A Phase 1, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Nirsevimab in Healthy Chinese Adults
Phase: PHASE1
Conditions: Evaluate PK Profile
Sponsor: AstraZeneca

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Protocol D5290C00007
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A Phase 1, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate the Pharmacokinetics, Safety, and Tolerability of 
Nirsevimab in Healthy Chinese Adults
Sponsor Protocol Number:
D5290C00007
Investigational Product:
Nirsevimab (MEDI8897)
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden
Study Physician:
Phone: 
Contract Research Organization: IQVIA RDS (Shanghai) Co., Ltd.
3rd Floor, Building A, Fenglin International Tower
No. 388 Fenglin Road, Xuhui District, Shanghai 200032
Principal Investigator:
,
Shanghai, 200040,
China
Protocol History, Date:
Amendment 1, 04Dec2020
Replacing Original Protocol, 07Jun2020
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from AstraZeneca.
PPD
PPD
PPD

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Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment 1
04Dec2020
Original Protocol
07Jun2020
Amendment 1: 26 November 2020
This non-substantial amendment is executed due to Sponsor’s decision to adjust operational 
settings according to the suggestions from study site. The changes are made before study 
initiation.
Overall Rationale for the Amendment:
Changes are made to adapt to the feasibility of operation at the study site. Additional 
clarifications regarding procedures are also added to facilitate the operation. The amendment 
also includes the correction of inconsistencies throughout the document that have been 
identified since the finalization of the original clinical study protocol.
Protocol D5290C00007 Amendment 1-List of changes:
Section # and Name
Description of Change
Brief Rationale
Substantial
(Yes/No)
Section 3.1.1 
Overview, Figure 1
To correct days in Figure 1 for 
PK sampling
To correct days for PK sampling
to be consistent with Section 4.2
No
Section 4.1.2 Inclusion 
Criteria
To add description of “(the day 
of investigational product 
administration )” in inclusion 
criterion No.4
To clarify the inclusion criteria 
for definition of Day 1
No
Synopsis, Section 4.1.2 
Inclusion Criteria
To revise the upper limit of 
body mass index (BMI) for
inclusion from 24 kg/m2 to 
26 kg/m2 in inclusion criterion
No.5, and relative description in 
the synopsis
To revise the inclusion criteria 
due to feasibility considerations
No
Section 4.1.2 Inclusion 
Criteria
To add description of “as judged 
by the Investigator ” in inclusion 
criterion No.8
To clarify the inclusion criteria 
for enrollment of subjects 
according to subjects’ ECG 
readout will be judged by the 
Investigator
No
Section 4.1.3
Exclusion Criteria
To revise exclusion criterion
No.6 to “Receipt of any 
investigational drug therapy 
within 120 days prior to 
investigational product dosing 
or planned to receive any 
investigational drug therapy 
To clarify that it is the 
“planned” activity to be 
prevented
No

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Section # and Name
Description of Change
Brief Rationale
Substantial
(Yes/No)
within 150 days after 
investigational product dosing”
Section 4.1.3
Exclusion Criteria
To update exclusion criteria No. 
16 to “Evidence of infection (ie, 
positive laboratory test result) 
with hepatitis A, B, or C virus,
syphilis or human 
immunodeficiency virus.”
Revision made to add evidence 
of syphilis infection as one of 
the exclusion criteria due to high 
incidence rate in China
Section 4.1.3
Exclusion Criteria
To revise the laboratory 
assessments result limits in 
exclusion criterion No.17. White 
blood cell count from < 4 × 
109/L to < 3.5 × 109/L; platelet 
count from < 140 × 109/L to 
< 120 × 109/L
To revise the exclusion criteria 
according to the actual normal 
range set by study site
No
Section 4.1.3
Exclusion Criteria
To remove “barbiturates” from
exclusion criteria No. 17 e)
Revision made according to
commonly used urine drug 
screen test at site, considering 
the overall low prevalence of 
barbiturates abuse in China
Section 4.1.5 
Withdrawal from the 
study
To delete the statement 
“Subjects who have not received 
investigational product, 
regardless of reason, will not be 
followed.”
Revision made to match the 
actual operation procedure
No
Section 4.2 Schedule 
of Study Procedures
To update study procedures on
Day -1 and pre-dose on Day 1, 
added admission/discharge and 
revised footnotes for Table 4, 
Table 5 and Table 6 accordingly
Revision made on schedule of 
study procedures to include 2 
overnight stays at study site for
easier operation and to obtain 
better compliance
No
Section 4.2.1 
Enrollment/Screening 
Period and 
Section 4.3.2 Clinical 
Laboratory Tests
To revise the assessment of 
“HIV-1” to “HIV” at screening 
to clarify both HIV-1 and HIV 2 
antibodies will be tested.
Revision made to match the 
actual operation procedure as 
both HIV-1 and HIV-2 will be 
tested
No
Section 4.2.2
Treatment and Follow-
up Periods
To add the statement of 
“Randomization should occur 
before blood sampling” as 
footnote b in Table 5
Revision made to clarify the 
procedure of blood sample 
collection and randomization
No
Section 4.3.1 Medical 
History and Physical 
Examination, Height, 
Weight, and Vital 
Signs
To update timing of study 
procedures described in the 
section
Revision made to be consistent
with updated schedule of study 
procedures due to added
overnight stay
No
Section 4.3.1 Medical 
History and Physical 
Examination, Height, 
Weight, and Vital 
Signs
To revise the title of Section 
4.3.1 from “Medical History and 
Physical Examination, Height, 
Weight, and Vital Signs” to 
“Medical History, Physical 
Revision made to match the 
actual operation procedure
No

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Section # and Name
Description of Change
Brief Rationale
Substantial
(Yes/No)
Examination, Height, Weight, 
Vital Signs and ECG”
Section 4.3.1 Medical 
History and Physical 
Examination, Height, 
Weight, and Vital 
Signs
To add the description of “(for 
any new findings since 
screening)”
Revision made to clarify the 
procedure of medical history 
collection on Day -1
No
Section 4.3.1 Medical 
History and Physical 
Examination, Height, 
Weight, and Vital 
Signs
Revised the sentence “The 
physical examination will 
include assessment of height 
and/or weight as noted in 
Table 4 and Table 5” to “The 
height and/or weight will be 
assessed as noted in Table 4”
Revision made for clearer 
instruction
No
Section 4.3.1 Medical 
History and Physical 
Examination, Height, 
Weight, and Vital 
Signs
To add the following description 
of ECG procedures:
At Screening, 12-lead ECG will 
be obtained after 5 minutes 
supine rest and prior to blood
draw. Skin must be cleaned, and 
electrodes should be positioned 
according to standard 12-lead 
ECG placement. All 12-lead 
ECGs will be recorded and 
evaluated by the Investigator. 
The Investigator will judge the 
overall interpretation as normal 
or abnormal. If abnormal, it will 
be decided whether the 
abnormality is clinically 
significant or not. The reason for 
the abnormality will be recorded 
in the eCRF. These ECGs will 
be documented in the eCRF by 
recording date, time, heart rate, 
overall assessment as normal 
and abnormal, and whether the 
abnormality is clinically 
significant or not.
All ECGs will be documented 
by recording date, time of 
collection, heart rate, PR, RR, 
QRS, and QT intervals from the 
12-lead ECG.
If indicated additional 12-lead 
ECG assessments can be made 
at the discretion of the 
Investigator. These assessments 
should be entered as an 
To add the description of ECG 
procedures at screening for clear 
instruction
No

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Section # and Name
Description of Change
Brief Rationale
Substantial
(Yes/No)
unscheduled assessment in the 
appropriate eCRF.
Section 4.3.2 Clinical 
Laboratory Test
To update timing of serum 
pregnancy test to Day -28 to 
Day -2 and urine pregnancy test 
to Day -1
Revision made to be consistent 
with Table 4 and Table 5
No
Section 4.3.2 Clinical 
Laboratory Test
To delete the sentence “if 
positive, confirmatory testing 
will be performed using 
hepatitis C virus polymerase 
chain reaction” and “if positive, 
confirmatory testing will be 
performed using HIV western 
blot”
To add syphilis test during
screening period
To remove barbiturates from 
“other safety tests”
Deletion made to match the 
actual operation procedure. Any 
positive test result at screening 
will meet the exclusion criteria 
and no confirmatory test will be 
done.
To add syphilis test according to 
site requirement due to high 
incidence in China.
To remove barbiturates 
according to commonly used 
urine drug screen test at site, 
considering the overall low 
prevalence of barbiturates abuse 
in China
No
Section 4.5.1
Identification of 
Investigational 
Products
To revise “investigational
product” to Nirsevimab” in the 
description under Table 7.
To clarify Nirsevimab storage 
requirement and packaging 
information
Section 4.5.1.3 
Treatment 
Administration
To revise the administration 
instruction of investigational 
product to “Investigational 
product (nirsevimab or placebo) 
should be administered IM in 
the central area and thicker 
portion of the deltoid” with 
more detail description
To add the description of 
treatment administration for 
clearer instruction
No
Section 4.5.1.3 
Treatment 
Administration
To update to “approximately 1 
inch” and add the description of 
“(2.54 cm)” following the 
original description of 1 inch
To specify the estimation of 
distance between injection sites 
using units (cm) adopted by 
study site
No
Section 4.7.1 
Permitted Concomitant 
Medications
To revise the description of 
“Investigators may prescribe 
concomitant medications or 
treatments deemed necessary to 
provide adequate supportive 
care.” to “Investigators may 
prescribe concomitant 
medications or treatments which 
is considered necessary for the 
subject’s safety and well-being.”
Revision made for readability
No
Section 4.4 Study or 
Study Component 
Suspension or 
To add (version 5.0) to address 
the version of National Cancer 
Institute Common Terminology 
Clarify version of NCI CTCAE 
used and keep wording
consistent with CTCAE 5.0.
No

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Section # and Name
Description of Change
Brief Rationale
Substantial
(Yes/No)
Termination and 
Section 4.8.4.2 
Analysis of Clinical 
Laboratory Parameters
Appendix B
Additional Safety 
Guidance
Criteria for Adverse Events
(NCI CTCAE)
Update CTCAE grading general 
principles according to 
CTCAE 5.0.
Section 5.5.3 Adverse 
Events Based on Signs 
and Symptoms
To revise the text “All AEs 
spontaneously reported by the 
subject or care provider or 
reported in response to the open 
question…” to “All AEs 
spontaneously reported by the 
subject or reported in response 
to the open question…”
Revision made as this is not 
applicable for the current study 
which enrolls healthy subjects
No
Section 5.5.4 Adverse 
Events Based on 
Examination and Tests
Add screening phase AE 
reporting clarification wording 
Add clarification wording of AE
reporting to keep GCP 
compliance and clinical 
feasibility
No
Section 6.5 
Investigator Coverage
The title is changed to 
“Investigator Coverage”
The text in Section 6.5 is revised 
to “Each subject will be 
provided with contact 
information for the Investigator.
When a subject visits a medical 
facility and requires any medical 
care (medication or treatment), 
the treating physician or health 
care provider should contact the 
Principal Investigator (or 
designee Investigator who has 
knowledge of the investigational 
product and the clinical study 
protocol) before any treatment is 
given to the subject.”
Revision made to match the 
actual operation procedure in 
China. Subject can either
contact the Principle 
Investigator or designee 
Investigator.
No
Section 7.3 Informed 
Consent
To revise the text “Ensure that 
any incentives for subjects who 
participate in the study…” to 
“Ensure that any reimbursement
for subjects who participate in 
the study…”
Revision made for readability
No

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PROTOCOL SYNOPSIS
TITLE
A Phase 1, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Pharmacokinetics, Safety, 
and Tolerability of Nirsevimab in Healthy Chinese Adults
HYPOTHESES
The primary and secondary research hypotheses are described below. No formal hypothesis is being tested 
statistically.
Primary Hypothesis
The pharmacokinetic (PK) profile of nirsevimab assessed up to 150 days after dose administration in Chinese 
subjects will be similar to subjects with different racial and ethnic backgrounds.
Secondary Hypothesis
A single dose of nirsevimab will be well tolerated in healthy Chinese adult subjects, with an acceptable safety 
profile. The incidence of antidrug antibody (ADA) to nirsevimab will be acceptable.
OBJECTIVES AND ASSOCIATED ENDPOINTS
Type
Objective
Endpoint
Primary
PK
To evaluate serum concentrations of 
nirsevimab
Summary of nirsevimab serum 
concentrations and estimated PK parameters 
(maximum observed concentration [Cmax], 
time to Cmax [Tmax], area under the 
concentration-time curve from time 0 to 
150 days [AUC0-150], and others if data 
permit)
Secondary
Safety
To evaluate the safety and tolerability of 
nirsevimab when administered as a 
single fixed intramuscular (IM) dose of 
300 mg to healthy Chinese adult subjects
•
Occurrence of all treatment-emergent 
adverse events (TEAEs), treatment-
emergent serious adverse events 
(TESAEs), adverse events of special 
interest (AESIs), and new onset 
chronic diseases (NOCDs)
•
Clinical laboratory assessments, vital 
signs
ADA
To evaluate ADA responses to 
nirsevimab in serum
Incidence of ADA to nirsevimab in serum
STUDY DESIGN
Study D5290C00007 is a Phase 1, randomized, double-blind, placebo-controlled study to evaluate the PK, 
safety and tolerability, and ADA of nirsevimab compared to placebo when administered as a single fixed IM 
dose of 300 mg to healthy Chinese adult subjects. Enrollment is planned at a single study center in China.
Approximately 24 subjects will be randomly assigned in a 3:1 ratio to receive nirsevimab (n = 18) or placebo 
(n = 6). All subjects will be followed for approximately 150 days after dosing to assess safety, PK, and ADA 
response.
TARGET SUBJECT POPULATION
Healthy male and female adult subjects aged 18 through 45 years with weight W 45 kg and X 110 kg and body 
mass index of 19 to 26 kg/m2 at the time of screening.

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TREATMENT GROUPS AND REGIMENS
Subjects will be randomly assigned to receive a single fixed IM dose of nirsevimab 300 mg (n = 18) or 
placebo (n = 6) on Day 1.
STATISTICAL METHODS
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be summarized by the number 
and percentage of subjects in each category. Continuous variables will be summarized by descriptive statistics. 
Additional details of statistical analyses will be described in the statistical analysis plan.
The PK Population will include all subjects who have received any dose of investigational product, and have 
at least one measurable post-dose serum PK observation and for whom PK blood samples are assumed not to 
be affected by factors such as important protocol deviations (to be determined prior to unblinding). PK 
analyses will be based on the PK Population.
The As-treated Population will include all subjects who are randomized into the study and who receive any 
amount of investigational product. Subjects will be included in the treatment group corresponding to the 
treatment actually received. Safety and ADA analyses will be based on the As-treated Population.
Sample Size
This study will randomize 
24 subjects of whom approximately 18 will receive nirsevimab and 
approximately 6 will receive placebo. Because all analyses will be descriptive in nature and no hypothesis is 
being tested statistically, no formal sample size calculation was performed. Current sample size and sampling 
scheme are selected to facilitate estimation and numerical comparison of Cmax, Tmax, and AUC0-150 between 
Chinese and non-Chinese adult subjects.
Pharmacokinetic Analyses
Serum concentrations of nirsevimab at selected time points will be evaluated to confirm that adequate 
exposures are maintained after dosing. Nirsevimab serum concentration data will be presented in descriptive 
statistics. Serum PK parameters such as Cmax, Tmax, and AUC0-150 will be estimated using noncompartmental 
analysis and summarized with descriptive statistics. The estimated PK parameters from the adult Chinese 
subjects from this study will be compared for similarity with those obtained from non-Chinese adult subjects
from the global Phase 1a Study D5290C00001. Notably, regression-dependent PK parameters such as t1/2 and 
apparent systemic clearance will not be estimated due to the limited sampling up to 150 days which would 
require at least 40% extrapolation of the total area under the concentration-time curve from time 0 to infinity. 
Nonetheless, the predictability and consistency of the PK properties of nirsevimab, as demonstrated in 
102 adults in the Phase 1a Study D5290C00001 and 984 infants in the Phase 1b/2a Study D5290C00002 and 
Phase 2b Study D5290C00003, support the hypothesis that the apparent clearance and other regression-
dependent PK parameters should be similar if the Cmax, Tmax, and AUC0-150 are shown to be similar.
Safety Analyses
All TEAEs will be summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term, severity, and relationship to investigational product. In addition, 
summaries of deaths and TESAEs will be provided. Other safety assessments will include the occurrence of 
AESIs defined as adverse events of anaphylaxis and other serious hypersensitivity reactions, including 
immune complex disease (eg, vasculitis, endocarditis, neuritis, glomerulonephritis), or thrombocytopenia 
following investigational product administration, and the occurrence of NOCDs following investigational 
product administration.
Safety of nirsevimab will also be assessed and measured by the summary of clinical laboratory measurements 
(ie, serum chemistry, hematology, and urinalysis) through 150 days postdose.
DSSUR[LPDWHO\

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Antidrug Antibody Analyses
The incidence of ADA to nirsevimab will be assessed and summarized by number and percentage of subjects 
who are ADA positive. The impact of ADA on PK, and association with TEAEs and TESAEs will be 
assessed, if data permit.
Interim Analyses
No interim analyses are planned.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................................. 2
PROTOCOL SYNOPSIS...................................................................................................... 7
TABLE OF CONTENTS.................................................................................................... 10
LIST OF ABBREVIATIONS ............................................................................................. 14
1
INTRODUCTION............................................................................................ 16
1.1
Disease Background ......................................................................................... 16
1.2
Nirsevimab Background ................................................................................... 17
1.3
Summary of Nonclinical Experience................................................................. 18
1.4
Summary of Clinical Experience....................................................................... 19
1.4.1
Phase 1a Study D5290C00001 .......................................................................... 19
1.4.2
Phase 1b/2a Study D5290C00002 ..................................................................... 20
1.4.3
Phase 2b Study D5290C00003.......................................................................... 22
1.5
Rationale for Conducting the Study .................................................................. 23
1.6
Benefit-Risk and Ethical Assessment................................................................ 24
1.7
Research Hypotheses ........................................................................................ 24
1.7.1
Primary Hypothesis .......................................................................................... 24
1.7.2
Secondary Hypotheses...................................................................................... 24
2
OBJECTIVES AND ENDPOINTS................................................................... 25
2.1
Primary Objective and Associated Endpoint ..................................................... 25
2.2
Secondary Objectives and Associated Endpoints............................................... 25
3
STUDY DESIGN ............................................................................................. 25
3.1
Description of the Study ................................................................................... 25
3.1.1
Overview.......................................................................................................... 25
3.1.2
Treatment Regimen........................................................................................... 26
3.2
Rationale for Dose, Population, and Endpoints ................................................. 26
3.2.1
Dose Rationale.................................................................................................. 26
3.2.2
Rationale for Study Population ......................................................................... 28
3.2.3
Rationale for Endpoints .................................................................................... 28
4
MATERIALS AND METHODS ...................................................................... 28
4.1
Subjects............................................................................................................ 28
4.1.1
Number of Subjects .......................................................................................... 28
4.1.2
Inclusion Criteria .............................................................................................. 28
4.1.3
Exclusion Criteria ............................................................................................. 29
4.1.4
Subject Enrollment and Randomization ............................................................ 31
4.1.5
Withdrawal from the Study............................................................................... 31
4.1.6
Discontinuation of Investigational Product........................................................ 31
4.1.7
Lost to Follow-up ............................................................................................. 32
4.1.8
Replacement of Subjects................................................................................... 32
4.1.9
Withdrawal of Informed Consent for Data and Biological Samples................... 32

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4.2
Schedule of Study Procedures........................................................................... 33
4.2.1
Enrollment/Screening Period ............................................................................ 33
4.2.2
Treatment and Follow-up Periods ..................................................................... 34
4.3
Description of Study Procedures....................................................................... 35
4.3.1
Medical History, Physical Examination, Height, Weight, Vital Signs and 
Electrocardiogram............................................................................................. 35
4.3.2
Clinical Laboratory Tests.................................................................................. 36
4.3.3
Pharmacokinetic Evaluation.............................................................................. 37
4.3.4
Antidrug Antibody Evaluation .......................................................................... 37
4.4
Study or Study Component Suspension or Termination..................................... 37
4.5
Investigational Products.................................................................................... 38
4.5.1
Identity of Investigational Products................................................................... 38
4.5.1.1
Investigational Product Inspection .................................................................... 39
4.5.1.2
Dose Preparation Steps ..................................................................................... 39
4.5.1.3
Treatment Administration................................................................................. 40
4.5.1.4
Monitoring of Dose Administration .................................................................. 40
4.5.1.5
Reporting Product Complaints .......................................................................... 40
4.5.2
Additional Study Medications........................................................................... 41
4.5.3
Labeling ........................................................................................................... 41
4.5.4
Storage ............................................................................................................. 41
4.5.5
Treatment Compliance...................................................................................... 41
4.5.6
Accountability .................................................................................................. 41
4.6
Treatment Assignment and Blinding ................................................................. 41
4.6.1
Methods for Assigning Treatment Groups......................................................... 41
4.6.2
Methods to Ensure Blinding.............................................................................. 42
4.6.3
Methods for Unblinding.................................................................................... 42
4.6.3.1
Unblinding in the Event of a Medical Emergency ............................................. 42
4.7
Restrictions During the Study and Concomitant Treatment(s) ........................... 43
4.7.1
Permitted Concomitant Medications ................................................................. 43
4.7.2
Prohibited Concomitant Medications ................................................................ 43
4.8
Statistical Evaluation ........................................................................................ 43
4.8.1
General Considerations..................................................................................... 43
4.8.2
Sample Size...................................................................................................... 44
4.8.3
Analysis of Pharmacokinetics ........................................................................... 44
4.8.4
Safety ............................................................................................................... 44
4.8.4.1
Analysis of Adverse Events .............................................................................. 44
4.8.4.2
Analysis of Clinical Laboratory Parameters ...................................................... 45
4.8.5
Analysis of Antidrug Antibody ......................................................................... 45
4.8.6
Interim Analysis ............................................................................................... 45
5
ASSESSMENT OF SAFETY ........................................................................... 45
5.1
Definition of Adverse Events............................................................................ 45
5.2
Definition of Serious Adverse Events ............................................................... 46
5.3
Definition of Adverse Events of Special Interest............................................... 46

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5.3.1
Anaphylaxis and Other Serious Hypersensitivity Reactions Including Immune 
Complex Disease .............................................................................................. 46
5.3.2
Thrombocytopenia............................................................................................ 47
5.4
Definition of New Onset Chronic Disease......................................................... 47
5.5
Recording of Adverse Events............................................................................ 47
5.5.1
Time Period for Collection of Adverse Events .................................................. 48
5.5.2
Follow-up of Unresolved Adverse Events......................................................... 48
5.5.3
Adverse Events Based on Signs and Symptoms ................................................ 48
5.5.4
Adverse Events Based on Examination and Tests.............................................. 48
5.5.5
Potential Hy’s Law and Hy’s Law..................................................................... 49
5.6
Reporting of Serious Adverse Events................................................................ 49
5.7
Other Events Requiring Immediate Reporting................................................... 50
5.7.1
Overdose .......................................................................................................... 50
5.7.2
Pregnancy......................................................................................................... 50
5.7.2.1
Maternal Exposure............................................................................................ 51
5.7.2.2
Paternal Exposure............................................................................................. 51
5.7.3
Medication Error............................................................................................... 51
5.7.4
Adverse Events of Special Interest.................................................................... 52
5.7.4.1
Anaphylaxis and Other Serious Hypersensitivity Reactions Including Immune 
Complex Disease .............................................................................................. 52
5.7.4.2
Thrombocytopenia............................................................................................ 53
5.7.5
New Onset Chronic Disease.............................................................................. 53
6
STUDY AND DATA MANAGEMENT........................................................... 53
6.1
Training of Study Site Personnel....................................................................... 53
6.2
Monitoring of the Study.................................................................................... 54
6.2.1
Source Data ...................................................................................................... 54
6.2.2
Study Agreements............................................................................................. 54
6.2.3
Archiving of Study Documents......................................................................... 54
6.3
Study Timetable and End of Study.................................................................... 54
6.4
Data Management............................................................................................. 55
6.5
Investigator Coverage....................................................................................... 55
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 55
7.1
Subject Data Protection..................................................................................... 55
7.2
Ethics and Regulatory Review .......................................................................... 56
7.3
Informed Consent ............................................................................................. 56
7.4
Changes to the Protocol and Informed Consent Form........................................ 57
7.5
Audits and Inspections...................................................................................... 57
8
REFERENCES................................................................................................. 58

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LIST OF TABLES
Table 1
Primary Objective and Associated Endpoint ............................................ 25
Table 2
Secondary Objectives and Associated Endpoints...................................... 25
Table 3
Exposure Comparison in Cynomolgus Monkey, and Human Adult and 
Pediatric Populations ............................................................................... 27
Table 4
Schedule of Screening Procedures ........................................................... 33
Table 5
Schedule of Treatment Period Procedures................................................ 34
Table 6
Schedule of Follow-up Period Procedures................................................ 35
Table 7
Identification of Investigational Products................................................. 39
Table A1
Highly Effective Methods of Contraception............................................. 61
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 26
LIST OF APPENDICES
Appendix A
Contraception Guidance........................................................................... 61
Appendix B
Additional Safety Guidance ..................................................................... 62
Appendix C
National Institute of Allergy and Infectious Disease and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.............. 66
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 67

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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
AUC0-Z
area under the concentration-time curve from time 0 to infinity
AUC0-150
area under the concentration-time curve from time 0 to 150 days
[hCG
beta human chorionic gonadotropin
CHD
congenital heart disease
CI
confidence interval
CLD
chronic lung disease
Cmax 
maximum observed concentration
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EU
European Union
Fc
fragment crystallizable
FcRn
neonatal Fc receptor
GA
gestational age
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IM
intramuscular(ly)
IRB
Institutional Review Board
IV
intravenous(ly)
IWRS
interactive web response system
LRTI
lower respiratory tract infection
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
NAb
neutralizing antibody

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Abbreviation or 
Specialized Term
Definition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NOCD
new onset chronic disease
PK
pharmacokinetic(s)
RRR
relative risk reduction
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SID
subject identification
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
Tmax
time to maximum observed concentration
ULN
upper limit of normal
URTI
upper respiratory tract infection
US
United States
wGA
weeks gestational age
YTE
M257Y/S259T/T261E

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1
INTRODUCTION
1.1
Disease Background
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract 
infection (LRTI) among infants and young children, resulting in annual epidemics worldwide 
(Jain et al 2015, PERCH 2019, Shi et al 2017). All children, including healthy term infants, 
are at risk for severe RSV lower respiratory illness with primary RSV infection during 
infancy. Ninety percent of children are infected with RSV in the first 2 years of life and up to 
40% of those will have LRTI (Greenough et al 2001, Meissner 2003, Parrott et al 1973). RSV 
LRTI, characterized predominantly as bronchiolitis or pneumonia, represents a serious illness 
with acute and perhaps long-term consequences to the developing lungs in these young 
children (Blanken et al 2013). It is estimated that RSV causes up to 90% of childhood 
bronchiolitis and up to 40% of pediatric pneumonias (Hall 2001). In 2015, an estimated 33.1 
million (uncertainty range, 21.6 to 50.3 million) new episodes of RSV-associated LRTI 
occurred worldwide in children < 5 years of age (28% of LRTI episodes), with approximately 
3.2 million (range, 2.7 to 3.8 million) episodes necessitating hospitalizations, leading to 
59,600 (range, 48,000 to 74,500) in-hospital deaths (Shi et al 2017).
Infants with severe LRTI may present with apnea, tachypnea, tachycardia, cyanosis, 
diminished breath sounds, wheezing, cough, nasal flaring, retraction, and listlessness. Poor gas 
exchange sets off a downward spiral in the infant’s condition, including hypoxia, increased 
respiratory effort, decreased ability to maintain adequate oral intake, and dehydration 
(Coffmann 2009). In the United States (US), RSV bronchiolitis was the leading cause of 
hospital admissions for infants < 1 year of age for any reason between 1997 and 1999 (Leader 
and Kohlhase 2002). Most children hospitalized with RSV infection, including those with 
severe illness and requiring intensive care, were previously healthy term infants and without 
comorbid conditions, making it difficult to identify specific subgroups to target for RSV 
prophylaxis (Hall 2012).
As noted above, hospitalization is well recognized as an important consequence of RSV 
illness. Additionally, a large percentage of the healthcare burden from RSV occurs outside the 
hospital (Carroll et al 2008, Hall et al 2009, Hall 2012, Paramore et al 2010) such that office 
visits and emergency department visits are more frequent than subsequent hospitalization, 
especially in healthy infants. The general severity of RSV infection observed among infants in 
outpatient settings is almost as severe as those observed in hospitalized infants, with 
symptoms including labored breathing requiring supplemental oxygen, wheezing, and fever 
(Hall 2012). While 95% of children hospitalized with RSV had labored respirations, similar 
percentages of outpatients were also observed to have labored respirations (85% of children 
cared for in emergency departments, and 73% of children treated in private practice settings) 
(Hall et al 2009). The outpatient burden and severity of disease accounts for a significant 
portion of the morbidity associated with RSV in all infants.

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In China, RSV has been identified in 23% to 38% of children diagnosed with LRTI in 
ambulatory and hospital settings (Tang et al 2008, Yu et al 2019, Zhang et al 2009, Zhang et 
al 2013b). Studies of severe acute respiratory infections in Harbin (northeastern China), 
Suzhou (eastern coastal China), Lanzhou (northwestern China), and Hong Kong reported that 
RSV infection is responsible for approximately one-quarter of hospital admissions among 
children < 5 years of age with acute respiratory illness (Hon et al 2012, Jin et al 2012, Zhang 
et al 2009, Zhang et al 2013a). RSV is the leading viral pathogen identified in children 
< 2 years of age hospitalized for LRTI in China, and is associated with significant morbidity, 
with mortality rates as high as 3.5% in children who develop severe disease (Feng et al 2014, 
Zhang et al 2013b). A study conducted from December 2011 to November 2012 among 
hospitalized children in Lanzhou identified RSV as the most common virus detected in 
children with pneumonia or bronchiolitis (Zhang et al 2014). In addition, direct medical costs 
have been found to be a source of economic burden to families of children with RSV-related 
hospitalization. Severe LRTI rates were 17.1% in RSV single infections and 11.1% in RSV 
associated with other viruses (Yan et al 2017). Given the substantial disease burden in the 
large China pediatric population (Zhang et al 2015), an effective RSV prevention strategy has 
the potential to provide an important public health benefit.
Prevention of RSV illness in all infants is a major public health priority. However, despite 
many years of attempted vaccine development (Kim et al 1969), there is no safe and effective 
vaccine for these children. The medical management for these patients with RSV illness is 
supportive care. Palivizumab (Synagis®) is the only approved agent for RSV prophylaxis, and 
its use is limited internationally to high-risk children (preterm infants X 35 weeks gestational 
age [wGA], children with chronic lung disease [CLD] of prematurity [also known as 
bronchopulmonary dysplasia], and children with hemodynamically significant congenital 
heart disease [CHD]). In China, palivizumab is not licensed and there are currently no 
available options for RSV prophylaxis.
1.2
Nirsevimab Background
Nirsevimab (MEDI8897) is briefly described below. Refer to the current Investigator’s 
Brochure for details.
Nirsevimab is a recombinant human immunoglobulin G (IgG)1 kappa monoclonal antibody 
(mAb) directed against the prefusion conformation of the RSV F protein. The antibody has 
been engineered with a triple amino acid substitution (YTE; M257Y/S259T/T261E 
[M252Y/S254T/T256E, according to the EU numbering system]) in the fragment 
crystallizable (Fc) region to prolong the terminal half-life (t1/2), which is expected to provide 
protection from serious RSV disease for the duration of the RSV season. Nirsevimab 
neutralizes RSV by binding the prefusion conformation of the RSV F protein at a site distinct 
from that bound by palivizumab. In nonclinical studies, nirsevimab was > 150-fold more 
potent than palivizumab in vitro and approximately 9-fold more potent than palivizumab in 

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vivo in the cotton rat model (Zhu et al 2017). Nirsevimab is currently under development by 
AstraZeneca (hereafter, the Sponsor) as a mAb for the passive immunization of all infants 
entering their first RSV season and children with CLD or CHD entering their first and second 
RSV season for the prevention of LRTI caused by RSV. Nirsevimab may provide a cost-
effective opportunity to protect all infants from RSV disease based on an improvement in 
potency and the extended t1/2 that is expected to support once-per-RSV-season dosing.
1.3
Summary of Nonclinical Experience
The potential clinical utility of nirsevimab and dose predictions of the antibody were 
evaluated in the cotton rat model of RSV infection. The pharmacokinetics (PK) of 1G7, the 
non-YTE version of nirsevimab, was evaluated in cotton rats following a single intramuscular 
(IM) dose of 0.25 to 3.0 mg/kg. Serum concentrations increased dose proportionally across the 
entire dose range with a terminal-phase elimination t1/2 of approximately 1 day. In cotton rats, 
a serum concentration of 6.8 ^g/mL resulted in a 3-log reduction in lung RSV titers and for 
Phase 2b was identified as the target serum concentration to maintain in children to provide 
antiviral activity against RSV over a typical 5-month RSV season.
The YTE amino acid substitutions introduced into nirsevimab do not impact RSV neutralizing 
activity when compared to the parental mAb, 1G7. Nirsevimab/1G7 showed potent antiviral 
activity in vitro against RSV A and B laboratory strains, clinical isolates, as well as 
palivizumab-resistant viruses. Nirsevimab/1G7 was > 150-fold more potent than 
palivizumab in vitro against the laboratory strains and > 50-fold more potent than 
palivizumab against clinical isolates based on the median half-maximal inhibitory 
concentration (Zhu et al 2017).
Toxicity, toxicokinetics, and immunogenicity of nirsevimab were evaluated in a Good 
Laboratory Practice-compliant repeat-dose intravenous (IV) and IM toxicology study 
conducted in cynomolgus monkeys. Cynomolgus monkeys represent a pharmacologically
relevant model for nonclinical safety assessment based on similar binding of nirsevimab to 
cynomolgus monkey neonatal Fc receptor (FcRn) compared to human FcRn. Toxicology 
studies in cynomolgus monkeys indicate that there is no evidence of nirsevimab toxicity in 
these animal models. Once weekly IV or IM administration (5 doses total) of nirsevimab to 
monkeys, up to and including 300 mg/kg IV or 300 mg IM dose levels, was not associated 
with any treatment-related adverse effects locally or systemically. The no-observed-adverse-
effect-level was considered to be 300 mg/kg IV and 300 mg IM. No antidrug antibody (ADA) 
was detected in any of the monkeys during the treatment phase. During the recovery phase, 
4 of 12 animals treated with nirsevimab and 0 of 6 control animals were ADA positive with 
variable impact on toxicokinetics. In addition, tissue cross-reactivity against cryosections of a 
full panel of adult and a selected panel of juvenile, neonatal, and fetal human tissues showed 
no staining of any tissues, as expected, given the target for nirsevimab is a non-endogenous 

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viral-specific target. Overall, data from nonclinical studies do not reveal any nirsevimab-
related safety concerns.
Details of these studies are included in the current Investigator’s Brochure.
1.4
Summary of Clinical Experience
Nirsevimab has been investigated in 3 completed clinical studies (see the current 
Investigator’s Brochure for additional detail on nirsevimab clinical development).
1.4.1
Phase 1a Study D5290C00001
Study D5290C00001 was a first-time-in-human Phase 1a, randomized, double-blind, placebo-
controlled, dose-escalation study conducted to evaluate the safety, tolerability, PK, and ADA 
of nirsevimab compared to placebo in healthy adult volunteers (Griffin et al 2017). This study 
was completed in June 2015. A total of 136 subjects were randomized and received a single 
fixed dose of nirsevimab (6 subjects each at doses of 300 mg IV, 1000 mg IV, 3000 mg IV, 
100 mg IM, and 78 subjects at 300 mg IM) or placebo (34 subjects). All subjects were 
followed for approximately 360 days after dosing.
Safety
The safety profile of nirsevimab was favorable, with similar proportions of treatment-
emergent adverse events (TEAEs) reported in the placebo (61.8%) group and the nirsevimab 
(62.7%) total group. Two treatment-emergent serious adverse events (TESAEs; gunshot 
wound and appendicitis) were reported in 2 nirsevimab subjects. TEAEs judged to be related 
to investigational product were reported in 29.4% of subjects in the placebo group, and 17.6% 
of subjects in the nirsevimab total group. The most frequent TEAEs in the nirsevimab total 
group included upper respiratory tract infection (URTI; 18.6%); headache (8.8%); urinary 
tract infection (5.9%); and dermatitis contact, musculoskeletal pain, nausea, and vomiting 
(4.9% each). The most frequently occurring TEAEs in the placebo group were headache 
(17.6%); URTI (8.8%); and nausea, increased blood creatine phosphokinase level, and 
paresthesia (5.9% each). There were no adverse events of special interest (AESIs) or new 
onset chronic diseases (NOCDs). There were no deaths. No safety signals in this healthy adult 
population were observed. These results demonstrated an acceptable safety profile for 
nirsevimab, including no observed hypersensitivity reactions, and supported further clinical 
studies of IM administration of 1 dose of nirsevimab in the target population of infants to 
provide protection for the duration of the RSV season.
Pharmacokinetics
A 2-compartment PK model adequately described the PK profile following both IV and IM 
administrations. Body weight was determined to be a significant covariate on systemic 
clearance and volume of distribution with allometric exponents. The mean population 

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clearance and volume of distribution were 42.3 mL/day and 2.8 L, respectively. The mean t1/2
of nirsevimab ranged from 85 to 117 days across dose groups, and bioavailability after IM 
administration was 77%. The predicted 3- to 4-fold increase in the t1/2 of nirsevimab compared 
to a standard IgG antibody was confirmed.
Antidrug Antibody
Post-baseline ADA was detected in 13.7% of subjects in the nirsevimab total group and 
15.2% of subjects in the placebo group, with a maximum titer of 1:800 and 1:400, 
respectively. On Day 361, ADA was detected in 5.3% of nirsevimab subjects and 10.7% of 
placebo subjects. The highest titer at Day 361 was 1:200 for both the nirsevimab and placebo 
groups. The presence and titer of ADA had no effect on the PK or safety profiles.
1.4.2
Phase 1b/2a Study D5290C00002
Study D5290C00002 was a Phase 1b/2a, randomized, double-blind, placebo-controlled, single 
ascending-dose study to evaluate safety, PK, and ADA of nirsevimab in healthy preterm 
infants (Domachowske et al 2018). The population enrolled was healthy preterm infants born 
between 32 weeks 0 days and 34 weeks 6 days gestation who would not receive RSV 
prophylaxis based on the American Academy of Pediatrics or other national or local 
guidelines. These subjects would not be receiving palivizumab, allowing for a placebo 
comparator group. A total of 89 infants from sites in the US, Chile, and South Africa were 
randomized and received a single IM dose of nirsevimab (10, 25, or 50 mg; 8, 31, and 
32 subjects, respectively) or placebo (18 subjects) and were followed for approximately 
360 days after dosing.
Safety
A total of 66 subjects (93.0%) in the nirsevimab group and 17 subjects (94.4%) in the placebo 
group reported at least 1 TEAE. No safety signals were observed with ascending dose levels. 
The majority of the events were mild or moderate in severity; only 2 TEAEs were assessed as 
W Grade 3 severity, and neither was considered to be related to investigational product by the 
Investigator. There were no deaths, AESIs, or NOCDs in any dose group.
Three nirsevimab subjects (4.2%) had a total of 5 TESAEs, none of which were considered 
related to investigational product by the Investigator; no subjects in the placebo group had a 
TESAE. One infant who received 25 mg of nirsevimab was hospitalized for LRTI. Real-time 
reverse transcriptase-polymerase chain reaction (RT-PCR) testing from the central laboratory 
was negative for RSV (but positive for human metapneumovirus [hMPV]); the illness 
resolved. The same infant was again hospitalized for LRTI, and subsequent RT-PCR testing 
was positive for RSV B; the event resolved. One infant who received 50 mg of nirsevimab 
was hospitalized for febrile convulsion; the infant recovered. A second infant who received 

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50 mg of nirsevimab was hospitalized for febrile convulsion and a concurrent LRTI. Testing 
for RSV was not performed, and the infant recovered from both events.
The most frequently reported TEAEs for the nirsevimab group were URTI (69.0%), 
gastroenteritis (29.6%), cough (25.4%), pyrexia (22.5%), and otitis media (21.1%). There 
were no trends by dose of nirsevimab for these events. The most frequently reported TEAEs 
in the placebo group were URTI (66.7%), anemia (33.3%), and gastroenteritis, cough, and 
otitis media (22.2% each). Skin rashes (defined as adverse events [AEs] that coded to the 
Medical Dictionary for Regulatory Activities [MedDRA] preferred terms of dermatitis, 
dermatitis allergic, dermatitis atopic, dermatitis contact, dermatitis diaper, dry skin, eczema, 
rash, and rash papular) were reported for 38.9% of subjects in the placebo group and 47.9% of 
subjects in the nirsevimab group. No skin events were consistent with hypersensitivity.
Pharmacokinetics
Nirsevimab exhibited a less-than-dose-proportional exposure increase between the 10- and 
25-mg doses; however, exposure increase was dose proportional between 25- and 50-mg 
doses. Following a single IM dose of 10, 25, or 50 mg, the estimated t1/2 of nirsevimab ranged 
from 62.5 to 72.9 days. On Day 151, 87% of the nirsevimab serum concentrations following 
the 50 mg IM dose were above the 90% effective concentration threshold of 6.8 ^g/mL.
Serum anti-RSV neutralizing antibody (NAb) titers increased dose-dependently following 
administration of nirsevimab and were higher than placebo by Day 8 and through Day 151. 
Serum nirsevimab concentrations were correlated with serum anti-RSV NAb across all the 
dose levels, confirming anti-RSV activity of nirsevimab.
Antidrug Antibody
ADA was not detected in any subject at Day 151. Post-baseline ADA was detected at Day 361 
only in 18/68 (26.5%) subjects, and there were 2 subjects with transient ADA-positive titers at 
Day 50 only who were ADA negative at Day 361. Overall, post-baseline ADA was detected in 
20/71 subjects (28.2%) in the nirsevimab group and 0/17 subjects (0%) in the placebo group. 
None of the post-baseline nirsevimab ADA-positive subjects were ADA positive at baseline; 
only one subject (in the placebo group) was ADA-positive at baseline. The highest titer 
detected was 1:25,600 (observed in 2 subjects [2.8%]). The 20 subjects in the nirsevimab
group who had ADA detected were positive for the presence of ADA targeting the YTE 
domain and 4 of the 20 subjects with samples available had neutralizing ADA antibody.
There was no impact of the presence of ADA on safety. ADAs did not appear to impact PK 
for 150 days after dosing, but there may have been an impact between Day 151 and Day 361.

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1.4.3
Phase 2b Study D5290C00003
Study D5290C00003 was a Phase 2b global, randomized, double-blind, placebo-controlled, 
single-dose study to evaluate the efficacy, safety, PK, and ADA of nirsevimab in healthy 
preterm infants, born between 29 weeks 0 days and 34 weeks 6 days gestational age (GA), 
entering their first RSV season. Subjects were not eligible for RSV prophylaxis with 
palivizumab based on the Joint Committee on Vaccination and Immunisation, American 
Academy of Pediatrics, or other local or national guidelines, allowing for a placebo 
comparator group. Overall, 1,453 subjects were randomized 2:1 to receive a single dose of 
50 mg IM nirsevimab or placebo. A total of 1,447 subjects were dosed, including 968 subjects 
in the nirsevimab group and 479 subjects in the placebo group. Subjects were followed for 
360 days after dosing.
Efficacy
Based on the analysis in the Intent-to-treat Population, a single dose of 50 mg IM nirsevimab 
resulted in a 70.1% (95% confidence interval [CI]: 52.3%, 81.2%; p < 0.0001) relative risk 
reduction (RRR) in the incidence of medically attended RSV-confirmed LRTI through Day 
151 when compared to placebo. Additionally, a 78.4% (95% CI: 51.9%, 90.3%; p = 0.0002) 
RRR in the incidence of RSV LRTI hospitalization through Day 151 was seen in the 
nirsevimab recipients when compared to placebo.
Safety
The safety profile of nirsevimab was comparable to that of placebo, with no identified risks. 
Overall, 86.2% of subjects in the nirsevimab group and 86.8% of subjects in the placebo 
group had at least 1 TEAE. TEAEs X 1 day post dose occurred in 2.5% of subjects in both 
groups. In comparison to the placebo group, the nirsevimab group had a lower incidence of 
TEAEs occurring X 7 days post dose (nirsevimab 12.5%, placebo 15.2%), TEAEs W Grade 3 
in severity (nirsevimab 8.0%, placebo 12.5%), or TESAEs (nirsevimab 11.2%, placebo 
16.9%). The majority of the TEAEs were mild or moderate in severity. The most common 
TESAEs, based on the nirsevimab group, were bronchiolitis (2.1% nirsevimab, 4.4% placebo), 
LRTI (1.4% nirsevimab, 2.7% placebo), bronchitis (1.4% nirsevimab, 2.3% placebo), and 
pneumonia (1.3% nirsevimab, 2.1% placebo). None of the TESAEs were considered related to 
investigational product by the Investigator. Five deaths were reported during the study through 
Day 361, including 2 subjects (0.2%) in the nirsevimab group and 3 subjects (0.6%) in the 
placebo group. None of the deaths were related to investigational product according to the 
Investigator.
Overall, the incidence of treatment-related TEAEs (nirsevimab 2.3%, placebo 2.1%); AESIs, 
including hypersensitivity, immune complex disease, and thrombocytopenia (nirsevimab 
0.5%, placebo 0.6%); and NOCDs (nirsevimab 0.4%, placebo 0.8%) was low and generally 
comparable between the placebo and nirsevimab groups. AESIs were reported in 5 subjects 

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(4 subjects with rash or rash macular and 1 subject with petechiae) in the nirsevimab and 
3 subjects (rash or rash papular) in the placebo group. All events were Grade 1 in severity. 
The TEAE of petechiae that was reported as an AESI was 1 day in duration and was reported 
by the Site Investigator based on description by the parent. There were no laboratory 
assessments for the petechiae.
TEAEs that involved the skin and subcutaneous tissues (including diaper rash) were collected 
as skin reactions, with a few exceptions for skin reactions that could be definitively diagnosed 
such as impetigo, varicella, and scabies. Skin reactions were reported in a similar percentage 
of subjects in both treatment groups (nirsevimab 32.9%, placebo 30.9%).
Pharmacokinetics
Following a single fixed 50-mg IM dose of nirsevimab, 97.8% of measurable Day 151 serum 
concentrations were above the nonclinical 90% effective concentration target of 6.8 ^g/mL. 
The mean (% coefficient of variation) area under the concentration-time curve from time 0 to 
infinity (AUC0-Z) and estimated apparent t1/2 were 5176.3 (35.0) day^g/mL and 
59.3 (9.6) days, respectively.
Antidrug Antibody
Overall, the rate and titers of ADA were low, and in post-baseline ADA-positive subjects 
there was no effect on PK, efficacy, or safety. Of the subjects who had serum samples 
available for testing, ADA was detected post baseline in 5.6% (52/929) of subjects in the 
nirsevimab group and 3.8% (18/469) of subjects in the placebo group. ADA titers ranged from 
1:50 to 1:6,400 in the nirsevimab group and from 1:50 to 1:400 in the placebo group. Of the 
nirsevimab subjects who were post-baseline ADA positive, ADA targeting the YTE domain 
was observed in 4/17 subjects (23.5%) on Day 151 and 23/30 subjects (76.7%) on Day 361. 
Three nirsevimab subjects had neutralizing ADA on Day 361.
1.5
Rationale for Conducting the Study
Prevention of RSV illnesses in all infants is a major public health priority (Giersing et al 
2019); however, despite almost 50 years of attempted vaccine development (Kim et al 1969, 
Mazur et al 2018), there are no licenced vaccines. While RSV prevention exists in the form of 
a specific RSV IgG (palivizumab) requiring 5 once monthly injections, it is not licensed for 
use in China. The mAb, nirsevimab, is being developed as a cost-effective opportunity to 
protect all infants from RSV disease based on improved potency and an extended t1/2, which is 
expected to support once per-RSV-season dosing.
The purpose of this study is to evaluate the PK, safety, tolerability, and immunogenicity of 
nirsevimab in healthy adult Chinese subjects. The results from this study will support drug 
registration in China.

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1.6
Benefit-Risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
To evaluate the clinical benefit-risk balance for nirsevimab, nonclinical and clinical data have 
been taken into consideration. Based on the risk of serious RSV disease in infants and high-
risk children, there is an established unmet medical need for the use of nirsevimab for 
prophylaxis in all infants entering their first RSV season and in high-risk- preterm infants and
children X 24 months of age with CLD or CHD. Benefits for nirsevimab over placebo include 
a clinically meaningful reduction in medically attended LRTI due to RSV in infants and 
expected similar benefit for high-risk children. Nirsevimab is not expected to offer benefit to 
the healthy Chinese adult subjects in this study. The PK, ADA, and safety results of this study 
will support the registration of nirsevimab in China.
Nirsevimab has no endogenous targets, and no safety concerns have been identified in 
nonclinical or clinical studies to date. The potential risks are based primarily on safety risks 
that may be observed with any immunoglobulin, including mAbs such as palivizumab. These 
potential risks include, but are not limited to, hypersensitivity (including anaphylaxis), 
immune complex disease, thrombocytopenia, and injection site reactions. To date, there have 
been no observed events of anaphylaxis, significant hypersensitivity reactions, immune 
complex disease, or thrombocytopenia attributable to nirsevimab in the clinical studies. 
Nonetheless, subjects in nirsevimab clinical studies will continue to be monitored for 
important potential risks, and routine pharmacovigilance and risk minimization activities will 
be performed accordingly.
The benefit-risk assessment for nirsevimab in prevention of RSV disease based on the 
development through Phase 2b is favorable.
1.7
Research Hypotheses
The primary and secondary research hypotheses are described below. No formal hypothesis is 
being tested statistically.
1.7.1
Primary Hypothesis
The PK profile of nirsevimab assessed up to 150 days after dose administration in Chinese 
subjects will be similar to subjects with different racial and ethnic backgrounds.
1.7.2
Secondary Hypotheses
A single dose of nirsevimab will be well tolerated in healthy Chinese adult subjects, with an 
acceptable safety profile. The incidence of ADA to nirsevimab will be acceptable.

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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 1
Primary Objective and Associated Endpoint
Type
Objective
Endpoint
PK
To evaluate serum concentrations of 
nirsevimab
Summary of nirsevimab serum 
concentrations and estimated PK parameters 
(Cmax, Tmax, AUC0-150, and others if data 
permit) 
AUC0-150 = area under the concentration-time curve from time 0 to 150 days; C max = maximum observed 
concentration; PK = pharmacokinetics; Tmax = time to maximum observed concentration.
2.2
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Safety
To evaluate the safety and tolerability of 
nirsevimab when administered as a single 
fixed IM dose of 300 mg to healthy Chinese 
adult subjects
•
Occurrence of all TEAEs, TESAEs,
AESIs, and NOCDs
•
Clinical laboratory assessments, vital
signs
ADA
To evaluate ADA responses to nirsevimab in 
serum
Incidence of ADA to nirsevimab in serum
ADA = antidrug antibody; AESI = adverse event of special interest; IM = intramuscular; NOCD = new onset 
chronic disease; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse 
event.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
Study D5290C00007 is a Phase 1, randomized, double-blind, placebo-controlled study to 
evaluate the PK, safety, and tolerability of nirsevimab compared to placebo when 
administered as a single fixed IM dose of 300 mg to healthy Chinese adult subjects. 
Enrollment is planned at a single study center in China.
24 subjects will be randomly assigned in a 3:1 ratio to receive nirsevimab 
(n = 18) or placebo (n = 6). All subjects will be followed for approximately 150 days after 
dosing to assess safety, PK, and ADA response.
$SSUR[LPDWHO\

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Figure 1
Study Flow Diagram
ADA = antidrug antibody; IM = intramuscular; PK = pharmacokinetics.
3.1.2
Treatment Regimen
Subjects will be randomly assigned to receive a single fixed IM dose of nirsevimab 300 mg 
(n = 18) or placebo (n = 6) on Day 1.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
Nirsevimab is supplied as a liquid product intended for IM administration. Nirsevimab is 
formulated at 100 mg/mL and is supplied as a sterile solution in a glass vial at nominal fill 
volume of 0.5 mL. Each vial contains 50 mg of nirsevimab. The proposed pediatric dosing 
regimen for nirsevimab is a single fixed IM dose of 50 mg for infants < 5 kg or 100 mg for 
infants W 5 kg body weight entering their first RSV season, and a single fixed IM dose of 
200 mg for high-risk children with CLD or CHD entering their second RSV season.
In the Phase 1a first-time-in-human Study D5290C00001, a total of 136 healthy adult subjects 
were randomized and received a single dose of nirsevimab (6 subjects each at doses of 300 mg 

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IV, 1000 mg IV, 3000 mg IV, and 100 mg IM; 78 subjects at 300 mg IM) or placebo 
(34 subjects). The IM dose was limited to 300 mg because this dose required 3 simultaneous 
1 mL IM injections, and more injections per dose were not considered practical. Higher doses 
to ensure safety exposure coverage were tested with IV administration (Table 3). Data 
demonstrated a favorable safety profile similar to placebo at all doses tested. A 2-
compartment PK model adequately described the PK profile following both IV and IM 
administrations. The mean t1/2 of nirsevimab ranged from 85 to 117 days across the dose 
groups, and bioavailability after IM administration was 77%. The predicted 3- to 4-fold 
increase in the t1/2 of nirsevimab compared to a standard IgG antibody was confirmed. A 
single 300-mg IM dose of nirsevimab will be administered in this Phase 1 study in Chinese 
adult subjects to confirm a similar PK profile in the Chinese population. Higher doses to 
provide safety exposure coverage were tested in Study D5290C00001 but will not be 
necessary in this Phase 1 study in China.
In addition, the highest anticipated maximum observed concentration (Cmax) and AUC0-Z
among all infants to be dosed with nirsevimab at 50 or 100 mg in the first season are predicted 
to be covered by exposures observed to date in the Phase 2b Study D5290C00003 population 
(> 29 to < 35 wGA), in cynomolgus monkey, or in human adults, and were demonstrated to be 
safe and well tolerated (Table 3).
Table 3
Exposure Comparison in Cynomolgus Monkey, and Human Adult and 
Pediatric Populations
Population
Nirsevimab
Dose
Cmax (Cg/mL)
Median (max)
AUC0-D
(CgEday/mL)
Median (max)
Cynomolgus monkey
Observed PK
300 mg IM
4,982 (6,080)a
90,560 (113,000)b
300 mg/kg IV
13,440 (19,000)a
193,300 (298,000)b
Adult
Observed PK from Phase 1a Study D5290C00001
300 mg IM
45.8 (78.4)
4,917 (9,956)
3000 mg IV
1,199 (1,465)
61,792 (71,918)
Pediatric (1st season)
Observed PK from Phase 1b/2a Study D5290C00002
50 mg IM
69.5 (109)
7,120 (11,300)
Pediatric (1st season)
Observed PK from Phase 2b Study D5290C00003
50 mg IM
66.2 (201)
14,220 (20,910)
AUC0-Z = area under the concentration-time curve from time 0 to infinity; AUCday1-31 = area under the concentration-time 
curve from Day 1 to 31; Cmax = maximum observed concentration; IM = intramuscular; IV = intravenous; 
max = maximum; PK = pharmacokinetics.
Data are reported as median and maximum observed.
Cmax after repeat dosing.
Based on AUCday1-31.

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3.2.2
Rationale for Study Population
Nirsevimab has the potential to address a serious unmet medical need by protecting all infants 
from RSV disease with once-per-season dosing. Palivizumab is not licensed in China and 
currently there are no other options available for the prevention of RSV disease. This Phase 1 
adult study is designed to assess the PK, ADA, safety, and tolerability of a single IM dose of 
nirsevimab in healthy Chinese adult subjects to support the registration of nirsevimab in 
China. The PK profile of nirsevimab assessed after dose administration in Chinese adult 
subjects will be compared to global adult subjects with different racial and ethnic 
backgrounds.
3.2.3
Rationale for Endpoints
Serum concentration of nirsevimab at selected time points will be evaluated as the primary 
endpoint to confirm that adequate serum exposures are maintain ed at least 5 months after 
dosing (ie, through Day 151; duration of a typical RSV season). The estimated PK parameters 
from the adult Chinese subjects in this study will be compared for similarity with those 
obtained from non-Chinese adult subjects from the global Phase 1a Study D5290C00001.
Nirsevimab being a mAb with a half-life extending YTE modification has a predictable linear 
PK profile across a range of doses studied both in adults and infants. Also, it does not have 
any internal targets; thus, it does not go through any target-mediated clearances to have the
potential to alter the PK profile past the 150 days from the injection. Therefore, the 150-day 
PK profile comparison based on only Cmax, tmax, and AUC0-150 assures the similarity of 
efficacious exposures as well as provides the opportunity to confirm the safety.
ADA will be measured at selected time points throughout the study up to Day 151.
Safety endpoints include TEAEs, TESAEs, AESIs (defined as hypersensitivity including 
anaphylaxis, immune complex disease, and thrombocytopenia), and NOCDs.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of approximately 24 subjects will be randomized to receive a single IM dose of either 
nirsevimab (n = 18) or placebo (n = 6).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Age 18 to 45 years, inclusive, at the time of screening.

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2
Written informed consent and any locally required authorization obtained from the 
subject prior to performing any protocol-related procedures, including screening 
evaluations.
3
Females of childbearing potential who are sexually active with a nonsterilized male 
partner must have used at least 1 highly effective method of contraception (see 
Appendix A for definition of females of childbearing potential and for a description of 
highly effective methods of contraception) from screening and must agree to continue 
using such precautions for 150 days after receipt of the dose of investigational product. It 
is strongly recommended for the male partner of a female subject to also use a male 
condom plus spermicide throughout this period. Cessation of contraception after this 
point should be discussed with a responsible physician. Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception.
(a) Females not of childbearing potential who are either permanently sterilized 
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or 
postmenopausal. Women < 50 years of age will be considered postmenopausal if they 
have been amenorrheic for W 12 months prior to the planned date of randomization 
without an alternative medical cause and have follicle-stimulating hormone levels in 
the postmenopausal range.
4
Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a male condom with spermicide from Day 1 (the day of investigational 
product administration) through 150 days after receipt of the dose of investigational 
product. It is strongly recommended for the female partner of a male subject to also use a 
highly effective method of contraception throughout this period, as described in 
Appendix A. In addition, male subjects must refrain from sperm donation while on study 
and for 150 days after the final dose of investigational product.
5
Weight W 45 kg and X 110 kg and body mass index of 19 to 26 kg/m2 at screening.
6
Healthy Chinese subjects (both male and female) based on medical history, physical 
examination, vital signs, and laboratory tests, as determined by the Investigator.
7
Normotensive (defined as systolic blood pressure < 140 mm Hg and diastolic blood 
pressure < 90 mm Hg).
8
Normal electrocardiogram (ECG) as judged by the Investigator at screening (within 28 
days prior to Day 1).
9
Ability to complete the follow-up period of 150 days following administration of 
investigational product as required by the protocol.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
Acute illness at study entry (pre-dose on Day 1). If, in the opinion of the Investigator, the 
illness is transient and of no medical importance, it would be permissible to reassess the 
subject for study and dosing eligibility after resolution as long as it is within the overall 
28-day study screening period.
2
Fever ! 99.5F (37.5C) on day of dosing.

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3
Any drug therapy within 14 days prior to Day 1 (except contraceptives). If, in the opinion 
of the Investigator, the medication was taken for a transient illness that has resolved, it 
would be permissible to reassess the subject for study and dosing eligibility after 
resolution as long as it is within the overall 28-day study screening period.
4
Blood donation or in any other way had a loss of blood in excess of 400 mL within 
6 months prior to study entry.
5
Receipt of immunoglobulin or blood products within 6 months prior to study entry.
6
Receipt of any investigational drug therapy within 120 days prior to investigational 
product dosing or planned to receive any investigational drug therapy within 150 days 
after investigational product dosing.
7
Receipt of any live vaccine within 30 days and other vaccines within 14 days prior to 
investigational product dosing.
8
Previous receipt of any marketed or investigational mAb.
9
Previous vaccination against RSV.
10 History of immunodeficiency or receipt of immunosuppressive medications during the 
prior year.
11 History of allergic disease or reactions likely to be exacerbated by any component of the 
investigational product or a history of drug or other allergy that, in the opinion of the 
investigator, contraindicates their participation.
12 History of asthma.
13 History of autoimmune disorder.
14 Previous medical history or evidence of an intercurrent illness that, in the Investigator’s 
opinion, may compromise the safety of the subject in the study.
15 Evidence of any systemic disease on physical examination.
16 Evidence of infection (ie, positive laboratory test result) with hepatitis A, B, or C virus,
syphilis, or human immunodeficiency virus.
17 Any of the following laboratory assessments at screening (must be within 28 days before 
study entry):
(a) Hemoglobin < 120 g/L for males and < 110 g/L for females
(b) White blood cell count < 3.5 × 109/L
(c) Platelet count < 120 × 109/L
(d) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, serum 
creatinine > upper limit of normal (ULN)
(e) Urine Class A drug screen positive for amphetamines, opiates, or cocaine
(f) Other abnormal laboratory values in the screening panel, which in the opinion of the 
Investigator, are judged to be clinically significant; other abnormal laboratory values 
in the screening panel which, in the opinion of the Investigator, are judged to 
potentially confound analysis of study results
18 Pregnant or nursing mother. All female subjects will be screened to rule out pregnancy 
prior to enrollment using serum beta human chorionic gonadotropin ([hCG) testing.

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19 Active alcohol or drug abuse or history of alcohol or drug abuse that, in the opinion of the 
Investigator, might compromise subject safety, study safety assessments, or ability of the 
subject to comply with study requirements.
20 Any condition that, in the opinion of the Investigator, would interfere with evaluation of 
the investigational product or interpretation of subject safety or study results.
21 Concurrent enrollment in another interventional study.
22 Employees of the Sponsor, clinical study site, or any other individuals involved with the 
conduct of the study, or immediate family members of such individuals.
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive web response system [IWRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not be 
randomized (if applicable) or receive investigational product. Rescreening is not permitted.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study at any time, without 
prejudice to further treatment. Subjects who withdraw consent will be asked about the 
reason(s) and the presence of any AEs. If the subject is willing, the subject will be seen and 
assessed by the Investigator. AEs will be followed up. If a subject withdraws from further 
participation in the study, then no further study visits or data collection should take place. The 
reason for withdrawal must be recorded in the eCRF.
Subjects who have received investigational product will be followed for protocol-specified 
assessments including follow-up of any AEs unless consent is withdrawn from further study 
participation or the subject is lost to follow-up (Section 4.1.7).
4.1.6
Discontinuation of Investigational Product
Not applicable as each subject will receive a single dose of investigational product.

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4.1.7
Lost to Follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
To prevent the subject from being lost to follow-up, it is recommended that the study sites 
maintain up-to-date contact details for subjects, including next of kin or other emergency 
contacts (if allowed by national regulation).
The Investigator should educate the subject on the importance of maintaining contact with the 
Investigator/study site throughout the study.
The following actions must be taken if a subject fails to return to the site for required study 
visits:
#
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.
#
Repeated attempts must be made to regain contact with the subject or next of 
kin/emergency contact by repeat telephone calls, emails, and/or certified letter. These 
contact attempts should be documented in the subject’s medical record.
Efforts to reach the subject should continue until the end of the study.
The subject will be classified as lost to follow-up only if he/she has failed to return for the 
required study visits and his/her vital status remains unknown at the end of the study, despite 
all above listed efforts.
4.1.8
Replacement of Subjects
Subjects will not be replaced.
4.1.9
Withdrawal of Informed Consent for Data and Biological Samples
The Sponsor ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a subject withdraws consent for further study participation, any samples collected prior to 
that time may still be given to and used by the Sponsor but no new data or samples will be 
collected unless specifically required to monitor safety of the subject.
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, the 
Sponsor is not obliged to destroy the results of this research.
The Principal Investigator:

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#
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to the Sponsor.
#
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.
#
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the signed document returned to the study site.
#
Ensures that the subject and the Sponsor are informed about the sample disposal.
The Sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
4.2
Schedule of Study Procedures
4.2.1
Enrollment/Screening Period
Table 4 shows all procedures to be conducted at the screening visit. Assessments should be 
performed in the order shown in the table.
Table 4
Schedule of Screening Procedures 
Study Period
Screening
Procedure / Study Day or Week
Day -28 to Day -2
Day -1
Written informed consent/ assignment of SID number
X
Medical history
X
Xa
Physical examination (complete)
X
Xa
Height, weight
X
Electrocardiogram (ECG)
X
X
Vital signs
X
X
Serum chemistryb
X
X
Hematologyb
X
X
Urinalysisb
X
X
Pregnancy testc
X
X
FSHd
X
Hepatitis A, B, C; HIV; Syphilis
X
Urine Class A drug screenb
X
X
Assessment of AEs/SAEs
X
X
Concomitant medications
X
X
Verify eligibility criteria
X
X

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Table 4
Schedule of Screening Procedures 
Study Period
Screening
Procedure / Study Day or Week
Day -28 to Day -2
Day -1
Admission 
X
ADA = antidrug antibody; AE = adverse event; [hCG = beta human chorionic gonadotropin; FSH = follicle-
stimulating hormone; HIV = human immunodeficiency virus; PK = pharmacokinetics; SAE = serious adverse 
event; SID = subject identification.
a
Update screening medical history and complete physical examination (any new findings since screening).
b
Screening serum chemistry and hematology assessments reviewed and found to be within normal limits by 
the Site Investigator. Serum chemistry assessments should be collected under fasting conditions (fasting 
starts 8 hours before sample collection). If serum chemistry, hematology, urinalysis and urine class A drug 
screen assessments at screening visit (Day -28 to Day -2) are performed within 7 days of randomization, the 
assessments at Day -1 can be omitted.
c
Female subjects only. Serum pregnancy test will be performed at screening visit (Day -28 to Day -2). Urine 
pregnancy test will be performed on Day -1 to confirm eligibility. Pregnancy test must be negative prior to 
dosing.
d
FSH will be tested only in women < 50 years of age who have been amenorrheic for W 12 months.
4.2.2
Treatment and Follow-up Periods
Investigational product is administered on Day 1. Table 5 and Table 6 show all procedures to 
be conducted on Day 1 and during the post-dose follow-up period, respectively.
Table 5
Schedule of Treatment Period Procedures
Procedure
Investigational Product Administration: Day 1
Pre-dose
Dosing
Post-dose
30 min post 
(± 5 min)
60 min post
(± 5 min)
Abbreviated Physical examination
X
Vital signsa
X
X
X
Blood sample for PK, ADA
X
Assessment of AEs/SAEs
X
X
X
X
Assessment of AESIs and NOCDs
X
X
X
Concomitant medications
X
Randomizationb
X
Investigational product administration
X
ADA = antidrug antibody; AE = adverse event; AESI = adverse event of special interest; IM = intramuscular; 
NOCD = new onset chronic disease; PK = pharmacokinetic; SAE = serious adverse event.
a
Vital signs will be monitored before and after IM administration of investigational product. Two pre-dose 
(within 60 minutes prior to dosing) blood pressure and heart rate readings should be obtained 5 minutes 
apart. Vital signs should be monitored within 60 minutes prior to dosing, and 30 and 60 (± 5 minutes) 
minutes after the administration of the investigational product.
b
Randomization should occur before blood sampling.

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Table 6
Schedule of Follow-up Period Procedures
Procedure
Post-dose Follow-up: Day (± Assessment Window [day])
2
4
6
8
15
(± 1d)
31
(± 2d)
91
(± 5d)
151
(± 10d)
Physical examinationa
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Serum chemistry
X
X
X
X
Hematology
X
X
X
X
Urinalysis
X
X
X
X
PK blood sample
X
(± 2h)
X
(± 3h)
X
(± 3h)
X
(± 3h)
X
X
X
X
ADA blood sample
X
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
Assessment of AESIs and 
NOCDs
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
Discharge
X
ADA = antidrug antibody; AE = adverse event; AESI = adverse event of special interest; d = day; h = hour; 
NOCD = new onset chronic disease; PK = pharmacokinetic; SAE = serious adverse event.
a
Abbreviated physical examinations will be performed at Day 2, Day 6, Day 15, Day 31 and Day 91. A 
complete physical examination should be performed on Day 151.
4.3
Description of Study Procedures
4.3.1
Medical History, Physical Examination, Height, Weight, Vital Signs
and Electrocardiogram
A complete medical history will be obtained at screening and a medical history update (for 
any new findings since screening) will be obtained on Day -1.
A complete physical examination will be performed at screening visit (Day -28 to Day -2), 
Day -1 (updated with any new findings since screening), and Day 151, and it will include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen, skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal 
(including spine and extremities) and neurological systems. An abbreviated physical 
examination will be performed at all other study visits, and it will include an assessment of 
general appearance, abdomen, cardiovascular, and respiratory systems. The height and/or 
weight will be performed as noted in Table 4.
Vital signs (temperature, blood pressure, respiratory rate, and heart rate measurements) will be 
collected at screening visit (Day -28 to Day -2), Day -1 and on Day 1 as defined in Table 4
and Table 5. Refer to Table 6 for the timings of assessments during the follow-up period.

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At Screening, 12-lead ECG will be obtained after 5 minutes supine rest and prior to blood
draw. Skin must be cleaned, and electrodes should be positioned according to standard 12-lead 
ECG placement. All 12-lead ECGs will be recorded and evaluated by the Investigator. The 
Investigator will judge the overall interpretation as normal or abnormal. If abnormal, it will be 
decided whether the abnormality is clinically significant or not. The reason for the 
abnormality will be recorded in the eCRF. These ECGs will be documented in the eCRF by 
recording date, time, heart rate, overall assessment as normal and abnormal, and whether the 
abnormality is clinically significant or not.
All ECGs will be documented by recording date, time of collection, heart rate, PR, RR, QRS, 
and QT intervals from the 12-lead ECG.
If indicated additional 12-lead ECG assessments can be made at the discretion of the 
Investigator. These assessments should be entered as an unscheduled assessment in the 
appropriate eCRF.
4.3.2
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.
Clinical laboratory safety tests will be performed at a local laboratory at or near the 
investigator site. Sample tubes and sample sizes may vary depending on laboratory method 
used and routine practice at the site. Abnormal laboratory results after randomization should 
be repeated as soon as possible (preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed (see Table 4, Table 5, and Table 6):
Serum Chemistry
•
AST
•
Gamma-glutamyltransferase
•
ALT
•
Glucose
•
Alkaline phosphatase (ALP)
•
Potassium
•
Calcium
•
Sodium
•
Chloride
•
Total bilirubin (TBL)
•
Creatinine 
•
Urea
Note for serum chemistries: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently.

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Hematology
•
White blood cell (WBC) count with differential
•
Hemoglobin
•
Red blood cell (RBC) count
•
Platelet count
•
Hematocrit
Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Bilirubin
•
Protein
•
Microscopy (including WBC/HPF, RBC/HPF)
Pregnancy Test (All Females of Childbearing Potential Only)
•
Serum beta human chorionic gonadotropin ([hCG; Day -28 to Day -2)
•
Urine hCG (on Day -1)
Other Safety Tests
•
Hepatitis A immunoglobulin M antibody, and hepatitis B surface antigen
•
Hepatitis C antibody screen
•
Human immunodeficiency virus (HIV) antibody screen, syphilis test
•
Urine Class A drug screen for amphetamines, opiates, and cocaine
•
Follicle-stimulating hormone (only for women < 50 years of age who have been amenorrheic for 
W 12 months at screening)
4.3.3
Pharmacokinetic Evaluation
Blood samples to evaluate the PK of nirsevimab in serum will be collected according to the 
scheduled time points (see Section 4.2). The concentration of nirsevimab in serum will be 
measured using validated assays.
4.3.4
Antidrug Antibody Evaluation
Blood samples to evaluate ADA responses to nirsevimab in serum will be collected according 
to the scheduled time points (see Section 4.2). ADA samples may also be further tested for 
characterization of the ADA response. Evaluations will be performed using validated 
immunoassays.
4.4
Study or Study Component Suspension or Termination
The Sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited to 
the following:

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1
Death in any subject in which the cause of death is assessed as related to investigational 
product
2
Anaphylactic reaction that is related to investigational product (see Appendix C for a 
definition of anaphylaxis)
3
Grade 3 and/or 4 hypersensitivity AEs based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0) grading scale that 
are assessed as related to nirsevimab in 2 or more subjects. Refer to Appendix B for 
events not covered in NCI CTCAE.
4
Two SAEs of the same type that are assessed as related to nirsevimab
5
Subject enrollment is unsatisfactory
6
Sponsor decision to terminate development
If the Sponsor determines that temporary suspension or termination of the study is required, 
the Sponsor will discuss the reasons for taking such action with the Investigator (or head of 
the medical institution, where applicable). When feasible, the Sponsor will provide advance 
notice to all participating Investigators (or head of the medical institution, where applicable) 
of the impending action.
If the study is suspended or terminated for safety reasons, the Sponsor will promptly inform 
the Investigator, head of the medical institution (where applicable), and/or institution 
conducting the study. The Sponsor will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the Investigator or head of the medical institution must 
inform the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the Sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs, when applicable) will be obtained prior to 
resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Products
The Sponsor will provide the Investigator(s) with investigational product (Table 7) using 
designated distribution centers.

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Table 7
Identification of Investigational Products
Investigational 
Product
Manufacturer
Concentration and Formulation as Supplied
Nirsevimab
MedImmune
Supplied as 50 mg (nominal) per vial solution.
The solution contains 100 mg/mL nirsevimab, 
 histidine/histidine-HCl, 
 arginine-
HCl, 
 sucrose, 
 polysorbate 
80, pH 6.0. The nominal fill volume is 0.5 mL.
Placebo
To be provided by study sites
Commercially available 0.9% (w/v) saline 
(sterile for human use)
HCl = hydrochloride; w/v = weight/volume.
Nirsevimab should be stored at 2°C to 8°C.
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.
Nirsevimab will be supplied to the site in open-labelled kits. Each kit has a unique number 
printed on all labels within the kit (ie, the outer carton label and the label of each vial).
Refer to Section 4.6.2 for information on coding of the container for blinding purposes.
See the Pharmacy Manual, which is prepared by the Sponsor, for additional information.
4.5.1.1
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. Refer to Table 7 for identification 
of investigational product.
If there are any defects noted with the investigational product, the Investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.5) for further instructions.
4.5.1.2
Dose Preparation Steps
No incompatibilities between nirsevimab and polycarbonate or polypropylene syringes have 
been observed.
Nirsevimab does not contain preservatives and any unused portion must be discarded. 
Total in-use storage time from needle puncture of the investigational product vial to start of 
administration should not exceed 4 hours at room temperature. If storage time exceeds these 
limits, a new vial should be used.
The dose administration steps are as follows:
CCI
CCI
CCI
CCI

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1
The required volume of nirsevimab (3 mL) will be obtained by withdrawing the contents 
of 6 investigational product vials into 3 appropriately sized syringes (ie, 2 vials per 
syringe). Normal saline placebo will be provided by the study sites and the required 
volume (3 mL) divided into 3 appropriately sized syringes. The maximum volume for 
each injection is 1 mL. Syringes used must be polycarbonate or polypropylene syringes. 
For ease of preparation, a 1.5 inch 19 gauge withdrawal needle should be used.
2
Switch the needle prior to administration.
3
Administer investigational product using the appropriate size needle ranging from 22 to 
25 gauge and 5/8 to 1.5 inches based on subject weight, as per standard of care.
4.5.1.3
Treatment Administration
The first day of dosing is considered Day 1.
Investigational product (nirsevimab or placebo) will be supplied by an unblinded 
investigational product manager. Blinding will be performed at the site level to ensure that 
nirsevimab and placebo are indistinguishable in appearance and are not labelled to reveal 
treatment identity.
Investigational product (nirsevimab or placebo) should be administered IM in the central area 
and thicker portion of the deltoid (ie, above the level of the armpit and below the acromion)
according to standard practice procedures for IM injections. The injection should be given 
using standard aseptic technique. The IM dose of nirsevimab or placebo should be given as 
3 separate 1 mL injections. Two injections given in the same deltoid muscle must be separated 
by approximately 1 inch (2.54 cm). The third injection will be given in the other deltoid 
muscle.
4.5.1.4
Monitoring of Dose Administration
Subjects will be monitored before and after investigational product administration through 
assessment of vital signs (temperature, blood pressure, heart rate, and respiratory rate). All 
vital signs should be obtained within 60 minutes prior to dosing, and at 30 minutes 
(± 5 minutes) and 60 minutes (± 5 minutes) post dose.
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
4.5.1.5
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the Sponsor’s 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to the Sponsor and investigated further with the Product 

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Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
Sponsor’s contact information for reporting product complaints:
Email:
Phone:
Mail:
MedImmune
Attn: Product Complaint Department
One MedImmune Way
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into local 
languages, as required.
4.5.4
Storage
Store investigational product at 2°C to 8°C.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.5.6
Accountability
The Investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to the Sponsor. All unused 
investigational product will be returned to a Sponsor-authorized depot or disposed of upon 
authorization by the Sponsor.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IWRS will be used for randomization to a treatment group and assignment of blinded 
investigational product kit numbers. A subject is considered randomized into the study when 
PPD
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the Investigator notifies the IWRS that the subject meets eligibility criteria and the IWRS 
provides the assignment of blinded investigational product kit numbers to the subject.
Subjects will be randomized using a 3:1 ratio to receive either nirsevimab (n = 18) or placebo 
(n = 6).
The procedure for using IWRS is as follows:
#
The Investigator or designee contacts the IWRS and provides the SID number and
subject’s baseline characteristic(s) used to verify that it is the same subject
#
Placebo (provided by site) or a vial from a nirsevimab kit will be assigned to the subject
#
Confirmation of this information is sent to the unblinded investigational product manager 
who prepares the investigational product to be dispensed to the subject per the response 
system and records the appropriate information in the investigational product 
accountability log
Investigational product (nirsevimab or placebo) must be administered the same day the 
investigational product is assigned. Total in-use storage time from needle puncture of the 
investigational product vial to administration should not exceed 4 hours at room temperature. 
If storage time exceeds these limits, a new vial should be used. If there is a delay in the 
administration of investigational product such that it will not be administered within the 
specified timeframe, the unblinded investigational product manager must be notified 
immediately.
4.6.2
Methods to Ensure Blinding
This is a double-blind study in which the site is using commercially available saline as the 
placebo. Nirsevimab and placebo are visually indistinguishable once in syringes. Neither the 
subject nor the Investigator or any of the site staff who are involved in the treatment or clinical 
evaluation of the subjects will be aware of the treatment received (ICH E9). In the event that 
treatment allocation for a subject becomes known to the Investigator or other blinded study 
staff involved in the management of study subjects, the Sponsor must be notified immediately. 
If the treatment allocation for a subject needs to be known to treat an individual subject for an 
AE, the Investigator must notify the Sponsor immediately. The site will maintain a written 
plan detailing which staff members are blinded/unblinded and the process of investigational 
product preparation and administration used to maintain the blind.
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the Investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IWRS manual. In general, unblinding 

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should only occur if management of the medical emergency would be different based on the
subject having received investigational product. In the majority of cases, the management of a 
medical emergency would be the same whether or not investigational product was received by 
the subject. If this was the case, the investigational product allocation should not be unblinded. 
In the event there is unblinding, the Investigator should promptly document and explain to the 
Sponsor the reason for any premature unblinding.
The Sponsor retains the right to unblind the treatment allocation for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the electronic case report form 
(eCRF).
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments which is considered 
necessary for the subject’s safety and well-being. Specifically, subjects may receive 
contraceptives during the study.
4.7.2
Prohibited Concomitant Medications
Other than contraceptives, use of concomitant medications including over-the-counter 
medications, herbal supplements, vitamins, etc from Day 1 through Day 15 post dose is 
discouraged. Subjects must be instructed not to take any medications, including over-the-
counter products, without first consulting with the Investigator.
4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. Additional details of statistical analyses will be 
described in the statistical analysis plan.
The PK Population will include all subjects who have received any dose of investigational 
product, and have at least one measurable post-dose serum PK observation and for whom PK 
blood samples are assumed not to be affected by factors such as important protocol deviations 
(to be determined prior to unblinding). PK analyses will be based on the PK Population.

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The As-treated Population will include all subjects who are randomized into the study and 
who receive any amount of investigational product. Subjects will be included in the treatment 
group corresponding to the treatment actually received. Safety and ADA analyses will be 
based on the As-treated Population.
4.8.2
Sample Size
This study will randomize approximately 24 subjects of whom approximately 18 will receive 
nirsevimab and approximately 6 will receive placebo. Because all analyses will be descriptive 
in nature and no hypothesis is being tested statistically, no formal sample size calculation was 
performed. Current sample size and sampling scheme are selected to facilitate estimation and 
numerical comparison of Cmax, time to maximum observed concentration (Tmax), and area 
under the concentration-time curve from time 0 to 150 days (AUC0-150) between Chinese and 
non-Chinese adult subjects.
4.8.3
Analysis of Pharmacokinetics
Serum concentrations of nirsevimab at selected time points will be evaluated to confirm that 
adequate exposures are maintained after dosing. Nirsevimab serum concentration data will be 
presented in descriptive statistics. Serum PK parameters such as Cmax, Tmax, and AUC0-150 will 
be estimated using noncompartmental analysis and summarized with descriptive statistics. The 
estimated PK parameters from the adult Chinese subjects from this study will be compared for 
similarity with those obtained from non-Chinese adult subjects from the global Phase 1a 
Study D5290C00001. This PK comparison will be presented separately from the clinical study 
report. Notably, regression-dependent PK parameters such as t1/2 and apparent systemic 
clearance will not be estimated due to the limited sampling up to 150 days which would 
require at least 40% extrapolation of the total AUC0-Z. Nonetheless, the predictability and 
consistency of the PK properties of nirsevimab as demonstrated in 102 adults in the Phase 1a 
Study D5290C00001 and 984 infants in the Phase 1b/2a Study D5290C00002 and Phase 2b 
Study D5290C00003 support the hypothesis that the apparent clearance and other regression-
dependent PK parameters should be similar if the Cmax, Tmax, and AUC0-150 are shown to be 
similar.
4.8.4
Safety
4.8.4.1
Analysis of Adverse Events
All AEs will be coded using MedDRA by system organ class and preferred term. Specific 
AEs will be counted once for each subject for calculating rates but will be presented in total in 
subject listings. In addition, if the same AE occurs multiple times within a particular subject, 
the highest severity and level of causality will be reported. All TEAEs will be summarized 
overall and by MedDRA system organ class and preferred term, severity, and relationship to 
investigational product. In addition, summaries of deaths and TESAEs will be provided. Other 
safety assessments will include the occurrence of AESIs defined as AEs of anaphylaxis and 

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other serious hypersensitivity reactions, including immune complex disease (eg, vasculitis, 
endocarditis, neuritis, glomerulonephritis), or thrombocytopenia following investigational 
product administration, and the occurrence of NOCDs following investigational product 
administration.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Laboratory parameters will be assessed at baseline as well as throughout the study. 
Frequencies of worst observed Grade 3-4 toxicity, as defined by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (version 5.0), will be presented for each 
laboratory parameter by treatment group. Also, laboratory parameters will be assessed by 
presenting tables containing information related to 2-grade (or greater) laboratory shifts from 
baseline as well as descriptively over time. Safety of nirsevimab will also be assessed and 
measured by the summary of clinical laboratory measurements (ie, serum chemistry, 
hematology, and urinalysis) through 150 days postdose.
4.8.5
Analysis of Antidrug Antibody
The incidence of ADA to nirsevimab will be assessed and summarized by number and 
percentage of subjects who are ADA positive. The impact of ADA on PK, and association 
with TEAEs and TESAEs will be assessed, if data permit.
4.8.6
Interim Analysis
No interim analysis is planned.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
The term AE is used to include both serious and nonserious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no investigational product has been administered.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 

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event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:
#
Results in death
#
Is immediately life-threatening
#
Requires inpatient hospitalization or prolongation of existing hospitalization
#
Results in persistent or significant disability/incapacity
#
Is a congenital anomaly/birth defect in offspring of the subject
#
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
Investigator to the Sponsor. An AESI may be serious or nonserious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
5.3.1
Anaphylaxis and Other Serious Hypersensitivity Reactions Including 
Immune Complex Disease
Administration of polyclonal immunoglobulin preparations and mAbs has been associated 
with anaphylaxis and other serious hypersensitivity reactions, including immune complex 
disease, that occurs during or after dosing. Anaphylaxis is a rare event, usually occurring after 
subsequent exposure to antigen, and it is most commonly accompanied by severe systemic 
skin and/or mucosal reactions. It is potentially a fatal, systemic allergic reaction that is distinct 
from simple allergic reactions (eg, rash, pruritus) because of the simultaneous involvement of 
several organ systems (Sampson et al 2006). A full definition of anaphylaxis is provided in 
Appendix C. See Section 5.5 for recording AEs. A hypersensitivity reaction is defined as an 
acute onset of an illness with involvement of the skin, mucosal tissue, or both during or after 
administration of investigational product (but does not meet the definition of anaphylaxis) 
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5.3.2
Thrombocytopenia
Thrombocytopenia is a disorder in which there is an abnormally low platelet count; a normal 
platelet count ranges from 150,000 to 450,000 platelets per ^L. The 3 major causes of low 
platelet counts include: 1) insufficient platelet synthesis in the bone marrow; 2) increased 
breakdown of platelets in the bloodstream; and 3) increased breakdown of platelets in the 
spleen or liver. General symptoms of thrombocytopenia include bleeding in the mouth and 
gums, bruising, nosebleeds, and petechiae (pinpoint red spots/rash). Severe bleeding is the 
major complication, which may occur in the brain or gastrointestinal tract. Drug-induced 
thrombocytopenia is a reversible form of thrombocytopenia that should be suspected in a 
subject who presents with new onset thrombocytopenia or recurrent episodes of acute 
thrombocytopenia, without an obvious alternative etiology. It is commonly induced by 
drug-dependent antibodies that cause platelet destruction or clearance by the 
reticuloendothelial system (drug-induced immune thrombocytopenia), and less commonly by 
drug-induced bone marrow suppression or autoimmune thrombocytopenia that is initiated by 
exposure to the offending drug but persists in its absence. The initial approach to the subject 
with suspected drug-induced thrombocytopenia involves confirming thrombocytopenia, 
establishing a temporal relationship to a drug, and eliminating other causes of 
thrombocytopenia. The diagnosis is made clinically by documenting prompt resolution of 
thrombocytopenia after discontinuation of the suspected drug (typically within 1 week). Most 
subjects with drug-induced thrombocytopenia require no specific treatment, as their platelet 
counts will recover promptly following withdrawal of the causative agent. See Section 5.5 for 
recording AEs.
5.4
Definition of New Onset Chronic Disease
An NOCD is a newly diagnosed medical condition that is of a chronic, ongoing nature. It is 
observed after receiving the investigational product and is assessed by the Investigator as 
medically significant. Examples of NOCDs include, but are not limited to diabetes, 
autoimmune disease (eg, lupus, rheumatoid arthritis), and neurological disease (eg, epilepsy). 
Events that would not be considered as NOCDs are mild eczema, diagnosis of a congenital 
anomaly present at study entry, or acute illness (eg, upper respiratory infection, otitis media, 
bronchitis). See Section 5.5 for recording AEs.
5.5
Recording of Adverse Events
AEs, including SAEs, AESIs, and NOCDs, will be recorded on the eCRF using a recognized 
medical term or diagnosis that accurately reflects the event. These events will be assessed by 
the Investigator for severity, relationship to the investigational product and study procedure(s), 
possible etiologies, and whether the event meets criteria of an SAE (see Section 5.2 and 5.6), 
or is an AESI or NOCD (see Section 5.3, 5.4 and 5.7) and therefore requires immediate 
notification to the Sponsor. See Appendix B for guidelines for assessment of severity and 
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If an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the AE form in the eCRF as an SAE.
5.5.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from the time of signature of informed consent through 
Day 151.
AESIs and NOCDs will be collected from the time of dosing through Day 151.
5.5.2
Follow-up of Unresolved Adverse Events
Any AE that is unresolved at the subject’s last visit will be followed up by the Investigator for 
as long as medically indicated, but without further recording in the eCRF. The Sponsor retains 
the right to request additional information for any subject with ongoing AE(s)/SAE(s) at the 
end of the study, if judged necessary.
5.5.3
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
(“Have you had any health problems since the previous visit/since you were last asked?”) 
from study site staff or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
5.5.4
Adverse Events Based on Examination and Tests
Abnormal results of examination and tests at screening (e.g. hematology, clinical chemistry, 
urinalysis, ECG, physical examination, vital signs, etc.) are regarded as existing conditions 
before ICF and will not be recorded as AE. Relevant clinically significant abnormality during
screening can be recorded as medical history according to investigator’s medical judgement.
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the clinical study report. An abnormal laboratory finding that requires medical intervention by 
the Investigator, or a finding judged by the Investigator as medically significant should be 
reported as an AE. If clinical sequelae are associated with a laboratory abnormality, the 
diagnosis or medical condition should be reported (eg, renal failure, hematuria) not the 
laboratory abnormality (eg, elevated creatinine, urine red blood cell increased).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia vs low hemoglobin value). In the 

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absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AEs.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
5.5.5
Potential Hy’s Law and Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT W 3 × ULN together with total bilirubin (TBL) W 2 × ULN 
may need to be reported as SAEs. Please refer to Appendix D for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s Law.
5.6
Reporting of Serious Adverse Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRBs/IECs, and Investigators.
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure and/or will notify the IRB/IEC, if appropriate 
according to local requirements.
All SAEs must be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel must 
inform the appropriate Sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event.
The designated study representative works with the Investigator to ensure that all the 
necessary information is provided to the Sponsor’s Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.

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For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform Sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated Sponsor 
representative(s).
If the EDC system is not available, then the Investigator or other study site personnel reports 
an SAE to the appropriate Sponsor representative by telephone. The Sponsor representative 
will advise the Investigator/study site personnel how to proceed.
5.7
Other Events Requiring Immediate Reporting
5.7.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of the 
assigned dosage in the study, unless otherwise specified in this protocol.
#
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
#
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on a Sponsor investigational product occurs during the study, then the 
Investigator or other site personnel should inform appropriate Sponsor representatives 
immediately, but no later than 24 hours after becoming aware of the event.
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor’s Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.6. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days.
5.7.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the Sponsor except for:
#
A pregnancy that is discovered before the study subject has received any investigational 
product.

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5.7.2.1
Maternal Exposure
If a subject is pregnant, investigational product should not be administered.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs during the course of the study, then the Investigator or other site 
personnel will inform the appropriate Sponsor representatives within 1 day, ie, immediately 
but no later than 24 hours after becoming aware of the event.
The designated study representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor’s Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 5.6) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
5.7.2.2
Paternal Exposure
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of dosing until 150 days after the last 
dose and as indicated by previous studies (preclinical and clinical) should, if possible, be 
followed up and documented.
5.7.3
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for a Sponsor investigational product that either causes harm to the 
subject or has the potential to cause harm to the subject.
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error:
#
Occurred

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#
Was identified and intercepted before the subject received the drug
#
Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
#
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject
#
Drug not administered as indicated, eg, wrong route or wrong site of administration
#
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature
#
Wrong subject received the medication (excluding IWRS errors)
#
Wrong drug administered to subject (excluding IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
#
Errors related to or resulting from IWRS including those which lead to one of the above 
listed events that would otherwise have been a medication error
#
Accidental overdose (will be captured as an overdose)
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate Sponsor representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is completed within 1 or 5 calendar days if there is an SAE associated with the 
medication error (see Section 5.6) and within 30 days for all other medication errors. 
Medication errors should be reported using a Medication Error Report Form.
5.7.4
Adverse Events of Special Interest
5.7.4.1
Anaphylaxis and Other Serious Hypersensitivity Reactions Including 
Immune Complex Disease
Events of hypersensitivity, including anaphylaxis (as defined in Appendix C), require that the 
Investigator or other site personnel inform appropriate Sponsor study representatives 
immediately, or no later than 24 hours of when he or she becomes aware of the event. The 
designated Sponsor study representative works with the Investigator to ensure that all relevant 
information is provided and entered in EDC. If the event is considered serious it must be 
reported as an SAE (see Section 5.6).

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Signs of hypersensitivity include urticaria, pruritus, angioedema, skin rash, difficulty 
breathing, and wheezing. Subjects will be provided a card with this information to aid in 
prompt identification and reporting of these signs. Subjects will be instructed to immediately 
report the occurrence of any of these findings to the site Investigator who should then report 
the events to appropriate Sponsor study representatives immediately, or no later than 
24 hours of when he or she becomes aware of the event. Events of immune complex disease 
(as defined in Section 5.3.1) require that the Investigator or other site personnel inform 
appropriate Sponsor study representatives immediately, or no later than 24 hours of when he 
or she becomes aware of the event. The designated Sponsor study representative works with 
the Investigator to ensure that all relevant information is provided and entered into EDC. If the 
event is considered serious it must be reported as an SAE (see Section 5.6).
5.7.4.2
Thrombocytopenia
Events of thrombocytopenia (platelet count < 120,000 per cL) require that the Investigator or 
other site personnel inform appropriate Sponsor study representatives immediately, or no 
later than 24 hours of when he or she becomes aware of the event. The designated Sponsor 
study representative works with the Investigator to ensure that all relevant information is 
provided and entered into EDC. If the event is considered serious it must be reported as an 
SAE (see Section 5.6).
5.7.5
New Onset Chronic Disease
If a case of NOCD occurs in the course of this study, the Investigator or other site personnel 
must inform appropriate Sponsor representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. The designated Sponsor study representative works with 
the Investigator to ensure that all relevant information is provided and entered into EDC. If the 
event is considered serious it must be reported as an SAE (see Section 5.6).
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a Sponsor representative will review and 
discuss the requirements of the protocol and related documents with the investigational staff 
and also train them in any study-specific procedures and system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).

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6.2
Monitoring of the Study
During the study, a Sponsor representative will have regular contacts with the study site, 
including visits to:
#
Provide information and support to the Investigator(s)
#
Confirm that facilities remain acceptable
#
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that investigational product accountability 
checks are being performed
#
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts)
#
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The Sponsor representative will be available between visits if the Investigator(s) or other staff 
at the site needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at the site should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail.
Agreements between the Sponsor and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment.

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Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Sections 4.1.5 and 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study.
6.4
Data Management
Data management will be performed by the Sponsor’s Data Management staff or other party
according to the Data Management Plan.
An EDC system will be used for data collection and query handling. The Investigator will 
ensure that data are recorded in the eCRFs as specified in the study protocol and in accordance 
with the eCRF instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Investigator Coverage
Each subject will be provided with contact information for the Investigator. When a subject 
visits a medical facility and requires any medical care (medication or treatment), the treating 
physician or health care provider should contact the Principal Investigator (or designee 
Investigator who has knowledge of the investigational product and the clinical study protocol) 
before any treatment is given to the subject.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the study, eg, demographic 
information, physical or mental health condition, laboratory test results, etc will only be 
collected with the subject’s informed consent. The Informed Consent Form will incorporate 
(or, in some cases, be accompanied by a separate document incorporating) wording that 
describes how subject data will be collected, used, and distributed in compliance with relevant 
data protection and privacy legislation.

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7.2
Ethics and Regulatory Review
The IRB/IEC responsible for the site must review and approve the final study protocol, 
including the final version of the Informed Consent Form and any other written information 
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising 
used to recruit subjects for the study. The Investigator is responsible for submitting these 
documents to the applicable IRB/IEC and distributing them to the study site staff.
The opinion of the IRB/IEC must be given in writing. The Investigator must provide a copy of 
the written approval to the Sponsor before enrollment of any subject into the study.
The Sponsor should approve any substantive modifications to the Informed Consent Form that 
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.
Before the study is initiated, the Sponsor will ensure that the national regulatory authority in 
China has been notified and their approval has been obtained, as required. The Sponsor will 
provide safety updates/reports according to local requirements, including SUSARs where 
relevant, to regulatory authorities, IRB/IEC, and Principal Investigators.
The Investigator is responsible for providing reports of any serious and unexpected adverse 
drug reactions from any other study conducted with the investigational product to the 
IRB/IEC. The Sponsor will provide this information to the Investigator so that he/she can 
meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. The Sponsor will develop a core 
informed consent form for use by all Investigators in the clinical study. The Sponsor must 
approve any modifications to the informed consent form that are needed to meet local 
requirements.
The Principal Investigator(s) at the site will:
#
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
#
Ensure each subject is notified that they are free to discontinue from the study at any time
#
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
#
Ensure each subject provides signed and dated informed consent before conducting any 
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#
Ensure the original, signed Informed Consent Form(s) is/are stored in the Investigator’s 
Study File
#
Ensure a copy of the signed Informed Consent Form is given to the subject
#
Ensure that any reimbursement for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an IRB/IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Investigators and 
the Sponsor. Any changes must be documented in a study protocol amendment.
For a substantial change to the protocol, the Sponsor will distribute amended versions of the 
protocol to the Principal Investigator(s). Before implementation, amended protocols must be 
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the informed consent form, 
advertising, and any other written information and/or materials resulting from the change to 
the protocol.
Any non-substantial changes will be communicated to or approved by the IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of the Sponsor, a regulatory authority, or an IRB/IEC may perform 
audits or inspections at the center, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements. The Investigator will contact the Sponsor immediately 
if contacted by a regulatory agency about an inspection at the site.

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8
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Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 
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Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
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regional, and national disease burden estimates of acute lower respiratory infections due to 
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direct medical cost of respiratory syncytial virus infection in children hospitalized in Suzhou, 
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Zhang Y, Yuan L, Zhang Y, Zhang X, Zheng M, Kyaw MH. Burden of respiratory syncytial 
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Appendix A
Contraception Guidance
For females of childbearing potential:
#
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or those who are not postmenopausal (defined as 12 months with no 
menses without an alternative medical cause).
#
A highly effective method of contraception is defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly. The acceptable 
methods of contraception are described in Table A1.
#
Female subjects must refrain from egg cell donation and breastfeeding while on study and 
for 150 days after the final dose of investigational product.
Table A1
Highly Effective Methods of Contraception 
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system (UIS)a
•
Bilateral tubal occlusion
•
Vasectomized partnerb
•
Sexual abstinencec
Combined (estrogen and progestogen containing 
hormonal contraception)

Oral (combined pill)

Injectable

Transdermal (patch)
Progestogen-only hormonal contraception associated 
with inhibition of ovulationd

Injectable

Implantable

Intravaginal
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method).

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Appendix B
Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from adverse event 
(AE) as it occurred, or it is suspected that use or continued use of the product would result in 
the subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:
#
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment
#
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
#
Intensive treatment in an emergency room or at home for allergic bronchospasm
#
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization
#
Development of drug dependency or drug abuse
Assessment of Severity
Assessment of severity is one of the responsibilities of the Investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the Investigator based upon 
medical judgment and the grading scales in NCI CTCAE version 5.0 for all events with an 

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assigned CTCAE grading. For those events without assigned CTCAE grades, the following 
general guideline from CTCAE should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living. 
Instrumental activities of daily living refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing 
money, etc.
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; 
limiting self care activities of daily living. Self care activities of daily 
living refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
A semi-colon indicates ‘or’ within the description of the grade.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
A guide to Interpreting the Causality Question
The Investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product.
#
Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?
#
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 

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or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties?
#
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?
#
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.
#
Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? The Sponsor would not normally recommend or 
support a re-challenge.
#
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?
In difficult cases, other factors could be considered such as:
#
Is this a recognized feature of overdose of the investigational product?
#
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
Relationship to Protocol Procedures
The Investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by Investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.

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Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).

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Appendix C
National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Disease (NAID) and Food Allergy and 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in 
onset and may cause death. They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories).
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient/subject (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient/subject (minutes to several 
hours):
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline

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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This appendix describes the process to be followed to identify and appropriately report cases 
of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of potential Hy’s Law and 
Hy’s Law events; this includes samples taken at scheduled study visits and other visits 
including all local laboratory evaluations even if collected outside of the study visits.
The Investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible potential Hy’s Law events.
The Investigator participates, together with the Sponsor’s clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury caused by the 
investigational product.
The Investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting AEs and serious adverse events (SAEs) according to the outcome of 
the review and assessment in line with standard safety reporting processes.
D 2
Definitions
D 2.1
Potential Hy’s Law
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) W 3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) W 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in alkaline 
phosphatase (ALP).
D 2.2
Hy’s Law
AST or ALT W 3 × ULN together with TBL W 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
ALP indicating cholestasis, viral hepatitis, or another drug.

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For potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:
#
ALT W 3 × ULN
#
AST W 3 × ULN
#
TBL W 2 × ULN
Local laboratories being used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
#
Notify the Sponsor study representative
#
Determine whether the subject meets PHL criteria (see Section D 3 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
#
Promptly enter the laboratory data into the laboratory eCRF
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet potential Hy’s Law criteria the Investigator will:
#
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol.
D 4.2
Potential Hy’s Law Criteria Met
If the subject does meet potential Hy’s Law criteria the Investigator will:
#
Notify the Sponsor study representative who will then inform the study team
#
Within 1 day of potential Hy’s Law criteria being met, the Investigator will report the 
case as an SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and 
causality assessment ‘yes/related’ according to clinical study protocol process for SAE 
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The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and the 
continuous review of data. Subsequent to this contact, the Investigator will:
#
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Complete follow-up SAE Form as required.
#
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.
#
Complete the relevant CRF Modules as information becomes available.
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law 
criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician will contact the Investigator to review available data and agree on whether there is 
an alternative explanation for meeting potential Hy’s Law criteria other than drug-induced 
liver injury (DILI) caused by the investigational product. This will ensure timely analysis and 
reporting to health authorities per local requirements from the date potential Hy’s Law criteria 
were met. The Study Physician and Global Safety Physician will also be involved in this 
review together with other subject matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:
#
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
#
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly
and follow the Sponsor’s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:
#
Send the updated SAE (report term ‘Hy’s Law’) according to the Sponsor’s standard 
processes.

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

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
As there is no alternative explanation for the Hy’s Law case, a causality assessment 
of ‘related’ should be assigned
If, there is an unavoidable delay of 15 calendar days in obtaining the information necessary to 
assess whether or not the case meets the criteria for Hy’s Law, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made:
#
Provide any further update to the previously submitted SAE of Potential Hy’s Law (report 
term now ‘Hy’s Law case’), ensuring causality assessment is related to the investigational 
product and seriousness criteria are medically important, according to the clinical study 
protocol process for SAE reporting
#
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are met. Update the previously submitted potential Hy’s Law 
SAE report following clinical study protocol process for SAE reporting, according to the 
outcome of the review and amend the reported term if an alternative explanation for the 
liver biochemistry elevations is determined.
D 6
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets potential Hy’s Law criteria on investigational 
product and has already met potential Hy’s Law criteria at a previous on investigational 
product visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
potential Hy’s Law is based on the nature of the alternative cause identified for the previous 
occurrence.
The Investigator should determine the cause for the previous occurrence of potential Hy’s 
Law criteria being met and answer the following question:
#
Was the alternative cause for the previous occurrence of potential Hy’s Law criteria being 
met found to be the disease under study eg, chronic or progressing malignant disease, 
severe infection, or liver disease?
If No: follow the process described in Section D 4.2 for reporting potential Hy’s Law as an 
SAE.
If Yes: Determine if there has been a significant change in the subject’s condition compared 
with when potential Hy’s Law criteria were previously met:
#
If there is no significant change no action is required

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#
If there is a significant change, follow the process described in Section D 4.2 for reporting 
potential Hy’s Law as an SAE
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
D 7
Laboratory Tests
To evaluate the underlying etiology of potential Hy’s Law cases, relevant laboratory tests may 
be performed as clinically indicated.
D 8
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: premarketing 
clinical evaluation’

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