to newborns, 
their weight must be collected over the 2 month follow-up period after treatment 
administration. 
- 
After we accurately describe the PK (which is influenced by weight) of bebtelovimab in 
pediatrics, we will have addressed the primary endpoint of this PK-based study, 
characterizing the pharmacokinetics of bebtelovimab after intravenous injection. 
 
Section # and Name 
Description of Change 
Brief Rationale 
2.2. Section 1.3. Schedule of 
Activities 
Adjusted weight 
collection with update to 
Schedule of Activities   
The purpose of this revision is to 
add the collection of body weight 
for the participants at each of the 
visits where PK samples are 
collected: Day 1, Day 5, Day 11, 
Day 29, ED and Day 60 (in 
addition to Day 0) in order to 
deliver the primary objective to 
assess the PK in the pediatric 
pharmacokinetic population after 
intravenous injection of 
bebtelovimab. 

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J2W-MC-PYAB (4.2) 
 
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1. 
Rationale for Addendum 
Eli Lilly and Company (Lilly) has a partnership with AbCellera Biologics Inc. (AbCellera; 
Vancouver, Canada) to develop neutralizing IgG1 monoclonal antibodies (mAbs) to the Spike 
(S) protein of severe acute respiratory syndrome coronavirus-2  (SARS-CoV-2) as a potential 
treatment for Coronavirus disease 2019 (COVID-19). Candidate antibody gene sequences have 
been selected from a convalescent COVID-19 United States patient’s serum using AbCellera’s 
core platform screening technologies. 
Bebtelovimab (LY3853113) is a novel, highly potent IgG1 neutralizing mAb that binds a unique 
RBD region of the S protein. Bebtelovimab can neutralize the Wuhan reference strain as well as 
individual residues present in recent variants of concern (e.g. K417N, N439K, L452R, E484K/Q, 
Q493R, N501Y, and D614G).  Critically, pseudovirus and/or authentic SARS-CoV-2 
neutralization assays demonstrate that bebtelovimab can neutralize all variants of interest or 
concern identified as of April 2022, including the Delta variant (B.1.617.2 and related AY 
sublineages lineages) and Omicron variant (B.1.1.529 [BA.1], BA.1.1 and BA.2 sublineages). 
Bebtelovimab is authorized (Emergency Use Authorization [EUA] 111) for the treatment of 
mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing 
at least 40 kg) who are at high risk for progressing to severe COVID-19 (FDA February 2022). 
EUA 111 was based on clinical data (BLAZE-4) from patients at low- and high-risk for severe 
disease as well as the beforementioned in vitro neutralization assay data. 
Currently, there are limited authorized treatments for pediatric outpatients under the age of 12 or 
those 12 to 17 and weighing less than 40 kg. While COVID-19–associated hospitalizations and 
deaths have occurred more frequently in adults, COVID-19 can also lead to severe outcomes in 
pediatric patients (Delahoy et al. 2021).  As in-person school and activities have increased, 
hospitalization rates among children have also increased, especially with the emergence of the 
Omicron variant. During the Delta- and Omicron-predominant periods, pediatric weekly 
hospitalization rates peaked at 7.1 per 100,000 children and adolescents for Omicron which was 
four times that of the Delta variant peak (1.8) (Marks et al. 2022). The highest increase in 
hospitalization rates in children aged 0–4 years was approximately five times as high during the 
peak week of the Omicron period (15.6) than during the Delta period (2.9) (Marks et al. 2022). 
Pediatric cases resulting in death have remained at 0.00-0.02% (AAP 2022). 
As in adults, outcomes in pediatric patients of all ages are generally worse in the presence of a 
number of comorbid conditions.  Pediatric patients without an underlying medical condition have 
also been susceptible to Multisystem Inflammatory Syndrome in Children (MIS-C) (CDC 2021; 
Reiff et al. 2022).   
The neutralizing mAbs bamlanivimab and etesevimab have been previously shown to be safe 
and effective with adult-matched dosing in pediatric patients with COVID-19, and based on this 
evidence, were given EUA across all pediatric age ranges (EUA 094; Eli Lilly and Company 
2022). However, with the emergence of the Omicron variant, there are no neutralizing mAb 
therapies authorized for use in pediatric patients <12 years of age or those 12 to 17 and weighing 
<40 kg since April 11, 2022. Considering bebtelovimab’s capacity to neutralize Omicron per 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
Page 6 
available in vitro neutralization assays and pharmacokinetic (PK) data, this proposed study 
addendum intends to investigate the PK and safety of bebtelovimab in pediatric patients with 
COVID-19  <12 years of age or 12 to 17 years of age and weighing <40 kg. 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
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2. 
Protocol Additions 
Participants enrolled in this addendum will follow the specified sections in this addendum in 
place of the corresponding sections in the main PYAB protocol. 
2.1. 
Section 1.2. Schema 
Participants enrolled into this addendum will enter treatment arm 23. 
 
Note:  Dose levels in treatment arms 22 and 23 are weight dependent. 
Addendum 3 contains information for treatment arms 20 and 21. Addendum 2.2 contains information for treatment 
arm 22. 
The main PYAB protocol contains information for treatment arms 1-19. 
Figure 1. 
Study J2W-MC-PYAB schema.  
 
 

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J2W-MC-PYAB (4.2) 
 
Page 8 
2.2. 
Section 1.3. Schedule of Activities 
2.2.1. Section 1.3.4. Treatment arm 23 
This SoA is for participants in treatment arm 23.  Please see Addendum Section 2.14, Appendix 10 for pediatric blood collection 
restrictions and guidance.  
Period I: Screening - Visit 1 procedures may be conducted over more than 1 day as long as all activities are completed within the 
allowable visit tolerance (where applicable).  
Period II: Treatment Period - For early discontinuations that occur before the last visit in treatment period, see the activities listed 
for ED in the following table. 
 
 

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J2W-MC-PYAB (4.2) 
 
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Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
The informed consent form must 
be signed before any protocol-
specific tests or procedures are 
performed. 
See Appendix 10.1, Section 
10.1.3 of the main PYAB 
protocol for additional details, 
including assent, as applicable. 
Informed 
Assent for 
pediatric 
participants 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent or legal guardian signs 
informed consent form and 
participant signs assent form, as 
appropriate per local 
requirements. 
Inclusion and 
exclusion 
criteria, review 
and confirm 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
should be confirmed prior to 
treatment assignment and 
administration of first dose of 
study intervention.  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes full date of birth, gender 
(sex), ethnicity and race 
Preexisting 
conditions and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtained from interview or 
available information. 
Prespecified 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes COVID-19 diagnosis 
date, onset of COVID-19 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
Page 10 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
symptoms, and comorbidities 
associated with severe COVID-
19 illness 
Prior treatments 
for indication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within the last 30 days.  
NSAIDs, antivirals, antibiotics, 
anti-malarials, corticosteroids, 
immunomodulators, monoclonal 
antibody treatment or any 
investigational treatments 
Prior non-
COVID vaccine 
treatments  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within the last 90 days 
Prior COVID 
vaccine 
treatments  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance use 
(alcohol, 
tobacco use)  
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Includes use of e-cigarettes, such 
as vaping 
 
Concomitant 
medications 
 
X 
X 
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 
X 
Any events that occur after 
signing the informed consent are 
considered AEs as defined in 
Section 10.3 of the main PYAB 
protocol. 
Additional details regarding 

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J2W-MC-PYAB (4.2) 
 
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Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
reporting frequency and method 
of detecting AEs and SAEs can 
be found in Section 8.3 of the 
main PYAB protocol. 
Physical Evaluation 
Height  
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
For participants ≥2 years of age 
Length 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only for participants <2 years of 
age 
Weight  
X 
X 
 
X 
 
 
 
X 
 
X 
 X 
 
X 
 
 
Hospitalization 
events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record if the following events 
occur or occurred since prior 
visit: 
• Emergency room visits 
• hospitalized 
• ICU admittance, and  
• Discharge 
Clinical status 
and concomitant 
procedures if 
participant is 
hospitalized 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Documentation from hospital 
records is acceptable if 
hospitalized at any time. 
Includes: 
• NEWS 2 Consciousness 
(ACVPU) 
• Additional organ support (e.g. 
ECMO, pressors, renal 
replacement) 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
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Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
• Supplemental oxygen and any 
means of ventilatory support, 
and 
• Vital signs 

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
Page 13 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Vital Signs 
X 
X 
  
X 
 
X 
 
X 
 
X 
X 
 
X 
 
Includes: body temperature, 
pulse rate, BP, respiratory rate, 
SpO2, and supplemental oxygen 
flow rate, method of delivery, if 
applicable, and oxygen support 
procedures. 
Documentation of hospital-based 
exam is acceptable. 
Record SpO2 while participant is 
at rest. 
Screening visit only: SpO2 
while breathing room air or 
while on chronic oxygen therapy 
and/or respiratory support due to 
underlying non-COVID-19 
related comorbidity.  Data not 
collected on CRF.  
Day 1 timing: 
• immediately before and after 
treatment administration 
• every 30 minutes for 1 hour 
after the administration.   
Only record temperature, pulse 
rate, BP and SpO2. Automation 
may be used.  See Section 8.2.2 
of the main PYAB protocol for 
data collected on CRF. 
All other outpatient/home visit 
study days: collect once.  

CONFIDENTIAL 
J2W-MC-PYAB (4.2) 
 
Page 14 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-
directed 
physical 
assessment 
 
X 
 
Symptom-directed physical 
assessment will be conducted at 
the discretion of the PI or 
qualified personnel per local 
regulations, as indicated based 
on participant status and standard 
of care. Excluding screening as it 
includes a physical examination. 
COVID-19 
Symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Day 1: assess prior to dosing 
The presence of absence of 
symptoms are collected from the 
participants or their parents/legal 
guardian. 
Laboratory Tests and Sample Collections 
Hematology 
 
X 
 
X 
 
  
 
X 
 
X 
X 
 
  
 
Day 1: before treatment 
administration 
All other days: sample may 
occur at any time during the day 
Lilly-designated central 
laboratory 

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J2W-MC-PYAB (4.2) 
 
Page 15 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Clinical 
Chemistry  
 
X 
 
X 
 
  
 
X 
 
X 
X 
 
  
 
Day 1: before treatment 
administration 
All other days: sample may 
occur at any time during the day 
Lilly-designated central 
laboratory 
Documentation 
of positive 
SARS-CoV-2 
viral infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for first positive test 
must be collected within 3 days 
prior to start of treatment 
administration.  
Local laboratory and/or Point-of-
Care testing. 
PD swab  
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
Swab is taken from both nostrils.  
Day 1: swab before treatment 
administration. 
Methods include nasopharyngeal 
(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.  
Lilly-designated central 
laboratory 

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J2W-MC-PYAB (4.2) 
 
Page 16 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Serum or Urine 
pregnancy 
(local) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy tests prior to the first 
dose of investigational product 
for females if 
• aged ≥10 years  
• <10 years at investigator’s 
discretion  
• menarche is reached or 
• there is reason to believe that 
the patient is sexually active.  
Local laboratory 
PK samples 
 
X* 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
*Day 1: immediately after end 
of treatment administration. 
All other scheduled samples may 
occur at any time during the day. 
Pharmacokinetic samples for 
participants <12 kg may be 
collected using alternative 
techniques. For those using a 
central line on Day 1, please see 
Addendum Section 2.14, 
Appendix 10. 
If participant is hospitalized and 
if sample is available, collect 
sample. 
Lilly-designated central 
laboratory  

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J2W-MC-PYAB (4.2) 
 
Page 17 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Immunogencity 
(ADA) samples 
 
X* 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
*Day 1:  collect before 
treatment administration.  
All other scheduled and 
unscheduled immunogenicity 
samples should be collected with 
a time-matched PK sample. 
No samples needed if participant 
is hospitalized or <12 kg. 
Lilly-designated central 
laboratory 
Randomization and Dosing 
Register visit 
with IWRS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Assignment via 
IWRS  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study 
Drug via IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 

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J2W-MC-PYAB (4.2) 
 
Page 18 
 
Period I 
Screening 
Period II 
Treatment Period 
Period III 
Post-
Treatment 
Follow-Up 
 
Study Day from 
Treatment 
Assignment 
 
1 
2, 3, 4 
5 
6 
7 
8, 9, 10 
11 
22 
29 
ED 
Follow-up 
if hospital 
inpatient 
on Day 29 
60 
85 
 
Visit interval 
tolerance (days) 
  
— 
— 
±1 
— 
(+1 
— 
±2 
±2 
±3 
±2 
Every 7 
days until 
discharge 
or Day 60 
±4 
±4 
 
Visit Detail 
 
O 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
T,I 
O,H 
O,H 
 
O,H 
T,I 
O = Outpatient clinic, H = Home 
Visit, T = Telephone,  
I = IT-Assisted Virtual Visit 
Administer 
Study 
Intervention 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention must be 
administered within 3 days from 
the time of first positive SARS-
CoV-2 test sample collection. 
For participants that receive 
dialysis on the same day as 
administration of study 
intervention, complete dialysis 
first followed by the study 
treatment. 
Participants will be monitored 
for at least 1 hour after 
completion of treatment 
administration.  
Abbreviations:  ACVPU = alert, consciousness, verbal, pain, unresponsive scale; ADA = anti-drug antibody; AEs = adverse events; BP = blood pressure; CRF = 
case report form; ECMO = Extracorporeal membrane oxygenation; ED = early discontinuation visit; ICU = intensive care unit; IWRS = interactive web-
response system; NP = nasopharyngeal; NSAIDS = non-steroidal anti-inflammatory drugs; PD = pharmacodynamics; PI = primary investigator; PK = 
pharmacokinetics; SAEs = serious adverse events; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SpO2 = saturation of peripheral oxygen.  
 
 

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2.3. 
Section 3.0. Objective and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
 
Characterize the pharmacokinetics of 
bebtelovimab after intravenous injection 
 
Area under the concentration-time curve (AUC) 
from 0 to infinity for bebtelovimab 
Secondary 
 
 
Safety description 
 
Safety assessments such as AEs and SAEs 
Exploratory 
 
 
Overall participant clinical status 
 
Proportion (percentage) of participants who 
experience the following events by Days 22, 29, 
60 and 85 
o 
COVID-19 related hospitalization 
(defined as ≥24 hours of acute care) or 
o 
death from any cause  
 
Proportion (percentage) of participants who 
experience the following events by Day 29 
o 
a COVID-19 related emergency room 
visit, or  
o 
COVID-19 related hospitalization 
(defined as ≥24 hours of acute care), or 
o 
death from any cause 
 
SARS-CoV-2 viral load reduction 
 
Change from baseline to  
o 
Day 5 
o 
Day 7 
o 
Day 11 
 
SARS-CoV-2 viral load area under the response-
time curve (AUC) 
 
Symptoms and resolution 
 
Time to absence of all symptoms  
 
Time to sustained absence of all symptoms 
 
Proportion of participants demonstrating absence 
of symptoms 
 
Characterize emergence of viral resistance to 
bebtelovimab 
 
Comparison from baseline to the last evaluable 
time point 
 
Safety 
 
Proportion (percentage) of participants who 
experience MIS-C 
Abbreviations:  AE = adverse event; MIS-C = multisystem inflammatory syndrome in children; SAE =serious 
adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.  
 

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2.4. 
Section 4.0. Study Design 
This addendum adds a single open-label treatment arm (Arm 23) to evaluate bebtelovimab 
administered as an intravenous injection to pediatric participants.  
2.4.1. Section 4.1.1. Design Outline 
Careful consideration was given to collect the necessary information to address the key scientific 
objectives of this pediatric study while also minimizing invasive procedures and overall patient 
burden, including through the use of comfort measures (e.g., EMLA cream) during blood draws.   
This table describes the visit types for this study. 
Study Day 
Visit Type 
1   
Outpatient clinic visit 
2, 3, 4, 6, 8, 9, 10, 22, and 85 (follow-
up visit) 
Telephone / IT-assisted virtual visits 
5, 7, 11, 29, ED and 60 (follow-up 
visit 
May be conducted as outpatient 
clinic or home visits  
Abbreviation: ED = early discontinuation.  
 
Refer to the SoA (Addendum Section 2.2.1) for the list of procedures in this study. 
2.5. 
Section 4.2. Scientific Rationale for Study Design 
COVID-19 is a severe viral respiratory infection caused by SARS-CoV-2 that affects all age 
groups (Hoang et al. 2020).   
SARS-CoV-2 Incidence in the Pediatric Population 
Children of all ages may be infected with SARS-CoV-2. As of April 2022, child COVID-19 
cases represented 19.0% of all COVID-19 cases reported, with an overall rate of 17,061 cases 
per 100,000 children in the US (AAP 2022). 
Severity of Disease 
While COVID-19–associated hospitalizations and deaths have occurred more frequently in 
adults (Delahoy et al. 2021), there are still pediatric patients who are infected with SARS-CoV-2 
that become hospitalized (0.1-1.5%), and 0.00%-0.02% of all pediatric cases result in death 
(AAP 2022). There are also concerns about potential later term sequela that may result in 
pediatric patients from SARS-CoV-2 infections (Hertting et al. 2021), including MIS-C, an 
uncommon (approximately 2.1 in 100,000 persons <21 years of age [Belay et al. 2021]) but 
potentially fatal condition that occurs approximately 2 to 6 weeks after infection (CDC 2021).  
As in adults, outcomes in pediatric patients of all ages are generally worse in the presence of a 
number of comorbid conditions, such as  
 medical complexity requiring long-term technological support,  
 obesity,  
 diabetes,  

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 asthma,  
 chronic lung disease,  
 sickle cell disease, or  
 immunosuppression.  
However, in severe disease resulting in hospitalization among pediatric patients, approximately 
one-third of hospitalizations occur in patients that do not have an underlying medical condition 
(Wanga et al. 2021; Woodruff et al. 2021).   
Unmet Need for Treatment 
Currently, there are limited authorized or approved therapies effective for the treatment of the 
Omicron variant of COVID-19 in non-hospitalized pediatric patients under 12 years of age or 12 
to 17 and weighing less than 40 kg body weight, which necessitates the urgent need to have 
access to experimental therapies.  
Extrapolation of Efficacy 
Efficacy will be fully extrapolated from adult data. The rationale behind this extrapolation of 
efficacy from adult efficacy studies to pediatric patients is based on 
 FDA guidance documents (FDA 2020; FDA February 2021; FDA December 2021) 
 the common initial stages of COVID-19 in  (adult and pediatric patients when viral 
infection and replication occurs 
 a similar (though usually less severe) course of SARS-CoV-2 infections in pediatric 
patients as compared to adults (Hoang et al. 2020)  
 the mechanism of action of bebtelovimab which, regardless of host, involves direct 
binding to the SARS-CoV-2 virus S protein at the ACE2 receptor binding site, and 
 previous extrapolation of pediatric COVID-19 efficacy from adult COVID-19 efficacy 
studies with bamlanivimab and etesevimab 
 
This extrapolation approach aligns with the FDA guidance document: Development of Anti-
Infective Drug Products for the Pediatric Population (FDA December 2021). This guidance 
states that extrapolation of effectiveness from adult populations to pediatric populations based on 
PK may be appropriate if the course of the disease and the effects of the drug are sufficiently 
similar in adult and pediatric patients. A similar approach for pediatrics is described in the FDA 
guidance document: COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention (FDA February 2021).  
2.6. 
Section 4.3. Justification for Dose 
An exposure-matching approach was implemented to determine pediatric doses that would result 
in similar serum concentrations to those achieved upon administration of 175 mg that is 
authorized in adults. The popPK model for bebtelovimab which included allometric scaling on 
clearance and volume parameters was used to predict the PK in pediatrics. For younger children 
weighing less than 12 kg (virtual patients drawn using NHANES database), a maturation 
function was included for clearance (Robbie et al. 2012). Based on exposure-matching, the table 

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below shows the doses depending on weight category.  Due to potential limitations of precision 
around administrations of doses, bebtelovimab may be diluted for participants at or below 6 kg in 
body weight. Details for dosing and dilution of bebtelovimab are located within the pharmacy 
preparation instructions.   
Weight group 
Bebtelovimab dose 
≥3.3 to ≤12 kg 
3 mg/kg 
>12 to ≤20 kg 
43.75 mg 
>20 to <40 kg 
87.5 mg 
≥40 kg 
175 mg 
 
Figure 2 shows that the PK model-predicted concentrations for these doses would be similar to 
adults. 
 
The shaded areas are the 90% prediction interval of each population 
Figure 2.  
Bebtelovimab PK model-predicted comparison of adult and 
pediatric serum concentrations. 
 

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2.7. 
Section 5.0. 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, verbal interview of the potential participant or their 
legal representative or family member, may be the source for disease characteristics and medical 
history, unless otherwise specified within the eligibility criteria. 
2.7.1. Section 5.1. Inclusion Criteria 
Participants are eligible to be included in this addendum only if all of the following criteria 
apply:  
1. This criterion is not applicable to participants in this addendum 
2. This criterion is not applicable to participants in this addendum 
3. This criterion is not applicable to participants in this addendum  
4. Must have first positive result sample of current SARS-CoV-2 viral infection ≤3 days 
prior to start of the administration 
5. Are males or females 
Reproductive and Contraceptive requirements are provided in the main PYAB protocol, 
Section 10.4, Appendix 4.  Contraceptive use by males or females should be consistent 
with local regulations for those participating in clinical studies.  
6. The participant and/or legally authorized representative understand and agree to comply 
with planned study procedures 
7. The participant and/or legally authorized representative agree to the collection of 
nasopharyngeal swabs and venous blood 
8. The participant or legally authorized representative give signed informed consent and/or 
assent as described in the main PYAB protocol, Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
27. This criterion is not applicable for participants in this addendum 
28. This criterion is not applicable for participants in this addendum  
36. Are 0 (≥ 38 weeks gestational age and ≥ 3.3 kg) to <12 years of age at the time of 
screening, or are 12 to 17 and weighing <40 kg. 
37. Have mild to moderate COVID-19 disease, including one or more of the following 
symptoms, within the last 7 days (FDA February 2021; CDC January 2022; CDC March 
2022.) 
 shortness of breath or difficulty 
breathing 
 nasal congestion or runny nose 
 fever 
 chills 
 sore throat 
 malaise 
 nausea 
 vomiting 
 diarrhea 
 cough 

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 tiredness 
 muscle or body aches and pain 
 headache 
 new loss of smell, or 
 new loss of taste 
 poor appetite or poor feeding 
(especially in babies under 1 year 
old). 
 
2.7.2. Section 5.2. Exclusion Criteria 
Participants are excluded from this addendum if any of the following criteria apply: 
9. SpO2 ≤ 93% on room air at sea level, or while on chronic oxygen therapy and/or 
respiratory support due to underlying non-COVID-19 related comorbidity, respiratory 
rate ≥30 per minute, and heart rate ≥125 per minute due to COVID-19 (FDA February 
2021) 
10. Require mechanical ventilation or anticipated impending need for mechanical ventilation 
due to COVID-19 
11. Have known allergies to any of the components used in the formulation of the 
interventions 
12. Have hemodynamic instability requiring use of pressors within 24 hours of 
randomization 
13. 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 
14. Have any co-morbidity requiring surgery within 7 days, or that is considered life-
threatening within 29 days 
15. Have any serious concomitant systemic disease, condition or disorder that, in the opinion 
of the investigator, should preclude participation in this study. 
16. This criterion is not applicable for participants in this addendum 
17. This criterion is not applicable for participants in this addendum 
18. This criterion is not applicable for participants in this addendum 
19. Have received treatment with a SARS-CoV-2 specific monoclonal antibody or remdesivir 
within 90 days before dosing 
20. Have received convalescent COVID-19 plasma treatment within 90 days before dosing  
21. This criterion is not applicable for participants in this addendum 
22. Have participated, within the last 30 days, in a clinical study involving an investigational 
intervention.  If the previous investigational intervention has a long half-life, 5 half-lives 
or 30 days, whichever is longer, should have passed. 
23. Are concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study 
24. Are currently pregnant or breast feeding 
25. Are investigator site personnel directly affiliated with this study 
29. This criterion is not applicable for participants in this addendum  

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31. Have a diagnosis of MIS-C in the opinion of the investigator 
32. Are currently hospitalized for treatment of COVID-19.  Other reasons for hospitalization 
are acceptable.  
 
2.8. 
Sectionn 6.1 Study Intervention(s) Administered 
Treatment Arm 23 
Intervention Name 
LY3853113 
Dose Formulation 
Solution 
Dosage Level(s) (mg) 
See Addendum Section 2.6 
Use 
Experimental 
IMP and NIMP 
IMP 
Sourcing 
From Lilly 
Packaging and 
Labeling 
Study Intervention will be provided 
in glass vials and will be labeled 
appropriately. 
Abbreviations: IMP = investigational medicinal product. 
 
Dose preparation and administration information may be found in the pharmacy preparation 
instructions. 
Participants should be monitored for at least 1 hour after completion of administration. The 
administration rate may be reduced as deemed necessary if an injection-related reaction is 
observed. 
Further details will be included in the pharmacy preparation instructions. The site must have 
resuscitation equipment, emergency drugs and appropriately training staff available during the 
administration and for at least 1 hour after the completion of the administration.  
 
 

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2.9. 
Section 8.1. Efficacy Assessments 
2.9.1. Section 8.1.2. Symptom Assessment for Pediatric Participants  
The presence or absence of symptoms associated with COVID-19 within the past 24 hours will 
be collected from participants or their parents/legal guardian.   
Signs and symptoms associated with COVID-19 should not be captured as AEs, unless more 
severe than expected.   
Symptoms include 
 shortness of breath or difficulty 
breathing 
 diarrhea 
 nasal congestion or runny nose 
 cough  
 fever  
 tiredness 
 chills 
 muscle or body aches and pain  
 sore throat 
 headache 
 malaise 
 new loss of smell 
 nausea 
 new loss of taste, and  
 vomiting 
 poor appetite or poor feeding, 
especially in babies under 1 year 
old. 
Source: FDA February 2021; CDC January 2022; CDC March 2022. 
 
2.10. 
Section 9.0. Statistical Considerations 
2.10.1. 
Section 9.1. Statistical Hypotheses 
This is an open-label study with a primary objective of assessing PK and secondary objective of 
describing safety. The PK of bebtelovimab administered via a weight-adjusting dosing scheme is 
hypothesized to be well-characterized and consistent with adult exposure.  
2.10.2. 
Section 9.2. Sample Size Determination 
There is an urgent unmet need among pediatric patients since there are no approved vaccines for 
the prevention of COVID-19 in pediatric patients <5 years of age and no FDA-approved 
therapies effective for treatment of the Omicron variant in patients <12 years or outside the 
existing bebtelovimab EUA criteria.  Consequently, this study will include SARS-CoV-2 
positive pediatric patients with mild to moderate disease that are 0 (≥38 weeks gestational age 
and ≥ 3.3 kg) to <12 years of age, or 12 to 17 years of age and weighing <40 kg. 
 

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The planned sample size is approximately 50 participants that are 0 (≥38 weeks gestational age 
and ≥ 3.3 kg) to 12 years of age, with a minimum of 5 participants in each of these age groups 
 0 to <2 
 2 to <6 years, and  
 6 to <12 years 
Participants who are 12 to 17 years of age and weighing less than 40 kg can be enrolled into the 
study until approximately 50 participants that are 0 (≥38 weeks gestational age and and ≥ 3.3 kg) 
to 12 years of age are fully enrolled. 
Fifty participants would provide adequate study power to target a 95% confidence interval within 
60% to 140% of the geometric mean estimates of clearance and volume of distribution (Wang et 
al. 2012) for bebtelovimab as can be seen in Figure 3. 
 
Figure 3.  
Estimated study power to target a 95% confidence interval within 
60% to 140% of the geometric mean estimates of clearance and 
volume of distribution. 
The anticipated risks of bebtelovimab are low, based on the known mechanism of action for 
human-derived neutralizing antibodies in acute viral disease states. Bebtelovimab is a highly 
specific mAb directed at a foreign (nonhuman) epitope(s). The complementarity determining 
regions of this mAb were derived from B lymphocytes of convalescent naturally SARS-CoV-2-
infected patients and thus has undergone natural positive and negative selection pressures in 
vivo. No clinically relevant off-target binding has been observed in tissue cross-reactivity (TCR) 
studies of membrane targets in human tissues. Therefore, off-target binding and TCR are 
considered unlikely. 

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The safety profile of bebtelovimab is expected to be similar to that of bamlanivimab and 
etesevimab based on their similar mechanism of action. Because the observed safety profile of 
bamlanivimab and etesevimab was similar between adults and pediatric patients, it is reasonable 
to expect a similar safety profile with bebtelovimab in pediatric patients. Importantly, clinical 
trial results of low- and high-risk adults with mild-to-moderate COVID-19 receiving 
bebtelovimab indicate that the observed risks are monitorable (such as infusion-related reactions, 
pruritis, rash that were reported in <1% of trial participants) and manageable in the clinical 
setting. 
Efficacy will be fully extrapolated from adult data. Considering there is no expectation that risk 
status for severe disease has any impact on PK and safety findings, pediatric patients with mild-
to-moderate disease are not required to have a risk factor for severe disease to enroll into the 
study. Benefit in symptom relief is a reasonable expectation for enrolling patients regardless of 
risk status, and the wider pool of potential participants is expected to expedite enrollment. 
2.10.3. 
Section 9.3. Populations for Analyses 
This table defines the pediatric populations for analysis. 
Pediatric Population for Analysis 
Description 
Pharmacokinetic 
All pediatric participants who received a full dose of 
study intervention and have at least one evaluable PK 
sample. 
Safety 
All pediatric participants who received study 
intervention.  
Efficacy 
All pediatric participants who received study 
intervention and provided at least one post-baseline 
measure for the relevant endpoint.  
2.10.4. 
Section 9.4. Statistical Analyses 
2.10.4.1. 
Section 9.4.1. General Considerations 
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
Unless otherwise specified, all endpoints will be summarized descriptively.  Descriptive 
summaries will include  
 number of participants  
 mean, standard deviation, median, minimum and maximum for continuous measures, and  
 frequency counts and percentages for categorical measures. 
Analyses will be performed overall and separately by age group.  The age groups are defined as 
 0 to <2 years, 
 2 to <6 years,  
 6 to <12 years, and 
 12 to 17 and weighing <40kg 
Additional details may be provided in the statistical analysis plan. 

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2.10.4.2. Section 9.4.2. Primary Endpoint 
Treatment Arm 23 
The primary objective is to assess PK in the pediatric pharmacokinetic population. The primary 
parameter for analysis is the area under the concentration-time curve (AUC) from 0 to infinity.  
Other parameters, such as half-life, apparent clearance, and apparent volume of distribution, may 
be reported. 
2.10.4.3. Section 9.4.3. Secondary Endpoints 
The secondary objective is to describe safety. The pediatric safety population is described in 
Addendum Section 2.10.3.  Safety analyses will consist of summaries by preferred term within 
system organ class of treatment-emergent adverse events and serious adverse events (including 
reason for seriousness).  The incidence of any treatment administrations that are interrupted or 
incomplete due to an adverse event will also be summarized, along with the incidence of 
immediate or non-immediate hypersensitivity events. 
2.10.4.4. Section 9.4.3.4. Pharmacokinetic and Pharmacodynamic Analyses 
Bebtelovimab concentration data may be analyzed using a population PK approach via nonlinear 
mixed-effects modeling with the NONMEM software.  In addition, the effects of participant 
factors, such as weight, age and gender on PK parameters may be evaluated.  If antidrug 
antibody is detected from immunogenicity testing and data are available, its impact on 
bebtelovimab PK may also be evaluated. 
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 5, 7, and 11) 
 AUC. 
Additional PK/PD concentration-response analysis may be performed.  
2.10.5. 
Section 9.5. Interim Analyses 
An interim analysis may be conducted to evaluate safety in support of regulatory interactions. 
This interim may include all pediatric data available at that time and relevant analyses. 
Early review of PK data may be planned but is not considered a formal interim analysis. 
The approximate timing, decision criteria, and statistical methods associated with each possible 
modification to this study will be fully described in the statistical analysis plan. 
2.10.6. 
Section 9.6 Assessment Committee (AC) 
The sponsor will form an AC to analyze the interim safety data.  To minimize any bias 
introduced into the conduct and analysis of the study, the addendum specific analysis plan will 
be approved prior to the first interim analysis. 
The primary goal of the AC is to review the interim results to facilitate the safety of study 
participants while maintaining the validity and scientific merit of the study.  Information gained 

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from these analyses will not be reported to study sites or the broader study team beyond the AC 
until the final DBL for the cohort. 
Overall AC structure information is in the main PYAB Protocol Section 10.1.5.  Details of the 
AC will be provided in the Addendum (4) SAP. 
2.11. 
Section 10.1.11. Investigator Information 
Physicians with specialties, including, but not limited to pediatrics, infectious disease, acute or 
critical care, pulmonary disease, immunology, or other appropriate specialties may participate as 
investigators for this addendum. 
An investigator or sub-investigator must also confirm that they have clinical experience to 
adequately manage participants in a particular age range in order for the site to enroll participants 
in that respective age range. The age ranges are 
 less than 1 year of age 
 1 to 11 years of age, and 
 12 to 17 years of age. 
This addendum will be conducted at a diverse group of sites that may include academic and 
community affiliated outpatient clinics and emergency departments, as well as other locations 
where children may be seen for outpatient care. Clinicians providing care in such settings may 
include pediatricians, neonatologists, family practitioners, emergency room specialists, and other 
physicians. The investigator requirements are written to reflect this reality of pediatric patient 
care in outpatient settings during the pandemic.  
 
 

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2.12. 
Section 10.6. Appendix 6: Recommended Laboratory Testing for 
Hypersensitivity Events 
 
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory tests results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up pre-dose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
Timing 
Sample Type 
Laboratory Test a 
Collect from 30 minutes to 4 hours 
after the start of the event.  
● 
Note: The optimal collection 
time is from 1 to 2 hours after 
the start of event. 
Serum 
total tryptase 
Serum 
complements (C3, C3a, and C5a) 
Serum 
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine panel 
that includes these 3 cytokines) 
Collect only if not already collected 
on the same day as the event. 
● 
Note: If collecting, collect up 
to 12 hours after the start of the 
event. 
Serum 
Bebtelovimab anti-drug antibodies (ADA) 
Serum 
Bebtelovimab concentration 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 

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2.13. 
Section 10.7. Appendix 7: Liver Safety Suggested Actions and 
Follow-up Assessments 
 
Close Hepatic Monitoring 
This table describes when close hepatic monitoring should occur. 
If a participant with baseline results 
of ...  
develops the following elevations… 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN 
ALP <1.5× ULN 
ALP ≥2× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥1.5× baseline (except for participants with 
Gilbert’s syndrome) 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin. 
Notes: All ULN values should be age adjusted (AAULN). 
 
The laboratory tests listed in Section 10.2, Appendix 2 of the main PYAB protocol, including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase, should 
be repeated within 48 to 72 hours to confirm the abnormality and to determine whether it is 
increasing or decreasing, if one or more of the conditions in the table above occur. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  
At a minimum, this evaluation should include physical examination and a thorough medical 
history, including symptoms, recent illnesses (for example, heart failure, systemic infection, 
hypotension, or seizures), recent travel, history of concomitant medications (including over-the-
counter), herbal and dietary supplements, history of alcohol drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks if the 
participant’s clinical condition and laboratory results stabilize.  Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels.   
Special care should be taken to minimize the volume of blood taken during hepatic monitoring. 
Comprehensive Hepatic Evaluation   
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 

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If a participant with baseline 
results of...  
develops the following elevations… 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN with hepatic signs/symptoms*, or  
ALT or AST ≥5× ULN 
ALP <1.5× ULN 
ALP ≥3× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline with hepatic signs/symptoms*, or 
ALT or AST ≥3× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥2× baseline (except for participants with Gilbert’s syndrome)  
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin. 
*Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia >5%. 
Notes:  All ULN values should be age adjusted (AAULN). 
 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR and direct bilirubin, if total bilirubin was 
elevated.  
Based on the participant’s age and weight, medical history and initial results, further testing 
should be considered in consultation with the Lilly-designated medical monitor, including tests 
for viral hepatitis A, B, C, E, autoimmune hepatitis, or an abdominal imaging study (for 
example, ultrasound, MRI, or CT scan).  Consider additional tests, based on the medical history 
and clinical picture, including tests for hepatitis D virus (HDV), cytomegalovirus (CMV), 
Epstein-Barr virus (EBV), acetaminophen levels, acetaminophen protein adducts, urine 
toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and blood 
phosphatidylethanol.  
Special care should be taken to prioritize more pertinent blood tests and minimize the volume of 
blood taken during hepatic evaluation. Based on the circumstances and the investigator’s 
assessment of the participant’s clinical condition, the investigator should consider referring the 
participant for a pediatric hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy as deemed appropriate for the clinical condition and 
participant’s age.   
 
 

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Hepatic Evaluation Testing 
Please refer to main protocol for the complete list of tests for evaluation.   
For participants ≥ 4.4 kg, assays will use a Lilly-designated laboratory or local laboratory. 
For participants <4.4 kg assays will use only a local laboratory. 
The microbiology blood and urine assay must use a local laboratory. 
Additional hepatic data collection in study participants who have abnormal liver tests 
Additional hepatic safety data collection in hepatic safety case report forms (CRF) should be 
performed in study participants if one or more of these conditions occur during the study: 
If a participant with baseline 
results of...  
develops the following elevations… 
ALT <1.5× ULN 
Serum ALT to ≥5× ULN on 2 or more consecutive blood tests  
ALT ≥1.5× ULN 
Serum ALT to ≥3× ULN on 2 or more consecutive blood tests 
TBL <1.5× ULN 
TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome) 
TBL ≥1.5× ULN 
TBL to ≥2× baseline 
ALP <1.5× ULN 
Serum ALP to ≥2× ULN on 2 or more consecutive blood tests 
ALP ≥1.5× ULN 
Serum ALP ≥2× baseline on 2 or more consecutive blood tests 
 
Or 
If a hepatic event is considered a serious adverse event, or 
If discontinuation of intervention is due to a hepatic event. 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; TBL = total bilirubin. 
Notes:  All ULN values should be age adjusted (AAULN). 
The interval between the 2 consecutive blood tests should be at least 2 days. 
 
 

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2.14. 
Section 10.10. Appendix 10: Blood Collection Restrictions and 
Guidance for Pediatric Participants 
Sampling Restrictions 
Blood draws are not allowed from dialysis shunts or catheters, apheresis catheters or arterial 
catheters. 
No ADA samples for participants <12 kg 
Due to blood volume restrictions, participants <12 kg will not have immunogenicity (ADA) 
samples taken.   
Minimizing the number of blood draws and venipunctures 
Blood draws should be consolidated, and the number of attempts should be kept to the minimum 
number required and in keeping with local guidelines and procedures.   
To avoid multiple venipunctures in a single day, blood samples may be obtained via a peripheral 
intravenous (IV) catheter.  For this study, a peripherally inserted central catheter (PICC) is not 
considered to be a peripheral IV catheter.   
Use of existing central line  
If a participant in this addendum already has central venous access, for example, via a port or 
PICC line, as part of their non-COVID-19 clinical care, intervention may be infused (single 
infusion) via this route if these requirements are met: 
 The participant’s parents or legal guardians give their permission to use the established 
central intravenous access route to administer study intervention, AND  
 The site consults with the medical team that is using the established central intravenous 
access route to provide clinical care and obtains their permission to use this route to 
administer study intervention, AND  
 The site investigator determines who is appropriately trained and qualified to access and 
infuse study intervention via central venous access routes in pediatric participants and 
delegates the authority to do such procedures to those individuals, AND  
 The delegated site personnel follow good clinical practices (GCPs) and the site’s 
established procedure for preventing infections and administering drugs via a central 
intravenous access route. 
For Day 1 sample collection: It is acceptable to draw the end of infusion sample approximately 1 
hour (±15 min) after the end of infusion, but not immediately following the end of the infusion. 

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Use of existing central line for mobile study visits 
During mobile study visits, study nurses may obtain blood samples via a central venous access 
route (for example, port or PICC line) if these requirements are met: 
 The participant’s parents or legal guardians give their permission to use the established 
central intravenous access route (for example, port or PICC line) to obtain blood samples 
during mobile study visits, AND  
 The site staff consults with the medical team that is using the established central venous 
access route to provide clinical care and obtains their permission to use this route to 
obtain blood samples during mobile study visits, AND  
 The site investigator determines who is appropriately trained and qualified to access and 
obtain blood samples via central venous access routes in pediatric participants and 
delegates the authority to do such procedures to those individuals, AND  
 The delegated site personnel follow GCPs and the site’s established procedure for 
preventing infections when obtaining blood samples via a central venous access route.  
Consult with the Lilly medical monitor if there are any questions about this requirement. 
For Day 1 sample collection: It is acceptable to draw the end of infusion sample approximately 1 
hour (±15 min) after the end of infusion, but not immediately following the end of the infusion. 
Use of anesthetics or devices to ease discomfort with venipunctures 
To ease discomfort associated with venipunctures, these options are allowed in the study per 
local prescribing information,  
 local anesthetic creams, for example, EMLA or ELA-max  
 needleless devices for injecting local anesthetics, for example, a J-Tip, and  
 local vibration devices, for example, a Buzzy.   
Pharmacokinetic sampling 
To avoid contamination with infused intervention, blood samples for pharmacokinetic purposes 
on the day of infusion should never be obtained using the same venous access site that is used for 
infusion of study intervention.  In addition, pharmacokinetic samples on the day of infusion 
should be obtained from a venous access site on the opposite side of the body from the site of 
intervention infusion. 
 

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3. 
References 
[AAP]. American Academy of Pediatrics. Children and COVID-19: state-level data report. April 
2022. Accessed April 5, 2022. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-
19-infections/children-and-covid-19-state-level-data-report/ 
Belay ED, Abrams J, Oster ME, et al. Trends in Geographic and Temporal Distribution of US 
Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic. JAMA 
Pediatr. 2021;175(8):837–845. doi:10.1001/jamapediatrics.2021.0630 
[CDC] Centers for Disease Control and Prevention. Breastfeeding and caring for newborns if 
you have COVID-19. Webiste page last updated January 20, 2022. Accessed April 5, 2022. 
Available at: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/pregnancy-
breastfeeding.html 
[CDC] Centers for Disease Control and Prevention. Multisystem inflammatory syndrome in 
children (MIS-C): information for healthcare providers about talking with families and 
caregivers. Website page last updated December 14, 2021. Accessed April 5, 2022. Available 
at: https://www.cdc.gov/mis/mis-c/hcp/provider-families.html 
[CDC] Centers for Disease Control and Prevention. Symptoms of COVID-19. Website page last 
updated March 22, 2022. Accessed April 5, 2022. Available at: 
https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html 
Delahoy MJ, Ujamaa D, Whitaker M, et al. Hospitalizations associated with COVID-19 among 
children and adolescents — COVID-NET, 14 States, March 1, 2020–August 14, 2021. MMWR 
Morb Mortal Wkly Rep. 2021;70:1255–1260. http://dx.doi.org/10.15585/mmwr.mm7036e2 
Eli Lilly and Company. Fact sheet for health care providers. Emergency use authorization (EUA) 
of bamlanivimab and etesevimab. January 2022. Accessed April 5, 2022. 
https://pi.lilly.com/eua/bam-and-ete-eua-factsheet-hcp.pdf 
[FDA] Food & Drug Administration. Guidance for industry. COVID-19: developing drugs and 
biological products for treatment or prevention. February 2021. Accessed February 23, 2021. 
https://www.fda.gov/media/137926/download 
[FDA] Food & Drug Administration. Guidance for industry. Development of anti-infective drug 
products for the pediatric population. December 2021. Accessed April 5, 2022. 
https://www.fda.gov/media/139586/download 
[FDA] Food & Drug Administration. Guidance for industry. Pediatric study plans: content of and 
process for submitting initial pediatric study plans and amended initial pediatric study plans. 
July 2020. Accessed February 23, 2022. https://www.fda.gov/media/86340/download 
[FDA] Food & Drug Administration. Letter of Authorization. Eli Lilly Bebtelovimab Emergency 
Use Authorization. February 2022. Accessed February 24, 2022. 
https://www.fda.gov/media/156151/download 
Hertting O. More research is needed on the long-term effects of COVID-19 on children and 
adolescents. Acta Paediatr. 2021;110(3):744-745. doi: 10.1111/apa.15731. Epub 2021 Jan 4. 
Hoang A, Chorath K, Moreira A, et al. COVID-19 in 7780 pediatric patients: A systematic 
review. EClinicalMedicine. 2020;24:100433. https://doi.org/10.1016/j.eclinm.2020.100433 

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Marks KJ, Whitaker M, Anglin O, et al. Hospitalizations of children and adolescents with 
laboratory-confirmed COVID-19 — COVID-NET, 14 States, July 2021–January 2022. 
MMWR Morb Mortal Wkly Rep. 2022;71:271–278. 
http://dx.doi.org/10.15585/mmwr.mm7107e4 
Reiff DD, Cron RQ. Who would have predicted multisystem inflammatory syndrome in 
children? Curr Rheumatol Rep. 2022;Feb 12:1-11. https://doi.org/10.1007/s11926-022-01056-
8 
Robbie GJ, Zhao L, Mondick J, et al. Population pharmacokinetics of palivizumab, a humanized 
anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob 
Agents Chemother. 2012;56(9):4927-4936. https://doi.org/10.1128/aac.06446-11 
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-
therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405-407. 
https://doi.org/10.1016/j.healun.2020.03.012 
Wang Y, Jadhav PR, Lala M, et al. Clarification on precision criteria to derive sample size when 
designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2012;52(10):1601-1606. 
https://doi.org/10.1177/0091270011422812 
Wanga V, Gerdes ME, Shi DS, et al. Characteristics and clinical outcomes of children and 
adolescents aged <18 years hospitalized with COVID-19 — six Hospitals, United States, July–
August 2021. MMWR Morb Mortal Wkly Rep. 2022;70(5152):1766–1772. 
http://dx.doi.org/10.15585/mmwr.mm705152a3 
Woodruff RC, Campbell AP, Taylor CA, et al. Risk factors for severe COVID-19 in children. 
Pediatrics. 2021;149(1):37-48. https://doi.org/10.1542/peds.2021-053418 

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4. Supporting Documentation 
4.1. Protocol Addendum Revision History 
Revision 4.1  
Overall Rationale for the Revision: 
The purpose of this revision is to adjust Inclusion Criterion 36 so that the lower age limit is 38 
weeks gestational age, and the lower weight limit is 3.3 kg. This adjustment accounted for the 
lack of an accepted corrective safety factor to determine acceptable exposure limits for process-
related impurities for pre-term infants. 
Section # and Name 
Description of Change 
Brief Rationale 
2.6 Section 4.3. Justification 
for Dose;  
2.7.1 Section 5.1. Inclusion 
Criteria;  
2.10.2 Section 9.2. Sample 
Size Determination 
Modified lower age and 
weight limits for 
participants 
Adjustment made due to the lack 
of an accepted corrective safety 
factor to determine acceptable 
exposure limits for process-
related impurities for pre-term 
infants 
 

Signature Page for VV-CLIN-068441 v1.0
Signature Page for VV-CLIN-068441 v1.0
Approval
01-Jul-2022 18:36:00 GMT+0000
Approval
01-Jul-2022 23:02:58 GMT+0000
Approved on 01 Jul 2022 GMT
PPD
PPD