A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (Trial H4: AZD7442)
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 H4: AZD7442)
 Version 2.0 
09 April 2021
  NCT05780437

Appendix H4: AZD7442 – version 2.0 (09 April 2021) 
 
The content of this appendix is confidential and should only be viewed 
by persons covered by the CDA entered between AstraZeneca and NIAID 
in relation to the TICO/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.4.1. Introduction and rationale for studying the agent 
AZD8895 and AZD1061, known collectively as AZD7442, are two fully human 
neutralizing immunoglobulin G (IgG)-1 kappa monoclonal antibodies (mAb) that target 
two distinct epitopes on the receptor-binding domain of the spike protein of SARS-CoV-
2 [1]. They neutralize SARS-CoV-2 in live virus assays, preventing viral entry into human 
cells and subsequent viral replication [1]. This mechanism is expected to result in a 
clinically important decrease in viral replication, mitigating the severity of disease in 
patients in whom ongoing viral replication is an important driver of COVID-19 
pathophysiology.  
 
AstraZeneca (AZ) is a global, science-led biopharmaceutical business.  Its innovative 
medicines are used by millions of patients worldwide. AZD7442 is made by AstraZeneca.  
The two monoclonal antibodies of which it is comprised were derived from B cells isolated 
from people who recovered from SARS-CoV-2 infection [1]. Out of hundreds of anti-
SARS-CoV2 antibodies that were screened, these two monoclonal antibodies were 
selected for affinity to SARS-CoV-2 spike protein domains, neutralization potency, and 
their developability.  They were subsequently modified by two sets of triple amino acid 
substitutions in their Fc regions, TM (L234F/L235E/P331S), intended to diminish blinding 
to cellular Fc receptors, and YTE (M252Y/S254T/T256E), intended to prolong their 
elimination half-lives  [1] 
 
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 the combination of AZD8895 and 
AZD1061 together with remdesivir may provide additive, if not synergistic, antiviral 
effects and hence, contribute to improvement of time to sustained recovery.  
 
AstraZeneca is evaluating the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of AZD7442 in 60 volunteers, in a randomized, placebo-
controlled, single-ascending-dose, Phase 1, first in human study (Study D8850C00001; 
NCT04507256) ) [2]. This study is ongoing and preliminary safety, tolerability, PK and 
PD data from these may inform the dose level administered in this study. 
  
H4.1.1 Potential risk and benefits from AZD7442  
Anticipated risk is considered low, based on the known mechanism of action for human-
derived neutralizing antibodies against viral proteins in acute viral disease states [3, 4].  
AZD7442 is comprised of two highly specific mAbs directed at viral epitope(s) not found 
in healthy humans. The complementarity determining regions (CDRs) of AZD8895 and 

AZD1061 are identical to the parent mAbs derived from B lymphocytes of naturally 
convalescent SARS-CoV-2-infected patients [1]. In the Fc domain of both mAbs, three 
amino acids were substituted (YTE; M252Y/S254T/T256E) to extend the half-life of the 
antibodies to approximately 80 days  by increasing binding to FcRn [5, 6]. As the 
antibodies target viral epitopes, off-target binding is considered unlikely, and this 
expectation was confirmed by the absence of AZD7442-binding to human and 
cynomolgus monkey tissues in a tissue cross-reactivity study [7].   
 
AZD7442 is comprised of two antibodies (AZD8895 and AZD1061) which neutralize 
SARS-CoV-2 by binding to unique, non-overlapping epitopes on the RBD of the viral 
spike protein, which is responsible for receptor binding and cellular fusion. Both 
AZD8895 and AZD1061 bind the RBD with nanomolar affinity and are individually 
capable of sterically blocking the virus from engaging its cellular receptor, hACE2. In 
both IgG and Fab formats, AZD8895 and AZD1061 were individually capable of blocking 
SARS-CoV-2 spike RBD binding to hACE2 in competition binding assays [7] . 
Furthermore, the two antibodies demonstrate concurrent binding to RBD on the SARS-
CoV-2 spike protein, as evidenced by both binding competition assays and electron 
microscopy images showing both Fabs bound simultaneously [1, 7]. Whereas AZD8895 
binds the open conformation of the spike protein, which exposes the residues that 
mediate ACE2 interaction, AZD1061 binds to both the open and the closed conformation 
[1] This binding translates to potent neutralization of SARS-CoV-2 infection by AZD7442 
in microneutralization assays and focus reduction neutralization tests, with IC50 values 
between 10 to 26 ng/mL [7]. The two mAbs also demonstrate potent neutralization of 
SARS-CoV-2 and pseudovirus in vitro [1, 7]. The parental versions of AZD8895 (COV2-
2196) and AZD1061 (COV2-2130) provided protection from SARS-CoV-2 infection in 
several in vivo models, including mice and non-human primates [1]. These mAbs 
reduced viral load in the lungs of animals, whether administered prophylactically or up to 
12 hours after virus infection. The reduction in viral load corresponded to reduced 
alveolar damage and inflammation in the lungs of infected animals. AZD7442 was 
additionally evaluated in rhesus macaques in both prophylactic and treatment settings. 
Intravenous administration of 4 mg/kg or 40 mg/kg AZD7442 resulted in expected mAb 
concentrations in the serum that provided peak neutralizing antibody titers that ranged 
from 50,000 to 1,768,000 and prevented replication of SARS-CoV-2 in the nasal 
mucosae and lungs of infected animals [7]. AZD7442 administration 24 hours after 
infection limited replication of SARS-CoV-2 such that viral replicating RNA was only 
detected up to 4 days post-infection as compared to 8 days post-infection in infected 
animals that received isotype control mAb [7].Collectively, these data demonstrate that 
the mAbs that comprise AZD7442 potently neutralize SARS-CoV-2 in vitro and are 
efficacious in animal challenge models when administered prophylactically or 
therapeutically.    
  
Potential risks for infusion of an IgG1 mAb directed towards 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.   
 
The pathophysiology for SARS-CoV-2 is not well understood. Reports of fatal acute 
respiratory disease with uncontrolled pulmonary inflammation and increased secretion 
of proinflammatory cytokines is suggestive of a cytokine storm, especially in patients who 
are critically ill [8-10]. These reports have led to the speculation that SARS-CoV-2 may 
bear some resemblance to SARS-CoV and MERS-CoV, which have been associated 
with reports of antibody-mediated enhancement (ADE) of disease in some in vivo models 
that was attributed to Fc receptor-mediated uptake of virus-antibody complexes into cells 
such as alveolar macrophages, resulting in an overstimulation of the host immune 
response [11-18]. To date, there is no evidence of ADE of disease associated with 
COVID-19 in humans, although it remains a theoretical risk that is being closely 
monitored. Additionally, limited experience with the use of convalescent serum as a 
treatment for patients with severe COVID-19 has not indicated safety concerns [19]. To 
reduce the theoretical risk of antibody-dependent enhancement  of disease (ADE; see 
below), three additional amino acid substitutions (TM; L234F/L235E/P331S) were 
incorporated in the Fc domain of both mAbs, which reduces their binding to Fc gamma 
receptors (FcγR) and complement proteins and thereby reducing effector functions [20]. 
The TM substitutions have been used in several other AstraZeneca mAb programs in 
oncology and autoimmune diseases that have been studied in the clinic; all have shown 
an acceptable safety profile [21, 22].  
 
The non-clinical safety program includes: 1) a GLP-compliant tissue cross reactivity 
(TCR) study assessing AZD7442 binding to a panel of 32 human and cynomolgus 
monkey tissues and 2) a GLP-compliant, single-dose toxicology study in cynomolgus 
monkeys of 8 weeks duration with 2- and 8-week follow up. Data from the complete GLP 
TCR study demonstrated that no binding was observed to any of the human or 
cynomolgus tissues tested. In the GLP toxicology study, administration of AZD7442 via 
IV infusion or IM injection was well tolerated in cynomolgus monkeys at a dose level of 
600 mg/kg (combination of 300 mg/kg of AZD8895 and 300 mg/kg of AZD1061) and 150 
mg/kg (75 mg/kg of each antibody), respectively. In the 2-week and 8-week phases of 
the GLP toxicology study there were no AZD7442-related adverse changes in any 
endpoint examined including safety pharmacology endpoints like ECG, BP, HR and BT 
and assessments of CNS and respiratory endpoints. The doses of 600 mg/kg IV and 150 
mg/kg IM are considered the single dose No Observed Adverse Event Levels (NOAELs). 
Together, the lack of binding to any tissues in the GLP TCR study and the tolerability in 
the single dose tox study support the safety of the proposed clinical plans for AZD7442. 
 
The first in humans Phase 1 study of AZD7442 enrolled 60 subjects, randomized 5:1, 
AZD7442:placebo, in a single-ascending dose study of 5 equal cohorts that assessed 
AZD7442 doses of 300 mg IM (150 mg of AZD8895 and 150 mg of AZD1061 
administered as separate intramuscular injections), 300 mg IV (150 mg of AZD8895 and 

150 mg of AZD1061 administered as separate sequential IV infusions), 1000 mg IV (500 
mg of AZD8895 and 500 mg of AZD1061 administered as separate sequential IV 
infusions), 3000 mg IV (1500 mg of AZD8895 and 1500 mg of AZD1061 administered 
as separate sequential IV infusions), and 3000 mg IV (1500 mg of AZD8895 and 1500 
mg of AZD1061 co-administered as a mixed IV infusions).  The second interim analysis, 
reporting cumulative data after the last subject dosed had completed 7 days post-dose, 
identified no serious adverse events, no adverse events of greater than mild to moderate 
severity, no hypersensitivity reactions, no injection site reactions, no infusion reactions, 
and no imbalance between the placebo and active treatment arms. 
 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of AZD7442 may be found in the Investigator’s 
Brochure, Participant Information Leaflet, and/or Development Safety Update Report. 
 
Given the data on AZD7442 from the on-going Phase 1 study [2, 7], the well-described 
safety profile of other therapeutic human monoclonal antibodies with foreign (non-
human) targets, and the limited disease directed therapeutic options for patients with 
COVID-19 illness, the overall benefit-risk assessment of this study is considered 
favorable. 
 
H4.1.2 Motivation for agent selection by the ACTIV Trial Oversight Committee (TOC) 
The ACTIV-2/3 Agent Selection Committee (ASC) reviewed the AstraZeneca (AZ) 
SARS-CoV-2 neutralizing antibody cocktail AZD7442 (AZD8895 & AZD1061) and voted 
in favor of the agent proceeding into ACTIV-2 and ACTIV-3, and the TOC endorsed that 
recommendation.  AZ’s AZD7442 cocktail was supported because AZ presented detailed 
epitope binding data (e.g., negative stained electron microscopy); robust preclinical 
supporting data (e.g., PK, tolerability, efficacy); and detailed information about Fc 
modifications and their likely effects.  For preclinical data for viral neutralization, live virus 
neutralization against the original Washington strain of SARS-CoV-2 showed  [USA-
WA1/2020, AZD8895] 9/NA | 32/NA ng/mL, [USA-WA1/2020, AZD1061] 32/NA | 115/NA 
ng/mL, and [USA-WA1/2020, AZD7442] 10/NA | 26/NA ng/mL for the individual 
antibodies and the cocktail, respectively. For viral binding, AZ showed that their 
antibodies  bound to S protein RBD - AZD1061: K444, G447 and AZD8895: F486, N487 
with strong affinity RBD, AZD8895/1061]: 2.15E-9/2.18E-9 M and [Spike trimer, 
AZD8895/1061]: 3.41E-9/5.29E-9 M.  This was particularly important because the ASC 
initially approved the AZ cocktail to move forward while the tissue cross reactivity studies 
were still in process.  These assays in humans and non-human primates have since read 
out negative.  AZD7442 also showed excellent in vivo preclinical efficacy in mice and 
non-human primates.   
Both AZ antibodies are human neutralizing immunoglobulin G1 that bind distinct epitopes 
in receptor binding domain (RBD) in spike protein of SARS-CoV-2 virus. They are both 
YTE (M257Y, S259T, T261E) & TM FcGR (L234F, L235E, P331S) modified isoforms of 
monoclonal antibodies. While the YTE modification improves the half-life of antibodies 
to provide prolonged duration of protection and extended therapeutic treatment window, 

the TM modification reduces binding activity to human Fc receptors, thereby minimizing 
the potential risk of Fc-mediated antibody-dependent enhancement. 
In addition, the ASC appreciated that AZ had already filed their pre-submission for 
Investigational New Drug (IND) and was targeting filing for its full IND in early September. 
AZ’s Phase I study was targeted be complete by mid-October, with the candidate agent 
ready to enter ACTIV clinical trials by late November pending Phase I results. While it 
was the second neutralizing antibody cocktail selected for the ACTIV trials, AZD7442 did 
have slightly different binding sites and Fc modifications for its antibodies that the ASC 
considered to be of value to study against the other agents already selected for the trial. 
Finally, the ASC found the manufacturing and scalability strategy for AZ sufficient for the 
full trial and beyond. 
AstraZeneca’s medicines are used worldwide. AstraZeneca has stated that generally 
their intent is to pursue licensure in countries where pivotal trials are conducted. 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.  
H4.1.3 Justification for dose chosen for AZD7442   
 
Human efficacious doses for AZD7442 were evaluated using in vitro potency data (virus 
neutralizing activity of AZD7442 against SARS-CoV-2) and PK data. In addition, a 
viral‑dynamic model was developed to understand the pharmacodynamic effects of 
AZD7442 inhibiting a SARS-CoV-2 infection and the resulting immune response. In the 
viral‑dynamic model the AZD7442 partition ratio between lung epithelial lining fluid -to-
serum is assumed as 1% and the potency (IC80; inhibiting SARS-CoV-2 by 80%) as 40 
ng/mL. With the dose of 600 mg IV predicted to result in exposures in the ELF that 
exceed the IC80, this dose when administered before the time of peak viral load (~ 7 
days after day of infection) is expected to result in reduction of the peak viral load and 
earlier eradication of the viral load. When administered after the peak viral load has been 
reached, AZD7442 is still expected to result in earlier viral load eradication compared to 
when drug is not present. 
  
IV was selected over IM as the administration route for this treatment study because peak 
concentrations are achieved immediately after IV administration while it takes > 7 days 
after IM injection to achieve peak concentrations and early treatment is critical for this 
patient population.   Also, the peak concentrations following IV infusion are about two 
times higher than following IM injection at the same dose level and higher Cmax may be 
correlated with better efficacy. The available observed AZD7442 concentration data over 
the first 60 days in Phase 1 study D8850C00001 is shown in Figure 1 below. 
 
 
 

 
 
Figure 1: Mean (SD) Serum AZD7442 concentration over time in Phase 1 Study 
D8850C00001 in healthy volunteers 
 
Based on the above justifications and the available safety data, the following dose of 
AZD7442 has been chosen for study in ACTIV-3: 600 mg IV (equating to 300 mg 
AZD8895 + 300 mg AZD1061).There are no significant safety concerns about using the 
600 mg dose of AZD7442, as side effects in antibody therapy are not generally dose-
dependent and doses higher than this dose has been tested in the Phase 1 study to 
confirm the safety. 
 
H4.2. Agent specific eligibility criteria 
In addition to the inclusion and exclusion criteria outlined in the master protocol, the 
following patients will be excluded:  
1. pregnant women  
2. nursing mothers  
3. women of child-bearing potential who are unwilling to acknowledge the strong 
advice to abstain from sexual intercourse with men or practice appropriate 
contraception through the entire 18 months of the study 
4. men who are unwilling to acknowledge the strong advice to abstain from sexual 
intercourse with women of child-bearing potential or to use barrier contraception 
through the entire 18 months of the study. 
 
No other specific inclusion or exclusion criteria need to be altered. 
 
0 
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AZ07442300mglM 
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AZ07442 300mg IV 
AZ074421000mg N 
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AZ07442 3000mg r.t{2sequef0811rlustoo;) 
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50 
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In addition, prior to the initial futility assessment which is performed when approximately 
150 participants have been enrolled on AZD7442 and 150 on placebo, patients on high-
flow oxygen or non-invasive ventilation (category 5 of the pulmonary ordinal outcome) will 
be excluded. These patients may be eligible for the trial if the initial futility assessment is 
passed by this agent. 
H4.3. Description of investigational agent 
H4.3.1. Administration and duration 
See the PIM and Pharmacy Procedures for details. See also section H4.5 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 during the infusion and every 30 minutes 
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 AZD7442/ 
placebo is completed. 
 
H4.3.2. Formulation and preparation 
AZD7442 (AZD8895 and AZD1061) is provided in separate vials containing 1.5 mL 
solution each containing 150 mg of AZD8895 or 150 mg of AZD1061. AZD7442 
(AZD8895 and AZD1061) must be stored between 2ºC and 8ºC.  
A total of 2 vials of AZD88995 and two vials of AZD1061 are required for the dosing of 
the solution at 600 mg (see Table H4.1).  Placebo is normal saline from local supply.  
Detailed instructions for preparing the infusion bag for the investigational agent are 
described in the pharmacy procedures for this agent.  
The master protocol, general procedures described in the PIM, and pharmacy 
procedures for preparing and dispensing the infusion by the unblinded pharmacist will 
be followed. 
 
Table H4.1. Study medication overview.  
Intervention Name 
Placebo 
AZD7442   
Dose Formulation 
0.9% (w/v) saline 
AZD8895: single-use vial (100 mg/mL) 
AZD1061: single-use vial (100 mg/mL) 
Dosage Level(s) (mg) 
Not applicable 
600 mg dose (300 mg AZD8895 and 300 mg 
AZD1061) 
 

Dose Volume (mL) 
Refer to pharmacy 
procedures 
Refer to pharmacy procedures 
Route of 
administration 
IV infusion 
IV infusion 
Use 
Placebo 
Experimental 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Commercially available 
0.9% (w/v) saline 
AstraZeneca 
Packaging and 
Labeling 
Commercially available 
0.9% (w/v) saline 
Study Intervention will be provided in single-
use 10R vials, individually packaged in a 
carton, and labeled appropriately 
 
H4.3.3 Supply, distribution, and accountability 
Procedures for ordering and accepting drug, for maintaining inventory of AZD7442 
(AZD8895 and AZD1061), and for breaking the blind in the event of a medical emergency 
will be described in the Pharmacy Procedures. 
H4.3.4. 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. 
 
H4.3.5. Precautionary medications 
The clinical site should have necessary equipment and medications for the management 
of any infusion reaction (see section H4.5 below).  
 
Premedication for infusions is not planned.  
 
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 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 premedication given will be documented as a concomitant 
therapy. 
H4.4. Clinical and laboratory evaluations 
 
H4.4.1 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.  
 

H4.4.2 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 AZD7442. Serum samples for 
determination of ADA will be tested at PPD Inc. on behalf of AstraZeneca, using a 
validated assay. Unscheduled samples for ADA analysis should be collected in response 
to suspected immune-related AEs. A tiered testing scheme will be employed, with the 
first step being screening. Samples found positive in the screening step will be tested in 
the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo endpoint titer determination.  Remaining volume from the PK sample may also 
be used for immunogenicity assessments as needed.   
 
H4.4.3. Pharmacokinetic Assessments 
At the visits specified in the master protocol (Days 0, 5, 28, and 90) venous blood 
samples will be collected to determine AZD7442 serum concentration for 
pharmacokinetic assessment. The PK/Immunogenicity assessment will require 2 mL 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. The PK assessment will use the same 2 ml serum aliquot specified in the 
Immunogenicity assessment section above (H4.4.2). Analysis of samples from placebo-
treated subjects is not planned. Remaining sample used for PK may be pooled and used 
for exploratory metabolism, pharmacodynamic, virologic, or bioanalytical method 
experiments as deemed appropriate.  
 
 
H4.5. 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. 
H4.5.1. 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) [23]. 
H4.5.2. 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 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 0.9% (w/v) saline and IV bags, similarly shrouded.  

H4.5.3. 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 AZD7442/placebo, its use should be 
permanently discontinued. 
If a participant is not infused with AZD744/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. 
H4.5.4. Adverse Events of Special Interest (AESI) 
The following are AESIs for the agent AZD7442 or placebo for AZD7442:  
• Infusion-related reactions 
• Allergic/hypersensitivity reactions 
 
H4.5.5. Incident Pregnancy in Participants or Their Partners 
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study.   
The participant will then be followed to determine the outcome of the pregnancy and 
reported on the Pregnancy Outcome eCRF.  
If an investigator learns that a male participant’s partner has become pregnant while 
the male participant is in this study, the investigator is asked to attempt to obtain 
information on the pregnancy, including its outcome, after obtaining consent from the 
pregnant partner.  The outcome of the pregnancy will be reported on the Pregnancy 
Outcome eCRF. 
 
 
 
H4.6. References 
 
1. 
Zost, S.J., et al., Potently neutralizing and protective human antibodies against 
SARS-CoV-2. Nature, 2020. 584(7821): p. 443-449. 
2. 
AstraZeneca. Study to Evaluate the Safety, Tolerability and Pharmacokinetics of 
AZD7442 
in 
Healthy 
Adults. 
Available 
from: 
https://ClinicalTrials.gov/show/NCT04507256. 
3. 
Domachowske, J.B., et al., Safety, Tolerability and Pharmacokinetics of MEDI8897, 
an Extended Half-life Single-dose Respiratory Syncytial Virus Prefusion F-targeting 
Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants. 
Pediatr Infect Dis J, 2018. 37(9): p. 886-892. 

4. 
Griffin, M.P., et al., Safety, Tolerability, and Pharmacokinetics of MEDI8897, the 
Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an 
Extended Half-Life, in Healthy Adults. Antimicrob Agents Chemother, 2017. 61(3). 
5. 
Dall'Acqua, W.F., P.A. Kiener, and H. Wu, Properties of human IgG1s engineered for 
enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem, 2006. 281(33): 
p. 23514-24. 
6. 
Robbie, G.J., et al., A novel investigational Fc-modified humanized monoclonal 
antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob 
Agents Chemother, 2013. 57(12): p. 6147-53. 
7. 
AstraZeneca, Investigator's Brochure: AZD7442, Combination Product of Two 
Monoclonal Antibodies (AZD8895 and AZD1061);D8850, D8851, Indication: 
Prophylaxis and Treatment of COVID-19;edition 2.0, 06 October 2020. 
8. 
Chen, N., et al., Epidemiological and clinical characteristics of 99 cases of 2019 novel 
coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 2020. 
395(10223): p. 507-513. 
9. 
Guan, W.J., et al., Clinical Characteristics of Coronavirus Disease 2019 in China. N 
Engl J Med, 2020. 382(18): p. 1708-1720. 
10. 
Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in 
Wuhan, China. Lancet, 2020. 395(10223): p. 497-506. 
11. 
Bolles, M., et al., A double-inactivated severe acute respiratory syndrome coronavirus 
vaccine provides incomplete protection in mice and induces increased eosinophilic 
proinflammatory pulmonary response upon challenge. J Virol, 2011. 85(23): p. 
12201-15. 
12. 
Clay, C., et al., Primary severe acute respiratory syndrome coronavirus infection 
limits replication but not lung inflammation upon homologous rechallenge. J Virol, 
2012. 86(8): p. 4234-44. 
13. 
Liu, L., et al., Anti-spike IgG causes severe acute lung injury by skewing macrophage 
responses during acute SARS-CoV infection. JCI Insight, 2019. 4(4). 
14. 
Tseng, C.T., et al., Immunization with SARS coronavirus vaccines leads to pulmonary 
immunopathology on challenge with the SARS virus. PLoS One, 2012. 7(4): p. 
e35421. 
15. 
Wan, Y., et al., Molecular Mechanism for Antibody-Dependent Enhancement of 
Coronavirus Entry. J Virol, 2020. 94(5). 
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