A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (Trial H1: LY3819253 (LY-CoV555))
Phase: PHASE3
Conditions: COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 A Multicenter, Adaptive, 
Randomized, Blinded Controlled 
Trial of the Safety and Efficacy of 
Investigational Therapeutics for 
Hospitalized Patients With 
COVID-19 (Trial H1: 
LY3819253
(LY-CoV555))
 Version 1.0
 16 July 2020
  NCT05780268

Therapeutics for Inpatients with COVID-19 (TICO) Master Protocol 
Version 1.0, 27 Jul 2020 
 
 
IND # 151543 
 
Appendix H1-1 
 
Appendix H1: LY3819253 (LY-CoV555) – version 1.0 (16th July 2020) 
 
The content of this appendix is confidential and should only be viewed 
by persons covered by the CDA entered between Lilly and NIAID in 
relation to the ACTIV-3 study.   
 
This appendix provides detailed information pertaining to the study of this investigational 
agent. If not stated otherwise, the text in the master protocol gives the approach that will 
be taken to study this agent.    
H.1.1. Introduction and rationale for studying the agent 
LY3819253 is a neutralizing immunoglobulin G (IgG)-1 monoclonal antibody (mAb) to 
the receptor binding domain (RBD) of the S protein of SARS-CoV-2 being developed 
as a potential treatment and prophylaxis for COVID-19. This antibody blocks S protein 
attachment to human angiotensin-converting enzyme 2 (ACE2) receptors, preventing 
subsequent viral entry into human cells and viral replication. This is expected to result 
in a clinically important decrease in viral replication, mitigating the severity of disease in 
patients in who ongoing viral replication is an important driver of COVID-19 
pathophysiology.  
 
LY3819253 is made by Lilly Research Laboratories, Eli Lilly and Company, in 
partnership with AbCellera Biologics Inc. (AbCellera; Vancouver, Canada), and is 
derived from a person, who recovered from SARS-CoV-2 infection. 
 
Whereas one antiviral agent (remdesivir) has been demonstrated to have clinical 
benefit in the target population for this trial and is now part of standard-of-care (see 
Appendix I), it is plausible that additional antiviral effects from LY3819253 in 
combination with the antiviral agent may provide additive, if not synergistic, antiviral 
effects and hence, contribute to improvement in time to sustained recovery.  
 
Lilly 
is 
evaluating 
the 
safety, 
tolerability, 
pharmacokinetics 
(PK), 
and 
pharmacodynamics (PD) of LY3819253 in participants hospitalized for COVID-19, in a 
randomized, placebo-controlled, double-blind, sponsor-unblinded, single-ascending-
dose, 
Phase 
1, 
first 
in 
human 
study 
(Study 
J2W-MC-PYAA 
[PYAA]) 
(NCT04411628)(1). Lilly is also evaluating the safety, tolerability, PK and PD of 
LY3819253 in a phase 2, randomized, double-blind, placebo-controlled, dose ranging 
study in non-hospitalized participants with mild to moderate COVID-19 Illness (Study 
J2W-MC-PYAB [BLAZE-1]) (NCT04427501)(2). Both studies are ongoing and 
preliminary safety, tolerability, PK and PD data from these may inform the dose level 
administered in this study. 
  
H1.1.1 Potential risk and benefits from LY3819253 
Anticipated risk is considered low, based on the known mechanism of action for human 
derived neutralizing antibodies in acute viral disease states.  LY3819253 is a highly 
specific mAb directed at foreign (non-human) epitope(s).  The complementarity 
determining regions (CDRs) of the mAb were derived from B lymphocytes of a naturally 
convalescent SARS-CoV-2-infected patient and, thus, have undergone natural positive 
and negative selection pressures in vivo, unlike humanized antibodies generated in 

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Appendix H1-2 
 
mice.  Therefore, off-target binding and tissue cross-reactivity are considered unlikely, 
which is further supported by the absence of binding to membranes of human tissue in 
a tissue cross-reactivity study.   
 
Potential risks for infusion of an IgG1 mAb directed toward a microbial pathogen are 
mostly associated with either infusion-related immediate and non-immediate 
hypersensitivity reactions, or infusion-related cytokine release syndrome. Signs and 
symptoms of infusion-related immediate hypersensitivity reactions may include, but are 
not limited to: anaphylaxis, angioedema, bronchospasm, chills, diarrhea, hypotension, 
itching, skin rash, shortness of breath, urticarial, tachycardia, and throat irritation or 
chest tightness. Additional signs and symptoms associated with cytokine release 
syndrome may also include fever, headache, myalgia, nausea, and vomiting. 
 
The single infusion in this study will be administered at a controlled rate, the study 
participants will be monitored closely, and adjustments in the infusion rate will be made 
and/or the infusion paused or stopped as well as any supportive measures instituted as 
per local practice, if indicated.   
 
A theoretical risk is that LY3819253 may cause antibody-dependent enhancement 
(ADE) of viral replication (section 3.2).  This is based on responses observed to some 
monoclonal antibody therapies used in other unrelated viral diseases, Dengue and Zika 
virus infections.  Unlike ADE associated with Dengue and Zika virus infections, this 
phenomenon has not been clearly established for coronavirus infections, such as 
severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome 
(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 has not indicated safety concerns (3). 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.  Both in vitro and in vivo (non-human primate) experiments have been 
completed, and no evidence of ADE of infection was observed at sub-neutralizing 
concentrations of LY3819253. 
 
The potential benefit of LY3819253 is, that the clinical course of COVID-19 may be 
improved, which may include a faster recovery from COVID-19.   
 
In Study PYAA, 24 adult participants were randomized and received either LY3819253 
or placebo through 03 July 2020.  A total of 18 participants received LY3819253 (6 
participants each receiving either 700 mg, 2800 mg or 7000 mg) and 6 received 
placebo.  
 
Based on preliminary data from the data cutoff date of 03 July 2020 in Study PYAA, 
LY3819253 has been well tolerated by participants and no deaths, serious adverse 
events (SAEs) or discontinuations due to adverse events (AEs) have been reported. 
No AEs of infusion-related reaction (IRR) considered to be related to LY3819253 by the 
Principal Investigator (PI) have been reported in this study. Overall, the frequency of 
treatment-emergent adverse events (TEAEs) in Study PYAA was 23 in 10 participants 
dosed with LY3819253 (across all doses) or placebo. There were a similar number of 

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Appendix H1-3 
 
TEAEs across all groups. Most TEAEs reported were mild to moderate in severity. 
There have been no dose-limiting safety issues identified. Of the data received to date, 
PK/PD were within expected limits.  
 
In Study PYAB, 26 adult participants entered and were randomized to receive either 
placebo or LY3819253 at doses of 700 mg or 2800 mg (the 7000mg cohort was 
initiated on 03 July 2020).  Based on the data cutoff date of 03 July 2020, no deaths, 
SAEs or discontinuations have been reported. The study remains blinded.  
 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of LY3819253 may be found in the Investigator’s 
Brochure, Participant Information Leaflet, and/or Development Safety Update Report. 
 
Given the data on LY3819253 from the on-going Phase 1 and Phase 2 studies, the 
well-described safety profile of other therapeutic monoclonal antibodies, and the limited 
disease directed therapeutic options for patients with COVID-19 illness, the overall 
benefit-risk assessment of this study is considered favorable. 
 
H1.1.2 Motivation for agent selection by the ACTIV Trial Oversight Committee (TOC) 
The Lilly antibody LY3819253 discovered in partnership with AbCellera was identified 
from over 400 antibody sequences isolated from blood of a convalescent SARS-CoV-2 
infected patient and is a very high affinity binder of the receptor binding domain (RBD) 
of the viral S-protein.  In live virus neutralization in vitro assays, LY3819253 has very 
high potency against SARS-CoV-2. Based on current information available to the TOC,  
LY3819253 appears to have an excellent potency profile among the RBD antibodies 
available. Further, the Lilly data demonstrate binding to both the ACE-2-interacting and 
the resting state of the RBD, neutralization across multiple strains of live virus, and 
binding across RBD known mutations of SARS-CoV-2, which provides encouraging 
evidence of a low risk of viral reactivation. 
LY3819253 has an open IND, and a single-ascending-dose study in hospitalized 
patients has already begun (NCT04411628). The Lilly strategy, assuming safety and 
tolerability, is, to rapidly advance into efficacy studies in hospitalized and ambulatory 
patients. Clinical trial materials are sufficient to support the general investigative plan, 
and Lilly will begin drug substance commercial manufacturing at risk at their 
Branchburg, NJ site with plans for drug product manufacturing at their parenteral fill 
facility in Indianapolis, IN. 
Lilly’s statement regarding plans for licensure: Lilly is a global pharmaceutical company 
and attempts to bring important medical breakthroughs to as many patients in as many 
countries as possible. It would therefore be our general intent to pursue licensure in 
countries where the trial occurs. In the case of the COVID-19 pandemic, the actual 
decision to pursue licensure will be impacted by other factors which may include: status 
of the COVID pandemic in the country and medical need, availability of other therapies 
including vaccines, available drug supply and other supply feasibility issues, and other 
regulatory considerations.  

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Appendix H1-4 
 
H1.1.3 Justification for dose chosen for LY3819253 
The dose levels of LY3819253 administered in this study are informed by Study J2W-
MC-PYAA (PYAA) and J2W-MC-PYAB (BLAZE-1). In both studies, 700, 2800, and 
7000 mg doses are being evaluated. Based on safety results from the studies 
mentioned above, the dose to be used is 7000 mg irrespective of body weight.  
 
The projected human half-life is expected to be in the 2-4 weeks range. 
 
This dose is selected to minimize potential concerns about underdosing and thus failing 
to detect an efficacy signal for an efficacious therapy. There are no significant safety 
concerns about using the 7000 mg dose, as side effects in antibody therapy are not 
generally dose-dependent. 
 
H1.2. Agent specific eligibility criteria 
     In addition to those outlined in the master protocol. 
H1.2.1 Inclusion Criteria 
1) Non-pregnant female participants who are of reproductive potential and male 
participants who are able to father a child must abstain from male/female sexual 
intercourse or 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 and 
for 90 days after investigational agent is administered.  
 
Highly effective methods of contraception (less than 1% failure rate) include, but are 
not limited to: 
• combination oral contraceptives 
• implanted contraceptives 
• intrauterine devices 
Effective methods of contraception include, but are not limited to:  
• diaphragms and cervical caps with spermicide 
• cervical sponges 
• condoms with spermicide 
 
NOTE: 
• 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), and withdrawal are not acceptable methods of 
contraception.  
 
Participants not of reproductive potential are eligible without requiring the use of a 
contraceptive method. Participant-reported history is acceptable documentation of 
surgical sterilization and menopause. 

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Appendix H1-5 
 
Participants with pregnant partners should use condoms during vaginal intercourse 
through 90 days after investigational agent administration. 
 
Participants should refrain from sperm donation through 90 days after 
investigational agent administration. 
  
NOTE: Reproductive potential is defined as patients who have reached menarche, 
who have not been post-menopausal for at least 12 consecutive months with 
follicle-stimulating hormone (FSH) ≥ 40 IU/ml or 24 consecutive months if an FSH is 
not available, who have not undergone surgical sterilization, who do not have other 
clinical condition that could induce amenorrhea, who are not taking medications 
such as oral contraceptives, hormones, gonadotropin releasing hormone, anti-
estrogens, selective estrogen receptor modulators (SERMs) or chemotherapy that 
could induce amenorrhea. Individuals with permanent infertility due to an alternate 
medical cause (e.g. Mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied. 
 
H1.3. Description of investigational agent 
H1.3.1. Administration and duration 
See the PIM and Pharmacy Procedures for details. See also section H1.5 below for 
guidance on the clinical management of the infusion, including infusion-related 
reactions. 
The infusion rate may be reduced as deemed necessary, if an infusion reaction is 
observed. Participants will be closely monitored every 30 minutes during the infusion 
and for at least 2 hours after completion of the infusion. Additional monitoring may be 
necessary based on clinical judgement of the study investigator(s) and/or site staff, and 
in accordance with the master protocol. The site must have resuscitation equipment, 
emergency drugs and appropriately trained staff available during the infusion and for at 
least 2 hours after the completion of the infusion. 
 
If a participant has not already received the relevant dose of remdesivir at the day of 
enrolment, and has no contraindications to start remdesivir, it is recommended (but not 
required) that the relevant dose of remdesivir is infused after the infusion of LY3819253 
/placebo is completed. 
 
H1.3.2. Formulation and preparation 
LY3819253 is provided in vials of 20 ml solution containing 700 mg antibody each. 
LY3819253 must be stored between 2ºC and 8ºC. 
A total of 10 vials is required for dosing of the agent at 7000 mg (see table H1.1). 
Placebo is normal saline. The study medication is prepared by a unblinded pharmacist 
at the local pharmacy. To ensure blinding of the participant and clinical staff a colored 
sleeve will be placed over the infusion bags used (see PIM and Pharmacy 
Procedures). 

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Appendix H1-6 
 
LY3819253 should be prepared and dispensed as soon as possible after 
randomization. Infusions should be completed within 4 hours after the infusion has 
been prepared by the pharmacist. 
 
Table H1.1. Study medication overview.  
Intervention Name 
Placebo 
LY3819253 
Dose Formulation 
0.9% sodium chloride solution 
Solution  
Dosage Level(s) (mg) 
Not applicable 
7000 
Route of administration 
IV infusion 
IV infusion 
Use 
Placebo 
Experimental 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Commercially 
available 
0.9% 
sodium chloride solution 
From Lilly 
Packaging and 
Labeling 
Commercially 
available 
0.9% 
sodium chloride solution 
Study Intervention will be provided 
in glass vials and will be labeled 
appropriately 
 
 
H1.3.3 Supply, distribution, and accountability 
Procedures for ordering and accepting drug, for maintaining inventory of LY3819253, 
and for breaking the blind in the event of a medical emergency will be described in the 
Pharmacy Procedures. 
H1.3.4. Contraindicated medications 
No medication is known to be contraindicated in patients receiving the investigational 
agent. Whenever a concomitant medication or the study agent is initiated or a dose 
changed, investigators must review the concomitant medication’s prescribing 
information and the relevant protocol appendix/appendices, as well as the most recent 
package insert, Investigator’s Brochure, or updated information from DCR, NIAID to 
obtain the most current information on drug interactions, contraindications, and 
precautions. 
 
H1.3.5. Precautionary medications 
The clinical site should have necessary equipment and medications for the 
management of any infusion reaction (see section H1.5 below).  
 
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 recommend premedication, if the 
frequency of infusion reactions among participants warrants it. If minor infusion 
reactions are observed, administration of acetaminophen, 500 mg to 1000 mg, 
antihistamines and/or other appropriately indicated medications may be given prior to 

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Appendix H1-7 
 
the start of infusions for subsequent participants. The decision to implement 
premedication for infusions in subsequent participants will be made by the investigator 
and sponsor and recorded in the study documentation. Any premedications given will 
be documented as a concomitant therapy. 
H1.4. Clinical and laboratory evaluations 
 
H1.4.1 Timing of Assessments 
Appendix B outlines the clinical and laboratory monitoring. Assessment and reporting 
of AEs (section 10.1.1), SAEs (section 10.1.2) and unanticipated problems (section 
10.1.3) and their severity, causality (section 10.1.5) and expectedness (section 10.1.6) 
is performed as outlined in the relevant section of the master protocol.  
 
H1.4.2 Immunogenicity Assessments 
At the visits specified in the master protocol (Days 0, 28, and 90) venous blood 
samples will be collected to determine antibody production against LY3819253. 
Immunogenicity may be assessed by a validated assay designed to detect ADAs in the 
presence of LY3819253 at a laboratory approved by Lilly. Antibodies may be further 
characterized for their ability to neutralize the activity of LY3819253. Remaining volume 
from the PK sample may also be used for immunogenicity assessments as needed.   
 
H1.4.3. Pharmacokinetic Assessments 
At the visits specified in the master protocol (Days 0, 1, 5, 28, and 90) venous blood 
samples will be collected to determine LY3819253 serum concentration for 
pharmacokinetic assessment. The PK/Immunogenicity assessment will require 2mL of 
the serum collected, as described in the Master Protocol Appendix B as “Research 
Sample Storage”.  PK samples may be assessed by a validated assay at a 
bioanalytical lab designated by Lilly. The PK assessment will use the same 2ml serum 
aliquot specified in the Immunogenicity assessment section above (4.2). Analysis of 
samples from placebo-treated subjects is not planned. Remaining sample used for PK 
may be pooled and used for exploratory metabolism or bioanalytical method 
experiments as deemed appropriate.  
H1.5. Clinical management issues 
All participants should be monitored closely for 2 hours after the infusion, as there is a 
risk of infusion reaction and hypersensitivity (including anaphylaxis) with any biological 
agent. 
H1.5.1. 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.  
Infusion-related reactions’ severity will be assessed and reported using the Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected version 2.1 (July 2017) (Table H1.2). 
Table H1.2. Overview of severity grading of infusion-related reactions. 

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Appendix H1-8 
 
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 (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, Corrected 
Version 2.1 (July 2017)(4). 
H1.5.2. Site Needs 
The clinical site should have necessary equipment, medications, adequately qualified 
and experienced staff with appropriate medical cover for the management of any 
infusion reaction, which may include, but is not limited to, oxygen, IV fluid, epinephrine 
(/adrenaline), acetaminophen (/paracetamol) and antihistamine. 
The pharmacy must use amber-colored Ultraviolet Light-Inhibiting (UVLI) protective 
bags to place over the infusion bag. The pharmacy will be provided with labels to be 
placed on the IV bag before dispensing (refer to the Pharmacy Procedures). 
The pharmacy is required to provide normal saline and IV bags, similarly shrouded.  
H1.5.3. Management of Infusion Reactions including Discontinuation 
Investigators will use their clinical judgement and standard of care to evaluate and 
manage all infusion reactions. If an infusion reaction occurs, then supportive care 
should be used in accordance with the signs and symptoms. If a severe and potentially 
life-threatening infusion reaction occurs with LY3819253 /placebo, its use should be 
permanently discontinued. 

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Appendix H1-9 
 
If a participant is not infused with LY3819253 /placebo or the complete infusion is not 
given, all follow-up procedures and reporting’s outlined in the master protocol 
(Appendix B for overview), should be adhered to as indicated. 
 
H1.5.4. Adverse Events of Special Interest (AESI) 
The following are AESIs for the agent LY3819253 or placebo for LY3819253:  
• Infusion-related reactions 
• Allergic/hypersensitivity reactions 
 
H1.6. References 
1. https://clinicaltrials.gov/ct2/show/NCT04411628 (PYAA trial) 
2. https://clinicaltrials.gov/ct2/show/NCT04427501 (BLAZE-1 trial) 
3. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma 
therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-6. 
4. https://rsc.niaid.nih.gov/clinical-research-sites/grading-severity-adult-pediatric-adverse-
events-corrected-version-two-one (DAIDS AE severity grading; link also outlined in 
appendix D)