Clinical trial NCT04484935
Conditions: RSV Infection
Keywords: LRTI by RSV infection
Sponsor: AstraZeneca
Start date: 2020-08-19; Completion date: 2023-02-17
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study D5290C00008 is a Phase 2, open-label, uncontrolled, single-dose study to evaluate the safety and tolerability, pharmacokinetic(s) (PK), occurrence of antidrug antibody (ADA), and efficacy of nirsevimab in immunocompromised children who are ≤ 24 months of age at the time of dose administration. Approximately 100 subjects will be enrolled. Subjects will be followed for approximately 1 year after dose administration.

Detailed description:
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) among infants and young children, resulting in annual epidemics in Japan. Children with congenital or acquired immunodeficiencies, transplant recipients, and those receiving immunosuppressive therapy are at increased risk for severe RSV-associated LRTI with prolonged viral shedding and higher viral loads, resulting in prolonged hospitalizations, admissions to the intensive care unit (ICU), and the need for mechanical ventilation. Palivizumab (Synagis®) is the only approved agent for RSV prophylaxis, and its half-life (t1/2) is approximately 1 month, infants and young children need to receive monthly intramuscular doses of palivizumab throughout the RSV season to maintain protection. This constitutes a significant burden on healthcare providers as well as the infants/children and their families.

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.

Arms: arm 1: 1st RSV season: 50mg nirsevimab

1. st RSV season: 100mg nirsevimab
2. nd RSV season: 200mg nirsevimab
Interventions: intervention 1: Nirsevimab
Intervention descriptions: intervention 1: Single fixed IM dose of nirsevimab 50 mg if body weight \< 5 kg or 100 mg if body weight ≥ 5 kg, and subjects entering their second RSV season will receive a single fixed IM dose of nirsevimab 200 mg

Protocol documents:
Prot_000.pdf: 
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A Phase 2, Open-label, Uncontrolled, Single-dose Study to 
Evaluate the Safety and Tolerability, Pharmacokinetics, and 
Occurrence of Antidrug Antibody for Nirsevimab in 
Immunocompromised Children ≤24 Months of Age
Sponsor Protocol Number:
D5290C00008
Investigational Product:
Nirsevimab (MEDI8897)
Sponsor:
AstraZeneca AB, SE-151 85 Södertälje, Sweden
Medical Monitor:
AstraZeneca, BioPharmaceuticals R&D
Contract Research Organization: IQVIA
Protocol History, Date:
Original Protocol, 27 Jan2020
Amendment 1, 24Apr2020
Amendment 2, 17Dec2020
Amendment 3, 23June2021
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from AstraZeneca.
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3 (CSP for global use)
23 June 2021
Amendment 2
17 Dec 2020
Amendment 1
24 April 2020
Original Protocol
27 Jan 2020
Descriptions of Amendments 1 and 2 are included in Section 9.
Protocol Amendment 3 (dated 23 June 2021)
The principal reason for this amendment is to revise the protocol to be globally applicable, in 
line with the decision to expand the study to include countries other than Japan, where the 
study is currently ongoing. At the time of the original protocol and Amendments 1 and 2, the 
study was planned to be conducted in Japan only. By expanding the study to additional 
countries and increasing the sample size, immunocompromised children with different 
underlying causes from different countries can be included in the study, supporting the safety 
evaluation in a diverse population. Additionally the increase in sample size aligns with the 
design and number of participants pre-determined for other high risk populations under study 
within the program.
Section(s)
Description of Change
Brief Rationale
Title Page
Study title revised to not include 
‘Japanese’
For global applicability.
Title Page
Name of medical monitor changed.
Assignment of new medical monitor.
Title page
1 Introduction
4.5 Investigational Product
Sponsor name changed from 
MedImmune to AstraZeneca
To clarify that MedImmune is a fully 
owned subsidiary of AstraZeneca.
Synopsis 
2.2 Secondary Objectives
3.2.2 Rationale for 
Endpoints
4.8.4 Analysis of 
Pharmacokinetics
Pharmacokinetic endpoints revised to 
include only concentration of 
nirsevimab.
The sparse PK sampling in this study 
does not allow for accurate non-
compartmental analysis.
Synopsis
2.3 Exploratory Objectives
4.3.4 Healthcare Resource 
Utilisation
4.8.7.4 Healthcare 
Resource Utilisation
Duration of use for prescription and 
OTC medications has been deleted 
from the description of the exploratory 
objective related to healthcare resource 
utilization.
To be consistent with other 
nirsevimab studies on data analysis.
Synopsis
3.1 Description of Study
Additional countries added to study 
description.
Additional countries added to support 
global recruitment and data 
collection in this 


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Section(s)
Description of Change
Brief Rationale
immunocompromised population 
with varying underlying causes of 
this condition and to meet the 
increase in sample size.
Synopsis
3.1 Description of Study
4.1.1. Number of Subjects
4.8.2 Sample Size
Increased sample size from 30 to 
approximately 100 subjects.
The revision to 100 subjects allows 
for the study of 
immunocompromised children and 
the various causes for this condition 
globally. Further, the data from this 
study will support the evaluation of 
safety in a diverse population, which 
could potentially facilitate the 
examination of subpopulations.
Synopsis 
4.8.1 General 
Considerations
4.8.8 Interim Analysis
Addition of interim analysis.
An interim analysis will be 
conducted to allow for an early
assessment of PK and safety in this 
study population.
Synopsis
4.8.1 General 
Considerations
Text added that data will be 
summarized for the overall study 
population, as well as for Japan only.
To include summaries as per original 
protocol (Japan only) in addition to 
summaries for the global study 
population. 
4.2.2 Treatment and 
Follow-up Period
Previous 4.3.7 Clinical 
Laboratory Tests
Clinical chemistry and hematology
removed from visit schedule (Section 
4.2.2).
Previous Section 4.3.7 removed (not 
applicable).
In order to minimize the volume of 
blood collected, and to harmonize 
with other nirsevimab studies in 
children with RSV, clinical 
laboratory data will not be collected 
outside of Japan. 
Considering that nirsevimab is a 
monoclonal antibody with no 
endogenous target, available data 
from previous nirsevimab studies, 
and experience from other drugs
(palivizumab and motavizumab) in 
the same pharmacological class, the 
risk of observing laboratory 
abnormalities associated with 
nirsevimab is considered to be very 
low, and routine monitoring of 
clinical laboratory measurements is 
not deemed necessary.
4.2.2 Treatment and 
Follow-up Periods
Study Visit 3 replaced with telephone 
call, consecutive visits renumbered 
accordingly.
To reduce the number of visits at the 
clinic and to harmonize with other 
nirsevimab studies in children with 
RSV.
4.3.6 Estimate of Volume 
of Blood to be Collected
Estimated volume of blood to be 
collected has been revised.
Revised in line with no clinical 
laboratory data collected outside of 
Japan. 
4.5.1.4 Reporting Product 
Complaints
Contact details for report complaints 
updated.
Mail address has changed.
Previous 4.7.3 Guidance 
for Additional Palivizumab 
Section deleted.
Section is applicable to Japan only.


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Section(s)
Description of Change
Brief Rationale
Administration after 
Day 151
New section 
4.8.9 Data Monitoring 
Committee
New section describing an independent 
data monitoring committee, which will 
review safety data.
To provide additional safety 
oversight by an independent 
monitoring committee for this global 
study.
5.3.1.1 Immediate 
Hypersensitivity, Including 
Anaphylaxis 
5.7.3.1 Immediate 
Hypersensitivity, Including 
Anaphylaxis
Description of hypersensitivity revised 
to be more specific.
To provide more specific information 
to Investigators. 
5.7.3.3 Thrombocytopenia
Revised text regarding reporting of 
thrombocytopenia.
To provide clearer information to 
Investigators for reporting events of 
unexpected thrombocytopenia when 
considered by the Investigator to be 
clinically relevant with unknown 
etiology.
Previous 5.7.5 Defect 
Reporting
Section deleted.
Section applicable to Japan only.
7.1 Ethical Conduct of the 
Study
Description of Japan-specific 
regulations removed.
For global applicability.
Appendix C
Revised to align with no collection of 
laboratory data.
For global applicability.
Throughout
Minor editorial revisions.
Minor, therefore, were not 
summarized.
RSV = respiratory syncytial virus; OTC = over the counter; PK = pharmacokinetic.


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PROTOCOL SYNOPSIS
TITLE
A Phase 2, Open-label, Uncontrolled, Single-dose Study to Evaluate the Safety and Tolerability, 
Pharmacokinetics, and Occurrence of Antidrug Antibody for Nirsevimab in Immunocompromised Children 
≤24 Months of Age
OBJECTIVES AND ASSOCIATED ENDPOINTS
Type
Objective
Endpoint
Primary
Safety
To evaluate the safety and tolerability of 
nirsevimab when administered to 
immunocompromised children 
≤24 months of age
All treatment-emergent adverse events 
(TEAEs), treatment emergent serious 
adverse events (TESAEs), adverse events 
of special interest (AESIs), and new onset 
chronic diseases (NOCDs)
Secondary
PK
To evaluate the PK of nirsevimab
Summary of nirsevimab serum 
concentrations
Antidrug 
antibody (ADA)
To evaluate ADA responses to 
nirsevimab in serum
Incidence of ADA to nirsevimab in serum
Efficacy
To assess the efficacy of nirsevimab 
when administered as a single 
intramuscular (IM) dose to infants ≤ 24 
months of age
Incidence of medically attended lower 
respiratory tract infection (LRTI; inpatient 
and outpatient) and hospitalizations due to 
reverse transcriptase-polymerase chain 
reaction (RT-PCR)-confirmed respiratory 
syncytial virus (RSV) through 150 days 
after administration of nirsevimab
Exploratory
Healthcare 
resource 
utilization (HRU)
To assess HRU for nirsevimab recipients
Magnitude of HRU (eg, number of 
admissions to hospitals and intensive care 
units [ICUs] and duration of stay; number 
of subjects who require respiratory support 
and supplemental oxygen and duration of 
use; number and type of outpatient visits, 
eg, emergency room [ER], urgent care, 
outpatient clinic; and number of 
prescription and over-the-counter [OTC] 
medications) for nirsevimab recipients
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STUDY DESIGN
Study D5290C00008 is a Phase 2, open-label, uncontrolled, single-dose study, planned to be conducted in 
South Africa, the United States, and the European Union, in addition to Japan, where the study in currently 
ongoing, to evaluate the safety and tolerability, PK, occurrence of ADA, and efficacy of nirsevimab in 
immunocompromised children who are ≤24 months of age at the time of dose administration. Approximately 
100 subjects will be enrolled. Subjects will be followed for approximately 1 year after dose administration.
TARGET SUBJECT POPULATION
Neonates, infants, and young children ≤24 months of age at the time of dose administration, with 
immunodeficiency.
TREATMENT GROUPS AND REGIMENS
Subjects entering their first RSV season will receive a single fixed IM dose of nirsevimab 50 mg if body 
weight < 5 kg or 100 mg if body weight ≥5 kg (n = ~ 50), and subjects entering their second RSV season will 
receive a single fixed IM dose of nirsevimab 200 mg (n = ~ 50).
STATISTICAL METHODS 
Sample Size
A total of approximately 100 subjects are planned to receive a single IM dose of nirsevimab to evaluate the 
safety, PK, ADA, and efficacy, which will be assessed descriptively. The originally proposed sample size of 
30 was based on a similarly designed palivizumab study in a similar population, and it is expected to be 
sufficient in establishing a PK profile that allows extrapolation of efficacy and safety data from the Phase 2b 
(D5290C00003) and Phase 3 (
 studies in healthy preterm and term infants to the target 
immunocompromised population. The updated sample size of 100 allows for the collection of data from a 
larger, global cohort of immunocompromised children with different underlying conditions.
 
 
Statistical Analyses
There are 2 planned analyses for this study: an interim analysis and a final analysis. The interim analysis will 
be conducted when subjects enrolled globally by end of 2021 have been followed through Day 151. For the 
interim analysis, all safety, PK, ADA and efficacy data available at the time of the data cut-off for subjects 
enrolled by end of 2021 will be analyzed. A minimum of approximately of 30 subjects is expected to be 
sufficient in establishing a PK profile for efficacy and safety extrapolation at the time of the interim analysis. 
The final analysis will be conducted after all subjects have completed the last visit of the study (ie, Day 361). 
Data will be summarized for the overall study population, as well as for Japan only.
Safety Analyses
Adverse events will be graded according to the current version of the National Cancer Institute Common 
Terminology Criteria for Adverse Events where applicable for pediatric assessments. AEs will be coded 
according to the Medical Dictionary for Regulatory Activities, and the type, incidence, severity, and 
relationship to investigational product will be summarized. Other safety assessments will include the 
occurrence of AESIs defined as AEs of immediate hypersensitivity (including anaphylaxis), 
thrombocytopenia, and immune complex disease (eg, vasculitis, endocarditis, neuritis, glomerulonephritis) 
following investigational product administration, and the occurrence of NOCDs following investigational 
product administration.
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Pharmacokinetic Analyses
Serum concentrations of nirsevimab at selected time points will be evaluated to confirm that adequate 
exposures for protection from RSV LRTI are maintained for at least 5 months after dosing. Nirsevimab serum 
concentration data will be presented in descriptive statistics. 
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 the association with TEAEs and TESAEs, will be 
assessed, if data permit.
Efficacy Analyses
The incidence of medically attended RSV LRTI (inpatient and outpatient) through 150 days post dose, based 
on RSV test results (performed centrally using RT-PCR) and objective protocol-defined LRTI criteria, will be 
summarized for all dosed subjects. For subjects with multiple medically attended RSV LRTI events, only the 
first occurrence will be used in the analysis.
The incidence of RSV hospitalization through 150 days after dose will also be summarized. Additional 
analyses will include summarizing RSV positive LRTI endpoints using results from either the central or local 
laboratory.
Additional Analyses
 
Healthcare Resource Utilization
The magnitude of HRU (eg, number of admissions to hospitals and ICUs and duration of stay; number of 
subjects who require respiratory support and supplemental oxygen and the duration of use; number and types 
of outpatient visits, eg, ER, urgent care, outpatient clinic; and number of prescriptions and OTC medications 
use) will be summarized.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 2
PROTOCOL SYNOPSIS...................................................................................................... 5
LIST OF ABBREVIATIONS ............................................................................................. 12
1
INTRODUCTION............................................................................................ 14
1.1
Disease Background ......................................................................................... 14
1.2
Nirsevimab Background ................................................................................... 15
1.3
Summary of Nonclinical Experience................................................................. 15
1.4
Summary of Clinical Experience....................................................................... 16
1.4.1
Phase 1a Study D5290C00001 .......................................................................... 17
1.4.2
Phase 1b/2a Study D5290C00002 ..................................................................... 18
1.4.3
Phase 2b Study D5290C00003.......................................................................... 19
1.5
Rationale for Conducting the Study .................................................................. 21
1.6
Benefit-Risk and Ethical Assessment................................................................ 22
2
OBJECTIVES AND ENDPOINTS................................................................... 22
2.1
Primary Objective and Associated Endpoint ..................................................... 22
2.2
Secondary Objectives and Associated Endpoints............................................... 23
2.3
Exploratory Objectives and Associated Endpoints ............................................ 23
3
STUDY DESIGN ............................................................................................. 24
3.1
Description of the Study ................................................................................... 24
3.1.1
Overview.......................................................................................................... 24
3.1.2
Treatment Regimen........................................................................................... 26
3.2
Rationale for Dose, Population, and Endpoints ................................................. 27
3.2.1
Dose Rationale.................................................................................................. 27
3.2.2
Rationale for Study Population ......................................................................... 27
3.2.3
Rationale for Endpoints .................................................................................... 28
4
MATERIALS AND METHODS ...................................................................... 29
4.1
Subjects ............................................................................................................ 29
4.1.1
Number of Subjects .......................................................................................... 29
4.1.2
Inclusion Criteria .............................................................................................. 29
4.1.3
Exclusion Criteria ............................................................................................. 30
4.1.4
Subject Enrollment and Randomization ............................................................ 30
4.1.5
Withdrawal from the Study............................................................................... 31
4.1.6
Discontinuation of Investigational Product........................................................ 31
4.1.7
Replacement of Subjects................................................................................... 31
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples................... 31
4.2
Schedule of Study Procedures........................................................................... 32
4.2.1
Enrollment/Screening Period ............................................................................ 32
4.2.2
Treatment and Follow-up Periods ..................................................................... 32
4.3
Description of Study Procedures....................................................................... 35




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5.2
Definition of Serious Adverse Events ............................................................... 48
5.3
Definition of Adverse Events of Special Interest............................................... 49
5.3.1
Serious Hypersensitivity (Including Anaphylaxis and Immune Complex 
Disease)............................................................................................................ 49
5.3.1.1
Immediate Hypersensitivity, Including Anaphylaxis ......................................... 49
5.3.1.2
Immune Complex Disease ................................................................................ 49
5.3.2
Thrombocytopenia............................................................................................ 50
5.4
Definition of New Onset Chronic Disease......................................................... 50
5.5
Recording of Adverse Events............................................................................ 50
5.5.1
Time Period for Collection of Adverse Events .................................................. 51
5.5.2
Follow-up of Unresolved Adverse Events......................................................... 51
5.5.3
Deaths .............................................................................................................. 51
5.5.4
Potential Hy’s Law and Hy’s Law..................................................................... 51
5.6
Reporting of Serious Adverse Events................................................................ 51
5.7
Other Events Requiring Immediate Reporting................................................... 53
5.7.1
Overdose .......................................................................................................... 53
5.7.2
Medication Error............................................................................................... 53
5.7.3
Adverse Events of Special Interest.................................................................... 54
5.7.3.1
Immediate Hypersensitivity, Including Anaphylaxis ......................................... 54
5.7.3.2
Immune Complex Disease ................................................................................ 54
5.7.3.3
Thrombocytopenia............................................................................................ 55
5.7.4
New Onset Chronic Disease.............................................................................. 55
6
STUDY AND DATA MANAGEMENT........................................................... 55
6.1
Training of Study Site Personnel....................................................................... 55
6.2
Monitoring of the Study.................................................................................... 55
6.2.1
Source Data ...................................................................................................... 56
6.2.2
Study Agreements............................................................................................. 56
6.2.3
Archiving of Study Documents......................................................................... 57
6.3
Study Timetable and End of Study.................................................................... 57
6.4
Data Management............................................................................................. 57
6.5
Medical Monitor Coverage ............................................................................... 58
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 58
7.1
Ethical Conduct of the Study............................................................................. 58
7.2
Subject Data Protection..................................................................................... 58
7.3
Ethics and Regulatory Review .......................................................................... 58
7.4
Informed Consent ............................................................................................. 59
7.5
Changes to the Protocol and Informed Consent Form........................................ 60
7.6
Audits and Inspections...................................................................................... 60
8
REFERENCES................................................................................................. 61
9
CHANGES TO THE PROTOCOL ................................................................... 64
9.1
Protocol Amendment 1 dated 24 April 2020 ..................................................... 64


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9.2
Protocol Amendment 2 dated 17 Dec 2020 ....................................................... 64
LIST OF TABLES
Table 1
Primary Objective and Associated Endpoints........................................... 23
Table 2
Secondary Objectives and Associated Endpoints...................................... 23
Table 3
Exploratory Objectives and Associated Endpoints ................................... 23
Table 4
Schedule of Screening Procedures ........................................................... 32
Table 5
Schedule of Treatment and Post-Dose Follow-up Procedures................... 33
Table 6
Criteria for Meeting the Protocol-Defined Endpoint of Medically 
Attended RSV LRTI................................................................................ 36
Table 7
Volume of Blood to be Collected............................................................. 40
Table 8
Identification of Investigational Product .................................................. 41
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 26
LIST OF APPENDICES
Appendix A
Additional Safety Guidance ..................................................................... 66
Appendix B
National Institute of Allergy and Infectious Disease and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.............. 69
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 70


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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
AST
aspartate aminotransferase
AUC0-∞
area under the concentration-time curve from time 0 to infinity
CHD
congenital heart disease
CI
confidence interval
CLD
chronic lung disease
CSR
clinical study report
eCRF
electronic case report form
EDC
electronic data capture
EU
European Union
Fc
fragment crystallizable
FcRn
neonatal Fc receptor
FDA
Food and Drug Administration
GA
gestational age
GCP
Good Clinical Practice
GMC
geometric mean concentration
GMFR
geometric mean fold rise
hMPV
human metapneumovirus
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IM
intramuscular(ly)
IRB
Institutional Review Board
IV
intravenous(ly)
LRTI
lower respiratory tract infection
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
NAb
neutralizing antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events


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Abbreviation or 
Specialized Term
Definition
NOCD
new onset chronic disease
OTC
over-the-counter
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
ULN
upper limit of normal
URTI
upper respiratory tract infection
US
United States
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 
(Hall et al, 2009; Shay et al, 1999; Shi et al, 2017; Stockman et al, 2012). 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). Children < 1 year of age had an estimated 2.3 million hospital admissions. 
The overall mortality due to RSV LRTI was estimated to be as high as 118,200 (uncertainty 
range, 94,600 to 149,400) (Shi et al, 2017).
Children with congenital or acquired immunodeficiencies, transplant recipients, and those 
receiving immunosuppressive therapy are at increased risk for severe RSV-associated LRTI 
with prolonged viral shedding and higher viral loads (Resch et al, 2009), resulting in 
prolonged hospitalizations (11.5 to 24 days), admissions to the intensive care unit (ICU), and 
the need for mechanical ventilation (Asner et al, 2013; Manzoni et al, 2017; Moyes et al, 
2013). Among immunocompromised children hospitalized with RSV, ICU admission rates of 
19% or higher have been reported (Asner et al, 2013; Rowan et al, 2018). In addition, 
RSV-associated mortality rates can reach 60% in untreated children with immunodeficiencies, 
compared to a mortality rate of less than 0.5% in healthy infants with RSV (Asner et al, 2013).
Prevention of RSV illness in all infants is a major public health priority. However, despite 
many years of attempted vaccine development (Kim H. W. et al, 1969), there is no licensed 
vaccine for these children. Currently, the primary management of RSV-associated LRTI 
includes supportive care such as supplemental oxygen and mechanical ventilation. Other 
therapies such as ribavirin and immunoglobulins may be used to treat RSV infection in 
immunocompromised patients, but their effectiveness remains unclear (Asner et al, 2013; Kim 
E. et al, 2014; Rowan et al, 2018). 
Palivizumab (Synagis®) is the only approved agent for RSV prophylaxis, and its use is limited 
internationally to high-risk children: preterm infants ≤35 weeks gestational age (GA), 


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children with chronic lung disease (CLD) of prematurity (also known as bronchopulmonary 
dysplasia), and children with hemodynamically significant congenital heart disease (CHD). In 
Japan, palivizumab received approval in 2013 for an additional indication in children 
≤24 months of age with immunocompromised medical conditions or Down syndrome. 
Approval of this new indication was based on an open-label study that evaluated the efficacy, 
pharmacokinetics (PK), and safety of palivizumab in 28 immunocompromised Japanese 
children. In that study, the serum trough concentrations were comparable with 
Western-approved, indicated pediatric populations and Japanese-approved, indicated pediatric 
populations (preterm infants and children with bronchopulmonary dysplasia or 
hemodynamically significant CHD) (Mori et al, 2014). A larger postmarketing surveillance 
study with 312 Japanese children ≤ 24 months of age with immunocompromised medical 
conditions or Down syndrome demonstrated that palivizumab is generally safe and effective 
in this population (Kashiwagi et al, 2018). However, because its half-life (t1/2) is 
approximately 1 month, infants and young children need to receive monthly intramuscular 
(IM) doses of palivizumab throughout the RSV season to maintain protection. This constitutes 
a significant burden on healthcare providers as well as the infants/children and their families.
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 European Union {EU numbering system}) in the 
fragment crystallizable (Fc) region to prolong the 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 vivo in the cotton rat model 
(Zhu et al, 2017). Nirsevimab is currently under development by AstraZeneca (hereafter, the 
Sponsor) 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 PK of 1G7, the non-YTE version of 


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nirsevimab, was evaluated in cotton rats following a single 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 μg/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 the 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 
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).


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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, 1,000 mg IV, 3,000 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 
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 


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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 the 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 United States (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 
≥ 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 
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, 
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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 μg/mL.
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 
substitution and 4 of the 20 subjects with samples available had neutralizing ADA.
There was no impact of the presence of ADA on safety. ADAs did not appear to impact PK 
for 150 days after dosing. Serum anti-RSV neutralizing antibody 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 neutralizing antibody across all the dose levels, confirming anti-RSV activity of 
nirsevimab.
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 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 approximately 360 days after dosing. 


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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 similar to that of placebo, with no new 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 ≤1 day post dose occurred in 2.5% of subjects in both 
groups. In comparison to the placebo group, the nirsevimab group had a numerically lower 
incidence of TEAEs occurring ≤7 days post dose (nirsevimab 12.5%, placebo 15.2%), 
TEAEs ≥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 considered to be 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 
(4 subjects with rash or rash macular and 1 subject with petechiae) in the nirsevimab group 
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%).


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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 μg/mL. 
The mean (% coefficient of variation) area under the concentration-time curve from time 0 to 
infinity (AUC0-∞) and estimated apparent t1/2 were 5,176.3 (35.0) day⋅μg/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 apparent effect on PK 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 NAb on Day 361.
1.5
Rationale for Conducting the Study
Prevention of RSV illnesses in all infants is a major public health priority; however, despite 
more than 50 years of attempted vaccine development, there are no licensed vaccines. While 
RSV prevention exists in the form of a specific RSV IgG (palivizumab) requiring 5 once-
monthly injections, it is licensed only for infants who experience the greatest morbidity and 
mortality from RSV: preterm infants born ≤ 35 weeks GA, children with CLD of prematurity, 
children with hemodynamically significant CHD and, in Japan, children ≤24 months of age 
with immunocompromised conditions and Down syndrome. 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 nirsevimab clinical development program includes 2 pivotal studies for infants entering 
their first RSV season: the completed Phase 2b study (D5290C00003) and an ongoing Phase 3 
study (D5290C00004) in healthy late term and term infants. Because of the significant 
advantage of one dose per RSV-season that nirsevimab would provide, the Sponsor recognizes 
the potentially important benefits for the pediatric population receiving palivizumab who must 
receive monthly injections during the RSV-season for protection. A Phase 2/3 study 
(D5290C0005) is currently being conducted in the high-risk palivizumab-eligible population 
entering their first and second RSV seasons. In addition, this Phase 2 study is planned to 
support an indication for a single dose of nirsevimab at the start of the RSV season in 
immunocompromised children who are ≤ 24 months of age. 
Primarily, the PK data in this study will be used to assess whether nirsevimab systemic 
exposure is altered in this population as compared to healthy infants. The effects of immune 


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status on exposure will be evaluated using population PK methods. Assuming similar 
exposure-response relationship, exposure matching principles will be used to support 
extrapolation of the observed clinical efficacy of nirsevimab from the Phase 2b, and Phase 3 
studies in heathy infants. 
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 ≤ 24 months of age with CLD or CHD. Additionally, in Japan, palivizumab is 
approved for use in immunocompromised children ≤ 24 months of age. Children in this study 
(ie, ≤ 24 months of age with an immunocompromised medical condition) who receive 
nirsevimab may potentially benefit by being protected against serious RSV disease. 
Nirsevimab is expected to provide similar efficacy benefits as palivizumab with the advantage 
of requiring a single IM dose instead of the 5 IM doses required for palivizumab.
Nirsevimab has no endogenous targets, and no safety concerns were identified in nonclinical 
studies. 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. 
2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
The primary objective and associated endpoints are described in Table 1.


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Table 1
Primary Objective and Associated Endpoints
Type
Objective
Endpoint
Safety
To evaluate the safety and tolerability of 
nirsevimab when administered to 
immunocompromised children ≤ 24 months 
of age
All TEAEs, TESAEs, AESIs, and NOCDs
AESI = adverse event of special interest; NOCD = new onset chronic disease; TEAE = treatment-emergent 
adverse event; TESAE = treatment-emergent serious adverse event.
2.2
Secondary Objectives and Associated Endpoints
The secondary objectives and associated endpoints are described in Table 2.
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
PK
To evaluate the PK of nirsevimab
Summary of nirsevimab serum concentrations
ADA
To evaluate ADA responses to nirsevimab 
in serum
Incidence of ADA to nirsevimab in serum
Efficacy
To assess the efficacy of nirsevimab when 
administered as a single IM dose to infants 
≤24 months of age
Incidence of medically attended LRTI 
(inpatient and outpatient) and hospitalizations 
due to RT-PCR-confirmed RSV through 
150 days after administration of nirsevimab
ADA = antidrug antibody; IM = intramuscular; LRTI = lower respiratory tract infection; 
PK = pharmacokinetics; RSV = respiratory syncytial virus; RT-PCR = reverse transcriptase-polymerase chain 
reaction.
2.3
Exploratory Objectives and Associated Endpoints
The exploratory objectives and associated endpoints are described in Table 3.
Table 3
Exploratory Objectives and Associated Endpoints
Type
Objective
Endpoint
CCI


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Table 3
Exploratory Objectives and Associated Endpoints
Type
Objective
Endpoint
HRU
To assess HRU for nirsevimab recipients
Magnitude of HRU (eg, number of 
admissions to hospitals and ICUs and 
duration of stay; number of subjects who 
require respiratory support and supplemental 
oxygen and duration of use; number and type 
of outpatient visits, eg, ER, urgent care, 
outpatient clinic; and number of prescription 
and OTC medications) for nirsevimab 
recipients
ER = emergency room; HRU = healthcare resource utilization; ICU = intensive care unit; OTC = over-the-
counter; RSV = respiratory syncytial virus.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
Study D5290C00008 is a Phase 2, open-label, uncontrolled single-dose study to assess the 
safety and tolerability, PK, occurrence of ADA, and efficacy of nirsevimab in 
immunocompromised children who are ≤ 24 months of age at the time of dose administration. 
The study is planned to be conducted in South Africa, the US, and the EU, in addition to 
Japan, where the study is currently ongoing. Approximately 100 subjects will be enrolled. 
Approximately 50 subjects entering their first RSV season will receive nirsevimab as a single,
fixed IM dose of 50 mg if body weight < 5 kg or 100 mg if body weight ≥ 5 kg. 
Approximately 50 subjects entering their second RSV season will receive nirsevimab as a 
single, fixed IM dose of 200 mg. Subjects will be followed approximately 1 year after dose 
administration. 
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical 
attention for a respiratory illness (inpatient or outpatient setting) will be evaluated for the 
occurrence of LRTI. All subjects found to have a LRTI and all subjects who require 
hospitalization for a respiratory infection, even if there is not a diagnosis of LRTI, should have 
respiratory samples obtained and respiratory assessment forms completed. Samples should be 
collected for all of these respiratory events, even those not meeting the protocol-defined 
endpoint of LRTI. Subjects who have a primary hospitalization for a respiratory infection (ie, 
upper or lower respiratory tract), a respiratory deterioration during a hospitalization, or who 
seek outpatient medical attention (including emergency room [ER] visits) for a lower 
respiratory illness, will be assessed clinically for the presence of LRTI and for RSV by central 
laboratory diagnostic testing of respiratory secretions.
CCI


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In addition to the clinical assessment of LRTI, there is a protocol definition using objective 
criteria for the determination of a protocol-defined medically attended LRTI. To meet the 
protocol-defined endpoint of medically attended LRTI, subjects with signs of LRTI must have 
documented at least one physical examination finding of rhonchi, rales, crackles, or wheeze 
AND at least 1 of the following clinical signs:

Increased respiratory rate at rest (age < 2 months, ≥ 60 breaths/min; age 2 to 6 months, 
≥50 breaths/min; age > 6 months, ≥ 40 breaths/min), OR

Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1,800 meters or < 92% at 
altitudes > 1,800 meters), OR

Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new 
onset apnea, nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting) 
or dehydration secondary to inadequate oral intake due to respiratory distress (need for IV 
fluid).
Testing for RSV will be performed centrally using the US Food and Drug Administration 
(FDA)-cleared and Conformité Européenne or European Conformity-marked in vitro 
diagnostic real-time RT-PCR assay (Lyra RSV + hMPV Assay, Quidel, San Diego, CA; 
www.quidel.com). A diagnosis of RSV LRTI requires having a respiratory sample positive for 
RSV by the central laboratory RT-PCR.


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Figure 1
Study Flow Diagram
IM = intramuscular; LRTI = lower respiratory tract infection; n = number of patients; RSV = respiratory 
syncytial virus.
The endpoints to be measured in this study are described in Section 2.
3.1.2
Treatment Regimen
As this is a single-arm study, all subjects will receive nirsevimab. Subjects who are in their 
first year of life AND entering their first RSV season at the time of dose administration will 
receive nirsevimab as a single, fixed IM dose of 50 mg if body weight < 5 kg or 100 mg if 
body weight ≥ 5 kg (n = ~ 50). Subjects in their second year of life AND entering their second 
RSV season at the time of dose administration will receive nirsevimab as a single, fixed IM 
dose of 200 mg (n = ~ 50). 


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3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
A single fixed 50-mg IM dose was shown to be efficacious in the Phase 2b Study 
D5290C00003 in preterm infants (29 to < 35 weeks GA) in their first RSV season. 
Model-based analyses of the Phase 2b clinical PK and efficacy data identified a projected 
serum AUC0-∞of 13.4 day⋅mg/mL as the protective exposure threshold. The risk of medically 
attended RSV-confirmed LRTI over the course of the RSV season was significantly lower in 
infants with higher projected AUC0-∞. Infants with AUC0-∞above 13.4 day⋅mg/mL had a 
statistically significant higher probability of protection based on exposure-response analysis 
using Cox proportional hazard regression. Although, the fixed 50-mg dose resulted in 
clinically efficacious exposures for 97% of infants weighing < 5 kg in the Phase 2b study, this 
dose was suboptimal for infants weighing ≥ 5 kg in this study. Overall, 3% and 59% of the 
infants in groups weighing < 5 kg and ≥ 5 kg, respectively, were in the lowest AUC0-∞quartile 
(4.5 to 13.4 day⋅mg/mL) that was determined to be suboptimal. Additionally, a cut point 
analysis of the weight-normalized doses of all treated infants revealed that a 10 mg/kg dose 
was the corresponding clinically efficacious and protective threshold dose. Henceforth, based 
on these analyses, a stratified fixed dosing strategy by weight bands is proposed to ensure an 
adequate dose to maintain nirsevimab serum concentrations above the target area under the 
concentration-time curve throughout the RSV season. Based on dose optimization analysis 
designed to maximize the proportion of infants with clinically efficacious nirsevimab serum 
exposure, for infants entering their first RSV season a single fixed 50-mg IM dose is proposed 
for infants with body weight < 5 kg, while a single fixed 100-mg dose is proposed for infants 
weighing ≥ 5 kg. The body weight range for the majority of children entering their second 
RSV season is expected to be approximately 8.5 to 15 kg at the time of dosing. Therefore, 
with the same rationale, a single fixed 200-mg dose of nirsevimab is proposed for subjects 
entering their second RSV season to achieve and maintain efficacious exposure during the 
entire second RSV season. There have been no reports that IgG1 kappa mAb compounds 
show obvious ethnic differences. 
3.2.2
Rationale for Study Population
Children with immunodeficiencies are at increased risk for severe RSV disease, leading to 
prolonged hospitalizations, admission to the ICU, and mechanical ventilation (Manzoni et al, 
2017; Welliver, 2003). Currently, there is no specific treatment for RSV infection. In Japan, 
palivizumab is approved for the prevention of RSV infection in children with 
immunocompromised conditions. Palivizumab has been found to be generally safe and 
effective in this population (Kashiwagi et al, 2018; Mori et al, 2014), but because of its t1/2 of 
approximately 1 month, infants and young children need to receive monthly IM doses of 
palivizumab throughout the RSV-season to maintain protection.


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Nirsevimab has the potential to provide significant improvement over palivizumab based on 
its demonstrated increased potency and extended t1/2. Because of the significant advantage of 
one dose per RSV season that nirsevimab would provide, the Sponsor recognizes the 
potentially important benefits for the current pediatric population receiving palivizumab. This 
Phase 2 study is planned to evaluate the safety and tolerability, PK, ADA, and efficacy of 
nirsevimab in immunocompromised children ≤ 24 months of age.
3.2.3
Rationale for Endpoints
Nirsevimab is being developed to provide RSV immunoprophylaxis for all infants and young 
children, including immunocompromised children ≤ 24 months of age. The primary endpoint 
for this study is safety and tolerability. The standard measures of TEAEs/TESAEs, AESIs, 
and NOCDs will be used for this assessment. All subjects will be followed for approximately 
1 year after dosing with nirsevimab. 
Serum concentrations of nirsevimab at selected time points will be evaluated as a secondary 
endpoint to confirm that serum concentrations are maintained at an efficacious level for at 
least 5 months after dosing. PK data will be summarized by descriptive statistics. PK data 
obtained in this study will be compared to the PK data from the Phase 2b, Phase 3, and the 
Phase 2/3 studies. For infants and children who require hospitalization for LRTI or any 
respiratory infection, an additional serum sample for measurement of nirsevimab 
concentration and ADA will be obtained contemporaneous with time of hospitalization. 
To determine nirsevimab serum levels post dosing and to correlate with the potential 
development of ADA, serum concentrations will be measured up to 360 days post dose. ADA 
to nirsevimab will be measured at selected time points throughout the study and up to 
360 days post dose.
This study will also summarize efficacy of nirsevimab in terms of incidence of RSV LRTI. 
RSV results in a significant burden of disease consisting of hospitalization, visits to the ER, 
and visits to outpatient clinics. This endpoint is designed to allow the capture of this total 
burden of disease. A separate endpoint of RSV hospitalization will also be evaluated. 
Exploratory endpoints will examine 
 
 
 
 
 
 
.
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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of approximately 100 subjects will be enrolled. 
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1.
Neonate, infant, or young child ≤ 24 months of age who, per Investigator judgment, are: 
(a) In their first year of life AND entering their first RSV season at the time of dose 
administration 
OR
(b) In their second year of life AND entering their second RSV season at the time of 
dose administration 
2.
The subject must meet at least 1 of the following conditions at the time of informed 
consent.
(a) Diagnosed with combined immunodeficiency (severe combined immunodeficiency, 
X-linked hyper-immunoglobulin M [IgM] syndrome, etc); antibody deficiency 
(X-linked agammaglobulinemia, common variable immunodeficiency, non-X-linked 
hyper-IgM syndromes, etc); or other immunodeficiency (Wiskott-Aldrich syndrome, 
DiGeorge syndrome, etc), or
(b) Diagnosed with human immunodeficiency virus infection, or
(c) History of organ or bone marrow transplantation, or
(d) Subject is receiving immunosuppressive chemotherapy, or
(e) Subject is receiving systemic high-dose corticosteroid therapy (prednisone 
equivalents ≥ 0.5 mg/kg every other day, other than inhaler or topical use), or
(f) Subject is receiving other immunosuppressive therapy (eg, azathioprine, 
methotrexate, mizoribine, mycophenolate mofetil, cyclophosphamide, cyclosporine, 
tacrolimus, cytokine inhibitors, etc)
All efforts will be made to recruit subjects for representation across all the 
immunocompromised conditions indicated in inclusion criteria (a) - (f).
3.
Written informed consent and any locally required authorization obtained from the 
subject’s parent(s)/legal representative(s) prior to performing any protocol-related 
procedures, including screening evaluations.
4.
Subject’s parent(s)/legal representative(s) able to understand and comply with the 
requirements of the protocol including follow-up visits as judged by the Investigator.
5.
Subject is available to complete the follow-up period, which will be approximately 1 year 
after receipt of nirsevimab.


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4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1.
Subject who meets any of the indications other than (including those approved for 
palivizumab in Japan) the immunocompromised conditions below.
(a) Subject born at ≤ 28 weeks gestation and is ≤ 12 months of age 
(b) Subject born at 29 to 35 weeks gestation and is ≤ 6 months of age 
(c) Age ≤ 24 months with a history of bronchopulmonary dysplasia requiring medical 
management within the past 6 months 
(d) Age ≤24 months with current hemodynamically significant CHD 
(e) Age ≤ 24 months with Down syndrome
2.
Requirement for oxygen supplementation, mechanical ventilation, extracorporeal 
membrane oxygenation, continuous positive airway pressure, or other mechanical 
respiratory or cardiac support at screening.
3.
A current, active infection, including RSV infection, at the time of screening or at the 
time of investigational product administration.
4.
Any fever (≥100.4°F [≥38.0°C], regardless of route) or acute illness within 7 days prior 
to investigational product administration.
5.
Any serious concurrent medical condition (renal failure, hepatic dysfunction, suspected 
active or chronic hepatitis infection, seizure disorder, unstable neurologic disorder, etc), 
except those resulting in an immune deficiency condition.
6.
Clinically significant congenital anomaly of the respiratory tract.
7.
Receipt of palivizumab.
8.
Any known allergy or history of allergic reaction to any component of nirsevimab.
9.
Any known allergy or history of allergic reaction to immunoglobulin products, blood 
products, or other foreign proteins.
10. Concurrent enrollment in another interventional study, or prior receipt of any 
investigational agent.
11. Anticipated survival of less than 1 year at the time of informed consent.
12. Any condition that, in the opinion of the Investigator, would interfere with evaluation of 
the investigational product or interpretation of study results.
13. Children of 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, 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. 


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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), 
including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
receive investigational product. The Investigator must consult with the Sponsor before a 
subject who has failed screening may be considered for rescreening.
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.
4.1.6
Discontinuation of Investigational Product
Each subject will receive a single IM dose of investigational product. An individual subject 
will not receive investigational product if any of the following occur in the subject in question:

Withdrawal of consent 

Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation 
Subjects who have received any investigational product will be followed for protocol-
specified assessments including follow-up of any AEs unless consent is withdrawn 
specifically from further study participation (Section 4.1.5) or the subject is lost to follow-up. 
Subjects who have not received investigational product, regardless of reason, will not be 
followed.
4.1.7
Replacement of Subjects
Subjects will not be replaced.
4.1.8
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.
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 -30 to Day -1
Written informed consent/assignment of SID number
X
Medical history
X
Physical examination 
X
Weight
X
Vital signs
X
Blood sample for PK, ADA, 
 
a
X
Assessment of AEs/SAEs
X
Concomitant medications
X
Verify eligibility criteria
X
ADA = antidrug antibody; AE = adverse event; PK = pharmacokinetics; RSV = respiratory syncytial virus; 
SAE = serious adverse event; SID = subject identification.
a
If Visit 1/Screening and Visit 2/Day 1 do not occur on the same day, blood sample for PK/ADA/
 
 can be collected at either Visit 1/Screening or Visit 2/Day 1 predose.
4.2.2
Treatment and Follow-up Periods
Investigational product is administered on Day 1/Visit 2. Table 5 shows all procedures to be 
conducted on Day 1 and during the post-dose follow-up period, respectively.
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Table 5
Schedule of Treatment and Post-Dose Follow-up Procedures
Study Period
Dosing
Post-dose Follow-up 
Visit Number
V2 a
Telephone 
Call
V3
V4
V5
V6 
Telephone 
Call
Telephone 
Call
LRTI
Skin 
Reaction
Procedure/ 
Study Day
D1
D8 (± 2 
days)
D31 
(± 2 days)
D91 
(± 2 days)
D151 
(± 7 days)
D361
(± 7 days)
Q2W
D1-151
(± 5 days)
Monthly 
after 
D151-361 
(± 5 days)
D1-361 
D1-361 
Assessment of skin 
reaction
Xe
Telephone contactf
X
X
HRU g
X
ADA = antidrug antibody; AE = adverse event; AESI = adverse event of special interest; D = Day; ER = emergency room; HRU = healthcare resource 
utilization; ICU = intensive care unit; LRTI = lower respiratory tract infection; NOCDs = new onset chronic diseases; OTC = over-the-counter; 
PK = pharmacokinetic; Q2W = once every 2 weeks; RSV = respiratory syncytial virus; SAE = serious adverse event; V = visit.
a
V2/D1 and V1/Screening can occur on the same day.
b
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) should be obtained within 60 minutes prior to dosing, and at 30 minutes 
(± 5 minutes) and 60 minutes (± 5 minutes) post dose.
c
If V1/Screening and V2/D1 do not occur on the same day, blood sample PK/ADA/
 can be collected at either 
V1/Screening or V2/D1.
d
Nasal samples will be collected for all LRTIs (inpatient or outpatient) and all subjects hospitalized with any respiratory infection (upper or lower) within 
2 days after the diagnosis by a healthcare provider. Blood samples will be collected from all subjects hospitalized with LRTI or any respiratory infection 
within 2 days following hospital admission.
e
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction regardless of severity, duration, time of onset post dosing, or 
relationship to investigational product.
f
Telephone contact must be verbal communication. Written communication via text, email, or other written form is not acceptable.
g
HRU includes admission and duration of hospital and ICU stay, number of subjects who require respiratory support and supplemental oxygen use, 
duration of respiratory support and supplemental oxygen use, number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and number 
and days of prescription and OTC medication. 
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4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Lower Respiratory Tract Infection
Subjects will be monitored throughout the study for LRTI (see Table 5). All subjects seeking 
medical attention for a respiratory illness (in either the inpatient or outpatient setting) will be 
evaluated for the occurrence of LRTI (Table 6). All subjects found to have an LRTI and all 
subjects who require hospitalization for a respiratory infection, even if there is not a diagnosis 
of LRTI, should have respiratory samples obtained and respiratory assessment forms 
completed. Samples should be collected for all of these respiratory events, even those not 
meeting the protocol definition of LRTI. Subjects who have a primary hospitalization for a 
respiratory infection (ie, upper or lower tract) or a respiratory deterioration during a 
hospitalization, or who seek outpatient medical attention (including ER visits) for a lower 
respiratory illness, will be assessed clinically for the presence of LRTI and for RSV by central 
laboratory diagnostic testing of respiratory secretions. Testing for RSV will be performed 
centrally using the US FDA-cleared and Conformité Européenne or European 
Conformity-marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV + hMPV assay, 
Quidel Corporation, San Diego, CA). A diagnosis of RSV LRTI requires having a respiratory 
sample positive for RSV by the central laboratory RT-PCR.
In addition to the clinical assessment of LRTI, there is a protocol definition using objective 
criteria for the determination of protocol-defined medically attended LRTI. To meet the 
protocol-defined endpoint of medically attended LRTI, subjects with signs of LRTI must have 
documented at least one physical examination finding of rhonchi, rales, crackles, or wheeze 
AND at least one of the following clinical signs:
•
Increased respiratory rate at rest (age: < 2 months, ≥ 60 breaths/min; 2 to 6 months, 
≥50 breaths/min; > 6 months, ≥40 breaths/min), OR
•
Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1,800 meters or < 92% at 
altitudes > 1,800 meters), OR
•
Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new 
onset apnea, nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting) or 
dehydration secondary to inadequate oral intake due to respiratory distress (need for IV 
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Table 6
Criteria for Meeting the Protocol-Defined Endpoint of Medically 
Attended RSV LRTI 
RSV 
*Lower Respiratory Tract
*Medical Significance
RSV Confirmed: 
•
Positive by central 
laboratory RT-PCR assay
Documented PE findings 
localizing to lower respiratory 
tract: 
•
Rhonchi
•
Rales
•
Crackles
•
Wheeze
Objective measures of clinical severity: 
•
Increased respiratory rate
•
Hypoxemia
•
Acute hypoxic or ventilatory failure
•
New onset apnea
•
Nasal flaring
•
Retractions
•
Grunting
•
Dehydration due to respiratory 
distress
LRTI = lower respiratory tract infection; PE = physical examination; RSV = respiratory syncytial virus; 
RT-PCR = reverse transcriptase-polymerase chain reaction. 
*Note: One item from each column is required to meet the protocol-defined endpoint of RSV LRTI.
RSV Hospitalization
An RSV hospitalization is defined as either (1) a respiratory hospitalization with a positive 
RSV test within approximately 2 days of hospital admission (primary) or (2) a new onset of 
respiratory symptoms in an already hospitalized subject, with an objective measure of 
worsening respiratory status and positive RSV test (nosocomial). Primary and nosocomial 
RSV hospitalization are further defined below. 
Primary RSV Hospitalization
RSV diagnostic testing will be performed on respiratory secretions obtained within 
approximately 2 days before or after admission for subjects hospitalized for respiratory 
infection (upper or lower respiratory tract). If the RSV diagnostic test (performed centrally via 
RT-PCR) is positive, the hospitalization will be classified as a primary RSV hospitalization. 
Deaths that can be demonstrated as caused by RSV (by autopsy or clinical history and 
virologic evidence) will also be considered as primary RSV hospitalization endpoints.
Nosocomial RSV Hospitalization
Subjects hospitalized for a respiratory illness or non-respiratory illness whose RSV diagnostic 
test is negative may develop nosocomial RSV illness during the study.
If signs (such as retractions, rhonchi, wheezing, crackles, or rales) of a new lower respiratory 
illness occur during a hospitalization, whatever the reason for hospitalization, and there is an 
objective measure of worsening respiratory status (that is, new requirement for supplemental 
oxygen, increase in supplemental oxygen requirement from prior to the onset of symptoms, or 
need for new or additional mechanical ventilation), a specimen will be collected within 
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central laboratory. For any subject who is hospitalized for a respiratory infection (upper or 
lower respiratory tract), the subject must return to his/her baseline respiratory status or be 
clearly resolving the preceding respiratory illness before a subsequent respiratory deterioration 
for a nosocomial RSV hospitalization event can be determined.
If the RSV diagnostic test (performed centrally via RT-PCR) is positive, the subsequent 
hospital days will count as a nosocomial RSV hospitalization. The days of RSV 
hospitalization will be counted beginning with the start of the respiratory deterioration that 
resulted in the RSV diagnostic test.
RSV LRTI Outpatient Events
Subjects who seek outpatient medical attention, including ER and urgent care visits, for an 
LRTI should have respiratory secretions obtained within approximately 2 days after the initial 
healthcare provider assessment.
Respiratory Secretions for RSV Detection 
Respiratory secretions for RSV testing must be collected from all subjects with LRTIs 
(inpatient or outpatient) and from all hospitalized subjects with any new respiratory infection 
(upper or lower) within approximately 2 days after the initial healthcare provider assessment 
and diagnosis. Nasal secretions will be obtained unless the subject is intubated, and then 
tracheal secretions may be obtained.
Respiratory secretions will be tested in a central laboratory for RSV using the US FDA-
cleared and Conformité Européenne or European Conformity-marked in vitro diagnostic real-
time RT-PCR assay (Lyra RSV + hMPV assay; Quidel Corporation, San Diego, CA). Testing 
may include other respiratory pathogens.
The respiratory samples will be retained at AstraZeneca or designee for a maximum of 15 
years following the issue of the CSR to properly address potential questions from regulatory 
authorities.
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4.3.2
Medical History and Physical Examination, Weight, and Vital Signs
A complete medical history will be obtained at screening and a medical history update will be 
obtained on the day of dosing and during the follow-up period, as defined in Section 4.2. 
Assessment will include history and current medical conditions, past or present cardiovascular 
disorders, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, 
hematologic, immunologic, dermatological, psychiatric, genitourinary, drug and surgical 
history, or any other diseases or disorders.
A physical examination will be performed at screening, on the day of dosing, and during the 
follow-up period, as defined in Section 4.2. The physical examination will include assessment 
of weight at screening and at each study visit mentioned above.
Vital signs (temperature, blood pressure, respiratory rate, and heart rate measurements) will be 
collected at screening, on the day of dosing, and during the follow-up period, as defined in 
Section 4.2. On Day 1, vital signs will be monitored before and after administration of 
investigational product. 
Baseline information will be collected on breastfeeding, smoking in the household, and if the 
infant attends day care.
4.3.3
Pharmacokinetics, Antidrug Antibody, and 
A blood sample for assessment of PK and ADA will be collected through Day 361 according 
to the schedule defined in Section 4.2. 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.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements to properly address potential questions from 
regulatory authorities, after which they will be destroyed. 

Pharmacokinetic and ADA samples will be disposed of 6 months after issuance of the 
draft Bioanalytical Report. 

Remaining PK sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. 
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4.3.3.1
Pharmacokinetic Evaluation
Blood samples to evaluate the PK of nirsevimab in serum will be collected according to 
scheduled time points. Blood samples for PK evaluation will also be collected from subjects 
hospitalized with LRTI or any respiratory infection within approximately 2 days following 
hospitalization. See the collection schedule in Section 4.2. The concentration of nirsevimab in 
serum will be measured using validated assays.
4.3.3.2
Antidrug Antibody Evaluation
Blood samples to evaluate ADA responses to nirsevimab in serum will be collected according 
to scheduled time points. Blood samples will also be collected for ADA response from 
subjects hospitalized with LRTI or any respiratory infection within approximately 2 days 
following hospitalization. See the collection schedule in Section 4.2. Evaluations will be 
performed using validated immunoassays. 
4.3.4
Healthcare Resource Utilization
Information on HRU will be collected for all events of medically attended LRTI through 
Day 361 (see Section 4.2). This will include admission to, and duration of hospital and ICU 
stay, number of subjects who require respiratory support and supplemental oxygen use, 
duration of respiratory support and supplemental oxygen use, number and type of outpatient 
visits (eg, ER, urgent care, outpatient clinic), and the number of prescription and 
over-the-counter (OTC) medications. 
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4.3.5
Skin Reactions
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction 
through Day 361 to assist in determination of the etiology of the reaction (see Section 4.2). 
Information will be collected regardless of event severity, duration, time of onset post dosing, 
or relationship to investigational product. Parents/legal representatives of study subjects will 
be given a hypersensitivity card and instructed to call the study site immediately for signs of 
hypersensitivity or allergic reaction. Sites must notify the Sponsor within 24 hours of 
knowledge of such events. For any skin or skin-related reactions, including all rashes that 
occur within 7 days after dosing, the infant will be brought to the study site as soon as possible 
for evaluation.
4.3.6
Estimate of Volume of Blood to be Collected
Blood volume estimates are provided in Table 7 by visit/study day. For all subjects 
hospitalized with LRTI or any respiratory infection, an additional blood sample will be 
collected within 2 days following hospital admission. 
Table 7
Volume of Blood to be Collected 
Visit/Study Day
Estimated Blood Volume
Visit 1/Screening or Visit 2/Day 1
1.5 mL
Visit 3/Day 31
1.5 mL
Visit 5/Day 151
1.5 mL
Visit 6/Day 361
1.5 mL
Total
6.0 mL
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: 

Death in any subject in which the cause of death is assessed as related to investigational 
product (in this case, the study will be paused for the Sponsor’s safety review committee 
to evaluate the events).

Anaphylactic reaction that is related to investigational product (see Appendix B for a 
definition of anaphylaxis; in this case, the study will be paused for the Sponsor’s safety 
review committee to evaluate the events).

Grade 3 and/or 4 hypersensitivity AEs based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) grading scale that are assessed 
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Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.
Investigational product will be supplied to the site in open-labeled 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).
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 8 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 4.5.1.4) for further instructions.
4.5.1.2
Dose Preparation Steps and Treatment Administration
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: 
1.
Infants in the first year of life and entering their first RSV season at time of dosing
(a) Infants < 5 kg body weight at time of dosing:
A dose of 50 mg (ie, 0.5 mL) nirsevimab will be obtained by withdrawing the entire 
contents of 1 investigational product vial with an appropriately sized syringe, and 
administered as 1 single (ie, 0.5 mL) injection.
(b) Infants ≥ 5 kg body weight at time of dosing:
A dose of 100 mg (ie, 1.0 mL) nirsevimab will be obtained by withdrawing the entire 
contents of 2 investigational product vials with an appropriately sized syringe and 
administered as 1 single (ie, 1.0 mL) injection.
2.
Children in the second year of life and entering their second RSV season at time of 
dosing
A dose of 200 mg (ie, 2.0 mL) nirsevimab will be obtained by withdrawing the entire 
contents of 4 investigational product vials with an appropriately sized syringe and 
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3.
Switch the needle prior to administration.
4.
Nirsevimab should be administered in the anterolateral aspect of the thigh according to 
standard practice procedures for IM injections. The injection should be given using 
standard aseptic technique. Subjects receiving the 200-mg dose (administered as 
2 injections) should receive 1 injection in each thigh. The maximum volume to be 
administered with each injection is 1.0 mL.
5.
Nirsevimab should be administered using the appropriate size needle ranging from 22 to 
25 gauge and 5/8 to 1.0 inches based on muscle size and weight of the subject.
The investigational product will not be delivered until the contract is completed between the 
study site and Sponsor (and/or designee). The investigational product manager, who is 
designated by the head of the study site, is responsible for managing the investigational 
product from receipt by the study site until the return of all unused investigational product, 
after the contract is concluded between the study site and the Sponsor (and/or designee).
4.5.1.3
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.
4.5.1.4
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 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
Sponsor contact information for reporting product complaints:
Email
Phone:
PPD
PPD


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Mail:AstraZeneca
Attn:
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.
The site’s designated investigational product manager should ensure that the investigational 
product supplies are stored at the correct temperature. If the storage conditions are found to be 
outside the specified range, the process outlined in the Pharmacy Manual should be followed.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.5.6
Accountability
The head of the study site 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
Investigational product 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 study monitor 
must be notified immediately.
PPD


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4.6.2
Methods to Ensure Blinding
This study is not blinded.
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 end of the clinical phase of the study (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 deemed necessary to 
provide adequate supportive care, including routine vitamins and iron.
4.7.2
Prohibited Concomitant Medications
Use of any new medications from Day 1 through Day 15 post dose should be avoided if 
possible. This includes OTC medications (except for routine vitamins and iron) and herbal 
supplements. Subjects’ parent(s)/legal representatives should be instructed not to administer 
any new medications, including OTC products, without first consulting with the Investigator.
4.8
Statistical Evaluation
4.8.1
General Considerations
There are 2 planned analyses for this study: an interim analysis and a final analysis. The 
interim analysis will be conducted when subjects enrolled globally by end of 2021 have been 
followed through Day 151. For the interim analysis, all safety, PK, ADA, and efficacy data 
collected for subjects enrolled globally in 2021 will be analyzed. A minimum of 
approximately of 30 subjects is expected to be sufficient in establishing a PK profile for 
efficacy and safety extrapolation at the time of the interim analysis. The final analysis will be 
conducted after all subjects have completed the last visit of the study (ie, Day 361).
Categorical data will be summarized by the number and percentage of subjects in each 
category. Continuous variables will be summarized by mean, median, standard deviation, 
minimum, and maximum. In general, unless stated otherwise, baseline will be defined as the 
last non-missing value prior to dosing. 
Data will be summarized for the overall study population, as well as for Japan only.
Data analyses will be conducted using the SAS® System Version 9.4 or higher (SAS Institute 
Inc., Cary, NC) in a SAS GRID environment.


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4.8.2
Sample Size
A total of approximately 100 subjects are planned to receive a single IM dose of nirsevimab to 
evaluate the safety, PK, ADA, and efficacy, which will be assessed descriptively. The 
originally proposed sample size was based on a similarly designed palivizumab study in a 
similar population (Mori et al, 2014), and it is expected to be sufficient in establishing a PK 
profile that allows extrapolation of efficacy and safety data from the Phase 2b (D5290C00003) 
and 
 studies in healthy preterm and term infants to the target 
immunocompromised population. The updated sample size of 100 allows for the collection of 
PK and safety data from a larger cohort of immunocompromised children. The revised sample 
size of 100 subjects allows for the study of immunocompromised children and the various 
causes for this condition globally. Further, the data from this study will support the evaluation 
of safety in a diverse population, which could potentially facilitate the examination of 
subpopulations.
 
4.8.3
Safety
AEs will be graded according to the current version of the NCI CTCAE (or Appendix A) 
where applicable for pediatric assessments. AEs will be coded by MedDRA and the type, 
incidence, severity, and relationship to study drug will be summarized. Other safety 
assessments will include the occurrence of AESIs defined as AEs of immediate
hypersensitivity (including anaphylaxis), thrombocytopenia, and immune complex disease 
(eg, vasculitis, endocarditis, neuritis, glomerulonephritis) following study drug administration, 
and the occurrence of NOCDs following study drug administration.
4.8.4
Analysis of Pharmacokinetics
Serum concentrations of nirsevimab at selected time points will be evaluated to confirm that 
adequate exposures for protection from RSV LRTI are maintained for at least 5 months after 
dosing. Nirsevimab serum concentration data will be presented in descriptive statistics. 
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 the association 
with TEAEs and TESAEs, will be assessed, if data permit.
4.8.6
Efficacy
The incidence of medically attended RSV LRTI (inpatient and outpatient) through 150 days 
post dose, based on RSV test results (performed centrally using RT-PCR) and objective 
CCI
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protocol-defined LRTI criteria, will be summarized for all dosed subjects. For subjects with 
multiple medically attended RSV LRTI events, only the first occurrence will be used in the 
analysis.
The incidence of RSV hospitalization through 150 days after dose will also be summarized. 
Additional analyses will include summarizing RSV-positive LRTI endpoints using results 
from either the central laboratory or local laboratory.
4.8.7
Additional Analyses
4.8.7.4
Healthcare Resource Utilization
The magnitude of HRU (eg, number of admissions to hospitals and ICUs and duration of stay; 
number of subjects who require respiratory support and supplemental oxygen and the duration 
of use; number and types of outpatient visits, eg, ER, urgent care, outpatient clinic; and 
number of prescription and OTC medications) will be summarized.
4.8.8
Interim Analysis
An interim analysis will be conducted when subjects enrolled globally by the end of 2021 
have been followed through Day 151. For the interim analysis, all safety, PK, ADA and 
efficacy data available at the time of the data cut-off for subjects enrolled globally by end of 
2021 will be analyzed. A minimum of approximately of 30 subjects is expected to be 
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sufficient in establishing a PK profile for efficacy and safety extrapolation at the time of the 
interim analysis.
4.8.9
Data Monitoring Committee
An independent data monitoring committee will review the safety data regularly and make 
recommendations regarding further study conduct.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject 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 if judged by the Investigator as medically significant), 
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 
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 
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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
Serious Hypersensitivity (Including Anaphylaxis and Immune Complex 
Disease)
5.3.1.1
Immediate Hypersensitivity, Including Anaphylaxis
Administration of polyclonal immunoglobulin preparations and mAbs has been associated 
with immediate (type I) hypersensitivity (including anaphylaxis) that occurs during or after 
dosing. An immediate hypersensitivity reaction is defined as an acute onset of an illness with 
involvement of the skin, mucosal tissue, or both that occurs during or after administration of 
investigational product (but does not meet the definition of anaphylaxis). 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 B. See Section 5.5 for recording AEs.
5.3.1.2
Immune Complex Disease
Immune complex disease can manifest in the form of a number of conditions such as 
vasculitis, endocarditis, neuritis, glomerulonephritis, serum sickness, and arthralgias. 
Drug-induced immune complex (type III) hypersensitivity reactions can occur when the host 
immune system generates antibodies to drug resulting in soluble circulating antigen-antibody 
complexes formation and their deposition in blood vessels. Subsequently this initiates tissue 
damaging inflammatory reactions mediated by complement and/or leukocytes and mast cells. 
The pathology and clinical manifestations are dependent on the tissues/organs involved, with 
vascular, skin, and renal tissues being common sites of injury. Common examples of immune
complex hypersensitivity reactions are serum sickness (systemic) and Arthus reactions (local). 
The clinical manifestations of serum sickness include skin rash, fever, malaise, and 
polyarthralgias or polyarthritis. Symptoms typically develop 1 to 2 weeks after first exposure 
to antigen and usually resolve in several weeks after withdrawal of the causative agent. Serum 
sickness needs to be differentiated from other ‘serum-sickness-like’ reactions that have a 
similar clinical presentation (eg, viral infections, anti-seizure drugs), but are believed to have 
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been reported with mAbs (eg, rituximab, infliximab). Clinical presentation and time to onset 
should be considered for the diagnosis and differentiation of these reactions. Diagnosis of 
these suspected reactions is best confirmed via biopsy of the affected tissues. See Section 5.5
for recording AEs. 
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 μL. 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 


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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 Sections 5.2 and 5.6), 
or is an AESI or NOCD (see Sections 5.3, 5.4, and 5.7) and therefore requires immediate 
notification to the Sponsor. See Appendix A for guidelines for assessment of severity and 
relationship to investigational product. 
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 361.
AESIs and NOCDs will be collected from the time of dosing through Day 361.
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
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period, must 
be reported as SAEs. A post-mortem (autopsy) may be helpful in the assessment of the cause 
of death and, if performed, a copy of the post-mortem results should be forwarded to the 
Sponsor representative(s) within the usual timeframes (refer to Section 5.6 for additional 
information).
5.5.4
Potential Hy’s Law and Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of aspartate aminotranserase (AST) or alanine aminotransferase 
(ALT) ≥3 × upper limit of normal (ULN) together with total bilirubin (TBL) ≥2 × ULN may 
need to be reported as SAEs. Please refer to Appendix C 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 of an SAE by the Investigator to the Sponsor 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. 


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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, head of the medical institution, 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 the head of the medical 
institution and 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.
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 contacts 
the Sponsor representative by telephone. The Sponsor representative will give guidance on 
how to proceed. 


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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 
that specified in the Investigator’s Brochure, 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
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

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

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
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 

Wrong subject received the medication 

Wrong drug administered to subject 
Examples of events that do not require reporting as medication errors in clinical studies:

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.
5.7.3
Adverse Events of Special Interest 
5.7.3.1
Immediate Hypersensitivity, Including Anaphylaxis
Events of immediate (Type 1) hypersensitivity, including anaphylaxis (as defined in 
Appendix B), 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).
Signs of immediate hypersensitivity include urticaria, pruritus, angioedema, skin rash, 
difficulty breathing, and wheezing. Parent(s)/legal representatives will be provided a card with 
this information to aid in prompt identification and reporting of these signs. Parent(s)/legal 
representatives 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.
5.7.3.2
Immune Complex Disease
Events of immune complex disease (as defined in Section 5.3.1.2) require that the Investigator 
or other site personnel inform appropriate Sponsor study representatives immediately, or no 


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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).
5.7.3.3
Thrombocytopenia
Events of unexpected thrombocytopenia (platelet count < 120,000 per µL) that the 
Investigator judges to be both clinically significant and of unknown etiology require the 
Investigator or other site personnel to 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
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).
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


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
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)
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.
Direct Access to Source Data 
The head of the study site and the Principal Investigator/Investigator will cooperate for 
monitoring and auditing by the Sponsor (or designee) and accept inspection by the IRB/IEC or 
regulatory authorities. All study documents such as raw data will be open for direct access to 
source data at the request of the monitor and the auditor of the Sponsor (or designee), the IRB, 
or regulatory authorities.
The monitor(s) will verify data from the eCRFs against source data before the Principal 
Investigator signs the eCRFs to ensure accuracy and completeness of documentation and 
assure that the Principal Investigator has submitted the eCRFs to the Sponsor. If the 
Investigator wishes to amend the collected eCRFs, the monitor will ensure that the Principal 
Investigator has recorded the amendment with signature and date and provided this to the 
Sponsor.
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.


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6.2.3
Archiving of Study Documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
Document File and Period of Retention 
All study documents (including letters from the Sponsor) should be retained in the study 
document file by the Principal Investigator. The monitor will regularly check the file to ensure 
that all relevant documents are retained. The contents of the file may be audited/inspected by 
the Sponsor’s auditor, regulatory authorities, or IRB/IEC.
Period of Record Retention 
The study site (and the Principal Investigator) will retain the essential documents as specified 
by GCP (eg, source document such as medical records, contract, signed informed consent
form). Essential documents should be retained at the study site for 15 years in principle 
following completion of the study, or per regulatory obligations if longer, and thereafter 
destroyed only after agreement with the Sponsor. However, this is not always applied to those 
that are not preservable such as blood samples. In the event of any inconsistency between the 
above-mentioned contents and the contract with the study site, the contract shall prevail. 
These documents should be retained for a longer period, however, if needed by the Sponsor, 
and the specific period and method of retention will be separately discussed between the study 
site and the Sponsor (or designee). The Sponsor should notify the head of the study site in 
writing when the study-related records are no longer needed. The records must be managed by 
a responsible person appointed by the head of the study site.
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. 
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.


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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
Medical Monitor Coverage
Each subject will be provided with contact information of the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or healthcare provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Ethical Conduct of the Study
The study will be conducted in compliance with the Declaration of Helsinki, the clinical study 
protocol, ICH/GCP, and any local standard. 
7.2
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 trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, 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. 
7.3
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 head of the medical institution is responsible for 
submitting these documents to the applicable IRB/IEC and distributing them to the study site 
staff.


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The opinion of the IRB/IEC must be given in writing. The head of the medical institution 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 
the respective country 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 Principal 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 via the head of the medical institution. The Sponsor will provide this information to 
the Investigator so that he/she can meet these reporting requirements. The head of study site is 
responsible for providing the report and on keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol but, in any case, at least once a year.
7.4
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’s legal guardian is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study

Ensure each subject’s legal guardian is notified that they are free to discontinue from the 
study at any time

Ensure that each subject’s legal guardian is given the opportunity to ask questions and 
allowed time to consider the information provided

Ensure each subject’s legal guardian provides signed and dated informed consent before 
conducting any procedure specifically for the study

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’s legal guardian


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
Ensure that any incentives for subjects and/or their legal guardians 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
7.5
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 7.3) 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.
7.6
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
REFERENCES
Asner S, Stephens D, Pedulla P, Richardson SE, Robinson J, Allen U. Risk factors and 
outcomes for respiratory syncytial virus-related infections in immunocompromised children. 
Pediatr Infect Dis J. 2013;32(10):1073-6.
Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL et al. 
Dutch, RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy 
preterm infants. N Engl J Med. 2013;368(19):1791-9.
Domachowske JB, Khan AA, Esser MT, Jensen K, Takas T, Villafana T et al. Safety, 
Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-life Single-dose 
Respiratory Syncytial Virus Prefusion F-targeting Monoclonal Antibody Administered as a 
Single Dose to Healthy Preterm Infants. Pediatr Infect Dis J. 2018;37(9):886-92.
Greenough A, Cox S, Alexander J, Lenney W, Turnbull F, Burgess S et al. Health care 
utilisation of infants with chronic lung disease, related to hospitalisation for RSV infection. 
Arch Dis Child. 2001;85(6):463-8.
Griffin MP, Khan AA, Esser MT, Jensen K, Takas T, Kankam MK et al. Safety, Tolerability, 
and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting 
Monoclonal Antibody with an Extended Half-Life, in Healthy Adults. Antimicrob Agents 
Chemother. 2017;61(3). pii: e01714-16.
Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 
2001;344(25):1917-28.
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA et al. The burden 
of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588-98.
Kashiwagi T, Okada Y, Nomoto K. Palivizumab Prophylaxis Against Respiratory Syncytial 
Virus Infection in Children with Immunocompromised Conditions or Down Syndrome: A 
Multicenter, Post-Marketing Surveillance in Japan. Paediatr Drugs. 2018;20(1):97-104.
Kim E, Okada K, Beeler JA, Crim RL, Piedra PA, Gilbert BE et al. Development of an 
adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, 
immunogenicity, and enhanced disease in a cotton rat model. J Virol. 2014;88(9):5100-8.
Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K et al. Respiratory 
syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. 
Am J Epidemiol. 1969;89(4):422-34.


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Maifeld SV, Ro B, Mok H, Chu M, Yu L, Yamagata R et al. Development of 
electrochemiluminescent serology assays to measure the humoral response to antigens of 
respiratory syncytial virus. PLoS One. 2016;11(4):e0153019.
Manzoni P, Figueras-Aloy J, Simoes EAF, Checchia PA, Fauroux B, Bont L et al. Defining 
the Incidence and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus 
Infection Among Children with Chronic Diseases. Infect Dis Ther. 2017;6(3):383-411.
Meissner HC. Selected populations at increased risk from respiratory syncytial virus infection. 
Pediatr Infect Dis J. 2003;22(2 Suppl):S40-5.
Mori M, Onodera M, Morimoto A, Kosaka Y, Morio T, Notario GF et al. Palivizumab use in 
Japanese infants and children with immunocompromised conditions. Pediatr Infect Dis J. 
2014;33(11):1183-5.
Moyes J, Cohen C, Pretorius M, Groome M, von Gottberg A, Wolter N et al. Epidemiology of 
respiratory syncytial virus-associated acute lower respiratory tract infection hospitalizations 
among HIV-infected and HIV-uninfected South African children, 2010-2011. J Infect Dis. 
2013;208 Suppl 3S217-26.
Parrott RH, Kim HW, Arrobio JO, Hodes DS, Murphy BR, Brandt CD et al. Epidemiology of 
respiratory syncytial virus infection in Washington, D.C. II. Infection and disease with respect 
to age, immunologic status, race and sex. Am J Epidemiol. 1973;98(4):289-300.
Resch B, Manzoni P, Lanari M. Severe respiratory syncytial virus (RSV) infection in infants 
with neuromuscular diseases and immune deficiency syndromes. Paediatr Respir Rev. 
2009;10(3):148-53.
Rowan CM, Gertz SJ, Zinter MS, Moffet J, Bajwa RPS, Barnum JL et al. A multicenter 
investigation of respiratory syncytial viral infection in children with hematopoietic cell 
transplantation. Transpl Infect Dis. 2018;20(3):e12882.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, 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(2):391-7.
Shambaugh C, Azshirvani S, Yu L, Pache J, Lambert SL, Zuo F et al. Development of a high-
throughput respiratory syncytial virus fluorescent focus-based microneutralization assay. Clin 
Vaccine Immunol. 2017;24(12).
Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-
associated hospitalizations among US children, 1980-1996. JAMA. 1999;282(15):1440-6.


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Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD et al. Global, 
regional, and national disease burden estimates of acute lower respiratory infections due to 
respiratory syncytial virus in young children in 2015: a systematic review and modelling 
study. Lancet. 2017;390(10098):946-58.
Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virus-
associated hospitalizations among infants and young children in the United States, 1997-2006. 
Pediatr Infect Dis J. 2012;31(1):5-9.
Welliver RC. Review of epidemiology and clinical risk factors for severe respiratory syncytial 
virus (RSV) infection. J Pediatr. 2003;143(5 Suppl):S112-7.
Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J et al. A highly 
potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci 
Transl Med. 2017;9(388).


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9
CHANGES TO THE PROTOCOL 
At the time of the original protocol and Amendments 1 and 2, this study was planned to be 
conducted only in Japan. Amendments 1 and 2 are described below. Amendment 3, which
revised the protocol for global use, is described before the Protocol Synopsis.
9.1
Protocol Amendment 1 dated 24 April 2020
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1.
The protocol was amended to include the following substantial changes:
1.
Section 5.5.4 (Potential Hy’s Law and Hy’s Law): New section required per protocol 
template for studies that include laboratory assessments.
2.
Section 5.6 (Reporting of Serious Adverse Events): Change in email address for SAE 
reporting.
3.
Appendix C (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law): New appendix required per protocol template for studies that 
include laboratory assessments.
9.2
Protocol Amendment 2 dated 17 Dec 2020 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2.
1.
Cover page: updated Medical Monitor information.
2.
Incorporated protocol revisions in  “Addendum for domestic use of the Clinical Study 
Protocol D5290C00008, Version 2.0 dated 03Jun2020”.
(a) Section 4.1.2 “Inclusion Criteria”: added clarification for inclusion criteria 2 that all 
efforts will be made to recruit subjects into different subtypes 2 (a) to 2 (f)
(b) Section 4.3.7 “Clinical Laboratory Tests”: newly added section
(c) Section 4.5.1.2 “Dose Preparation Steps and Treatment Administration”: removed the 
word “placebo” as it is not applicable to the study
(d) Section 7.1 “Ethical Conduct of the Study”: newly added section
(e) Section 7.3 “Ethics and Regulatory Review”: added at end of the section, site head’s 
responsibility
3.
Section 3.1.1 “Overview”: updated the arm description in Figure 1.
4.
Section 3.1.2 “Treatment Regimen”: clarified target populations are “subjects in first year 
of life and entering their first RSV season at dose administration” and “Subjects in second 
year of life and entering their second RSV season at dose administration”.
5.
Section 4.1.2 “Inclusion Criteria”: updated inclusion criteria 1 to reflect target 
populations, and clarified this eligibility criterion is assessed per Investigator judgment
6.
Section 4.2.2 “Treatment and Follow-up Periods”: Table 5, remove “as needed” from the 
visit number description for “LRTI” and “Skin Reactions”.


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7.
Section 4.3.1.1 “Lower Respiratory Tract Infection”: Table 6, added reference to the 
footnote in table for lower respiratory tract and medical significance for clarity.
8.
Section 4.3.1.1 “Lower Respiratory Tract Infection”: subsection “Respiratory Secretions 
for RSV Detection”, added sample storage and destruction details. 
9.
Section 4.3.3 “Pharmacokinetics, Antidrug Antibody, and RSV Serology”: added sample 
storage and destruction details.
10. Section 4.3.3.3 “RSV Neutralizing Antibody Evaluation”: clarified that Analyses will be 
performed using an updated version of the RSV NAb assay previously described.
11. Section 4.5.1.2 “Dose Preparation Steps and Treatment Administration”: clarified target 
population.
12. Section 4.7.3 “Guidance for Additional Palivizumab Administration after Day151”: 
newly added section in addendum 2.0 dated 03Jun20; further updates made to clarify the 
palivizumab use on study. 
13. Appendix B: formatted numbering.


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Appendix A
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 an 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 severity categories of Grade 1 to 5, as defined below.


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Grade 1
An event of mild intensity that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2
An event of moderate intensity that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly affects 
the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death.
Grade 5
Death as a result of an event.
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) 
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.


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
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.
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 B
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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Template 18.0
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
C 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law cases and Hy’s Law cases. 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. For 
example, potential Hy’s Law criteria could be met by an elevated ALT from a central 
laboratory and/or elevated TBL from a local laboratory.
The Investigator will also review 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 Sponsor 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 SAEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
C 2
Definitions
C 2.1
Potential Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in alkaline 
phosphatase.
C 2.2
Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
alkaline phosphatase indicating cholestasis, viral hepatitis, or another drug.


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Template 18.0
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.
C 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 ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The Investigator will, without delay, review each new laboratory report and, if the 
identification criteria are met, will:

Notify the Sponsor study representative

Repeat the test (new blood draw) without delay

Determine whether the participant meets potential Hy’s Law criteria (see Section C 2 for 
definition) by reviewing any laboratory reports from all previous visits

Complete the appropriate unscheduled laboratory case report form (CRF) module(s) with 
the original local laboratory test result.
C 4
Follow-up
C 4.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet potential Hy’s Law criteria the Investigator will:

Inform the Sponsor study representative that the participant has not met potential Hy’s 
Law criteria.

Perform follow-up on subsequent laboratory results, as applicable.
C 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 
reporting.


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Template 18.0
The medical monitor contacts the Investigator, to provide guidance, discuss and agree on 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 medical monitor. 

Complete the relevant CRF Modules as information becomes available.
C 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 medical 
monitor will contact the Investigator in order 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 caused by the investigational product, to ensure timely analysis and 
reporting to health authorities per local requirements from the date potential Hy’s Law criteria 
were met. The medical monitor 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 an 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, update the previously submitted potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following 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:


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Template 18.0

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

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 over 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 are related to the 
investigational product and seriousness criteria is 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 still 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.
C 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 study treatment 
and has already met potential Hy’s Law criteria at a previous on study treatment 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 iIvestigator 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 C 4.2, for reporting potential Hy’s Law as an 
SAE.


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Template 18.0
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

If there is a significant change follow the process described in Section C 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 medical monitor if there is any uncertainty.
C 7
Laboratory Tests
To evaluate the underlying etiology of potential Hy’s Law cases, relevant laboratory tests may 
be performed as clinically indicated.
C 8
References
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5290c00008-csp-amendment-v3
Document Title:
D5290C00008 Clinical Study Protocol Amendment version 3
Document ID:
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
24-Jun-2021 12:37 UTC
Content Approval
24-Jun-2021 12:40 UTC
Content Approval
24-Jun-2021 12:47 UTC
Content Approval
PPD
PPD
PPD
CCI
CCI

SAP_001.pdf: 
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Statistical Analysis Plan Amendment
Study Code
D5290C00008
Edition Number
3
Date
17 November 2022
A Phase 2, Open-label, Uncontrolled, Single-dose Study to 
Evaluate the Safety and Tolerability, Pharmacokinetics, and 
Occurrence of Antidrug Antibody for Nirsevimab in 
Immunocompromised Children ≤ 24 Months of Age






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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical Classification System
CBC
complete blood count
CI
confidence interval
COVID-19
coronavirus disease 2019
CPAP
Continuous Positive Airway Pressure 
CSP
clinical study protocol
CSR
clinical study report
CV
coefficient of variation
DAIDS
Division of AIDS
DCO
data cut-off
eCRF
electronic case report form
ED
emergency department
FDA
Food and Drug Administration
GMC
geometric mean concentration
GMFR
geometric mean-fold rise
HRU
healthcare resource utilization
ICU
intensive care unit
IM
intramuscular
IP
investigational product
IPD
important protocol deviation
LLOQ
lower limit of quantification
LRTI
lower respiratory tract infection
MedDRA
Medical Dictionary for Regulatory Activities
nAb
neutralizing anti-drug antibody
NOCD
new onset chronic diseases
OTC
over-the-counter
PK
pharmacokinetics
PT
preferred term


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Abbreviation or special 
term
Explanation
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal
US
United States
WBC
white blood cell count
YTE
M257Y/S259T/T261E triple amino acid substitution


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AMENDMENT HISTORY
Version
Date
Description of change
1.0
30 June 2020
Initial signed version
Amendment 1
21 December 
2021
Key change compared to previous signed version is the 
expansion of the study from Japanese to a Global study.
Other minor changes are listed below:

Editorial changes for clarification.

Section 1.2 and 1.3, updated as per protocol to 
increase number of sample size and study 
expansion.

Section 2.1, added new analysis set for Japan 
population only.

Section 2.2.1, added an summary for IPDs which 
are related to COVID-19.

Section 3.1.3, updated the analysis of skin reactions 
(including hypersensitivity reactions) to two 
separate analyses of skin reactions and skin
hypersensitivity reactions.  

Section 3.3.4, removed the number and type of 
outpatient visits.

Section 4.1, changed the number of planned 
analysis from one to two, an interim analysis and a 
final analysis.
Also added a description for visit-based summaries 
for ADA, 
 
and clinical laboratory data.
Also added a description to explain that the 
presentation of analysis tables is to be presented by 
season and total. 

Section 4.1.1, updated treatment group from 
MEDI8897 to nirsevimab.

Section 4.1.4, updated imputation rules for partial 
AEs dates and added imputation rule for partial 
concomitant medications dates.

Section 4.1.5, new section added for 
implementation of data cut-off at interim analysis.

Section 4.2.1, added a new summary for subjects 
enrolment by hemisphere, country and site. 

Section 4.2.2, removed RSV season from the 
summary of demographic and baseline 
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characteristics, and added gestational age and 
summary of inclusion criteria 2.

Section 4.2.4.1, added the summary of IP-related 
AEs, AESI based on investigator assessment, AESI 
based on selected MedDRA PT codes, skin 
reactions and skin hypersensitivity reactions.

Section 4.2.4.2, added description for AESI based 
on investigator assessment and AESI based on 
selected MedDRA PT codes.

Section 4.2.4.3, split the analysis of skin reactions 
(including hypersensitivity reactions) to two 
separate analyses of skin reactions, and skin 
hypersensitivity reactions.

Section 4.2.4.5, remove subgroup analysis by RSV 
season. And added one extra subgroup to the 
subgroup analysis by AE onset time relative to 
dosing.

Section 4.2.5.1, added description for PK analysis.

Section 0, added description for the analysis of 
ADA.

Section 4.2.5.3, removed the summary of incidence 
of MA RSV LRTI by inpatient and outpatient 
settings. The analysis with break down by 
hospitalization setting is also removed. The 
summary of central or local testing are presented 
separately.
Added a new table, Table 1 to describe the analysis 
endpoints. 

Section 284.2.6.1 and Section 4.2.6.2, added new 
summaries and analyses for PK and ADA.

Section 4.2.6.4, removed the summary of visiting 
outpatient facilities. And added a description to 
report HRU by the analysis endpoints described in 
Table 1.
Also updated the analysis of OTC medication to 
pre-specified OTC medication 
(analgesics/antipyretics), pre-specified prescription 
medication (systemic antibacterial agents) and anti-
wheezing medication.

Section 4.2.7.1, added a text to explain that clinical 
laboratory data will only be presented for Japan 
population.


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
Section 4.2.7.3, added a summary for medical 
history and summary for vaccination received 
within ±14 days of IP dosing.

Section 4.2.7.4, new section added analyses to
examine impact on analyses due to COVID-19 
pandemic.

Section 5.1 and Section 5.2, new sections added for 
interim analysis and data monitoring committee.

Section 2.1, updated analysis sets to ‘as-treated 
population’ and ‘as-treated Japan subpopulation’.

Section 3.3.4, added ‘number and type of outpatient 
visits’ back to the HRU measures.

Sections 3.1  and 4.2.4.1, updated MedDRA version 
to 24.1 or higher.

Section 4.2.4.1, added IP related AESIs based on 
investigator assessment.

Sections 4.2.4.2 and 4.2.4.3, added new analysis by 
highest severity.

Section 4.2.5.1, added a new PK analysis of 
nirsevimab serum concentration by inclusion 
criterion number 2.

Section 0, added that ADA results will not be 
imputed and added derivations for treatment-
emergent ADA negative and treatment-emergent 
ADA positive.

Section 4.2.6.4, added back summary of visiting 
outpatient facilities.

Appendix 2, updated analysis window for 
PK/ADA/RSV.

Appendix 4, new appendix.

Section 1.2, study design updated based on 
information provided by note-to-file memo, where 
recruitment is based on subjects age and weight and 
not RSV season.

Section 4.1, updated the presentation of data from 
being by subjects age at dosing to actual dose 
administered, ‘nirsevimab 50mg/100mg’ and 
‘nirsevimab 200mg’.

Section 4.2.5.1, added new spaghetti plots for 
subjects nirsevimab serum concentration over time 


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by disease conditions under inclusion criterion 
number 2.

Section 4.2.5.2, updated analysis groups to 
‘nirsevimab 50mg/100mg’ and ‘nirsevimab 
200mg’.

Section 4.2.5.3, added new analysis of MA LRTI 
and MA LRTI with hospitalization.

Sections 4.2.6.1 and 4.2.6.2, changed box plots to 
line plots.

Appendix 2, updated and added new table to clarify 
timepoints for PK analysis between Global and 
Japanese subjects.
Amendment 2
15 June 2022

Section 4.1.5 specified the data cut-off 
(16May2022) and indicated that this data cut-off
will be displayed in the header of the tables, listings 
and figures.

Section 5.1 added the name of the document with 
the tables, listings and figures.
Amendment 3 
16 Nov 2022

During the study conduct a need for a second 
interim analysis was identified and details are 
included in Section 5.2.

For the deviation of summary statistics for PK data, 
new rules are defined to be in-lines with other 
nirsevimab studies (
) (Section 
4.1).
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1
STUDY DETAILS
This is the statistical analysis plan (SAP) for study D5290C00008. The SAP expands on the 
statistical analyses specified in the clinical study protocol (CSP). Any changes to any
specifications in the CSP will be described in Section 6 of this document.
This SAP is based on the CSP Amendment Version 3.0, dated 23 June 2021 (global 
amendment), and 4 July 2021 (Japan amendment).
1.1
Study objectives
The study objectives are to evaluate the safety and tolerability, pharmacokinetics (PK),
occurrence of anti-drug antibody (ADA) and efficacy for nirsevimab in immunocompromised 
children ≤ 24 months of age.
1.1.1
Primary objective
The primary objective is to evaluate the safety and tolerability of nirsevimab when 
administered to immunocompromised children ≤ 24 months of age.
1.1.2
Secondary objectives
The secondary objectives are:

To evaluate the PK of nirsevimab.

To evaluate the ADA responses to nirsevimab in serum.

To assess the efficacy of nirsevimab when administered as a single intramuscular (IM) 
dose to infants ≤24 months of age.
1.1.3
Exploratory objectives
The exploratory objectives are:

To assess healthcare resource utilization (HRU) for nirsevimab recipients.
1.2
Study design
This is a Phase 2, open-label, uncontrolled single-dose study to assess the safety and 
tolerability, PK, occurrence of ADA, and efficacy of nirsevimab in immunocompromised 
children who are ≤ 24 months of age at the time of dose administration. The study is planned 
to be conducted in South Africa, the United States, and the European Union, in addition to 
Japan, where enrolment in the study originated. Approximately 100 subjects will be enrolled. 
Due to atypical RSV circulation and RSV seasons in 2020/2021, the RSV season will not be 
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considered for dose selection. The dose of nirsevimab is administered only based on the age 
and body weight regardless of the first or second RSV season subjects is entering. Subjects 
who are in their first year of life at the time of dose administration will receive nirsevimab as a 
single, fixed IM dose of 50 mg if body weight < 5 kg or 100 mg if body weight ≥ 5 kg. 
Subjects in their second year of life at the time of dose administration will receive nirsevimab 
as a single, fixed IM dose of 200 mg. Subjects will be followed up for approximately 1 year 
after dose administration.
A flow diagram of the study design is presented in Figure 1.
Figure 1 Study Flow Diagram
IM = intramuscular; LRTI = lower respiratory tract infection; n = number of subjects; RSV = respiratory
syncytial virus.


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1.3
Number of subjects
A total of approximately 100 subjects are planned to receive a single IM dose of nirsevimab to 
evaluate the safety, PK, ADA, and efficacy, which will be assessed descriptively. The original 
proposed sample size, as stated in the original CSP dated 27 January 2020, was based on a 
similarly designed palivizumab study in a similar population (Mori, et al. 2014), and it is 
expected to be sufficient in establishing a PK profile that allows extrapolation of efficacy and 
safety data from the Phase 2b (D5290C00003) and Phase 3 (
) studies in healthy 
preterm and term infants to the target immunocompromised population. The updated sample 
size of 100, from the original sample size of 30 as stated in the original CSP, allows for the 
collection of PK and safety data from a larger cohort of immunocompromised children, and 
for the study of immunocompromised children and the various causes for this condition 
globally. Further, the data from this study will support the evaluation of safety in a diverse 
population, which could potentially facilitate the examination of subpopulations.
 
 
Subjects will not be replaced.
2
ANALYSIS SETS
2.1
Definition of analysis set
The analysis sets defined in this study are the as-treated population and the as-treated Japan 
subpopulation. All analyses performed are to be conducted on these populations unless stated 
otherwise.
The as-treated population includes all subjects who are enrolled (once written informed 
consent is obtained) and received any dose of nirsevimab.
The as-treated Japan subpopulation is a subset of the as-treated population and includes only
subjects who were enrolled in sites located in Japan.
2.2
Violations and deviations
Subjects who do not meet eligibility criteria but are still enrolled will be analyzed according to 
the analysis set described in Section 2.1. There is no intention to perform a per-protocol 
analysis in this study. 
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2.2.1
Important protocol deviations
Important protocol deviations (IPDs) are a subset of protocol deviations that may significantly 
impact the completeness, accuracy and/or reliability of the study data or that may significantly 
affect a subject’s rights, safety, or well-being.
Only important protocol deviations will be summarized and listed in the clinical study report
(CSR). The number and percentage of subjects with at least one IPD will be summarized by 
the categorization of protocol deviations. The number and percentage of subjects whose IPDs 
are related to COVID-19 will also be provided. A list of IPDs will be reviewed and finalized 
by the medical advisors and statisticians prior to database lock. Full details are described in 
the Protocol Deviation Management Plan.
3
PRIMARY, SECONDARY AND EXPLORATORY VARIABLES
3.1
Primary variables
The following safety data will be collected: treatment-emergent adverse events (TEAEs), 
treatment-emergent serious adverse events (TESAEs), adverse events of special interest 
(AESIs), skin reactions, and new onset chronic diseases (NOCDs).
Adverse events and serious adverse events (SAEs) will be collected from the time of signature 
of informed consent through Day 361. Adverse events of special interest and NOCDs will be 
collected from the time of dosing through Day 361. Adverse events will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA), Version 24.1 or 
higher. 
3.1.1
Treatment-emergent adverse events and serious treatment-emergent 
adverse events (TEAEs and TESAEs)
Treatment-emergent adverse events are defined as AEs whose onset occurs after receiving 
nirsevimab and within 360 days post dose. Adverse events with completely missing onset 
dates and a stop date after the start date of receiving nirsevimab (or unknown stop date) will 
also be considered treatment emergent. A TESAE is an TEAE which is serious.
3.1.2
Adverse events of special interest (AESIs)
An AESI is an AE of scientific and medical interest specific to the understanding of the 
investigational product (IP), nirsevimab and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or nonserious. 
Adverse events of special interest are defined as AEs of immediate (type I) hypersensitivity 
(including anaphylaxis), thrombocytopenia, and immune complex disease (eg, vasculitis, 
endocarditis, neuritis, glomerulonephritis, serum sickness, and arthralgias) following the 
administration of nirsevimab. 


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3.1.3
Skin reactions and skin hypersensitivity reactions
All skin reactions and skin reactions identified as hypersensitivity/allergic reactions and the 
incidence and relationship to IP will be summarized by SOC and PT. It will be done for any 
post-dosing skin or skin hypersensitivity reactions through Day 361 to assist in determination 
of the etiology of the reaction. Information will be collected regardless of event severity, 
duration, time of onset post dosing, or relationship to IP.
3.1.4
New onset chronic disease (NOCD)
An NOCD is a newly diagnosed medical condition that is of a chronic, ongoing nature. It is 
observed after receiving nirsevimab 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). 
3.2
Secondary variables
3.2.1
Pharmacokinetic (PK) variables
The PK variable is nirsevimab serum concentration.
3.2.2
Anti-drug antibodies (ADA) variable
The ADA variable is the incidence of ADA to nirsevimab in serum. The impact of ADA on 
PK, and the association with TEAEs and TESAEs, will be assessed, if data permit.
3.2.3
Efficacy variables
The efficacy variables are the incidence of protocol-defined medically attended lower 
respiratory tract infections (LRTI) (inpatient and outpatient) due to reverse transcriptase-
polymerase chain reaction (RT-PCR)-confirmed RSV, also described as the medically 
attended RSV LRTI, and the incidence of protocol-defined hospitalizations due to RT-PCR-
confirmed RSV, also described as RSV LRTI hospitalization, through 150 days post dose,
after 150 days post dose, and through 360 days post dose. For subjects with multiple 
medically attended RSV LRTI events (inpatient or outpatient) or multiple RSV LRTI 
hospitalizations, only the first occurrence will be used in the analysis, unless stated otherwise.
The determination of medically attended RSV LRTI will be based on objective clinical LRTI 
criteria (described in Section 4.3.1.1 of the CSP and in Appendix 1 of this SAP) and RSV 
central laboratory test results. Protocol-defined medically attended LRTI will be identified 
when at least one item of “Physical exam findings” and at least one item of “Clinical signs of 
severe disease” from ‘Respiratory Illness Assessment’ eCRF page are selected as ‘yes’. If 
there are multiple assessment settings associated with the same event, then assessment data of 
those visits will be combined to determine whether the event meets criteria for the protocol-
defined medically attended RSV LRTI.


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Testing for RSV will be performed centrally using a United States Food and Drug 
Administration (US FDA)-cleared and Conformité Européenne or European Conformity
marked in vitro diagnostic real-time RT-PCR assay. The RSV test results obtained from 
analyzing the respiratory secretions using a validated RSV RT-PCR assay for the detection of 
RSV A or RSV B are performed in a central laboratory. Respiratory syncytial virus tests are 
also performed by local laboratories, if available, and the test results are captured in the 
‘Respiratory Illness Assessment’ eCRF page. 
The events of “RSV LRTI hospitalization” are a subset of “medically attended RSV LRTI,” 
which are determined based on objective clinical LRTI criteria (described in Section 4.3.1.1 of 
the CSP and in Appendix 1 of this SAP) and RSV test results obtained from central laboratory 
using a validated RSV RT-PCR assay for the detection of RSV A or RSV B. If any of the 
settings associated with the medically attended RSV LRTI is hospitalization, then this 
medically attended RSV LRTI will be counted as RSV LRTI hospitalization. 
3.3
Exploratory variables
3.3.4
Healthcare resource utilization (HRU)
The magnitude of HRU will be measured by:

the number of admissions to hospitals and duration of stay; 

the number of admissions to the intensive care units (ICUs) and duration of stay; 

the number of subjects who require respiratory support (using Continuous Positive 
Airway Pressure [CPAP] or mechanical ventilation) and duration of use, and the number 
of subjects requiring supplemental oxygen and duration of use;

number and type of outpatient visits, eg, outpatient emergency department (ED), urgent 
care, outpatient clinic;

the number of pre-specified over-the-counter (OTC) medications (analgesics/antipyretics)
use; 

the number of pre-specified prescription medication (systemic antibacterial agents) use; 
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
the number of anti-wheezing medication use.
4
ANALYSIS METHODS
All analyses described will be conducted on the as-treated population and as-treated Japan 
subpopulation as defined in Section 2.1 unless stated otherwise.
No formal statistical comparisons are planned.
4.1
General principles
There are 2 planned analyses for this study: an interim analysis and a final analysis. The 
interim analysis will be conducted when subjects enrolled globally by the end of 2021 have 
been followed through Day 151. The final analysis will be conducted when all subjects have 
completed the last visit of the study (Day 361). The data will be validated as defined in the 
Data Management Plan.

For the visit-based summaries for PK/ADA, 
 
and clinical laboratory data, the summaries will be based on the scheduled visits using
adjusted analysis-defined visit windows. The adjusted analysis-defined windows will be 
based on the collection schedule listed in the CSP and summaries will be windowed to the 
closest scheduled visit for those data. Visit windows have been constructed so that every 
observation collected can be allocated to a particular visit. All data will be included in the 
listings. If multiple readings are recorded within a single analysis-defined visit window, 
the following rules will apply: If there are 2 or more valid, non-missing observations 
within the same visit window, and

if they are on different days, then the non-missing one which is closest to the 
scheduled visit day will be used in the analysis.

if they are on the same day which is closest to the scheduled visit day, then the non-
missing one with the later collection time will be used in the analysis.

If 2 or more valid observations are equidistant from the scheduled visit, and

if they are on different days, then the non-missing post-dose observation with the 
earlier collection date will be used in the analysis for the post-baseline observations, 
and the non-missing pre-dose observation with the later collection date will be used 
in the analysis for the screening observations.

if they are on the same day, then the non-missing observation with the later collection 
time will be used in the analysis.

For LRTI visits or unscheduled visits, if 2 or more valid observations are collected on the 
same day, then the non-missing observation with the later collection time will be included
in the analysis. 

If a visit window does not contain any observations, then the data will remain missing.

For the visit-based summaries for ADA, if both ADA positive and negative samples are
available within a subject’s visit, ADA positive will be reported.
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
For summary Statistics of PK data following rules apply:

Handling of samples below LLOQ, samples should be imputed to the LLOQ (0.5 
µg/mL)

Summary statistics should not be presented in case of >=50% of samples <LLOQ 
(see specific details of reporting in Section 4.1.7)
For assignment of data to adjusted analysis-defined visit windows, study day will be defined 
as defined in Section 4.1.3.
The adjusted analysis-defined windows for PK/ADA, 
 
are defined in Appendix 2, and for clinical laboratory data are defined in Appendix 3.
Data will be summarized for the overall study population, as well as for Japan only. Data will 
also be presented by the actual dose administered; ‘nirsevimab 50mg/100mg’, ‘nirsevimab 
200mg’ and ‘total’, unless stated otherwise.
Data analyses will be performed by IQVIA under the direction of AstraZeneca using the 
SAS® System Version 9.4 or higher (SAS Institute Inc., Cary, NC) in a SAS GRID 
environment.
4.1.1
General data reporting conventions    
Categorical data will be summarized by the number and percentage of subjects in each 
category. Percentages will be rounded to 1 decimal place. Continuous variables will be 
summarized by mean, median, standard deviation (SD), minimum, and maximum, unless 
stated otherwise. The mean and median will be presented with one more decimal place than 
the raw data. The standard deviation will be presented with two more decimal places than the 
raw data. Minimum and maximum values will have the same number of decimal places as the 
raw data.
Data collected at unscheduled visits will not be included in summaries by timepoint or visit 
unless stated otherwise. Data collected at unscheduled visits will be presented in listings.
In tables and listings, treatment group will be presented as ‘nirsevimab’. 
4.1.2
Definition of baseline
Baseline will be defined as the last non-missing value prior to administration of nirsevimab, 
unless stated otherwise.
4.1.3
Derivation of study day
Study day will be calculated as follows:

If the evaluation date is on or after the administration date of nirsevimab: 
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study day = date of evaluation – administration date of nirsevimab + 1

If the evaluation date is before the administration date of nirsevimab:
study day = date of evaluation – administration date of nirsevimab
4.1.4
Handling of missing data
No imputation for missing data will be applied except for the partial dates.
4.1.4.1
General imputation rule for partial dates
•
Partial dates where only the year is known:

For start dates assume January 1st;

For stop dates assume December 31st.
•
Partial dates where only the month and year are known:

For start dates assume the first of the month;

For stop dates assume the end of the month.
4.1.4.2
Imputation rule for partial AE start date
•
When AE range is available: 
Step 1: For partial AE start dates, regardless if only the year is known, or only the month and 
year are known, first use the following rule to impute AE start date:
a.
Assume (dose date + 1 day) if AE started ≤7 days after dosing;
b. Assume (dose date + 7 days) if AE started 8 - 14 days after dosing;
c.
Assume (dose date + 14 days) if AE started >14 days after dosing.
Step 2: After getting an imputed AE start date from Step 1, compare the imputed AE start date 
with the partial AE start date:

If partial AE start date where only the year is known: 
-
If the year of partial AE start date is the same as imputed AE start date 
from Step 1, then use imputed AE start date from Step 1; 
-
If the year of partial AE start date is different from the year of imputed 
AE start date from Step 1, assume partial AE start date as January 1st;
-
If the imputed AE start date is after AE end date, then set AE start date 
the same as AE end date.

If partial AE start date where only the year and month are known:
-
If the year and month of partial AE start date are the same as imputed 
AE start date from Step 1, then use imputed AE start date from Step 1; 
-
Otherwise, assume partial AE start date as the first day of the month. 
-
If the imputed AE start date is after AE end date, then set AE start date 
the same as AE end date.
•
When AE range is not available:

If partial AE start date where only the year is known, 
-
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i. If AE does not occur on the same day of dosing, then AE start 
date is one day after dosing date; 
ii. Otherwise, AE start date is the same as dosing date.
-
If different year from dosing date, assume January 1st. 

If partial AE start date where only the year and month are known, 
-
If the same year and month as dosing date:
i. If AE does not occur on the same day of dosing, then AE start 
date is one day after dosing date; 
ii. Otherwise, AE start date is the same as dosing date.
-
Otherwise, assume the first day of that month.
4.1.4.3
Imputation rule for partial concomitant medications dates
•
If a concomitant medication is not associated with an AE:
a.
Apply general imputation rule described in Section 4.1.4.1 wherever it fits.
•
If a concomitant medication is associated with an AE:
a.
The concomitant medication start date will be imputed with either observed or 
imputed AE start date described in Section 4.1.4.2. If there are multiple associated 
AEs, the earliest AE start date either observed or imputed will be used for 
imputation. 
b. The concomitant medication end date will be imputed by the general imputation 
rule described in Section 4.1.4.1 for end date whenever fits. Then compare the 
imputed concomitant medication start date or end date with the data cut-off and 
apply the implementation rule for data cut-off for interim analysis described in
Section 4.1.5. If the imputed concomitant medication end date is after the end of 
study date, then the concomitant medication end date will be replaced with the end 
of study date.
4.1.5 Implementation of data cut-off (DCO) for interim analysis
The principle is to only report the data collected up to the DCO date (16May2022) for the 
interim analysis. 

Partial dates will be imputed before applying DCO.

Records with start date after DCO will be removed in SDTM datasets

If end date is after DCO, then end date will be reset as missing, event status will be reset 
as ongoing in SDTM datasets if applicable.
The date of DCO is displayed in the header of tables, listings and figures for DCO applied 
outputs as: ‘Interim Analysis: Data cut-off = 16MAY2022’. If outputs are produced before IA 
a prefix is added as ‘Pre-‘.
4.1.6
Character values of clinical laboratory variables
Quantitative laboratory measurements reported as “< X” or “≤ X”, ie, below the lower limit of 
quantification, or “> X” or “≥ X”, ie, above the upper limit of quantification, will be converted 


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to half of X or X for the purpose of quantitative summaries, but will be presented as recorded, 
ie, as “< X” or “> X” in the listings.
For ADA titer reported as “< X” or “≤ X”, refer to Section 0 for details.
4.1.7
Reporting PK concentration
Individual compound concentrations below the lower limit of Quantification (LLOQ) of the 
assay are reported as NQ (not quantifiable) with the LLOQ defined in the Tables, Figures and 
Listings (TFLs).
For descriptive statistics:

If, at a given time point, 50% or less of the plasma concentrations are not quantifiable 
(NQ), the geomean, coefficient of variation (CV), geoSD, arithmetic mean and 
standard deviation (SD) are calculated by substituting the limit of quantification 
(LOQ) for values which are NQ.

If more than 50%, but not all, of the concentrations are NQ, the geomean, CV, geoSD, 
arithmetic mean, and SD are reported as not calculable (NC). The max value is 
reported from the individual data, and the min and median are set to NQ.

If all the concentrations are NQ, the geomean and arithmetic mean are reported as NQ 
and the CV, geoSD and SD as NC.

The number of values below LLOQ are reported for each time point along with the 
total number of collected values.
Three observations >LLOQ are required as a minimum for a plasma concentration to be 
summarized. Two values are presented as a minimum and maximum with the other summary 
statistics as NC.
For consistency, the same plasma concentration values are used in the mean data graphs as 
those given in the descriptive statistics summary table for each time point. 
4.2
Analysis methods
4.2.1
Subject disposition and completion status
A summary of subject eligibility, reasons for screen failure, reasons for early discontinuation 
and enrolment status as well as treatment received (including summary of subjects enrolled 
but not dosed) will be provided. In addition, disposition of subjects throughout the study,
number of subjects who completed Day 151 for inclusion in the efficacy evaluation and 
number of subjects who completed the study (Day 361) as planned, will be provided. The 


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denominators for this summary will include all subjects who were enrolled and dosed unless 
stated otherwise. In addition, subjects who discontinued the study will also be listed.
Subjects enrolment will be presented by hemisphere, country, and site, with the date of first 
and last subjects IP administration, and the date last subject evaluated. This will be presented 
for the as-treated population only.
The number of subjects in the as-treated population and the as-treated Japan subpopulation 
will be provided.
4.2.2
Demographic and baseline characteristics
A summary of demographic information related to sex, ethnicity, race, age at IP 
administration (months) calculated from eCRF, age category at IP administration calculated 
from eCRF (age < 12 months, age ≥ 12 months), birth weight (kg), birth weight category 
(weight ≤ 2.5 kg, weight > 2.5 kg), gestational age (weeks), multiple birth (yes/no), siblings 
enrolled in the study (yes/no), ever breastfed (yes/no), currently breastfed (yes/no), smokers in 
the household currently (yes/no), currently in day care (yes/no), weight (kg) on Day 1, weight 
category on Day 1 (weight < 5 kg, weight ≥5 kg to < 10 kg, weight ≥ 10 kg), subjects who 
met the subcategories of inclusion criteria 2 will be provided. Subjects will be excluded from 
the summary (eg, means and percentages) of an individual parameter if data are missing.
In addition, a summary of family history of atopy (including asthma, hay fever, eczema, 
wheezing) will be provided.
4.2.3
Study drug exposure and treatment compliance
Due to the simplicity of dosing for this study, exposure is summarized in the Subject 
Disposition table under “Subjects enrolled and dosed”.
Treatment compliance will be presented by the number and percentage of subjects who have 
received a full dose of nirsevimab. For subjects who did not receive a full dose of nirsevimab, 
the number and percentage of subjects who received > 50% of full dose, 50% of full dose and 
< 50% of full dose will also be provided.
4.2.4
Primary analyses
Treatment-emergent AEs, TESAEs, AESIs, skin reactions, and NOCDs will be summarized 
using descriptive statistics. 
No safety data will be imputed. The handling of partial dates for AEs is described in Section
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4.2.4.1
Treatment-emergent adverse events and treatment-emergent serious adverse 
events (TEAEs and TESAEs)
Adverse events will be coded by MedDRA, Version 24.1 or higher. 
The number and percentage of subjects with TEAEs in any category; TESAEs in any 
category; IP related TEAEs; IP related TESAEs; TEAEs with ≥ grade 3 severity; TESAEs 
with ≥ grade 3 severity; IP related TEAEs with ≥ grade 3 severity; IP related TESAEs with ≥ 
grade 3 severity; TEAEs with outcome of death; AESIs based on investigator assessment; IP 
related AESIs based on investigator assessment; AESI based on selected MedDRA PT codes; 
IP related AESIs based on selected MedDRA PT codes; NOCDs; IP related NOCDs; skin 
reactions; and IP related skin reactions; skin hypersensitivity reactions; and IP related skin 
hypersensitivity reactions will be provided. In the count of subjects with TEAEs, subjects with 
multiple events in the same category will be counted only once in that category. In addition, if 
the same AE occurs multiple times within a particular subject, the highest severity and level of 
relationship observed will be reported.
Adverse events with outcome of death can be identified in the ‘Adverse Events’ eCRF page, 
when “Outcome of AE” is flagged as ‘Fatal’. Other parameters such as “Serious”, “AE 
toxicity grade”, “Relationship, investigational product”, “Adverse event of special interest”
(based on investigator assessment), “NOCD”, and “Skin reaction” can also be identified in the 
same ‘Adverse Events’ eCRF page.
All TEAEs and TESAEs will be provided by the number and percentage of subjects with the 
categorization by MedDRA system organ class (SOC) and preferred term (PT), the total 
number of TEAEs and TESAEs will also be provided. Key information such as subject 
identifier, sex, age, country, TEAE with SOC and PT, start and stop date of TEAE , duration 
of TEAE, TESAE and type of TESAE, outcome of TEAE, action taken with nirsevimab and 
causality to nirsevimab, will be listed for subjects with TEAEs.
The number and percentage of subjects with TEAEs, as well as categorization by MedDRA 
SOC and PT, and the highest severity will be provided.
The number and percentage of subjects with IP related TEAEs and TESAEs, as well as 
categorization by MedDRA SOC and PT will be provided.
The number and percentage of subjects with TEAEs with outcome of death, as well as 
categorization by MedDRA SOC and PT will be provided. Key information similar to those 
mentioned above will be listed for subjects with outcome of death.
Non-treatment-emergent AEs/ SAEs, defined as AEs/SAEs that occur prior to administration 
of nirsevimab or after Day 361, will be presented in an AE listing.


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4.2.4.2
Adverse events of special interest (AESIs)
Investigators have been requested to identify the AESIs in reporting. The primary 
interpretation of data will be made upon those events with investigator assessment. In 
addition, a supplementary analysis is conducted which runs the narrow Standardised
MedDRA Queries (SMQs) for hypersensitivity, the narrow and broad SMQS for anaphylactic
reactions, and a study specific query based on compatible PTs for thrombocytopenia and
immune complex disease occurring in the database. Narrow hypersensitivity SMQs include
some PTs of immune complex disease. These SMQs and PTs will be provided by the medical
monitor in a separate document before DBL of each analysis.
See Section 3.1.2 for definition of AESIs.
The number and percentage of subjects with treatment-emergent AESIs, as well as 
categorization by MedDRA SOC and PT and the total number of AESIs will be provided.
The number and percentage of subjects with treatment-emergent AESIs, as well as 
categorization by MedDRA SOC and PT, and the highest severity will also be provided.
Key information similar to those mentioned in the TEAE section will be listed for subjects 
with AESIs.
4.2.4.3
Skin reactions and skin hypersensitivity reactions
The incidence of treatment-emergent skin reactions, skin hypersensitivity reactions and the 
relationship to IP will be summarized by MedDRA SOC and PT, and the total number of skin 
reactions and skin hypersensitivity reactions will also be provided. A listing of subjects with 
skin reactions will also be provided.
The number and percentage of subjects with treatment-emergent skin reactions, as well as 
categorization by MedDRA SOC and PT, and the highest severity will also be provided.
The number and percentage of subjects with a hypersensitivity/allergic reaction, skin reaction 
etiology, types of skin reaction, skin reaction distribution, location of skin reaction, history of 
recent viral illness, the accompanied systemic symptoms and types of drugs exposure to 
within 14 days of the onset of skin reaction symptoms, as reported on the dedicated eCRF 
page, will be provided.
4.2.4.4
New onset chronic diseases (NOCDs)
New onset chronic diseases will be assessed and identified by the Investigator and recorded in 
the eCRF. The analysis of NOCD will be performed on AEs which have ‘yes’ selected for 
“NOCD” in the ‘Adverse Events’ eCRF page.


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The number and percentage of subjects that are defined as NOCD, as well as categorization by 
MedDRA SOC and PT, and the total number of NOCD will be provided. Key information 
similar to those mentioned in the TEAE section will be listed for subjects with TEAEs that are 
defined as NOCDs.
4.2.4.5
Subgroup analyses
The following subgroup analysis will be performed on the primary analyses. 
Subgroups by AE onset time relative to dosing
All AE start dates relative to administration date of nirsevimab will be calculated according to 
study day defined in Section 4.1.3. The categories for this subgroup are:

‘within 1 day’ of administration of nirsevimab; defined as study day ≤ 1.

‘within 3 days’ of administration of nirsevimab; defined as study day ≤ 3.

‘within 7 days’ of administration of nirsevimab; defined as study day ≤ 7.

‘within 14 days’ of administration of nirsevimab; defined as study day ≤ 14.
The primary analyses described in the above sections will be repeated for this subgroup
analysis.
4.2.5
Secondary analyses
4.2.5.1
Pharmacokinetics
Nirsevimab serum concentration data for each nominal sampling time will be summarized by 
dose using descriptive statistics, including n < lower limit of quantification (LLOQ), 
geometric mean, geometric coefficient of variation (CV) (%), geometric SD, geometric mean 
+/- geometric SD, and the summary statistics listed in Section 4.1.1, and a listing of 
nirsevimab serum concentrations will also be provided. Line plot of geometric mean of 
nirsevimab serum concentration on log-normal scale will be plotted by scheduled visit. 
Geometric mean and other summary statistics are derived from planned visit day +/- 14 days.
Nirsevimab serum concentration at each scheduled visit will be summarized by subject 
disease conditions as defined in inclusion criterion number 2, see Appendix 4. The summary 
statistics of number of subjects, mean, SD, minimum and maximum will be provided. A series 
of spaghetti plots, will be created for each of the disease conditions stated in inclusion 
criterion number 2, presenting individual subjects nirsevimab serum concentration over time.
Individual nirsevimab serum concentrations with geometric mean +/- geometric SD will be 
graphically illustrated, and summarized, by ADA status (ADA positive and ADA negative).
Definitions of ADA status are described in Section 0.  


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4.2.5.2
Anti-drug antibody (ADA)
Serum samples for ADA assessments will be conducted utilizing a tiered approach (screen, 
confirm, titer), and ADA data will be collected at scheduled visits shown in the CSP. ADA 
result from each sample will be reported as either positive or negative; samples without an 
ADA result will not be imputed. If the sample is positive, the ADA titer will be reported as 
well. In addition, the presence of neutralizing anti-drug antibody (nAb) and anti-YTE will be 
tested for all ADA-positive samples using validated ligand-binding assays. The nAb and anti-
YTE results will be reported as positive or negative.
The number of subjects in the as-treated population and the as-treated Japan subpopulation
(defined in Section 2.1) who fulfil the following the criteria will be determined. The 
percentage of ADA-positive subjects in each of the categories specified below will be 
calculated, using the number of subjects with any ADA result at baseline and/or post-baseline 
during the study as the denominator. A subject is defined as being ADA positive if a positive 
ADA result is available at any time, including baseline and all post-baseline measurements; 
otherwise ADA negative. Missing ADA result will not be imputed.

ADA positive at any visit; the percentage of ADA-positive subjects is known as ADA 
prevalence.

Treatment-emergent ADA defined as the sum of both treatment-induced and treatment-
boosted ADA; the percentage of subjects fulfilling this criterion is known as ADA 
incidence.

ADA positive at both post-baseline and baseline.

ADA positive post-baseline and not detected at baseline (treatment-induced ADA).

ADA not detected post-baseline and positive at baseline.

Treatment-emergent ADA-negative, defined as ADA-positive at any visit but not 
fulfilling the definition of treatment-emergent ADA-positive.

Treatment-emergent ADA positive with maximum titer higher than median of maximum 
titers. The median of maximum titers is calculated based on the maximum titer for each 
ADA-positive subject within the actual dose administered group; ‘nirsevimab 
50mg/100mg’ and ‘nirsevimab 200mg’ (including both baseline and post-baseline 
measurements).

Treatment-boosted ADA, defined as a baseline positive ADA titer that was boosted to a 
4-fold or higher level (greater than the analytical variance of the assay) following drug 
administration.

Persistently positive ADA, defined as negative at baseline and having at least 2 post-
baseline ADA positive measurements with at least 16 weeks (112 days) between the first 
and last positive measurement or an ADA positive result at the last available assessment.

Transiently positive ADA, defined as negative as baseline and having at least one post-
baseline ADA positive measurement and not fulfilling the conditions for persistently 
positive.

nAb positive at any visit (nAb prevalence).


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
nAb positive post-baseline only (nAb incidence)

anti-YTE positive at any visit (anti-YTE prevalence).

anti-YTE positive post-baseline only (anti-YTE incidence)
To evaluate the impact of ADA on safety, TEAE and TESAE by MedDRA SOC and PT will 
be summarized by ADA post-baseline status (ie, at least one post-baseline ADA positive or 
not through 360 days post dose).
Samples with ADA titer < 50 will be regarded as negative results and samples with ADA titer 
≤ 50 (borderline positive) will be regarded as positive results. The evaluation on the impact of 
ADA on PK is described in Section 4.2.5.1.
4.2.5.3
Efficacy analyses
The analyses of the efficacy endpoints, including the incidence of protocol-defined medically 
attended RSV LRTI (also described as the medically attended RSV LRTI) through 150 days 
post dose, as well as the incidence of protocol-defined RSV hospitalization (also described as 
the RSV LRTI hospitalization) through 150 days post dose. The incidence will be calculated 
as the proportion of subjects who meet the endpoint during the reporting period. Only 
summaries will be provided for the efficacy analyses unless stated otherwise. The summaries 
will be based on observed events.
Analysis of incidence of medically attended LRTI due to RT-PCR-confirmed RSV
An analysis window which captures all relevant respiratory samples that linked to respiratory 
illness events will be defined prior to database lock and the decision made will be 
documented. In addition, deaths that can be demonstrated as caused by RSV (by autopsy or 
clinical history and virologic evidence) will also be considered as medically attended RSV 
LRTI events.
The incidence of medically attended RSV LRTI (inpatient and outpatient) through 150 days 
post dose will be summarized, and a listing of subjects with medically attended RSV LRTI 
will also be provided. For subjects with multiple medically attended RSV LRTI events, only 
the first occurrence will be used in the summary. 
In addition, the incidence of medically attended RSV LRTI that occurred after 150 days post 
dose, and through 360 days post dose will be summarized.
The incidence of medically attended RSV LRTI by subtype (RSV A or RSV B) through 150 
days post dose, after 150 days post dose, and through 360 days post dose will be summarized.
Analysis of Incidence of RSV hospitalization
The events of “RSV hospitalization” are a subset of “medically attended RSV LRTI,” and
RSV test results are obtained from central laboratory. In addition, deaths that can be 


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demonstrated as caused by RSV (by autopsy or clinical history and virologic evidence) will 
also be considered as medically attended RSV hospitalization events.
The incidence of RSV hospitalization through 150 days after dosing will be summarized. For 
subjects with multiple RSV LRTI hospitalizations, only the first occurrence will be used in the 
analysis. RSV LRTI hospitalization will also be summarized by RSV subtype (RSV A or RSV 
B). This summary will be based on observed events and data summary will be presented 
through 150 days post dose, after 150 days post dose and through 360 days post dose.
Other efficacy analyses
An overall summary of subjects with any medically attended LRTI (protocol-defined or 
non-protocol-defined) or hospitalization due to any respiratory illness will be presented, and a 
listing capturing all relevant information will also be provided. The mapping between the AE 
terms and LRTI or non-LRTI will be finalized before the database lock. In this summary, a 
subject is reported only once even though he or she might have multiple events in the 
reporting period. In that occasion, the event with the highest severity level will be reported. 
The rules to define severity among multiple LRTI events for a subject are as follows: 
protocol-defined > non-protocol-defined, RSV > non-RSV, and hospitalization > outpatient. 
The rules to define severity among multiple hospitalizations due to any respiratory illness are
as follows: LRTI > non-LRTI, RSV > non-RSV. Incidence of all medically attended LRTI 
will be summarized by protocol-defined LRTI (RSV or non-RSV) and non-protocol-defined 
LRTI (RSV or non-RSV) with each further broken down by hospitalization or outpatient
status. 
A listing will be presented for each of the elements used to evaluate for the case definition of 
any medically attended LRTI (see Appendix 1 of this SAP). These elements include the 
following: rhonchi, rales, crackles, wheeze, increased respiratory rate, hypoxemia, acute 
hypoxic or ventilatory failure, new onset apnea, nasal flaring, retractions, grunting, 
dehydration due to respiratory distress. In this summary, a subject is reported once even 
though he or she might have the element multiple times during the reporting period.
For all medically attended LRTI events, RSV status (positive, negative or not done) will be 
summarized by central RT-PCR or local testing results. The proportion of each category will 
be calculated based on the total number of LRTI events. 
Apart from the medically attended RSV LRTI and medically attended RSV LRTI with 
hospitalization efficacy endpoints (listed as first two endpoints in Table 1), additional four
endpoints are also added to conduct similar analyses as mentioned above for exploratory 
purposes.


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Table 1 Population for medically attend RSV respiratory illness
Type of 
Endpoint
Endpoint
Protocol 
definition of 
LRTI
RSV test result
Investigators 
assessment of 
LRTI/URTI
Setting of 
care
Secondary 
Efficacy
MA RSV LRTI
Protocol 
defined
Positive (central RT-
PCR)
LRTI
Inpatient or 
outpatient
Secondary 
Efficacy
MA RSV LRTI with 
hospitalization
Protocol 
defined
Positive (central RT-
PCR)
LRTI
Inpatient
All above stated summaries will be based on observed events and data summary will be 
presented through 150 days post dose, after 150 days post dose, and through 360 days post 
dose.
Adverse events associated with all medically attended RSV LRTI will be summarized, as well 
as categorized by the MedDRA SOC and PT. Summaries will be presented through 150 days 
post dose, after 150 days post dose, and through 360 days post dose.
To evaluate the impact of ADA on efficacy, MA LRTI and MA LRTI with hospitalization 
will be summarized by ADA post-baseline status (ie, at least one post-baseline ADA positive 
or not through 360 days post dose).
4.2.6
Exploratory analyses
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4.2.6.4
Healthcare resource utilization (HRU)
Healthcare resource utilization will be measured as follows:

Admissions to hospitals and duration of stay.

Admissions to ICU and duration of stay.

Requiring respiratory support (using initial/increased CPAP or initial/increased 
mechanical ventilation) and the duration of use.

Uses and the duration of use of initial/increased supplemental oxygen.

Visits to out-patient facilities (urgent care, outpatient ED, outpatient clinic).

Prescription and OTC medications and duration of use.
These data will be provided through 360 days post dose and will be reported through 150 days 
post dose, after 150 days post dose, and through 360 days post dose.
Specifically, to report HRU, the following summaries will be repeated for the six endpoints 
described in Table 1. 
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
The number and percent of subjects who have had at least one of the following: 
hospitalization, ICU admission, requiring respiratory support, requiring supplemental 
oxygen, or visiting an outpatient facility. Similar summaries will be provided by 
respiratory support subtype (initial/increased CPAP or initial/increased mechanical 
ventilation) and the type of outpatient facility. The percentage will be calculated for time 
interval through 150 days post dose, after 150 days post dose, and through 360 days post 
dose. 

For each of the medical activities listed above, the total number of the activity for a 
subject who has had at least one respective event in the reporting time-period will be 
calculated and summarized. 

The total duration of each of the following (in days) will be calculated cumulatively 
through 360 days post dose and summarized: hospital stay, ICU stay, use of respiratory 
support, or use of supplemental oxygen for the subjects who has had at least one of the 
corresponding activities.
The duration of each hospitalization will be calculated from the admission or deterioration 
date to discharge date. If the discharge date is missing because the subject died in the hospital, 
the duration of that hospital stay will be calculated from admission to the death date, or end-
of-study date, whichever is the earliest. Total duration of hospitalization is the cumulated days 
of each hospital stay throughout the reporting time-period. 
Similarly, the duration of each ICU admission, use of respiratory support, or use of 
supplemental oxygen will be calculated from start date to stop date, and the total duration of 
each medical intervention for a subject is calculated by summing the duration of all 
occurrences in the time interval of interest. If the use of medical intervention occurred 
multiple times on the same day, the duration of uses in the same day will be counted only 
once.
In addition, the number of pre-specified OTC medication (analgesics/antipyretics) uses; the
number of pre-specified prescription medication (systemic antibacterial agents) uses; and the
number of anti-wheezing medication uses will be summarized through 150 days post dose,
except for the analgesics/antipyretics uses, which will be summarized through one week after
dosing. The Anatomical Therapeutic Chemical Classification System (ATC) codes for these 
medications will be provided in a separate file by the medical monitor prior to the database 
lock for the Interim Analysis.
The number and percentage of subjects with pre-specified OTC medications 
(analgesics/antipyretics) uses within one week after dosing will be provided. The number of 
uses per subject (for those with the medication use) will be summarized using descriptive 
statistics. The same summaries will be repeated for subjects with any co-administered routine 
childhood vaccination (ATC code: J07) within one week of dosing.
The number and percentage of subjects with pre-specified prescription medications (systemic
antibacterial agents) uses through 150 days post dose will be provided. The number of uses


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per subject (for those with the medication use) will be summarized through 150 days post dose
using descriptive statistics.
The number and percentage of subjects with anti-wheezing medications uses through 150 days
post dose will be provided. The number of uses per subject (for those with the medication use)
will be summarized through 150 days post dose using descriptive statistics.
4.2.7
Other analyses
4.2.7.1
Clinical laboratory parameters
Blood samples for determination of serum chemistry and hematology parameters will be taken 
at times detailed in the CSP. Clinical laboratory data will not be collected outside of Japan.
Summaries of clinical laboratory parameters will be presented for as-treated Japan 
subpopulation only.
A summary of laboratory parameters at each visit will be provided. Frequencies of worst 
observed Grade 3-4 toxicity, as defined by the Division of AIDS (DAIDS) Table for Grading 
the Severity of Adult and Pediatric Adverse Events [DAIDS RSC Regulatory Support Center 
2017] will be presented for each laboratory parameter listed below:

Complete blood count (CBC): hemoglobin, hematocrit, red blood cell count, platelet
count.

White blood cell count (WBC) with differential: white blood cell count.

Liver function: total bilirubin, aspartate aminotransferase (AST)/alanine aminotransferase 
(ALT).

Chemistry (general): creatinine, blood urea nitrogen.
Also, laboratory parameters will be assessed by presenting tables containing information 
associated with Grade 2 (or greater) laboratory shifts from baseline. All other serum chemistry 
and hematology parameters not listed above will be presented in the listings.
For laboratory values reported as lower than the LLOQ, a value equal to half of the limit of 
quantification will be imputed in the summaries. However, < LLOQ will be reported in the 
listings.
4.2.7.2
Potential Hy’s Law and Hy’s Law
A listing of subjects with TESAEs reported as Potential Hy’s Law under the serious criteria of 
‘Important medical event’ with key information such as subject identifier, sex, age, ALT, 
ALT × upper limit of normal (ULN), AST, AST × ULN, Total Bilirubin, Total Bilirubin × 
ULN at each visit will be provided.
4.2.7.3
Other safety analyses
Additional data collected throughout the study include screen failure characteristics, 
significant findings in medical history, vital signs, overdose report, vaccines and concomitant 


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medications. Data listings will be provided for these data. A listing of subjects who have taken 
palivizumab through 360 days post dose will also be provided.
Medical history findings and those that are ongoing at the time of signed informed consent 
will be summarized by SOC and PT.
In addition, the total number of vaccine doses received within ±14 days of IP dosing, will be 
summarized for each vaccine group. The number of subjects with co-administered vaccine 
doses within ±14 days of IP dosing will be summarized. The percentage will be calculated 
using subjects who received co-administered vaccine doses within ±14 days of IP dosing as 
the denominator. The ATC codes for these vaccines will be provided in a separate file by the 
medical monitor prior to each DBL.
4.2.7.4
Impact on analyses due to COVID-19 pandemic
The Coronavirus disease 2019 (COVID-19) pandemic has posted challenges in study 
conduction (including performing scheduled visit, and sample collection etc.)
Efforts are ongoing to collect outstanding data via alternative means where possible, when on-
site visits cannot be performed. The following summaries have been added to assess the 
impact of the pandemic.

Protocol deviations, including sample collections or visits missed due to COVID-19 
related protocol deviations will be described separately in the CSR. These deviations will 
be identifiable in the database with a ‘COVID’ prefix.

Confirmed or suspected cases of COVID-19 will be summarized and included as AEs as 
appropriate.

The number of scheduled visit impacted due to COVID-19 pandemic and number of 
subjects with visit impacted due to COVID-19 pandemic. 
5
OTHER ANALYSES
5.1
Interim analysis
An interim analysis will be conducted when subjects enrolled globally by end of 2021 have 
been followed through Day 151. For the interim analysis, all safety, PK, ADA, and efficacy 
data collected for subjects enrolled globally in 2021 will be analyzed. A minimum of 
approximately of 30 subjects is expected to be sufficient in establishing a PK profile for 
efficacy and safety extrapolation at the time of the interim analysis.
The specifications of the tables, figures and listings for the interim analysis are included in the 
document named ‘
’.
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5.2
Second Interim Analysis
A new interim analysis will be conducted when subjects enrolled globally have been followed 
through Day 151. This lock has not been pre-planned in original protocol or amendment and it 
is documented though this amendment to SAP number 3. The interim analyses TFLs that will 
be produced are the same as those detailed in Section 5.1 except that it will include all patients 
globally recruited and followed up through to Day 151.
The specifications of the tables, figures and listings for the interim analysis are included in the 
document named ‘
5.3
Data monitoring committee
An independent data monitoring committee will review the safety data regularly and make 
recommendations regarding further study conduct.
6
CHANGES OF ANALYSIS FROM PROTOCOL
An unplanned interim analysis will be performed as detailed in Section 5.2.
For the deviation of summary statistics for PK data, new rules are defined to be in-lines with 
other nirsevimab studies (
) (Section 4.1).
7
REFERENCES
2017. DAIDS RSC Regulatory Support Center. July. 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf.
Mori, M, M Onodera, A Morimoto, Y Kosaka, T Morio, and GF Notario. 2014. "Palivizumab 
use in Japanese infants and children with immunocompromised conditions." Pediatric 
Infectious Disease Journal 33(11):1183-5.
8
APPENDIX
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Appendix 1
Criteria for Meeting the Protocol-defined Endpoint of 
Medically Attended RSV LRTI


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Appendix 2
Analysis Window for PK/ADA/
 
Analysis window for PK assessment:
Protocol
Scheduled Study Day
Analysis Windows
Global
Day 1
≤1
Global
Day 31
2 - 91
Global
Day 151
92 - 255
Global
Day 361
≥ 256
Japan
Day 1
≤1
Japan
Day 8
2 – 20
Japan
Day 31
21 - 91
Japan
Day 151
92 - 255
Japan
Day 361
≥ 256
Analysis window for ADA/
Protocol
Scheduled Study Day
Analysis Windows
Global/Japan
Day 1
≤1
Global/Japan
Day 31
2 - 91
Global/Japan
Day 151
92 - 255
Global/Japan
Day 361
≥ 256
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Appendix 3
Analysis Window for Clinical Lab Data


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Appendix 4
Inclusion Criterion 2


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5290c00008-sap-ed-3
Document Title:
Statistical Analysis Plan Edition 3
Document ID:
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
21-Nov-2022 07:58 UTC
Content Approval
21-Nov-2022 07:13 UTC
Qualified Person Approval
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