A Phase IIIb Randomized Open-label Study of Nirsevimab (Versus no Intervention) in Preventing Hospitalizations Due to Respiratory Syncytial Virus in Infants (HARMONIE)
Phase: PHASE3
Conditions: RSV Immunization, Healthy Volunteer
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: 
A Phase IIIb randomized open-label study of nirsevimab (versus no intervention) in preventing 
hospitalizations due to respiratory syncytial virus in infants (HARMONIE) 
Study Code: VAS00006 (HARMONIE) 
Amendment Number: 3 
Compound: 526 − human Monoclonal Antibody Respiratory Syncytial Virus (RSV) 
Brief Title: 
Study of a single intramuscular dose of nirsevimab in the prevention of hospitalizations due to 
respiratory syncytial virus (RSV) infection in healthy term and preterm infants during the first 
year of life 
Study Phase: IIIb 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur 
14 Espace Henry Vallée, 69007 Lyon, France 
Manufacturer: 
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca PLC 
One MedImmune Way, Gaithersburg, Maryland, 20878, USA 
Regulatory Agency Identifier Numbers: 
EudraCT: 2022-000099-20 
WHO UTN: U1111-1272-2514 
Protocol Version Number: 5.0 
Approval Date: 05 FEB 2024 
Responsible medical officer (RMO), and designee(s), and pharmacovigilance (PV) representative 
names and contact information are provided in the investigator site file. 
The study centers, the Investigators at each center, and the Coordinating Investigators are listed in 
a separate document. 
                NCT: NCT05437510

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Document History 
Previous 
Version 
Date 
Comments 
1.0 
01 March 2022 
Version not approved by all IECs/IRBs 
2.0 
17 June 2022 
First version used in the study 
3.0 
19 July 2023 
Second version used in the study 
4.0 
01 February 2024 
Version not used in the study 
IEC: Independent Ethics Committee; IRB: Institutional Review Board 
Version in bold font has been approved by the IECs/IRBs and used in the study 
Amendment 2 – Version 4.0 (01-February-2024) 
The objectives of this amendment are: 
•
To extend the time window for signing the Addendum to the Inform Consent Form (ICF)
for UK’s participants.
•
To add routine immunization with Beyfortus® as reportable concomitant medications. For
countries where Beyfortus has been made commercially available during the study
conduct, the sites will be asked to report any routine immunization with Beyfortus.
•
To clarify the data collection during the 12-month extension period in case of wheeze
(including any concomitant medications during wheezing episodes) for UK reconsented
participants.
Amendment 3 – Version 5.0 (05-February-2024) 
The objective of this amendment is to clarify the definition of a wheezing episode (see 
Section 8.1.2.4). 

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Table of Contents  
Document History ............................................................................................................................ 2 
Table of Contents ............................................................................................................................. 3 
List of Tables .................................................................................................................................... 7 
List of Figures .................................................................................................................................. 8 
1 
Protocol Summary ............................................................................................................. 9 
1.1 
Synopsis ............................................................................................................................ 9 
1.2 
Schema ............................................................................................................................ 15 
1.3 
Schedule of Activities (SoA) .......................................................................................... 17 
2 
Introduction ..................................................................................................................... 24 
2.1 
Study Rationale ............................................................................................................... 24 
2.2 
Background ..................................................................................................................... 26 
2.3 
Benefit/Risk Assessment ................................................................................................ 28 
2.3.1 
Risks from Study Participation ..................................................................................... 28 
2.3.2 
Benefits from Study Participation ................................................................................ 29 
2.3.3 
COVID-19 Risk Assessment ........................................................................................ 29 
2.3.4 
Overall Benefit-Risk Conclusion .................................................................................. 29 
3 
Objectives and Endpoints ............................................................................................... 30 
4 
Study Design .................................................................................................................... 32 
4.1 
Overall Design ................................................................................................................ 32 
4.2 
Scientific Rationale for Study Design ............................................................................. 33 
4.3 
End of Study Definition .................................................................................................. 36 
5 
Study Population ............................................................................................................. 36 
5.1 
Inclusion Criteria ............................................................................................................ 37 
5.2 
Exclusion Criteria ........................................................................................................... 37 
5.3 
Lifestyle Considerations ................................................................................................. 38 
5.4 
Screen Failures ................................................................................................................ 38 
6 
Study Intervention and Concomitant Therapy ............................................................ 39 
6.1 
Study Intervention Administered .................................................................................... 39 

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6.2 
Preparation/Handling/Storage/Accountability ................................................................ 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 40 
6.3.1 
Randomization and Allocation Procedures .................................................................. 40 
6.3.2 
Blinding and Code-breaking Procedures ...................................................................... 41 
6.4 
Study Intervention Compliance ...................................................................................... 41 
6.5 
Dose Modification .......................................................................................................... 42 
6.6 
Continued Access to Study Intervention After the End of the Study ............................. 42 
6.7 
Treatment of Overdose.................................................................................................... 42 
6.8 
Concomitant Therapy ...................................................................................................... 42 
6.8.1 
Rescue Medicine ........................................................................................................... 43 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .......................................................................................... 43 
7.1 
Discontinuation of Study Intervention ............................................................................ 43 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 43 
7.3 
Lost to Follow-up ............................................................................................................ 44 
8 
Study Assessments and Procedures ............................................................................... 45 
8.1 
Efficacy Assessments ...................................................................................................... 45 
8.1.1 
Baseline Assessments at the Time of Immunization .................................................... 45 
8.1.2 
Efficacy Assessments ................................................................................................... 46 
8.1.2.1 
Definitions .................................................................................................................. 46 
8.1.2.2 
RSV LRTI Hospitalization ......................................................................................... 46 
8.1.2.3 
Very severe RSV LRTI .............................................................................................. 47 
8.1.2.4 
Wheeze ....................................................................................................................... 47 
8.1.3 
Immunogenicity Assessments ...................................................................................... 47 
8.2 
Safety Assessments ......................................................................................................... 47 
8.2.1 
Medical History ............................................................................................................ 48 
8.2.2 
Clinical Examination .................................................................................................... 48 
8.2.3 
Collection and Reporting of Adverse Events (AEs) ..................................................... 48 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting............... 49 
8.3.1 
Exemption to the Reporting of LRTI Hospitalizations as SAEs .................................. 50 
8.3.2 
Time Period and Frequency for Collecting AE and SAE Information ......................... 50 
8.3.3 
Method of Detecting AEs and SAEs ............................................................................ 51 
8.3.4 
Follow-up of AEs and SAEs ........................................................................................ 51 
8.3.5 
Regulatory Reporting Requirements for SAEs ............................................................ 52 
8.3.6 
Pregnancy ..................................................................................................................... 52 
8.3.7 
Adverse Events of Special Interest ............................................................................... 52 
8.3.8 
Medically Attended Adverse Events ............................................................................ 53 
8.3.9 
Health Measurement/Observation ................................................................................ 53 

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8.4 
Pharmacokinetics ............................................................................................................ 53 
8.5 
Genetics ........................................................................................................................... 53 
8.6 
Biomarkers ...................................................................................................................... 53 
8.7 
Medical Resource Utilization ......................................................................................... 53 
8.8 
Immunogenicity Assessments ......................................................................................... 54 
9 
Statistical Considerations ............................................................................................... 54 
9.1 
Statistical Hypotheses ..................................................................................................... 54 
9.2 
Sample Size Determination ............................................................................................. 54 
9.3 
Analysis Sets ................................................................................................................... 55 
9.4 
Statistical Analyses ......................................................................................................... 56 
9.4.1 
General Considerations ................................................................................................. 56 
9.4.2 
Primary Endpoint .......................................................................................................... 56 
9.4.3 
Secondary Endpoints .................................................................................................... 58 
9.4.3.1 
Very severe RSV LRTI .............................................................................................. 58 
9.4.3.2 
RSV LRTI Hospitalization in each country ............................................................... 58 
9.4.3.3 
Other secondary efficacy endpoints ........................................................................... 59 
9.4.4 
Exploratory Endpoints .................................................................................................. 59 
9.4.5 
Safety Analysis ............................................................................................................. 60 
9.5 
Interim Analyses ............................................................................................................. 60 
10 
Supporting Documentation and Operational Considerations .................................... 60 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations ............................ 60 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 60 
10.1.2 
Financial Disclosure ..................................................................................................... 62 
10.1.3 
Informed Consent Process ............................................................................................ 62 
10.1.4 
Data Protection ............................................................................................................. 63 
10.1.5 
Committees Structure ................................................................................................... 65 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 65 
10.1.7 
Data Quality Assurance ................................................................................................ 66 
10.1.8 
Source Documents ........................................................................................................ 67 
10.1.9 
Study and Site Start and Closure .................................................................................. 67 
10.1.10 
Publication Policy ......................................................................................................... 68 
10.2 
Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................... 68 
10.2.1 
Definition of AE ........................................................................................................... 68 
10.2.2 
Definition of SAE ......................................................................................................... 70 
10.2.3 
Recording and Follow-Up of AE and/or SAE .............................................................. 72 
10.2.4 
Reporting of SAEs ........................................................................................................ 74 
10.2.5 
Assessment of Intensity ................................................................................................ 74 

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10.2.5.1 
AE Intensity Grading Scale ........................................................................................ 75 
10.3 
Appendix: Country-specific Requirements ..................................................................... 75 
10.4 
Appendix: Risk-based Approach .................................................................................... 75 
10.5 
Appendix: Abbreviations ................................................................................................ 76 
10.6 
Appendix: Protocol Amendment History ....................................................................... 78 
11 
References ........................................................................................................................ 80 
12 
Sponsor Signature Page .................................................................................................. 85 
 
 

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List of Tables  
Table 1.1: Identity of study intervention ....................................................................................... 13 
Table 1.2: Schedule of activities ................................................................................................... 17 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 28 
Table 3.1: Objectives and endpoints ............................................................................................. 30 
Table 4.1: Overall design .............................................................................................................. 32 
Table 6.1: Identity of study intervention ....................................................................................... 39 
Table 6.2: Arms and Associated Study Interventions ................................................................... 40 
 
 
 
 

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List of Figures  
Figure 1.1 – Graphical study design .............................................................................................. 16 
 
 

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1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: 
A Phase IIIb randomized open-label study of nirsevimab (versus no intervention) in preventing 
hospitalizations due to respiratory syncytial virus in infants (HARMONIE) 
Brief Title: 
Study of a single intramuscular dose of nirsevimab in the prevention of hospitalizations due to 
respiratory syncytial virus (RSV) infection in healthy term and preterm infants during the first 
year of life 
Rationale: 
This study is being proposed to collect and analyze data on the safety of the monoclonal antibody 
(nirsevimab) and its efficacy compared to that of no intervention in preventing hospitalizationsa 
for lower respiratory tract infection (LRTI) due to RSV as confirmed by test (henceforth referred 
to as RSV LRTI hospitalization). Data will be collected from infants born during the RSV season 
as well as from infants born out of RSV season. The typical RSV season in the Northern 
Hemisphere spans approximately 5 months and usually starts in October or November. As the 
start and end dates of the RSV season may change in response to the actual circulation of RSV, in 
this study, the RSV season will be defined on country-by-country basis and will be based on 
country-specific epidemiological surveillance. 
The study will also assess health care utilization parameters associated with hospitalization for 
LRTI due to RSV as confirmed by test. This could provide some insights into the potential 
benefits of an all-infant nirsevimab implementation strategy. 
 
 
a “Hospitalization” is defined as the decision to admit to in-patient care by the treating physician. 

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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of nirsevimab in 
preventing RSV LRTI hospitalization 
compared to no intervention 
• 
Overall incidence of RSV LRTI hospitalization 
through the RSV season 
Key Secondary  
 
• 
To assess the efficacy of nirsevimab in 
preventing very severe RSV LRTI compared 
to no intervention 
• 
Incidence of very severe RSV LRTI defined as 
RSV LRTI hospitalization with oxygen 
saturation < 90% (at any time during 
hospitalization) and oxygen supplementation, 
through the RSV season 
• 
To assess the efficacy of nirsevimab in 
preventing RSV LRTI hospitalization 
compared to no intervention in each country 
• 
Incidence of RSV LRTI hospitalization through 
the RSV season in each country 
• 
To describe in each study group the 
incidence of RSV LRTI hospitalization and 
all-cause LRTI hospitalization in UK 
reconsented participants from D366 to D731 
• 
Incidence of RSV LRTI hospitalization 
• 
Incidence of hospitalization for all-cause LRTI 
Overall Design 
Type of design 
Open-label, multi-center, parallel 2-arm study: nirsevimab 
compared to no preventive RSV intervention 
Phase 
IIIb 
Control method 
Comparison to no preventive intervention 
Study population 
Healthy infants born ≥ 29 weeks gestational age (WGA) 
entering their first RSV season and not eligible for 
palivizumab (born either in-season or out-of-season) 
Countries 
France, Germany, and the United Kingdom 
Level and method of blinding 
Open-label 
Study intervention assignment method 
Randomization will be stratified by the following: 
• 
Country 
• 
Age group at time of randomization (ie, age ≤ 3.0 months, 
age > 3.0 to ≤ 6.0 months, age > 6.0 months) 
Brief Summary 
The purpose of this study is to determine the efficacy and safety of a single intramuscular (IM) 
dose of nirsevimab, compared to no intervention, for the prevention of hospitalizations due to 

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LRTI caused by confirmed RSV infection (henceforth referred to as RSV LRTI hospitalizations) 
in all infants under 12 months of age who are not eligible to receive palivizumab. 
Study Duration: 12 months post-dosing/randomization for France, Germany, and UK 
non-reconsented participants, 24 months post-dosing/randomization for UK reconsented 
participants. D01 will be the day of randomization (both study groups) and immunization 
(nirsevimab group). 
Treatment Duration: 1 IM injection 
Study Calendar: 
• Planned date of first participant in: 01 September 2022 
• Planned date of last participant in: 28 February 2023 
• Planned date of last visit last participant: 28 February 2025 
Note: As much as operationally feasible, the date of inclusion of the first participant will be 
aligned with the beginning of the RSV season. It is thus possible that the first participants 
are enrolled earlier than 01 September 2022. 
Visit Frequency: 1 in-person dosing/randomization visit, with monthly safety follow-up electronic 
contacts through the first 6 months post-dosing/randomization for all participants. The study will 
also include a 12-month (D366) follow-up telephone call. The D366 follow-up telephone call will 
be the final follow-up telephone call for France, Germany, and UK non-reconsented participants. 
The study will include a 18-month (D546) and a 24-month (D731, final telephone call) follow-up 
telephone calls for UK reconsented participants. 
Condition/Disease: RSV LRTI hospitalization. 
Study Hypotheses: Compared with no preventive intervention, a single IM nirsevimab dose 
(50 mg if weight < 5 kg or 100 mg if weight ≥ 5 kg) will prevent RSV LRTI hospitalizations in 
healthy infants born ≥ 29 WGA and entering their first RSV season in all 3 countries combined. 
Health Measurement/Observation: 
Participants will be followed for safety for up to 12 months (for France, Germany, and UK 
non-reconsented participants) or for up to 24 months (for UK reconsented participants) after the 
dosing/randomization visit (Visit 01) to collect information on the following: 
• Any immediate adverse events (AEs) reported in the 30 minutes after immunization 
• Presence of non-serious AEs until 30 days after Visit 01  
• Presence of serious adverse events (SAEs), adverse events of special interest (AESIs), and 
medically attended adverse events (MAAEs) up to D366 phone-call for all participants 
• Presence of SAEs (considered as related to the administration of the IMP by the 
Investigator) from D366 to D731 phone-call for UK reconsented participants 
Participants will be able to connect to the electronic diary (eDiary) at any time during the first 
year of the study. By answering to the eDiary’s Yes/No questions, they will be able to report any 
safety events that may occur in their infant, including hospitalizations, throughout the first year of 

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the study. An automatic monthly electronic message through the first 6 months post-
dosing/randomization will remind parents or legally acceptable representatives (LARs) of 
participants to report any safety events that occurred. Efficacy data (ie, RSV LRTI hospitalization 
and very severe RSV LRTI) will be collected through the participants' medical records and 
reported in the eCRF by the site personnel or designee. 
A follow-up phone call will be made to the parents or LARs of the participant by the site 
personnel or designee at D366 (end of the study for France, Germany, and non-reconsented UK 
participants) to collect any safety event that may have occurred in the 6-month period since the 
last electronic contact.  
Two additional follow-up phone calls – at D546 and D731 post-dosing/randomization (end of the 
study) – will be made to the parents or LARs of the UK reconsented participants by the site 
personnel to collect any LRTI hospitalizations or related SAEs that might have occurred from 
D366 to D731 post-dosing/randomization. A memory aid will be provided to the parents or LARs 
of the UK reconsented participants to record any of these events that may occur during the second 
year of the study. 
During the 12- and 24-month follow-up calls, the site investigator or staff designee will ask to 
parents/LARs of UK reconsented participants if the participants had experienced any medically 
attended cough, chest or breathing problems throughout the study period. After the 12-month 
follow-up phone call (when possible) and the 24-month follow-up phone call, the site investigator 
or staff designee (including third parties authorized by the site investigators) will access the UK 
reconsented participants’ medical record (general practitioner’s or hospital’s record) to determine 
if the medical event meets with the definition of wheeze provided by the Sponsor (see 
Section 8.1.2.4). If so, the event and related complementary information (including any medications 
prescribed during wheeze) will be retrospectively collected. 
Number of Participants: 
A total of 28 860 participants is expected to be randomized. This study is event driven.  
For each country, at least 74 events of RSV LRTI hospitalization through the RSV season are 
needed to ensure the 90% power to conclude the efficacy of nirsevimab in preventing RSV LRTI 
hospitalization in that country, compared to no intervention, taking the multiplicity adjustment 
into consideration.  
Intervention Groups and Duration: 
Eligible participants will be randomized in a 1:1 ratio to receive a single IM injection of 50 mg (if 
weight < 5 kg) or 100 mg (if weight ≥ 5 kg) of nirsevimab or no RSV preventive intervention on 
D01. Randomization will be stratified by country and by age group at the time of randomization 
(ie, age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, and age > 6.0 months). 
Participants will be followed for approximately 12 months after dosing/randomization for France, 
Germany, and UK non-reconsented participants and approximately 24 months after 
dosing/randomization for UK reconsented participants. 

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Study intervention 
The study intervention is described in Table 1.1. 
Table 1.1: Identity of study intervention  
Intervention Name 
Nirsevimab 
Use 
Experimental 
IMP and NIMP 
IMP 
Type  
Extended half-life monoclonal antibody 
Dose Form 
Sterile solution for injection 
Unit Dose Strength 
100 mg/mL 
Excipients/Diluent 
• 30 mM histidine/histidine-HCl 
• 80 mM arginine-HCl 
• 120 mM sucrose 
• 0.02% (w/v) polysorbate 80 
• pH 6.0 
 water for injection 
Dosage Levels 
0.5 mL presentation corresponding to 50 mg (if weight < 5 kg) or  
1.0 mL presentation corresponding to 100 mg (if weight ≥ 5 kg) 
at D01 
Number of Doses / Dosing Interval 
1 dose  
Route of Administration 
IM 
Site of Administration 
Anterolateral aspect of the thigh according to standard practice 
procedures for IM injections in infants 
Injection Site Side 
Either 
Sourcing 
Provided by AstraZeneca 
Packaging and Labeling 
AstraZeneca 
Current/Former Name or Alias 
n/a 
Batch Number 
TBD 
Storage Conditions 
The IMP will be stored in a refrigerator at a temperature ranging 
from +2°C to +8°C. The IMP must not be frozen, shaken, or 
exposed to light. Keep the prefilled syringe in the outer carton in 
order to protect from light. 
Abbreviations: IM, intramuscular; IMP, Investigational Medicinal Product; n/a, not applicable; NIMP, 
Non-Investigational Medicinal Product; TBD, to be determined 

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Statistical considerations: 
Primary endpoint 
The primary endpoint is the overall incidence of RSV LRTI hospitalization through the RSV 
season in healthy term and preterm infants in all 3 countries combined.  
The efficacy of nirsevimab in preventing RSV LRTI hospitalization compared to no RSV 
intervention will be estimated accounting for the follow-up time post-dosing/randomization up to 
the data cut-off date for the Primary Analysis as follows: 
(1- (CN / NN) / (CC / NC)) × 100% 
where: 
- 
CN and CC are the numbers of all RSV LRTI hospitalization through the RSV season in 
the nirsevimab and the no intervention groups, respectively.  
- 
NN and NC are the total person-time contributed by participants randomized in the 
nirsevimab and the no intervention groups, respectively.  
The 95% CI for the efficacy will be calculated by an exact method assuming a binomial 
distribution of the number of RSV LRTI hospitalization in the nirsevimab group conditional on 
the total number in both groups accounting for the follow-up time post-dosing/randomization.  
The superior efficacy of nirsevimab in preventing RSV LRTI hospitalization will be concluded if 
the lower bound of the efficacy is > 0%. The primary efficacy analysis of the primary endpoint 
will be performed on all randomized participants.  
Main secondary endpoints 
Very severe RSV LRTI 
A very severe RSV LRTI is defined as confirmed RSV LRTI hospitalization with oxygen 
saturation < 90% (at any time during hospitalization) and oxygen supplementation. 
If the efficacy of nirsevimab in preventing RSV LRTI hospitalization in all 3 countries combined 
is demonstrated in the primary efficacy analysis, the very severe RSV LRTI through the RSV 
season will be compared between the nirsevimab and no intervention groups on all randomized 
participants using the same method for the primary efficacy analysis of the primary endpoint. If 
the lower bound of the 95% CI for the efficacy is > 0%, the superior efficacy of nirsevimab in 
preventing very severe RSV LRTI compared to no intervention will be demonstrated. 
RSV LRTI Hospitalization in each country 
If the efficacy of nirsevimab in preventing very severe RSV LRTI compared to no intervention is 
concluded, the prevention of any RSV LRTI hospitalization by nirsevimab will be evaluated in 
each of the 3 countries. The same analysis as described for the primary efficacy analysis for the 
primary endpoint with Bonferroni-Holm procedure based on the adjusted CIs for the multiplicity 
adjustment will be used to calculate the efficacy on all randomized participants in each country. 
The superior efficacy of nirsevimab in preventing RSV LRTI hospitalization will be concluded for 
the country if the lower bound of the efficacy is > 0%. 

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Data Monitoring/Other Committee:  
No 
1.2 
Schema  
The graphical design of the VAS00006 (HARMONIE) study is presented in Figure 1.1. 

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Figure 1.1 – Graphical study design  
 

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1.3 
Schedule of Activities (SoA)  
Table 1.2: Schedule of activities  
Phase IIIb Study, 1 Visit, 1 Immunization (if randomly assigned to the nirsevimab group), 6 monthly follow-up contacts, 1 phone call at Day 
366 for all participants, 2 phone calls at Day 546 and Day 731 for UK reconsented participants, 12 months’ Duration Per Participant (France, 
Germany, and UK non-reconsented participants) or 24 months’ Duration Per Participant (UK reconsented participants) 
Visit (V)/Contact 
Collection 
of 
information 
in the eCRF 
V01 
6-month efficacy and safety follow-
up, monthly through the first 
6 months post-dosing/randomization 
12-month 
safety 
follow-up 
18-month 
safety follow-
up §§§ 
24-month 
safety follow-
up §§§ 
Study timelines 
(days [D]) 
D01 * 
D01-D181 
D366 
D546 
D731 
D31 D61 
D91 
D121 D151 D181 
Time interval 
NA 
V01 + 180 days 
V01 + 
365 days 
V01 + 545 days  V01 + 730 days 
Time windows 
NA 
[+14 days] 
[+14 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
In-person visit 
 
X 
 
 
 
 
 
 
 
 
 
Electronic reminders  
 
 
X† 
X† 
X† 
X† 
X† 
X† 
X† 
 
 
Phone Contact 
X 
 
 
 
 
 
 
 
X ‡‡ 
X **** 
X **** 
Informed consent  
X 
X # 
 
 
 
 
 
 
 
 
 

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Visit (V)/Contact 
Collection 
of 
information 
in the eCRF 
V01 
6-month efficacy and safety follow-
up, monthly through the first 
6 months post-dosing/randomization 
12-month 
safety 
follow-up 
18-month 
safety follow-
up §§§ 
24-month 
safety follow-
up §§§ 
Study timelines 
(days [D]) 
D01 * 
D01-D181 
D366 
D546 
D731 
D31 D61 
D91 
D121 D151 D181 
Time interval 
NA 
V01 + 180 days 
V01 + 
365 days 
V01 + 545 days  V01 + 730 days 
Time windows 
NA 
[+14 days] 
[+14 days] 
[+14 days] 
[+14 days] 
Addendum to Informed 
consent (for 
parents/LARs of UK 
participants only) †††† 
X 
 
 
 
 
 
 
 
X 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collection of 
demographic data 
X 
X 
 
 
 
 
 
 
 
 
 
Collection of medical 
history 
X 
Significant 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Collection of concomitant 
medications*** 
X 
Reportable 
concomitant 
medications 
X  
X 
X 
X 
X 
X 
X 
X 
X‡‡‡‡ 
X‡‡‡‡ 
Collection of concomitant 
vaccines 
X 
X ††† 
 
 
 
 
 
 
 
 
 
Measurement of 
participant’s weight 
X 
X 
 
 
 
 
 
 
 
 
 

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Visit (V)/Contact 
Collection 
of 
information 
in the eCRF 
V01 
6-month efficacy and safety follow-
up, monthly through the first 
6 months post-dosing/randomization 
12-month 
safety 
follow-up 
18-month 
safety follow-
up §§§ 
24-month 
safety follow-
up §§§ 
Study timelines 
(days [D]) 
D01 * 
D01-D181 
D366 
D546 
D731 
D31 D61 
D91 
D121 D151 D181 
Time interval 
NA 
V01 + 180 days 
V01 + 
365 days 
V01 + 545 days  V01 + 730 days 
Time windows 
NA 
[+14 days] 
[+14 days] 
[+14 days] 
[+14 days] 
Contact IRT system for 
participant randomization 
number allocation 
X 
X 
 
 
 
 
 
 
 
 
 
Contact IRT system for 
randomization and 
treatment allocation 
X 
X 
 
 
 
 
 
 
 
 
 
Pre-immunization 
temperature (only for the 
nirsevimab group) 
 
X 
 
 
 
 
 
 
 
 
 
Immunization (only for 
the nirsevimab group) 
X 
X‡‡‡ 
 
 
 
 
 
 
 
 
 
Immediate surveillance 
(30 min; only for the 
nirsevimab group) 
X 
X 
 
 
 
 
 
 
 
 
 
eDiary access provided ‡  
 
X 
 
 
 
 
 
 
 
 
 
Study card provided 
 
X §§§ 
 
 
 
 
 
 
 
 
 

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Visit (V)/Contact 
Collection 
of 
information 
in the eCRF 
V01 
6-month efficacy and safety follow-
up, monthly through the first 
6 months post-dosing/randomization 
12-month 
safety 
follow-up 
18-month 
safety follow-
up §§§ 
24-month 
safety follow-
up §§§ 
Study timelines 
(days [D]) 
D01 * 
D01-D181 
D366 
D546 
D731 
D31 D61 
D91 
D121 D151 D181 
Time interval 
NA 
V01 + 180 days 
V01 + 
365 days 
V01 + 545 days  V01 + 730 days 
Time windows 
NA 
[+14 days] 
[+14 days] 
[+14 days] 
[+14 days] 
Instruct participant’s 
parents/LARs on the 
reporting of follow-up 
information (ie, SAEs, 
MAAEs, AESIs, 
concomitant medications, 
and concomitant 
vaccines) 
 
X 
 
 
 
 
 
 
 
 
 
eDiary data reviewed § 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Memory Aid provided** 
 
 
 
 
 
 
 
 
X 
 
 
Memory Aid reviewed** 
 
 
 
 
 
 
 
 
 
X 
X 
Collection of non-serious 
adverse events †† 
X 
X†† 
X 
 
 
 
 
 
 
 
 
Collection of SAEs, 
AESIs, and MAAEs 
X 
To be reported at any time up to D366 
Related SAEs to be reported from 
D366 to D731 for UK reconsented 
participants only 
Diagnosis of LRTI ‡‡ 
X 
To be reported at any time up to D366 
To be reported from D366 to D731 
for UK reconsented participants 
only 

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Visit (V)/Contact 
Collection 
of 
information 
in the eCRF 
V01 
6-month efficacy and safety follow-
up, monthly through the first 
6 months post-dosing/randomization 
12-month 
safety 
follow-up 
18-month 
safety follow-
up §§§ 
24-month 
safety follow-
up §§§ 
Study timelines 
(days [D]) 
D01 * 
D01-D181 
D366 
D546 
D731 
D31 D61 
D91 
D121 D151 D181 
Time interval 
NA 
V01 + 180 days 
V01 + 
365 days 
V01 + 545 days  V01 + 730 days 
Time windows 
NA 
[+14 days] 
[+14 days] 
[+14 days] 
[+14 days] 
Collection of wheeze 
information §§§§ 
X 
 
 
 
 
 
 
 
X 
 
X 
12-month follow-up; End 
of participation record 
(for France, Germany, 
and non-reconsented UK 
participants only) §§ 
X 
 
 
 
 
 
 
 
X 
 
 
24-months follow-up, 
End of participation 
record (for UK 
reconsented participants 
only) 
X 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; CRF, case report form; D, Day; eCRF, electronic case report form; eDiary, electronic diary; IRT, interactive response 
technology; LAR, legally acceptable representative; LRTI, lower respiratory tract infection; MAAE, medically attended adverse event; min, minutes; RSV, respiratory syncytial virus; SAE, serious 
adverse event; V, Visit 
* 
D01 is the day of inclusion in the study (ie, verification of inclusion/exclusion criteria, dosing/randomization, access to eDiary, etc.) 
† 
Electronic reminders to participants’ parents or LARs to complete the eDiary in case of an AE or hospitalization. These reminders will be made through the eDiary on a monthly basis until 
6 months post-dosing/randomization and at 12 months post-dosing/randomization. It is to be noted that parents or LARs will be able to connect to the eDiary at any time during the first year of the 
study to report any health events that may occur. 
# 
Signature of the ICF by parents or LARs can be undertaken before V01. In countries where both parents or LARs are required to provide consent for their infant’s participation, signature of the 
ICF needs to be completed before dosing/randomization and any assessments done at V01. An electronic ICF process can be implemented if applicable as per country regulations. 
Other procedures/assessments such as checking inclusion/exclusion criteria must be performed on D01. 

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‡  
The Investigator or an authorized designee will provide parents or LARs instructions on how to use the eDiary to report AEs, hospitalizations or any health-related events in their infant, and on 
how to answer the monthly reminder. The Investigator or an authorized designee will also describe the process through which information on AEs and hospitalization will be collected by the call 
center. 
§ 
From D01 to D366, each time a health event is captured in the eDiary, a medical call center will contact parents or LARs to collect and report the health event’s information in the eCRF. The 
Investigator or an authorized designee will review information reported in the eCRF and interview the participants’ parents or LARs if any additional information needs to be collected.  
** 
From D366 to D731, UK reconsented participants’ parents/LARs are requested to capture in a memory aid any hospitalizations and emergency-room visits experienced by the participants. The 
memory aid will be reviewed by the investigator or site staff during the 18-month and 24 month follow-up calls to collect any information on SAE or LRTI hospitalizations that may have occurred 
since the previous contact. If an SAE is reported, the investigator or site staff will assess the relationship and only related SAE will be reported in the eCRF. 
†† 
Immediate AE occurring within 30 minutes after immunization will be collected on V01. 
‡‡ 
Assessment of LRTI (inpatient) requiring hospitalization. In case of hospitalization due to LRTI symptoms at any time during the study after randomization, an RSV test is to be performed as per 
the hospital routine practice. Test results and information about the LRTI hospitalization such as O2 saturation, respiratory rate, oxygen supplementation, intravenous fluid administration, 
admission to intensive care unit, date of admission and of discharge are to be collected retrospectively.  
It is to be noted that, for participants hospitalized due to LRTI symptoms whose participation in the study is prematurely terminated, the Investigator or designee may seek information on the LRTI 
hospitalization for the assessment of efficacy endpoints. This retrospective collection of information on LRTI hospitalization for participants withdrawn from the study will be possible only if the 
parents or LARs provided consent by ticking the corresponding box in the informed consent form. 
§§ 
A safety follow-up phone contact is to be made at 12 months post-dosing/randomization. For participants who have prematurely terminated the study (eg, no answer to monthly electronic contact 
within the first 6 months post-dosing/randomization), the site or authorized designee should attempt to contact them and complete this 12-month safety follow-up to identify the occurrence of any 
SAEs, MAAEs, and AESIs that had not yet been reported, except if they specified that they do not want to be contacted again and it is documented in the source document. 
*** 
Be certain to record concomitant medications at the time of dosing/randomization, including vaccine administered in the 14 days prior to Visit 01, during Visit 01, and up to 14 days after Visit 01. 
Concomitant reportable medications will be collected in the event of an AE (including an LRTI hospitalization) through a phone contact by the medical call center or through the participant’s 
medical records, as applicable. Sites will also be asked to report any routine immunization with nirsevimab (Beyfortus®). See Section 6.8 for details on concomitant reportable medications. 
††† Vaccine history is to be recorded in the eCRF. This includes vaccines co-administered during Visit 01, as well as vaccines administered up to 14 days before and up to 14 days after 
dosing/randomization. 
‡‡‡ Immunization is only for Group 1, the nirsevimab arm. Participants randomly assigned to Group 2 will receive no RSV preventive intervention. 
§§§ Parents or LARs of the participant will be instructed to keep a study card that indicates study participation. The study card is to be presented to the hospital in the event of hospitalization due to any 
cause. The site or the Investigator’s contact details should be reported on it. 
**** A safety follow-up phone contact is to be made at 18 months and at 24 months post-dosing/randomization for UK reconsented participants only. During these calls, the investigator or site staff will 
interview the participant’s parents/LARs to review the memory aid and collect any information on SAE or LRTI hospitalizations that may have occurred since the previous contact. If an SAE is 
reported, the investigator or site staff will assess the relationship and only related SAE will be reported in the eCRF. 
†††† Consent of the Addendum to Informed Consent Form can be obtained from parents/LARS at any time prior or after the D366 phone call (up to D731). An electronic ICF process or consent by 
email can be implemented if applicable as per country regulations. Following the D366 phone call, an on-site visit can be organized for participants’ parents/LARs unable to realize the e-consent or 
email consent in order to collect the paper consent. 
‡‡‡‡ Only concomitant medication related to related SAE and/or LRTI hospitalization will be collected. Sites will also be asked to report any routine immunization with nirsevimab (Beyfortus). 

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§§§§ During the 12- and 24-month follow-up call, the site investigator or staff designee will ask to parents/LARs of UK reconsented participants if the participants had experienced any medically attended 
cough, chest or breathing problems throughout the study period. After the 12-month follow-up phone call (when possible) and the 24-month follow-up phone call, the site investigator or staff designee 
(including third parties authorized by the site investigators) will access the UK reconsented participants’ medical record (general practitioner’s or hospital’s record) to determine if the medical event meets 
with the definition of wheeze provided by the Sponsor (see Section 8.1.2.4). If so, the event and related complementary information (including any medications prescribed during wheeze) will be 
retrospectively collected. 
 

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2 
Introduction  
Nirsevimab is being developed for the prevention of LRTI caused by RSV in all infants (healthy 
term or preterm infants, and infants with underlying conditions) entering their first RSV season. It 
is being developed under a commercial agreement between Sanofi and AstraZeneca. 
2.1 
Study Rationale  
Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes disease 
throughout life but particularly in the early years. It is the most common cause of acute respiratory 
illness in infants and is associated with significant morbidity and mortality.  
Currently, the only licensed preventive measure against RSV is palivizumab, a monoclonal 
antibody licensed for use in a small subset of the pediatric population. Although it depends on 
guidelines from recommending bodies in individual countries, the eligible pediatric population 
usually includes infants born at ≤ 35 weeks gestational age and up to 6 months of age at the start 
of the RSV season, and those with chronic lung disease and congenital heart disease up to 
24 months of agea. Overall, the group of eligible infants represents 2-6% of the birth cohort 
annually depending on each country’s guidelines (1) (2) (3). In the population of infants who do 
not qualify for palivizumab administration, the standard of care does not include any preventive 
measure and is limited to supportive care in the event of RSV infection.  
Nirsevimab is a recombinant human immunoglobulin G1 kappa monoclonal antibody that 
neutralizes RSV by binding to a highly conserved, neutralizing epitope on the prefusion 
conformation of the RSV F protein. This binding prevents the RSV F protein from mediating 
fusion between the viral and cellular membranes, which is an essential step for viral entry.  
The primary objective of the clinical development program for licensure was to demonstrate that 
nirsevimab will protect preterm and term infants from medically-attended lower respiratory tract 
infection (LRTI) caused by RT-PCR confirmed RSV during their first RSV season as measured 
by a significant reduction in disease incidence.  
The Phase IIb pivotal study conducted in healthy preterm infants born at ≥ 29 to < 35 weeks 
gestational age included a secondary endpoint specifying RSV-confirmed hospitalizations (4). 
Based on a similar study design, a Phase III study (MELODY) was conducted in healthy late 
preterm and term infants ≥ 35 weeks gestational age. It also included RSV hospitalizations as a 
secondary endpoint. In both studies, RSV hospitalizations was defined as the subset of cases 
 
a Recommendations from the French Haute Autorité de Santé: https://www.has-sante.fr/jcms/c_2756580/fr/synagis-
palivizumab; 
Recommendations from the British Joint Committee on Vaccination and Immunisation: https://www.nitag-
resource.org/sites/default/files/ddf283f66b77b34a6821e8d6f000947b74f6b68b_1.pdf; 
Recommendations from the German Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen 
Fachgesellschaften: https://www.awmf.org/uploads/tx_szleitlinien/048-012l_S2k_Prophylaxe-von-schweren_RSV-
Erkrankungen-Risikokindern-Palivizumab_2018-11.pdf 

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meeting the criteria for the primary endpoint (ie, medically-attended RSV LRTI) that were also 
hospitalized. 
During the planning of the MELODY study, it was recognized that the management of more 
serious RSV disease had been shifting to the outpatient setting (see Section 7b of FDA 2017) and 
that the incidence of RSV hospitalization in late preterm and term infants may be too low for the 
secondary endpoint to reach statistical significance within MELODY alone. This effect was 
compounded by the reduction in virus circulation and healthcare attendance as a result of public 
health measures taken during the COVID-19 pandemic, resulting in a much smaller number of 
hospitalizations. 
The decision to hospitalize an infant with respiratory illness is made upon the judgment of the 
attending physician, but these decisions are underpinned by national guidelines that determine sets 
of criteria that, when met, indicate illness requiring secondary care input. These guidelines are 
broadly similar internationally and include signs of increased respiratory effort (tachypnea 
> 50 breaths/minute, moderate or severe retractions), compromised oral intake or hypoxia, all of 
which are associated with very severe illness. Many guidelines set the threshold for hypoxia at 
90-92% oxygen saturation and this is widely accepted as an indicator of severe enough disease to 
require hospitalization. However, the decision to hospitalize is not contingent only on evident 
hypoxia as the presence of above-mentioned signs are also accepted as indicators of very severe 
disease (5).  
The hospitalization of an infant with RSV constitutes a significant individual, family, and 
healthcare burden (6). Preventing serious deterioration in clinical condition due to RSV infection 
to the point of requiring hospitalization –a widely accepted indicator of disease severity– is one of 
the primary aims of the management and prevention of RSV in infants. The impact of nirsevimab 
on hospitalization of infants with RSV and its inclusion in the approval process is of key 
importance to physicians, for use in their clinical decision making, and parents/LARs alike. 
Hospitalization of infant due to RSV LRTI does have some far-reaching consequences as as many 
as one-third of all children who are hospitalized due to RSV are unnecessarily treated with 
antibiotics (7), even though routine antibiotic therapy for bronchiolitis is discouraged (8) (9). The 
unnecessary use of antibiotics is associated with short term adverse events (gastrointestinal 
complaints, diarrhea, exanthema), increased selective pressure on resistant bacteria, and it displays 
an adverse impact on the composition of the infant’s microbiome (10). 
The nirsevimab clinical development program has demonstrated the safety profile of the product, 
supporting investigation in a larger population, and delivered convincing efficacy results in both 
preterm and term infant populations, supporting its use in all infants. 
In this context, an investigation of the prevention of hospitalizationa and of very severe disease 
due to RSV is planned for healthy late preterm and term infants, under conditions as similar as 
possible to the real world. 
 
a “Hospitalization” is defined as the decision to admit to in-patient care by the treating physician. 

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2.2 
Background  
RSV Seasonality 
In much of the Northern Hemisphere, including the UK, France, and Germany, RSV infection is a 
clearly identified winter illness with most cases observed over a period of approximately 5 months 
that usually starts in October or November. Whilst the timeframe can vary slightly from year to 
year, this period of approximately 5 months is commonly referred to as the “RSV season” in this 
region. In this study, “RSV season” will be used to refer to this period of increased RSV infection. 
For the purpose of efficacy analyses, the start and end dates of the RSV season will be defined on 
a country-by-country basis and will be based on country-specific epidemiological surveillance. As 
a result of the COVID-19 pandemic, the seasonality of RSV has been modified (11). During 2020, 
the circulation of RSV was substantially reduced, presumably due to the widespread 
implementation of non-pharmacological interventions such as face mask use, increased 
handwashing practices, social distancing, and travel restrictions. This reduced circulation of RSV 
produced a larger-than-usual RSV-susceptible population. 
RSV Infections Prevalence and Epidemiology 
Lower respiratory tract infection due to RSV, characterized predominantly as bronchiolitis or 
pneumonia, can manifest with acute and sometimes long-term consequences for the developing 
lungs of young infants and children (12). It is estimated that RSV infections account for around 
60% to 80% of infant bronchiolitis. In addition, RSV is one of the leading causes of pediatric 
pneumonia (up to 40% of pneumonias all causes in particular in infants and toddlers) (13).  
Children who have experienced severe RSV bronchiolitis in early life subsequently show an 
increased risk of recurrent wheeze (triggered by other respiratory viral infections), asthma, and 
possibly allergic sensitization later in life (14) (15) (16) (17) (18) (19) (20). Early childhood 
wheeze after RSV infection has a high prevalence. It has an impact on quality of life and is 
responsible for substantial health care costs (21) (22) (23) (24). Although the evidence 
establishing a causal association between RSV LRTI in early childhood and the development of 
recurrent wheeze or asthma in later childhood is still inconclusive, children with severe RSV 
infection in infancy have been observed to be prone to recurrent wheeze triggered by viral 
respiratory infections up to the age of 12 years (25) (26) (27) (28) (29). RSV infection 
pathogenesis is not well understood (12). However, it has been suggested that RSV bronchiolitis 
may interfere with normal lung development, immune maturation, or that it may be an early 
stimulus for those children already predisposed to wheeze by genetic susceptibility. 
Overall, about 90% of children will be infected with RSV in their first 2 years of life and up to 
40% of these will develop a LRTI with the initial episode (30) (31) (32) (33). RSV is a leading 
cause of hospitalization in infants globally, and the majority of hospitalized infants were born at 
term and did not have comorbidities (13) (34) (35). RSV infection is also one of the leading 
causes of acute respiratory distress syndrome in infants and a significant proportion of those 
children do not have predefined risk factors for a complicated RSV disease (36). Infants are at the 
highest risk for very severe RSV disease at the time they are entering their first RSV season (37) 
(38). They represent up to 75% of the hospitalizations due to RSV infections in children < 5 years 
of age (34) (35) (39) (40). 

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Severe RSV bronchiolitis requires treatment in the intensive care unit more often than 
bronchiolitis caused by other pathogens in particular due to necessity to utilize high flow nasal 
cannula respiratory support (41) (42) (43). Severe RSV acute respiratory infections are also a 
significant contributor to pediatric mortality (37) (44) (45), especially in infants younger than 3 
months of age (46). Infants with clinically significant preexisting neuromuscular impairment are 
at an increased risk for a complicated course of RSV infection and an increased RSV-related 
mortality which underscores the indication for passive immunization in these vulnerable patients 
(47) (48). In a comparative study, RSV infection in early infancy showed a more severe clinical 
course than COVID-19 (49). 
France 
Data on RSV-associated hospital admissions in children < 5 years of age during the 2010-2018 
period were extracted from the French national hospital discharge database (Programme de 
Médicalisation des Systèmes d’Information – PMSI). On average, 45 225 RSV-associated 
hospitalizations per RSV season were reported in France, with 69% of hospitalizations among 
children < 1 year of age. This amounts to approximately 28% of hospitalizations occurring among 
children < 1 year of age during an RSV season (35).  
Germany 
Interpretation of secondary data and modelling results are supported by results from active 
surveillance and testing of LRTI in prospective hospital studies in Germany. The PRI.DE study, a 
population-based study of viral LRTI in children < 3 years of age, calculated incidence rates of 11 
RSV hospitalizations per 1000 children (50). Similarly, a study of RSV-positive hospitalizations 
in children < 1 year of age in Kiel over a 7-year period described an incidence rate of 16 per 1000 
in children (51).  
UK 
In the UK, the burden of RSV infections in children < 5 years of age was estimated and RSV was 
found to be responsible for 12 primary care consultations (95% confidence interval [CI]: 11.9; 
12.1) and 0.9 admissions to the hospital (95% CI: 0.89; 0.90) annually per 100 children annually 
(52). The same study outlined that general practice (GP) consultations for RSV infections during 
the first year of life fluctuated between 13.9 per 100 children to up to 27.4 per 100 children for 
children born in March and November, respectively (52). 
*** 
This study will be conducted in the population of infants born ≥ 29 WGA for which the current 
standard of care involves no preventive option. Those infants who qualify for a palivizumab 
prescription based on routine practices will not be included.  
This study seeks to demonstrate the efficacy of nirsevimab in preventing RSV LRTI 
hospitalizations (a crucial determinant for recommending bodies) on a large scale while emulating 
real-world conditions, owing to the proposed use of nirsevimab in a vaccine-like program. 

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2.3 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events, the potential risks, and uncertainties of nirsevimab may be found in the 
Investigator’s Brochure (IB). 
2.3.1 
Risks from Study Participation  
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
Table 2.1: Potential risks of clinical significance and risk management  
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Risk Management 
Investigated Monoclonal Antibody: Nirsevimab 
Hypersensitivity, including 
anaphylaxis 
Refer to the IB Section 5.5 
(Summary of Risks) for more 
information regarding 
potential risks. 
All monoclonal antibodies have the 
potential to cause allergic reactions 
or anaphylaxis in individuals who 
may be sensitized to components of 
the monoclonal antibody. 
There have been no cases of 
hypersensitivity, including 
anaphylaxis, attributed to nirsevimab 
up to the cut-off for the IB (ie, 09 
April 2022). 
Exclusion criterion E04 for those 
at increased risk.  
Observation period after 
immunization for early detection 
and treatment. 
Addressed in IB (administration 
precautions, potential adverse 
events), defined AESI in the 
trial. 
Thrombocytopenia 
Refer to the IB Section 5.5 
for more information 
regarding potential risks 
Risk reported post approval for 
palivizumab 
There have been no cases of 
thrombocytopenia attributed to 
nirsevimab up to the cut-off for the 
IB (ie, 09 April 2022). 
Exclusion criterion E05 and E06 
for those at increased risk.  
Addressed in IB (administration 
precautions, potential adverse 
events), defined AESI in the 
trial. 
Immune complex disease 
Refer to the IB Section 5.5 
for more information 
regarding potential risks 
As a monoclonal antibody, 
nirsevimab can induce the 
development of ADAs and the 
occurrence of such ADAs could 
result in immune complex disease or 
altered nirsevimab levels or activity. 
There have been no cases of immune 
complex disease attributed to 
nirsevimab up to the cut-off for the 
IB (ie, 09 April 2022). 
No risk mitigation actions. 
Addressed in IB (potential 
adverse events), defined AESI in 
the trial. 

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2.3.2 
Benefits from Study Participation  
In a Phase IIb study, the incidence of RSV LRTI hospitalization was 78.4% lower (95% CI: 51.9; 
90.3) in the group of healthy preterm infants who were administered nirsevimab compared to the 
group administered a placebo (4). 
Also, since nirsevimab is an anti-viral monoclonal antibody that is highly specific to RSV, it is 
unlikely that it could interfere with the immune response to other vaccines. It is thus anticipated 
that nirsevimab could be concomitantly administered to infants with routine pediatric vaccines 
during the same clinic visit (53).  
Overall, and regardless of participants group allocation (ie, nirsevimab or no study intervention), 
study participation and study conduct are considered fundamental from the societal perspective 
towards the goal of finding a prophylaxis helping dampen both the individual and public health 
impact of RSV infections during the seasonal epidemic. 
2.3.3 
COVID-19 Risk Assessment  
COVID-19 Risk Assessment 
• 
Nirsevimab is a monoclonal antibody being developed for the prevention of RSV in all 
infants. Nirsevimab would not cause immune suppression. Therefore, the risk that a 
participant in this trial will contract COVID solely due to the administration of the study 
intervention will be similar to the risk that a person not participating in this trial will 
contract COVID. 
• 
Risk mitigation:  
• 
Delay the start of the study on a site-by-site basis, depending on each individual 
site safety restriction measures.  
• 
Continued risk assessment by the Investigator and Sponsor before deciding to start 
the trial.  
2.3.4 
Overall Benefit-Risk Conclusion  
Based on the favorable efficacy and safety profiles from the previous studies of nirsevimab in 
infants entering their first RSV season, nirsevimab offers the ability to provide protection against 
RSV lower respiratory tract disease. 
For participants randomly assigned to receive nirsevimab, considering the measures taken to 
minimize risk to enrolled participants, the potential risks that may result from study participation 
are balanced by the anticipated benefits that may be afforded to participants.  
For participants randomly assigned to the no intervention group, there are no unreasonable and 
significant risks of illness or injury foreseen.  
All participants will receive the standard of care and routine health care. This includes being 
informed on current recommendations on RSV prevention through hygiene measures. 

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3 
Objectives and Endpoints  
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of nirsevimab in 
preventing RSV LRTI hospitalization 
compared to no intervention 
• 
Overall incidence of RSV LRTI hospitalization 
through the RSV season  
Secondary 
 
• 
To assess the efficacy of nirsevimab in 
preventing very severe RSV LRTI 
compared to no intervention 
• 
Incidence of very severe RSV LRTI defined as 
RSV LRTI hospitalization with oxygen 
saturation < 90% (at any time during 
hospitalization) and oxygen supplementation, 
through the RSV season  
• 
To assess the efficacy of nirsevimab in 
preventing RSV LRTI hospitalization 
compared to no intervention in each country 
• 
Incidence of RSV LRTI hospitalization through 
the RSV season in each country 
• 
To assess the efficacy of nirsevimab in 
preventing hospitalizations for all-cause 
LRTI compared to no intervention 
• 
Incidence of hospitalizations for all-cause LRTI 
through the RSV season 
• 
To assess the efficacy of nirsevimab in 
preventing RSV LRTI hospitalization 
through 150 days post-dosing/randomization 
(overall and in each country) 
• 
Incidence of RSV LRTI hospitalization through 
150 days post-dosing/randomization (overall and 
in each country) 
• 
To assess the efficacy of nirsevimab in 
preventing very severe RSV LRTI through 
150 days post-dosing/randomization 
• 
Incidence of very severe RSV LRTI defined as 
RSV LRTI hospitalization with oxygen 
saturation < 90% (at any time during 
hospitalization) and oxygen supplementation, 
through 150 days post-dosing/randomization 
• 
To assess the efficacy of nirsevimab in 
preventing hospitalizations for all-cause 
LRTI through 150 days post-
dosing/randomization 
• 
Incidence of hospitalizations for all-cause LRTI 
through 150 days post-dosing/randomization 

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Objectives 
Endpoints 
• 
To further characterize the safety profile of 
nirsevimab 
• 
Any immediate adverse events (AEs) reported in 
the 30 minutes after immunization 
• 
Non-serious AEs from D01 (post-
dosing/randomization) to D31 
• 
Adverse events of special interest (AESIs) from 
D01 visit through 1-year post-
dosing/randomization or D366 
• 
Medically attended adverse events (MAAEs) 
from D01 visit through 1-year post-
dosing/randomization or D366 
• 
Serious adverse events (SAEs) from D01 visit 
through 1-year post-dosing/randomization or 
D366 
• 
Related SAEs from D366 to D731 for UK 
reconsented participants 
• 
To assess the efficacy of nirsevimab in 
preventing RSV LRTI hospitalization 
through 180 days post-dosing/randomization 
(overall and in each country) 
• 
Incidence of RSV LRTI hospitalization through 
180 days post-dosing/randomization (overall and 
in each country) 
• 
To assess the efficacy of nirsevimab in 
preventing hospitalizations for all-cause 
LRTI through 180 days post-
dosing/randomization 
• 
Incidence of hospitalizations for all-cause LRTI 
through 180 days post-dosing/randomization 
• 
To assess the incidence of RSV LRTI 
hospitalization from 181 days post-
dosing/randomization until D366 (overall 
and in each country)  
• 
Incidence of RSV LRTI hospitalization from 181 
days post-dosing/randomization until D366 
(overall and in each country) 
• 
To assess the incidence of hospitalizations 
for all-cause LRTI from 181 days post-
dosing/randomization until D366  
• 
Incidence of hospitalizations for all-cause LRTI 
from 181 days post-dosing/randomization until 
D366  
• 
To describe in each study group the 
incidence of RSV LRTI hospitalization and 
all-cause LRTI hospitalization in UK 
reconsented participants from D366 to D731 
• 
Incidence of RSV LRTI hospitalization 
• 
Incidence of hospitalizations for all-cause LRTI 
• 
To assess the incidence of recurrent wheeze 
in UK reconsented participants from D01 to 
D731 
• 
Incidence of recurrent wheeze  
Exploratory 
 
• 
To assess the efficacy of nirsevimab in 
preventing of very severe RSV LRTI 
through 180 days post-
dosing/randomization 
• 
Incidence of very severe RSV LRTI defined as 
RSV LRTI hospitalization with oxygen 
saturation < 90% (at any time during 
hospitalization) and oxygen supplementation, 
through 180 days post-dosing/randomization 

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Objectives 
Endpoints 
• 
To assess health care utilization  
• 
Duration of hospitalization 
• 
Admission to the intensive care unit and 
duration of stay 
• 
Number of participants who require oxygen 
supplementation 
• 
Number of participants who require intravenous 
fluid administration 
4 
Study Design  
4.1 
Overall Design  
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design  
Type of design 
Open-label, multi-center, parallel 2-arm study: 
nirsevimab compared to no preventive intervention for 
RSV 
Phase 
IIIb 
Control method 
Comparison to no preventive intervention 
Study population 
Healthy infants born ≥ 29 weeks gestational age (WGA) 
entering their first RSV season and not eligible for 
palivizumab (born either in-season or out-of-season) 
Level and method of blinding 
Open-label 
Study intervention assignment method 
Randomization will be stratified by the following: 
• 
Country 
• 
Age group at time of randomization (ie, age ≤ 3.0 
months, age > 3.0 to ≤ 6.0 months, age 
> 6.0 months) 
Number of participants 
28 860 participants 
Intervention groups 
Eligible participants will be randomized in a 1:1 ratio to 
receive a single IM injection of 50 mg (if weight < 5 kg) 
or 100 mg (if weight ≥ 5 kg) of nirsevimab or no RSV 
preventive intervention on D01 
Total duration of study participation 
12 months post-dosing/randomization for France, 
Germany, and UK non-reconsented participants and 24 
months post-dosing/randomization for UK reconsented 
participants 
Countries 
France, Germany, and the United Kingdom 

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Use of an Independent Data Monitoring 
Committee, Dose Escalation Committee, or 
similar review group 
No 
Study Calendar 
• Planned date of first participant in: 01 September 2022 
• Planned date of last participant in: 28 February 2023 
• Planned date of last visit last participant: 28 February 2025 
Note: As much as operationally feasible, the date of inclusion of the first participant will be 
aligned with the beginning of the RSV season. It is thus possible that the first participants 
are enrolled earlier than 01 September 2022. 
4.2 
Scientific Rationale for Study Design  
Rationale for the Study Design 
Nirsevimab has the potential to address a serious unmet medical need by protecting all infants 
from severe RSV disease and hospitalization with once per season dosing. A dose of 50 mg 
nirsevimab was first evaluated in healthy preterm infants born between ≥ 29 to < 35 WGA in a 
Phase IIb study with a favorable benefit-risk ratio. The evaluation of nirsevimab was then 
extended to a population of healthy term/late preterm infants born ≥ 35 WGA in a Phase III study 
(MELODY) with a dose of either 50 mg or 100 mg.  
This Phase IIIb study will further extend the evaluation of nirsevimab to infants without 
underlying medical conditions and assess its efficacy in preventing hospitalization due to RSV 
disease (henceforth referred to as RSV LRTI hospitalizations) in infants entering their first RSV 
season. 
In the available data from the completed pivotal nirsevimab studies, no increase in incidence or 
severity of disease in nirsevimab recipients as compared to placebo recipients was observed in the 
second RSV season. To reinforce these data, a follow-up extension of the HARMONIE study is 
intended to further address the evaluation of second season antibody-dependent enhancement of 
RSV disease in children who received nirsevimab prior to, or during their first RSV season. 
As of today, there is no approved RSV prophylaxis in the general infant population, thus 
precluding the set-up of a clinical study involving an active comparator arm. However, this 
situation offers the possibility to collect real-world data by adopting a mostly pragmatic study 
design (54). Indeed, and although the study participants will be randomized to receive either the 
investigational intervention (nirsevimab) or no intervention (standard of care), study procedures 
will be limited in scope and data collection will be done in such a way as to minimize the study 
imprint on participants and their parents/LARs. This study should also circumvent one of the 
known shortcomings of pragmatic studies –that is, the variability of the data collected– as efficacy 
objectives will all be assessed through a common very narrowly-defined endpoint kernel, namely 
infant RSV LRTI hospitalization. 

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Infant RSV LRTI hospitalization has been selected as the primary endpoint since hospitalization 
for LRTI due to RSV is a significant part of RSV burden of disease and the assessment of cases 
does not impose additional clinical procedures on participants or parents/LARs. The assessment of 
very severe RSV LRTI cases will be used as one of the main secondary endpoints as it will allow 
evaluating the impact of nirsevimab on the incidence of RSV infection in its rarer but direst 
manifestations. 
This study’s design does not permit blinding. Parents/LARs will know whether their infant 
received the study intervention or not and, depending on the enrollment setting (eg, hospital or 
medical office), the child’s pediatrician or the family doctor may be the person performing 
inclusion in the study, administering or not administering the study intervention, and later 
advising parents/LARs on the course of action in case of respiratory infection. These “real-world” 
conditions are bound to introduce some bias that the use of a blind assessor or of an adjudicating 
committee would not entirely alleviate (55). However, and although this study is open-labelled, 
the selection of a very robust and patient-oriented endpoint kernel (ie, RSV LRTI hospitalization) 
will allow for a scientifically sound and clinically relevant assessment of nirsevimab efficacy. 
Despite being a monoclonal antibody, nirsevimab will be administered by intramuscular injection 
like routine pediatric vaccinations. Furthermore, nirsevimab can be co-administered along with 
routine pediatric vaccines planned in the vaccination schedule of each country (53). This will 
facilitate its administration during routine appointments, making it possible to immunize the entire 
intervention cohort at the start of the season using existing healthcare appointments when 
possible. This, in line with the mostly pragmatic study design, will further help minimize the 
burden on parents/LARs of participants and on the healthcare system of each country. 
Rationale for the Study Population 
The participants to be enrolled are all infants from France, Germany, and UK, under the age of 12 
months entering their first RSV season that are not eligible to receive RSV prophylaxis with 
palivizumab, which indication is limited to infants with certain underlying conditions such as 
chronic lung disease, congenital heart disease, or very premature. 
In order to minimize the burden on sites, families and participants, while still answering the 
objective of this protocol amendment, it was decided to invite in the study extension only the UK 
participants, who represent 50% of the study population.  
Enrollment of Study Participants 
A total of 28 860 participants will be enrolled from sites in France, Germany, and the United 
Kingdom. The study will enroll infants born either out of the RSV season or in the RSV season. 
Definition of the RSV season 
There is an important variability of RSV seasonality from year to year in each country. The 
typical RSV season in the Northern Hemisphere (NH) last approximately 5 months and usually 
starts in October or November. Therefore, the “Out-of-Season” period refers to the approximately 
7 months period from March or April to September or October. The actual start date and length of 
the RSV season will depend on the actual circulation of RSV in the NH in 2022.  

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Cases of LRTI hospitalization will be collected throughout the study to ensure that all cases 
occurring during the next RSV season are captured. For the need of this study, the start and end 
dates of the RSV season will be defined on a country-by-country basis and will be based on 
country-specific epidemiological surveillance. For the mothers of infants to be born in-season, 
recruitment will start at 30 weeks gestation in women with an estimated delivery date during the 
RSV season. 
Rationale for the Collection of Safety Data 
Immediate AEs 
As nirsevimab is not a marketed product, a 30 minutes immediate surveillance period of infants 
enrolled in the nirsevimab group will be done on the site where immunization was performed. 
Non-serious AEs 
For a period of 30 days post-dosing/randomization, non-serious AEs will be captured in the eCRF 
for all study participants. The relation of AEs to interventional product will be determined by the 
Investigator. 
The use of the eDiary by parents and the process for reporting AEs in the eCRF is outlined in 
Section 8.2.3. 
Hospitalizations 
In this study, “LRTI hospitalizations” occurring up to 12 months post-dosing/randomization for 
all participants are considered as part of the efficacy assessments and “LRTI hospitalizations” 
occurring up to 24 months post-dosing/randomization for UK reconsented participants are 
considered as part of the descriptive analyses. Consequently, these LRTI hospitalizations will not 
be reported as SAEs. Definition of hospitalization, RSV LRTI hospitalization, and very severe 
RSV LRTI are provided in Section 8.1.2. 
It is to be noted that testing for RSV is expected to be performed by the hospital as part of routine 
practice. 
SAEs, AESIs, and MAAEs 
After dosing/randomization, all participants will be followed-up for SAEs, AESIs, and MAAEs up 
until the 12 months follow-up phone contact.  
Additionally, UK reconsented participants will be followed-up for SAEs until the 24-month 
follow-up phone contact. Only SAE considered as related by the investigator or site staff will be 
collected in the CRF. 
Rationale for Dose of Investigational Products 
In nonclinical cotton rat (Sigmodon genus) efficacy studies, MEDI8897 (ie, nirsevimab internal 
identifier) serum concentrations of 6.8 μg/mL were shown to result in a 3-log decrease in RSV 
titers in cotton rat lungs. A population PK model, developed using PK data from both a Phase Ia 
study in healthy adults and Phase Ib/IIa study in healthy preterm infants, was used to simulate PK 
profiles in the Phase IIb population. PK profiles were simulated in 1000 infants for each of the 

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following populations: preterm infants (29 to 35 WGA) at birth, full-term infants at birth, and full-
term infants at 12 months of age. A single 50 mg fixed IM dose of MEDI8897 was predicted to be 
the likely efficacious dose that would sustain serum concentrations above the target level of 
6.8 μg/mL in the majority of infants over the entire RSV season and provided complete protection 
for infants entering their first RSV season. 
In the Phase IIb study D5290C00003, a single fixed 50 mg IM dose was shown to be efficacious 
in preterm infants (29 to < 35 WGA) in their first RSV season. Model-based analyses of the 
Phase IIb 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 significantly 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 IIb study, this dose resulted in suboptimal exposures for infants 
weighing ≥ 5 kg. 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 maintenance of MEDI8897 serum concentrations above the target 
AUC throughout the RSV season. Based on dose optimization analysis designed to maximize the 
proportion of infants with clinically efficacious MEDI8897 serum exposure, a single fixed 50 mg 
IM dose is proposed for infants < 5 kg in their first RSV season while a single fixed 100 mg dose 
is proposed for infants weighing ≥ 5 kg entering their first RSV season. 
This dosing regime is used in two ongoing pivotal studies for registration, the Phase III study 
D5290C00004 (MELODY) and the Phase II/III study D5290C00005 (MEDLEY).  
4.3 
End of Study Definition  
A participant is considered to have completed the study if the parents or LARs have completed the 
last contact planned in the SoA (telephone contact at D366 for France, Germany, and UK 
non-reconsented participants and telephone contact at D731 for UK reconsented participants). 
The end of the study is defined as the date of the last contact of the last participant in the study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized. 
5 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 

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5.1 
Inclusion Criteria  
Participants are eligible for the study only if all of the following criteria are met: 
Age 
I01: Born at ≥ 29 weeks gestational age and aged 0 to 12 months (calendar age), who are entering 
their first RSV season on the day of randomization in the study (D01)a 
Informed Consent 
I02: Informed consent form has been signed and dated by the parent(s) or other LAR(s) (and by 
an independent witness if required by local regulations) 
Other 
I03: Participant and parent/LAR are able to attend the scheduled visit and to comply with all 
study proceduresb. 
5.2 
Exclusion Criteria  
Participants are not eligible for the study if any of the following criteria are met: 
Medical conditions 
E01: Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the past 3 months) 
E02: Active confirmed RSV infection at the time of dosing/randomization 
E03: Active LRTI at the time of dosing/randomization 
E04: Known systemic hypersensitivity to any of the study intervention components, or history of 
a life-threatening reaction to the study intervention used in the study or to a product 
containing any of the same substancesc 
E05: Laboratory-confirmed thrombocytopenia, or known thrombocytopenia, as reported by the 
parent/LAR, contraindicating intramuscular injection 
E06: Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular injection 
E07: Any condition that, in the opinion of the investigator, is at a stage where it might interfere 
with study conduct or completion 
 
a  “0 to 12 months” means from the day of birth to the day before the 13th month after birth.  
b  It is to be noted that “complying with all study procedures” includes the parents or LARs willingness to install the 
study's dedicated application on their smartphone. 
c  The components of study intervention(s) are listed in Section 6.1 of the protocol and in the Investigator’s 
Brochure (IB).  

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E08: Moderate or severe acute illness/infection (according to investigator judgment) or febrile 
illness (temperature ≥ 38.0°C [≥ 100.4°F]) on the day of study intervention administration. A 
prospective participant should not be included in the study until the condition has resolved or 
the febrile event has subsided 
Prior/concomitant therapy 
E09: Mother of the infant participant was administered an RSV vaccine during her pregnancy 
with the infant participant 
E10: Receipt of any monoclonal antibody by the infant participant 
E11: Receipt of immune globulins, blood or blood-derived products in the past 3 months by the 
infant participant 
Prior/concurrent clinical study experience 
E12: Participation at the time of study enrollment or planned participation during the present 
study period in another clinical study investigating a vaccine, drug, medical device, or 
medical procedurea 
Other exclusions 
E13: Eligible to receive palivizumab at time of inclusion (as per local guidelines) 
E14: In an emergency setting or hospitalized involuntarilyb 
E15: Identified as a natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study 
5.3 
Lifestyle Considerations  
No restrictions other than the ones listed in the exclusion criteria are required. 
5.4 
Screen Failures  
Screen failures are defined as participants whose parents or LARs consent to participate in the 
clinical study but are not subsequently randomly assigned to study intervention/no intervention. 
Screening information is recorded in the source documents. 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened. 
 
a It is to be noted that strictly observational studies do not fall under this exclusion criterion. 
b An infant in an emergency setting could include one who may be with next of kin or emergency services in case the 
parents are hospitalized, in jail, or dead. Involuntary hospitalization of an infant could be due to a court order or 
mediated by social services, without the consent of the parents. 

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6 
Study Intervention and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: Concomitant therapies such as vaccines or products administered outside of study protocol 
are not considered as study interventions and are reported in the eCRF as reportable medications 
(see Section 6.8). 
6.1 
Study Intervention Administered  
Study interventions are described in Table 6.1. 
Table 6.1: Identity of study intervention  
Intervention Name 
Nirsevimab 
Use 
Experimental 
IMP and NIMP 
IMP 
Type  
Extended half-life monoclonal antibody 
Dose Form 
Sterile solution for injection 
Unit Dose Strength(s) 
100 mg/mL 
Excipients/Diluent 
• 30 mM histidine/histidine-HCl 
• 80 mM arginine-HCl 
• 120 mM sucrose 
• 0.02% (w/v) polysorbate 80 
• pH 6.0  
water for injection 
Dosage Levels 
0.5 mL presentation corresponding to 50 mg (if weight < 5 kg) 
or  
1.0 mL presentation corresponding to 100 mg (if weight ≥ 5 kg) 
at D01 
Number of Doses / Dosing Interval 
1 dose 
Route of Administration 
IM 
Site of Administration 
Anterolateral aspect of the thigh according to standard practice 
procedures for IM injections in infants 
Injection Site Side 
Either 
Sourcing 
Provided by AstraZeneca 
Packaging and Labeling 
AstraZeneca 
Current/Former Name or Alias 
n/a 

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Batch Number 
TBD 
Storage Conditions 
The IMP will be stored in a refrigerator at a temperature ranging 
from +2°C to +8°C. The IMP must not be frozen, shaken, or 
exposed to light. Keep the prefilled syringe in the outer carton in 
order to protect from light. 
Abbreviations: IM, intramuscular; IMP, Investigational Medicinal Product; n/a, not applicable; NIMP, 
Non-Investigational Medicinal Product; TBD, to be determined 
The participant’s weight at enrollment will determine the dose of nirsevimab to be administered. 
The dose of nirsevimab will be 50 mg for participants weighting < 5 kg and 100 mg for 
participants ≥ 5 kg at D01. 
Study arms and associated study intervention are summarized in Table 6.2. 
Table 6.2: Arms and Associated Study Interventions  
Arm name 
Group 1 
Group 2 
Associated study interventions 
Nirsevimab 
No intervention 
6.2 
Preparation/Handling/Storage/Accountability  
Detailed guidance and information are provided in the investigator site file/regulatory binder. 
1) The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
3) The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4) Further guidance and information for the final disposition of unused study interventions are 
provided in the IMP operating manual. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1 
Randomization and Allocation Procedures  
On the day of randomization, participants who meet all the inclusion criteria but none of the 
exclusion criteria with a signed informed consent from the parent(s) or other LAR will be 

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randomly assigned to Group 1 (nirsevimab) or Group 2 (no intervention) in a 1:1 ratio, stratified 
according to country and age at the time of randomization (ie, age ≤ 3.0 months, age > 3.0 to 
≤ 6.0 months, and age > 6.0 months). 
Site staff will connect to the IRT, enter the identification and security information, and confirm a 
minimal amount of data in response to IRT prompts. The IRT will then provide the subject 
randomization number and the group assignment and have the site staff confirm it. The full 
detailed procedures for group allocation are described in the IRT user guidelines. If the participant 
is not eligible to participate in the study, then the information will only be recorded on the 
participant recruitment log. If the parents or LARs of a participant have signed the consent but the 
participant is not randomized, the participant number and the reason of the screening failure will 
be recorded in the IRT database and then transferred in the clinical database. 
Participant randomization numbers that are assigned by the IRT will consist of a 12-digit string (a 
3-digit country identifier, a 4-digit study center identifier, and a 5-digit participant identifier). For 
example, Participant 250000100005 is the fifth participant enrolled in Center Number 1 in France 
(250 being the France country code). Participant numbers should not be reassigned for any reason. 
The randomization codes will be kept securely in the IRT. 
6.3.2 
Blinding and Code-breaking Procedures  
Code-breaking procedures are not applicable as this is an open-label study.  
Blinding remains a methodological safeguard in clinical trials and is important for limiting bias, 
such as selection bias, detection bias, and performance bias. In this open-label pragmatic study, 
nirsevimab immunization will be compared to standard‑of‑care, ie, no intervention, and having a 
blinded third party or clinician assessing the patient outcomes is not feasible. Whether the 
compared groups will receive similar amount of attention cannot be ensured and this, in turn, can 
result in biased treatment effect estimates with uncertainties on the direction of the bias (under-
ascertainment/over-ascertainment). Methods that decrease risk of bias will be used, such as 
standardization of questionnaires, a narrowly-defined and objective primary outcome, and when 
possible electronic health records to retrieve the primary clinical endpoints. Response rates to the 
questionnaires between the 2 groups will inform about the risk of bias. 
6.4 
Study Intervention Compliance  
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1), and that any non-compliance is documented so that it can be accounted for in the data 
analyses: 
• Nirsevimab immunization will be performed by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose given to each participant, and unused or wasted doses 

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6.5 
Dose Modification  
Not applicable. 
6.6 
Continued Access to Study Intervention After the End of the Study  
Not applicable. 
6.7 
Treatment of Overdose  
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the investigator or other site personnel should: 
1) Contact the RMO immediately. 
2) Closely monitor the participant for any AE/SAE. 
3) Document the quantity of the excess of the overdose in the source documents. 
6.8 
Concomitant Therapy  
The following concomitant reportable medications will be collected: 
• Medications that may affect the interpretation of safety data (eg, an antipyretic or analgesic 
that could have reduced the intensity or frequency of an AE) 
• All vaccines administered within 14 days before and after dosing/randomization. It is to be 
noted that routine childhood vaccines scheduled at the time of the enrollment visit should 
be administered as planned 
• All medications administered within 14 days before and after admission for LRTI 
hospitalization  
• Routine immunization with nirsevimab (Beyfortus). For countries where Beyfortus has 
been made commercially available during the study conduct, the sites will be asked to 
report any routine immunization with Beyfortus. 
Reportable medications will be collected in the eCRF. Dosage, homeopathic medication, topical 
steroids, as well as topical, ophthalmic, and ear treatments will not be recorded (except topical 
analgesics applied at the injection site of study intervention). Inhaled steroids will be recorded only 
when prescribed during a wheezing episode (see below). 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
eCRF.  
For UK reconsented participants, the following concomitant medications will be collected: 
• Medications related to related SAE and/or LRTI hospitalization 
• Any medications prescribed during a wheezing episode. 

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Medications will be coded using the WHODrug dictionary.  
6.8.1 
Rescue Medicine  
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available at the study site in the event of an anaphylactic or other immediate allergic 
reaction. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Not applicable as there is only one immunization visit. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• 
A participant may be withdrawn from the study at any time at her/his parents or LARs request 
or may be withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• 
The reason for withdrawal should be clearly documented in the source documents and in the 
eCRF: Adverse Event, Lost to Follow-up, Protocol Deviation, or Withdrawal by Parents or 
LARs. 
• 
For participants hospitalized due to a LRTI symptoms who are withdrawn from the study, the 
Investigator or designee may seek information from the facility where medical attention was 
sought to complete the participant’s eCRF and assess the case. This retrospective collection 
of information on LRTI hospitalization for participants withdrawn from the study will be 
possible only if the parents or LARs provided consent by ticking the corresponding box in the 
informed consent form. 
• 
The participant will be permanently discontinued from the study at that time. 
• 
If the parents or LARs of the participant withdraw consent for disclosure of future 
information, the Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• 
Withdrawn participants will not be replaced. 

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Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
their parents or LARs and complete all scheduled safety follow-ups, except if they specified that 
they do not want to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information after last contact attempt on the 12-month follow-up 
for France, Germany, and UK non-reconsented participants and on the 24-month follow-up for 
UK reconsented participants. See Section 7.3 for definition of “lost to follow-up”. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if her or his parents or LARs cannot be 
contacted by the site or designee. 
The following actions must be taken if the parents or LARs of the participants do not follow-up on 
the monthly electronic contact (until 6 months after dosing/randomization) or cannot be contacted 
by phone at the end of the study as planned in the SoA: 
• 
For the monthly electronic contact: the electronic platform will send one reminder for 
3 consecutive days. If there is no answer after the e-reminders, the site and/or designee 
will call the parents or LARs of the participant as soon as possible, discuss the 
importance of answering the follow-up questions with them, and ascertain whether or not 
they wish their infant to continue participating in the study. 
It is to be noted that if both the electronic and phone reminders fail, the next monthly 
electronic contact (up until 6 months post-dosing/randomization) will take place. The 
participant will not be deemed lost to follow-up before the 12-months follow-up phone 
contact for France, Germany, and UK non-reconsented participants or the 24-months 
follow-up phone contact for UK reconsented participants takes place. 
• 
For the 12 months follow-up phone contact for France, Germany, and UK 
non-reconsented participants or the 24 months follow-up phone contact for UK 
reconsented participants, and before a participant is deemed lost to follow-up, the 
investigator or designee must make every effort to regain contact with the parents or 
LARs of the participants (where possible, 3 telephone calls and, if necessary, a certified 
letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record. 
Should the parents or LARs continue to be unreachable, the participant will be 
considered lost to follow-up. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 10.1. 

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8 
Study Assessments and Procedures  
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8.1 
Efficacy Assessments  
Planned time points for all efficacy assessments are provided in the SoA. 
Efficacy data for the first year of study and descriptive data for the second year of the study are 
collected through the participant’s medical records and reported in the eCRF. Hospitalizations will 
be reported by parents/LARs of participants through an eDiary for the first year of the study. From 
D01 to D366, each time a health event will be captured on the eDiary, a medical call center will 
contact parents/LARs to collect and report the health event’s information in the eCRF. The 
Investigator or delegated site staff will review information reported in the eCRF and interview the 
participants’ parents/LARs if any additional information needs to be collected. Parents/LARs who 
don’t have access to the eDiary will be requested to contact directly the investigation site to report 
any health event.  
From D366 to D731, UK reconsented participants’ parents/LARs will record in the memory aid 
any hospitalization that occurred. During the 18-month and 24 month phone calls, the Investigator 
or delegated site staff will interview parents/LARs to collect information reported in the memory 
aid and report only LRTI hospitalization’s information in the eCRF.  
During the 12- and 24-month follow-up calls, the site investigator or staff designee will ask to 
parents/LARs of UK reconsented participants if the participants had experienced any medically 
attended cough, chest or breathing problems throughout the study period. After the 12-month 
follow-up phone call (when possible) and the 24-month follow-up phone call, the site investigator 
or staff designee (including third parties authorized by the site investigators) will access the UK 
reconsented participants’ medical record (general practitioner’s or hospital’s record) to determine 
if the medical event meets with the definition of wheeze provided by the Sponsor (see 
Section 8.1.2.4). If so, the event and related complementary information (including any medications 
prescribed during wheeze) will be retrospectively collected. 
8.1.1 
Baseline Assessments at the Time of Immunization  
All parents or LARs will be asked to provide demographic information on the participant such as 
gestational age, date of birth (or month of birth, depending on local regulations), weight, gender, 
medical history, vaccine history, and postal code at the time of enrollment. The type of 
demographic information collected is determined by laws in each country. 

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8.1.2 
Efficacy Assessments  
Efficacy assessments will be based on RSV LRTI hospitalization throughout the study period 
(Section 8.1.2.2), and very severe RSV LRTI (Section 8.1.2.3) throughout the first year of the 
study (see Section 8.1.2.1), through 150 days post-dosing/randomization, and through 180 days 
post-dosing/randomization as described in Section 3.  
8.1.2.1 
Definitions  
“Hospitalization” is defined as the decision to admit to in-patient care by the treating physician. 
“RSV season” is the period of increased RSV infection. For the purpose of efficacy analyses, the 
start and end dates of the RSV season will be defined on a country-by-country basis and will be 
based on country-specific epidemiological surveillance. 
8.1.2.2 
RSV LRTI Hospitalization  
Participants will be monitored for RSV LRTI hospitalization.  
Parents or LARs can report the hospitalization through the eDiary (for the first year of the study 
for all the participants) which will trigger a contact by the site and/or designee. Site staff and/or 
designee will inquire about the hospitalization and report it in the eCRF. For the second year of 
the study, parents or LARs of UK reconsented participants will report hospitalizations in a 
memory aid. Information reported in the memory aid will be collected by sites during the 
18-month and 24-month phone calls. 
Whether a hospitalization is effectively due to an RSV LRTI or not will be assessed by the 
Investigator: 
• If the attending physician is the Investigator, the assessment of the case will be done directly 
as the participant information (eg, RSV test result and medical interventions) will be readily 
available.  
• If the attending physician is not the Investigator, the collection of participant information will 
be done retrospectively. In this situation, the Investigator or designee will seek the required 
information from the facility where medical attention was sought to complete the 
participant’s electronic case report form (eCRF).  
Based on the information captured, the Investigator will assess whether hospitalization was due to 
RSV LRTI and categorize the case accordingly. It is to be noted that testing for RSV is expected 
to be performed by the hospital as part of routine practice. 
Symptoms commonly associated with LRTI include (but are not limited to): 
• Clinical finding of rhonchi, rales, crackles, or wheeze, 
• Increased respiratory rate at rest (age: < 2 months, ≥ 60 breaths/min; 2 to 6 months, 
≥ 50 breaths/min; > 6 months, ≥ 40 breaths/min),  
• Hypoxemia (in room air: oxygen saturation < 95%) 

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Each potential case of RSV LRTI hospitalization should be documented with the RSV test result, 
the lowest rate of oxygen saturation recorded, duration of hospital stay, and the list of medical 
interventions leading to end of the hospitalization (eg, oxygen supplementation, intravenous fluid 
administration, admission to intensive care unit). 
It is to be noted that, for hospitalization due to respiratory infection, parents or LAR of the 
participant will be instructed to present the participant card (paper version or digital version 
through the eDiary) to the hospital. RSV test will be performed at the hospital as part of routine 
practice. The participant card will contain a reminder for RSV testing. 
8.1.2.3 
Very severe RSV LRTI  
A very severe RSV LRTI case is defined as: 
• RSV LRTI hospitalization 
• oxygen saturation < 90% (at any time during hospitalization) 
• oxygen supplementation 
With the addition of oxygen saturation < 90% and oxygen supplementation, very severe RSV 
LRTI cases are to be identified, described, and documented in the same way as RSV LRTI 
hospitalization (Section 8.1.2.2). 
8.1.2.4 
Wheeze  
During the 12- and 24-month follow-up call, the site investigator or staff designee will ask to 
parents/LARs of UK reconsented participants if the participants had experienced any medically 
attended cough, chest or breathing problems throughout the study period.  
After the 12-month follow-up phone call (when possible) and the 24-month follow-up phone call, 
the site investigator or staff designee (including third parties authorized by the site investigators) 
will access the UK reconsented participants’ medical record (general practitioner’s or hospital’s 
record) to determine if the medical event meets with the definition of wheeze provided by the 
Sponsor (see below). If so, the event and related complementary information (including any 
medications prescribed during wheeze) will be retrospectively collected. 
For this study, wheeze will be defined as a physician-diagnosed wheeze or asthma or related ear, 
nose and throat (ENT)/respiratory symptoms at an office visit or an illness for which the child was 
prescribed medication to treat an ENT/respiratory condition. 
8.1.3 
Immunogenicity Assessments  
No immunogenicity data will be obtained in the study. 
8.2 
Safety Assessments  
This section presents safety assessments other than adverse events which are presented in 
Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 

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Safety data are reported by parents/LARs of participants through an eDiary. From D01 to D366, 
each time a health event will be captured on the eDiary, a medical call center will contact 
parents/LARs to collect and report the health event’s information in the eCRF. The Investigator or 
delegate site staff will review information reported in the eCRF and interview the participants’ 
parents/LARs if any additional information needs to be collected. Parents/LARs who don’t have 
access to the eDiary will be requested to contact directly the investigation site to report any health 
event.  
From D366 to D731, UK reconsented participants’ parents/LARs will record in the memory aid 
any hospitalizations and emergency room visits that occurred. During the 18-month and 24-month 
phone calls, the Investigator or delegated site staff will interview parents/LARs to collect 
information reported in the memory aid and to assess the SAE relationship. Only the related SAE 
information will be collected in the eCRF. 
8.2.1 
Medical History  
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the participant is or has been followed by a physician or conditions/illnesses that could 
resume during the course of the study or lead to an SAE or to a repetitive outpatient care will be 
collected in the eCRF. 
Collected information will be coded.  
8.2.2 
Clinical Examination  
At Visit 01, the Investigator or a designee may perform a routine clinical examination. 
Information will be recorded in the source document. 
The weight at enrollment will be measured for all participants and recorded in both the source 
document and in the eCRF and in the IRT. 
For participants randomized in the nirsevimab group, pre-immunization temperature will be 
collected by the investigator as per routine practice and reported on the source document. 
Temperature of infants is taken to support ruling out of active infections. 
If a participant needs medical attention or is hospitalized during the study, information collected 
in the participant’s medical record will be reviewed, recorded in the eCRF, and the medical event 
assessed accordingly (ie, non-serious AEs within 30 days post-dosing/randomization, MAAEs, 
AESIs, and SAEs up to D366 for all participants or related SAEs from D366 to D731 for UK 
reconsented participants). 
8.2.3 
Collection and Reporting of Adverse Events (AEs)  
Immediate AEs 
Following immunization, parents or LARs of participants enrolled in the nirsevimab group will be 
requested to remain on site for the 30 minutes immediate surveillance of their infant. 

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Remote safety follow-up 
During the visit, parents or LARs of all participants will be provided access to the eDiary 
application. They will be instructed to log in the eDiary application and answer questions in case a 
health-related event occurs in their infant. Depending on the time post-dosing/randomization at 
which the infant’s health-related event occur, the investigator or designee will contact the infant’s 
parents or LARs to collect additional information. 
Detailed guidance and information on the handling of the eDiary, the monthly electronic contacts, 
the follow-up phone contacts, and on the completion of the eCRF are provided in the 
corresponding manuals included in the investigator site file or regulatory binder. 
A memory aid will be provided to UK reconsented participants’parents or LARs to collect any 
hospitalizations and emergency room visits occurring from D366 to D731 post-
dosing/randomization. During the 18-month and 24-month phone calls, the Investigator or 
delegated site staff will interview parents/LARs to collect information reported in the memory aid 
and to assess the SAE relationship. Only the related SAE information will be collected in the 
eCRF.  
Hospitalization 
As part of the safety follow-up, participants will be monitored for hospitalization through the 
eDiary during the first year of the study and through the memory aid during the second year of the 
study (only for UK reconsented participants). Parents or LARs will have to report hospitalization 
through the eDiary. Alternatively, parents or LARs can also directly contact the Investigator. 
Upon hospitalization of their infant, parents or LARs will be asked to present the study card to 
medical personnel. The participant card will:  
- Indicate participation in a clinical study  
- Invite medical personnel to provide contact details of the host medical facility.  
- Remind medical personnel that an RSV test should be conducted in case hospitalization is 
related to a respiratory illness. 
Hospitalization due to respiratory illness 
Hospitalization, RSV LRTI hospitalization, and very severe RSV LRTI are defined in 
Section 8.1.2. 
Hospitalizations due respiratory illness (including cases of very severe RSV LRTI) will be 
reported in a specific eCRF page. 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting  
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.2. 
When parents or LARs answer questions in the eDiary to report an health event in their infant, an 
investigation by the site or designee will be triggered to collect information on the AE in the 
eCRF. 

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The investigator and any designees are responsible for detecting through entries made by parents 
in the eDiary, documenting, and recording events that meet the definition of an AE or SAE and 
remain responsible for following up AEs that are serious, considered related to the study 
intervention or study procedures, or that caused the participant to discontinue the study (see 
Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.2. 
8.3.1 
Exemption to the Reporting of LRTI Hospitalizations as SAEs  
In this study, LRTI hospitalizations of any cause including RSV LRTI hospitalizations constitute 
the studied clinical outcome of interest; that is, they are constitutive of the efficacy endpoints. As 
a consequence, LRTI hospitalizations of any cause, including RSV LRTI hospitalizations, 
occurring during the study will not be considered and reported as SAEs. 
It is to be noted that, during the first year of the study, this exemption does not apply in the 
situation where the Investigator would consider the LRTI hospitalization to be related to the 
investigational product or to any LRTI hospitalization with a Fatal outcome. During the second 
year of the study, this exemption does not apply in the situation where the Investigator would 
consider the LRTI hospitalization to be related to the investigational product. In these situations, 
the events are to be reported as SAEs and the Investigator is required to follow the protocol-
specified process for reporting SAEs to the GPV Department (See Section 10.2.4). 
8.3.2 
Time Period and Frequency for Collecting AE and SAE Information  
Immediate Post-immunization Observation Period 
Participants enrolled in the nirsevimab group will be kept under observation for 30 minutes after 
immunization to ensure their safety. The post-immunization observation should be documented in 
the source document. 
Non-serious Adverse Events 
Non-serious adverse events will be collected from dosing/randomization (D01) until 30 days after 
immunization, ie, D31. 
The intensity grading scale for non-serious adverse events is presented in Appendix 10.2.5.1. 
Medically Attended Adverse Events (MAAEs) 
MAAEs will be collected from dosing/randomization (D01) to D366 phone call. 
Adverse Events of Special Interest (AESIs) 
AESIs will be collected from dosing/randomization (D01) to D366 phone call 
See Section 8.3.7 for the list of AESIs. 
SAEs 
Information on SAEs will be collected and assessed throughout the study, from 
dosing/randomization (D01) until 12 months after immunization (D366) for all participants. 

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Information on related SAEs will be collected and assessed from D366 until D731 
post-dosing/randomization for UK reconsented participants. Refer to Section 8.3.1 for the 
exemption of reporting LRTI hospitalizations as SAEs. 
It is to be noted that, since this study is seeking real-world data, part of the participants’ safety 
data will be collected retrospectively by the Investigator or designee. This means that, following 
the initial capture of information in the eDiary/memory aid by the parents or LARs, the 
Investigator or designee will be seeking additional or missing participant data from the medical 
facility where the medical visit or the hospitalization occurred to complete the corresponding 
eCRF. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.2. The investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the Sponsor. 
8.3.3 
Method of Detecting AEs and SAEs  
Individual eDiaries, specifically designed for this study by the Sponsor, will be made accessible to 
parents or LARs during Visit 01 at the study sites. The eDiaries will be used by parents or LARs 
to report health-related events occurring in participants, including unplanned medical visits and 
hospitalization. Individual memory aid will be provided to parents or LARs of UK reconsented 
participants to report any hospitalizations and emergency-room visits occurring from D366 to 
D731 post-dosing/randomization. 
The Investigator or a designee may interview the parents or LARs to collect and clarify 
information recorded in the eDiary/memory aid. All clinical study information gathered by the 
study site and/or designee will be reported electronically by the Investigator or designee using a 
web-based eCRF. Any information that was not documented in the eDiary will first be captured in 
the source document and then reported electronically. 
The 12-month follow-up will be done by interviewing by the investigator or delegated site staff all 
participants’ parents or LARs over the telephone to capture SAEs, MAAEs, and AESIs, if 
applicable. The 18- and 24-month follow-up will be done by interviewing UK reconsented 
participants’ parents or LARs over the telephone to capture related SAEs. 
8.3.4 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator and/or delegated site staff is required to 
proactively follow each participant during subsequent contacts, unless parents or LARs refuse 
further contact. All AEs that are considered by the Investigator as serious or related to the study 
intervention administered, or AEs of special interest (as defined in Section 8.3.7), will be followed 
during the conduct of the study until resolution, stabilization, or the participant is lost to follow-up 

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(as defined in Section 7.3). For related SAEs ongoing at last study contact, such follow-up may 
need to continue after the end of the study.  
Further information on follow-up procedures is provided in Appendix 10.2. 
8.3.5 
Regulatory Reporting Requirements for SAEs  
• 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
8.3.6 
Pregnancy  
Not applicable as the study does not include women of childbearing potential. 
8.3.7 
Adverse Events of Special Interest  
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s study intervention or program, for which ongoing monitoring and rapid communication 
by the investigator to the Sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the event, 
rapid communication by the study Sponsor to other parties (eg, regulators) might also be 
warranted. 
The following AEs will be assessed as AESIs throughout the study: 
• hypersensitivity, including anaphylaxis (56) 
• immune complex disease (57) 
• thrombocytopenia (58) 
The designated Sponsor study representative will work with the investigator to ensure that all 
relevant information is provided and entered in the eCRF. If the event is considered serious, it 
must be reported to the Sponsor by the Investigator as an SAE, ie, no later than 24 hours of when 
she or he becomes aware of the event as an SAE (Appendix 10.2). 

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8.3.8 
Medically Attended Adverse Events  
MAAEs will be collected using the same process as other AEs. 
See Appendix 10.2.1 for definition of MAAEs. 
8.3.9 
Health Measurement/Observation  
Participants’ parents or LARs will be able to report the occurrence of safety events in the eDiary 
during the first year of the study. In addition, and regardless of whether a safety event was 
captured during the month, there will be a monthly electronic contact with parents or LARs of the 
participant, via the eDiary application, to confirm that no health-related events went unreported 
during the month. The automated monthly electronic contacts will occur up to 6 months post-
dosing/randomization. If parents or LARs of the participant confirm that a safety event occurred 
during the past month, a phone investigations by the site staff and/or designee will be triggered, 
and the data will be recorded in the eCRF.  
At 12 months, a safety follow-up phone call will be made to the parents or LARs of the participant 
by the site personnel or designee. 
Parents or LARs of UK reconsented participants will be able to report any hospitalizations and 
emergency room visits that occurred from D366 to D731 post-dosing/randomization in the 
memory aid. 
8.4 
Pharmacokinetics  
Pharmacokinetics parameters are not evaluated in this study. 
8.5 
Genetics  
Genetics are not evaluated in this study. 
8.6 
Biomarkers  
No biomarkers are evaluated in this study. 
8.7 
Medical Resource Utilization  
For participants who report LRTI hospitalizations during the study, the investigator or designee 
will collect data about health care resource utilization associated with medical encounters. 
For each case of LRTI hospitalization, the data collected in the eCRF should: 
• Include the RSV test result, the lowest rate of oxygen saturation recorded, the duration of 
hospital stay, the list of medical interventions leading to end of the hospitalization (eg, 
oxygen supplementation, intravenous fluid administration, admission to intensive care 
unit), and outcome, and  
• Exclude procedures, tests, and encounters mandated by the protocol. 

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The sponsor may use the collected data to conduct economic analyses. 
Medical Resource Utilization will be evaluated in this study as an exploratory objective to 
investigate the effectiveness of nirsevimab compared with no preventive intervention in reducing 
utilization of key medical resources. Data on medical resource utilization will be collected either 
directly (if the attending physician is the Investigator) or retrospectively from the host hospital 
and/or the attending physician (if the attending physician is not the Investigator) to identify and 
measure the impact on these key medical resources arising from RSV LRTI hospitalization in 
infants. 
The evaluation of resource use will be based on RSV LRTI hospitalizations and duration of stay, 
utilization of oxygen supplementation, administration of intravenous fluid, and ICU admissions 
and duration of stay. 
8.8 
Immunogenicity Assessments  
See Section 8.1.3. 
9 
Statistical Considerations  
9.1 
Statistical Hypotheses  
The primary and key secondary efficacy objectives will be assessed in the Primary Analysis (see 
Section 9.4 for details of the Primary Analysis) by a hierarchical order. Details on statistical 
methods are provided in Section 9.4. 
For the primary objective, a superiority approach will be used to assess the efficacy of nirsevimab 
in preventing RSV LRTI hospitalization through the RSV season compared to no intervention in 
all 3 countries combined. Only if the superiority for the primary endpoint is demonstrated, a 
superiority approach will be used to assess the efficacy of nirsevimab in preventing very severe 
RSV LRTI through the RSV season compared to no intervention in all 3 countries combined, and 
no multiplicity adjustment is needed for this.  
If the superiority for very severe RSV LRTI through the RSV season is demonstrated, a 
superiority approach will be used to assess the efficacy of nirsevimab in preventing RSV LRTI 
hospitalization through RSV season compared to no intervention in each country separately. For 
this, Bonferroni adjustment of 2-sided α (ie, 0.05/3) is used to correct multiple testing in 
3 countries in the sample size calculation and Bonferroni-Holm procedure will be used in the 
statistical analysis. For other secondary objectives and observational objectives, no hypotheses 
will be tested and the analyses will be descriptive.  
9.2 
Sample Size Determination  
A total of 28 860 participants are expected to be enrolled of whom approximately 14 430 will 
receive nirsevimab and 14 430 will receive no intervention. This sample size is driven by the 

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demonstration of efficacy in preventing RSV LRTI hospitalization in each of 3 countries 
independently. 
Based on the reported incidence rates of RSV LRTI hospitalization in France, Germany, and the 
UK (2) (51) (52), assuming a 1.1% incidence rate on average in the control group (ie, receiving no 
intervention), 9620 participants need to be enrolled in each of the 3 countries (which is equivalent 
to 74 events of RSV LRTI in each country) to ensure the 90% power to detect 60% efficacy in 
each country with a 2-sided α of 1.66% taking the multiplicity adjustment using Bonferroni 
approach into consideration.  
The sample size of 28 860 participants has at least 99% power to detect 60% efficacy in 
preventing RSV LRTI hospitalizations in all 3 countries combined assuming an incidence rate of 
0.86% in the control group (the lowest reported in the 3 countries) with a 2-sided α of 5%, and 
approximately 95% power to detect 60% efficacy in preventing very severe RSV LRTI defined in 
the protocol assuming an incidence rate of 0.4% in the control group (59) with a 2-sided α of 5%. 
To ensure at least 90% power for very severe RSV LRTI, at least 61 events are needed.  
9.3 
Analysis Sets  
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Randomized 
Participants who were randomly assigned to either the nirsevimab group 
or the control group 
Safety Analysis Set (SafAS) 
Participants who received nirsevimab in the study and all randomized 
participants if randomized to the control group and who did not receive 
nirsevimab inadvertently. All participants will have their safety 
analyzed according to the study intervention they actually received. 
Per-Protocol Analysis Set 
(PPAS) 
All randomized participants who did not have at least one of the 
following protocol deviations:  
- 
Participant did not meet all protocol-specified inclusion criteria or 
met at least one of the protocol-specified exclusion criteria 
- 
Participant did not receive nirsevimab or the correct dose of 
nirsevimab if randomized to nirsevimab 
- 
Participant received nirsevimab if randomized to no intervention 
- 
Administration of nirsevimab was not done as per-protocol 
- 
Participant did not have at least one contact for efficacy follow-up 
after dosing/randomization 
- 
Any other protocol deviations identified during the study conduct 
as relevant to the exclusion from the PPAS 
All participants will have their efficacy endpoints analyzed according to 
the group they were randomized to. 

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9.4 
Statistical Analyses  
The statistical analysis plan (SAP) will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and key secondary endpoints. 
9.4.1 
General Considerations  
There will be 3 planned main analyses for this study: the Primary Analysis, the First Year 
Analysis, and the Second Year Analysis. The Primary Analysis will be conducted when at least 61 
events of RSV LRTI hospitalization in all 3 countries combined are observed, but no later than 30 
April 2023. All available data collected up to the data cut-off date will be analyzed at the time of 
the Primary Analysis. The First Year Analysis will be conducted when all participants have 
completed the scheduled 12-month safety follow up. It will include all data and planned analyses. 
The Second Year Analysis will be conducted when all UK reconsented participants have 
completed the scheduled 24-month safety follow-up. It will include all data and planned analyses. 
The efficacy analyses performed in the Primary Analysis will serve the purpose of evaluating the 
efficacy of nirsevimab in the study population. LRTI hospitalization will also be collected after 
the end of the RSV season and the efficacy will be calculated but only for descriptive purposes at 
the time of the First Year Analysis without the intention of a confirmatory conclusion. LRTI 
hospitalizations and wheezing episodes will also be collected at 24 months follow-up and at 12 
and 24 months follow-up, respectively, in UK reconsented participants but only for descriptive 
purposes at the time of the Second Year Analysis (without the intention of a confirmatory 
conclusion for LRTI hospitalizations). Therefore, no multiplicity adjustment is needed for the 3 
main analyses. 
9.4.2 
Primary Endpoint  
The primary endpoint is the overall incidence of RSV LRTI hospitalization through the RSV 
season in healthy term and preterm infants in all 3 countries combined. The determination of RSV 
LRTI hospitalization is based on the criteria described in Section 8.1.2.2. 
The efficacy of nirsevimab in preventing RSV LRTI hospitalization compared to no intervention 
will be estimated accounting for the follow-up time post-dosing/randomization up to the data cut-
off date for the Primary Analysis as follows: 
(1- (CN / NN) / (CC / NC)) × 100% 
where: 
- 
CN and CC are the numbers of RSV LRTI hospitalization through the RSV season in the 
nirsevimab and the control (ie, no intervention) groups, respectively.  
- 
NN and NC are the total person-time contributed by participants randomized in the 
nirsevimab and the control groups, respectively.  
The 95% CI for the efficacy will be calculated by an exact method assuming a binomial 
distribution of the number of RSV LRTI hospitalizations in the nirsevimab group conditional on 
the total number in both groups accounting for the follow-up time post-dosing/randomization.  

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The superior efficacy of nirsevimab in preventing RSV LRTI hospitalization will be concluded if 
the lower bound of the efficacy is > 0%. The primary efficacy analysis of the primary endpoint 
will be performed on all randomized participants.  
If a participant experiences multiple occurrences of the same primary endpoint, only the first 
episode will be considered. The following rules will be applied in the calculation of the total 
person-time for the follow-up time: 
- 
The start date for the follow-up will be the date of randomization for participants who are 
randomized to no intervention and the date of dosing for participants who are randomized 
to nirsevimab.  
- 
For the participants who do not have the primary endpoint at the time of the Primary 
Analysis, the end date for the efficacy follow-up will be the end of the RSV season, or the 
last available date with confirmation of no RSV LRTI hospitalization for the Primary 
Analysis whichever is earlier. The efficacy follow-up will be censored at the end date.  
- 
For the participants who have the primary endpoint at the time of the Primary Analysis, the 
end date for the efficacy follow-up will be the date of hospital admission.  
The above-described analysis on the primary endpoint will also be conducted on the PPAS.  
A sensitivity analysis using a Poisson regression model with robust variance will be performed on 
all randomized participants (60). The model contains the term of treatment group, and age group 
at randomization (ie, age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0 months) and country 
as covariates, adjusting for the log of the follow-up time as an offset. The efficacy of nirsevimab 
in preventing RSV LRTI hospitalization, defined as 1 minus Relative Risk, and its corresponding 
2-sided 95% CI will be estimated from the model. The same rule used in the analysis for the 
primary endpoint as described above for the calculation of total follow-up time will be applied to 
the calculation of the follow-up time.  
A Kaplan-Meier curve for time to first RSV LRTI hospitalization will be generated based on the 
observed events. The algorithm for time-to-event calculation is the same as that for follow-up time 
as above. Treatment group differences in time to first RSV LRTI hospitalization will be compared 
using the log-rank test stratified by country and age group at randomization. In addition, hazard 
ratio and the corresponding 95% CI will be obtained from the Cox proportional hazard model with 
age group at randomization and country as the covariates. The corresponding efficacy estimate is 
defined as (1-harzard ratio) × 100%.  
The subgroup analysis of the primary endpoint will be conducted on the following in all 
randomized participants using the exact method described above in the primary efficacy analysis: 
- 
Age group at randomization: age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, 
age > 6.0 months 
- 
Weight at randomization: weight < 5 kg, weight ≥ 5 kg 
- 
Gestational age: < 37 weeks, ≥ 37 weeks 
- 
Gender: male, female 
- 
Infants dosed in-season (dosed on or after the start date of RSV season) and before the 
start of the RSV season. 

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Note: please refer to Section 4.2 for a definition of the start and the end of RSV season 
Additional analyses if deemed necessary will be detailed in the SAP. 
9.4.3 
Secondary Endpoints  
9.4.3.1 
Very severe RSV LRTI  
If the efficacy of nirsevimab in preventing RSV LRTI hospitalization is demonstrated in the 
primary efficacy analysis, the very severe RSV LRTI through the RSV season will be compared 
between the nirsevimab and no intervention groups on all randomized participants using the same 
method for the primary efficacy analysis of the primary endpoint. The very severe RSV LRTI is a 
subset of RSV LRTI hospitalization with oxygen saturation < 90% (at any time during 
hospitalization) and oxygen supplementation. For participants with multiple very severe RSV 
LRTI episodes, only the first occurrence will be used in the analysis. If the lower bound of the 
95% CI for the efficacy is > 0%, the superior efficacy of nirsevimab in preventing very severe 
RSV LRTI compared to the control group is demonstrated.  
The above stated analysis on very severe RSV LRTI will be also conducted on the PPAS. The 
time to first very severe RSV LRTI will be analyzed using the Kaplan Meier curve and the Cox 
proportional hazard model, as described for the primary efficacy endpoint in Section 9.4.2, on all 
randomized participants.  
Incidence of the very severe RSV LRTI will be summarized by the following subgroups:  
- 
Age group at randomization: age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, 
age > 6.0 months 
- 
Weight at randomization: weight < 5 kg, weight ≥ 5 kg 
- 
Gestational age: < 37 weeks, ≥ 37 weeks 
- 
Gender: male, female 
- 
Infants dosed in-season (dosed on or after the start date of the RSV season) and before the 
start of the RSV season.  
- 
Country 
Note: please refer to Section 4.2 for a definition of the start and the end of RSV season 
Additional analyses if deemed necessary will be detailed in the SAP. 
9.4.3.2 
RSV LRTI Hospitalization in each country  
If the efficacy of nirsevimab in preventing very severe RSV LRTI compared to the control is 
concluded, RSV LRTI hospitalization will be evaluated in each of the 3 countries. The same 
analysis as described above in Section 9.4.2 the primary efficacy analysis for the primary endpoint 
with Bonferroni-Holm procedure based on the adjusted CIs for the multiplicity adjustment will be 
used to calculate the efficacy on all randomized participants in each country. The superior efficacy 

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of nirsevimab in preventing RSV LRTI hospitalization will be concluded for the country if the 
lower bound of the efficacy is > 0%.  
Additional analyses if deemed necessary will be detailed in the SAP. 
9.4.3.3 
Other secondary efficacy endpoints  
Efficacy and its 95% CIs for nirsevimab in reducing the following efficacy endpoints as compared 
to the control will be calculated using the exact method as described in the primary efficacy 
analysis for the exploratory purpose: 
- 
Overall hospitalization for all-cause LRTI in all 3 countries combined throughout the RSV 
season 
- 
RSV LRTI hospitalization through 150 days post-dosing/randomization (overall and in 
each country)  
- 
Very severe RSV LRTI in all 3 countries combined through 150 days post-
dosing/randomization 
- 
Overall hospitalization for all-cause LRTI in all 3 countries combined through 150 days 
post-dosing/randomization 
- 
RSV LRTI hospitalization through 180 days post-dosing/randomization (overall and in 
each country) 
- 
Overall hospitalization for all-cause LRTI in all 3 countries combined through 180 days 
post-dosing/randomization 
- 
Recurrent wheeze throughout the study period in UK reconsented participants  
Analyses for the above efficacy endpoints through 150 days post-dosing/randomization and 
through 180 days post-dosing/randomization will be performed only at the First Year Analysis 
after all data are collected. Details of the analyses and additional analyses if deemed necessary 
will be described in the SAP.  
Descriptive analyses of the incidence of RSV LRTI hospitalization and all-cause LRTI 
hospitalization and the incidence of recurrent wheeze with its 95% CIs for nirsevimab and the no 
intervention will be presented in UK reconsented participants. 
9.4.4 
Exploratory Endpoints  
Efficacy and its 95% CIs for nirsevimab in reducing the following efficacy endpoints as compared 
to the control will be calculated using the exact method as described in the primary efficacy 
analysis for the exploratory purpose: 
- 
Very severe RSV LRTI in all 3 countries combined through 180 days post-
dosing/randomization 
Analyses for the above efficacy endpoints through 180 days post-dosing/randomization will be 
performed only at the Final Analysis after all data are collected. Details of the analyses and 
additional analyses if deemed necessary will be described in the SAP.  

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For other exploratory endpoints, tabular summaries will be presented by the 2 arms. Categorical 
data will be summarized by the number and percentage of participants in each category. 
Continuous variables will be summarized by descriptive statistics. Additional details of statistical 
analyses will be described in the SAP. 
9.4.5 
Safety Analysis  
Safety endpoints will be analyzed based on the SafAS defined in Section 9.3. Safety of nirsevimab 
will be assessed by the occurrence of immediate AEs, non-serious AEs within 30 days post-
dosing/randomization, and MAAEs, SAEs, and AESIs following 12 months post-
dosing/randomization for all participants, related SAEs from D366 to D731 for UK reconsented 
participants. All AEs will be coded by MedDRA system organ class and preferred term. The type, 
incidence, and severity will be summarized by treatment group. Relationship to nirsevimab will 
also be summarized. 
In addition, all AEs (including immediate AEs, non-serious AEs within 30 days post-
dosing/randomization, and MAAEs, SAEs and AESIs) in neonates < 28 days of age at 
randomization will be summarized.  
9.5 
Interim Analyses  
A Primary Analysis is planned prior to the formal completion of the study. The efficacy analyses 
planned in the Primary Analysis will serve the purpose of evaluating the efficacy of nirsevimab in 
the study population. Efficacy data analyzed in the First Year and Second Year Analyses are 
exploratory therefore a multiplicity adjustment is not needed. These analyses will be conducted at 
the timepoints described in Section 9.4.1. 
10 Supporting Documentation and Operational Considerations  
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations  
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the eCRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. Similarly, “legally acceptable representative” is used in the protocol 
whereas “guardian” is used in the eCRF. 
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 

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• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, informed consent form (ICF), Investigator Brochure (IB), and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator or the 
Sponsor (according to local regulations) and reviewed and approved by the IRB/IEC before 
the study is initiated 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC  
• 
Determining whether an incidental finding (as per Sanofi policy) should be returned to a 
participant and, if it meets the appropriate criteria, to ensure the finding is returned (an 
incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
• In case the participant’s parents or LARs have decided to opt out, the Investigator 
must record in the site medical files that she/he does not want to know about such 
findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 

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• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the Investigator’s contract. 
10.1.3 Informed Consent Process  
An electronic or email informed consent process can be implemented (if applicable per country 
regulations). Regardless of whether an eConsent, an email ICF or a paper ICF is used: 
• The Investigator or her/his representative will explain the nature of the study to the parents or 
LARs of the participants and answer all questions regarding the study. 
• The parents or LARs of the participants must be informed that the participation of their infant 
is voluntary. The parents or LARs of the participants will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the 
sample ICF provided by the Sponsor. Any change to the content of the ICF must be approved 
by the Sponsor and the IEC / IRB prior to the form being used. 
• If new information becomes available that may be relevant to the participant parents’ or 
LARs’ willingness to continue participation in the study, this will be communicated to the 
parents or LARs in a timely manner. Such information will be provided via a revised ICF or 
an addendum to the original ICF. 
• The participants’ parents or LARs must be re-consented to the most current version of the 
ICF(s) during their participation in the study. 
• A copy of the ICF(s) must be provided to the parents or LARs of the participant. 

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Recruitment Procedures 
Infants will be recruited at hospitals, pediatric and general practice (GP) offices or other 
community-based clinics.  
Pre-screening of infants to be born in season will start at 30 weeks of gestation (ie, before birth). 
Inclusion in the study (D01) will occur immediately after birth (up to their first scheduled visit 
after discharge) in participating sites. The final decision as to whether the newborn will be 
included in the study shall be with the attending physician who is also responsible for the 
appropriate documenting of inclusion. Infants will be randomly assigned to either the intervention 
or the no intervention arm of the study. 
Recruitment of infants born out of season will be done at participating healthcare providers, eg, 
primary care offices or pediatric offices. Infants born out of season could also be enrolled at 
hospital if they are contacted by the hospital to schedule an appointment for enrolment. The date 
of inclusion (and dosing, for the nirsevimab arm) in the study (D01) is scheduled before or during 
the start of the RSV season. If possible, inclusion shall be done simultaneously with the 
mandatory health check-ups. 
Infants born out of season will be recruited either prior to or during the RSV season. For the 
mothers of infants to be born in season, recruiting will start at 30 weeks gestation in women with 
an estimated delivery date during the RSV season. Participants will be randomly assigned in a 1:1 
ratio to either the group that will be immunized with 1 dose of nirsevimab or the group that will 
receive no RSV preventative therapy. 
10.1.4 Data Protection  
All personal data collected and/or processed in relation to this study will be handled in compliance 
with all applicable Privacy & Data Protection laws and regulations, including the GDPR. The 
study Sponsor is the Sanofi company responsible for ensuring compliance with this matter, when 
processing data from any individual who may be included in the Sanofi databases, including 
Investigators, nurses, experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only by 
the unique identifier; participant names or any information which would make the participant 
identifiable will not be transferred to the Sponsor. 
• The parents or LARs of the participant must be informed that her/his personal study-related 
data will be used by the Sponsor in accordance with applicable data protection law. The level 

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of disclosure must also be explained to the participant’s parents or LARs as described in the 
informed consent. 
• The parents or LARs of the participant must be informed that her/his medical records may be 
examined by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The parents or LARs of the participant must be informed that their study-related data will be 
used for the whole “drug development program”, ie, for this trial as well as for the following 
steps necessary for the development of the investigational product, including to support 
negotiations with payers and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the study and/or the related contractual or pre-contractual 
relationship. They may be communicated to any company of the Sanofi group (“Sanofi”) or 
to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects.  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. The 
same rule applies in case the professionals are listed on a regulatory agencies disqualification 
list. 
• Personal data can be communicated to the following recipients:  
• Personnel within Sanofi or partners or service providers involved in the study  
• Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
• The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
• Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with any 
competent local regulatory authority. 

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• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates in 
the Shared Investigator Platform (SIP) and in the Transcelerate Investigator Registry (IR) 
project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). Therefore, 
personal data will be securely shared by Sanofi with other pharmaceutical company members 
of the Transcelerate project. This sharing allows Investigators to keep their data up-to-date 
once for all across pharmaceutical companies participating in the project, with the right to 
object to the transfer of the data to the Transcelerate project.  
• Professionals have the right to object to the processing, to request for access to and the 
rectification of their personal data, as well as their erasure (where applicable) by contacting 
the Sanofi Data Protection Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France 
(to contact Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-
privacy-policy/contact). 
10.1.5 Committees Structure  
Participant safety will be continuously monitored by the Sponsor’s internal safety review 
committee which includes safety signal detection at any time during the study. The Sponsor’s 
internal safety review committee, led by the PV representative and the RMO and designee(s), will 
be responsible for the unblinded review, assessment, and evaluation of safety data generated from 
this study. This committee is empowered to recommend a pause in recruitment and/or further 
immunization while it investigates any potential signal or concern. 
This study will not include an early safety data review.  
10.1.6 Dissemination of Clinical Study Data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical studies in participants are required to be submitted to peer-
reviewed journals following internal company review for accuracy, fair balance, and intellectual 
property. For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org. 

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Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data Quality Assurance  
• All participant data relating to the study will be recorded on eCRF and eDiary unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in eCRF/eDiary completion guidelines 
• The investigator and designees must permit study-related monitoring, audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to source data 
documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 

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10.1.8 Source Documents  
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, eDiary, medical and hospital 
records, screening logs, informed consent / assent forms, telephone contact logs, and worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and Site Start and Closure  
Details on which clinical supplies are provided by the Sponsor or the site are described in the 
contract and vendor manuals included in the investigator site file or regulatory binder. 
The study start date is considered the date of the first visit planned in the SoA of the first 
participant. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, the center study-site has all the documents 
necessary for archiving and a study-site closure visit has been performed  
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are not 
limited to: 
For study termination: 
• Discontinuation of further study intervention development 
• Information on the study intervention leads to doubt as to the benefit/risk ratio 
For site termination: 

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• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication Policy  
Information related to publication policy is described in the Investigator’s contract. 
10.2 Appendix: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
10.2.1 Definition of AE  
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiograms, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 

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• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
LRTI hospitalizations of any cause, including RSV LRTI hospitalization, occurring at any 
time post-dosing/randomization, will not be considered and reported as SAEs (see 
Section 8.3.1 for more information). 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.  
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 

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Other Definitions 
Adverse Reaction: 
An adverse reaction (AR) is any noxious and unintended response to a study intervention 
related to any dose.  
All AEs occurring at and around the IMP injection/administration site are to be considered by 
default as related to the IMP administered at that site and are therefore referred as 
injection/administration site ARs. 
All AEs which are not at and around the IMP injection/administration site, are referred as 
systemic AE. For each systemic AE, the investigator assesses the relationship to the IMP. 
Systemic AEs assessed as related to IMP are referred as systemic ARs. 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant AEs which occur within the first 
30 minutes after immunization. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
and rapid communication by the investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the study Sponsor to other parties (eg, regulators) 
might also be warranted. 
Medically Attended AE (MAAE)  
An MAAE is a new onset or a worsening of a condition that prompts the participant or 
participant’s parent/legally acceptable representative to seek unplanned medical advice at a 
physician’s office or Emergency Department. Physician contact made over the phone or by e-
mail will be considered a physician office visit for the purpose of MAAE collection. This 
includes medical advice seeking during the study visit or routine medical care. This definition 
excludes pediatric check-ups, follow-up visits of chronic conditions with an onset prior to entry 
in the study. 
10.2.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 

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c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is other medically important event 
• The term "Other medically important events" refers to events which do not meet any of the 
above seriousness criteria, but which are considered as serious based on investigator 
medical judgment  
• Medical or scientific judgment should be exercised by the investigator in deciding whether 
expedited reporting is appropriate in other situations such as significant medical events 
that may jeopardize the health of the participant or may require intervention to prevent one 
of the other outcomes listed in the above definition. These important medical events 
should also usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse, new-onset diabetes or 
autoimmune disease, or suspected transmission of any infectious agent via an authorized 
medicinal product. 
Note: Serious and severe are not synonymous. The term severe is often used to describe the 
intensity of a specific event as corresponding to Grade 3. This is not the same as serious, which is 
based on participant / event outcome or action criteria usually associated with events that pose a 
threat to a participant’s life or functioning. 

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10.2.3 Recording and Follow-Up of AE and/or SAE  
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the eCRF pages. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of Causal Relationship 
By convention, all AEs reported at the injection site are considered to be related to the IMP (see 
definition in Section 6) and therefore are referred to as reactions and do not require the 
Investigator’s opinion on relatedness.  
• Causal relationship of AEs and SAEs will be recorded as follows: 
• 
For non-serious AEs (except for non-serious AESIs), relationship to study intervention 
will usually be assessed by the Investigator only. 
• 
For SAEs and non-serious AESIs, relationship to study intervention will be assessed 
by both the Investigator and the Sponsor (except for injection site reactions which will 
be related by default). Sponsor assessment is entered in the GPV database only.   
• 
For SAEs only, the causal relationship to study procedures (related/not related to study 
procedures) will be assessed by both the Investigator and the Sponsor. Sponsor 
assessment is entered in the GPV database only. 
• The Investigator will assess the causal relationship between each AE and the study 
intervention administered as either not related or related, based on the following 
definitions: 
• 
Not related – The AE is clearly / most probably caused by other etiologies such as 
participants’ underlying condition, therapeutic intervention, or concomitant therapy; or 
the delay between immunization and the onset of the AE is incompatible with a causal 
relationship; or the AE started before the immunization (screening phase, if applicable) 

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• 
Related – There is a “reasonable possibility” that the AE was caused by the study 
intervention administered, meaning that there are facts (evidence) or arguments to 
suggest a causal relationship 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
• The investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causal relationship. 
• There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always makes an assessment of causal relationship for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The investigator may change his/her opinion of causal relationship in light of follow-up 
information and send an SAE follow-up report with the updated causal relationship 
assessment. 
• The causal relationship assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causal relationship of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, when available the investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information. 
• Serious adverse events likely to be related to the study intervention, that persist at the end of 
the study will be followed up by the Investigator until their complete disappearance or the 
stabilization of the participant’s condition. The Investigator will inform the Sponsor of the 
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10.2.4 Reporting of SAEs  
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. The site will enter the SAE data 
into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section). 
• Details regarding SAE reporting can be found in the eCRF completion guidelines in the 
investigator site file or regulatory binder. 
 
SAE Reporting to the Sponsor via Paper CRF 
• The SAE paper CRF can be sent to the Sponsor by one of the following means: 
• 
By fax, to the following number: +33 (0) 1 60 49 70 70 
• 
In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: CL-CPV-Receipt@sanofi.com  
 
Safety Emergency Call 
If, as per the Investigator's judgment, a participant experiences a medical emergency, the 
Investigator may contact the Sponsor's RMO for advice on how to address any study-related 
medical question or problem. If the RMO is not available, then the Investigator may contact the 
RMO Call Center—available 24 hours a day, 7 days a week—that will forward all safety 
emergency calls to the appropriate primary or back-up Sanofi Pasteur contact, as needed. The 
toll-free contact information for the Call Center is provided in the contact sheet in the 
investigator site file or regulatory binder. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department. 
10.2.5 Assessment of Intensity  
The investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”. 

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10.2.5.1 AE Intensity Grading Scale  
All AEs will be classified according to the following intensity scale: 
• Grade 1 
• 
eCRF: A type of adverse event 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. 
• 
No grading in eDiary/memory aid 
• Grade 2 
• 
eCRF: A type of adverse event that is usually alleviated with additional therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
• 
No grading in eDiary/memory aid 
• Grade 3 
• 
eCRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• 
No grading in eDiary/memory aid 
10.3 Appendix: Country-specific Requirements  
10.4 Appendix: Risk-based Approach  
ICH E6-R2 guideline for GCP is introducing the « risk-based approach » concept which permits 
to focus efforts on what is critical for a study and most specifically on Critical Data and Critical 
Processes. Critical data and processes are defined for the study with associated risks in the Study 
Risk Management Plan. 

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10.5 Appendix: Abbreviations  
AE 
 
Adverse Events 
AESI  
Adverse events of special interest 
AR 
 
Adverse reactions 
CRF  
Case report form 
CSR  
Clinical Study Report 
DMC  
Data Monitoring Committee 
eCRF  
electronic CRF 
eDiary  
electronic Diary  
FAS 
 
Full analysis set 
FVFS  
First Visit First Subject 
GCP  
Good Clinical Practice 
GDPR  
General Data Protection Regulation 
GPV  
Global Pharmacovigilance 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonisation 
IEC 
 
Independent Ethics Committees 
IM 
 
intramuscular 
IMP 
 
Investigational Medicinal Product 
IRB 
 
Institutional Review Boards 
IRT 
 
interactive response technology 
LAR  
legally acceptable representative  
LRTI  
lower respiratory tract infection 
LVFS  
Last Visit First Subject 
LVLS  
Last Visit Last Subject 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIMP  
Non-Investigational Medicinal Product 
PPAS  
Per-protocol analysis set 
PV 
 
pharmacovigilance 

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RMO  
Responsible Medical Officer 
RSV  
respiratory syncytial virus 
SAE  
Serious adverse events 
SafAS  
Safety Analysis Set 
SAP 
 
Statistical analysis plan 
SoA 
 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
TBD  
to be determined 
WGA  
weeks gestational age 
 
 

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10.6 Appendix: Protocol Amendment History  
The Protocol Amendment Rationale for the current amendment is located directly before the 
Table of Contents. 
 
Protocol update 1 – Version 2.0 (17 June 2022) 
Overall Rational for the Protocol Update 
VAS00006 protocol version 1.0 (dated 01 March 2022) was updated to extend the period during 
which LRTI hospitalizations are to be collected from 6 months to 12 months (ie, the entire study 
duration) post-dosing/randomization. This will help mitigate the variability of RSV seasonality 
and ensure that all LRTI hospitalizations occurring during next RSV season are captured. 
This updated version of the protocol also provides some additional information on a number of 
operational matters. As this is a multicenter study taking place in three countries, it is important to 
ensure that operational procedures are clearly described to decrease the risk of deviation from the 
study protocol. 
Among the clarifications brought with VAS00006 protocol version 2.0 are the following: 
• The measurement method of the infant’s temperature before dosing is to be performed as 
per routine practice. 
• It has been made explicit that the collection of adverse events starts after 
dosing/randomization on the day of inclusion (Visit 1). 
• The possibility to use an electronic Informed Consent process (applicable as per country 
regulations) was made explicit. 
• It was made clearer that Informed Consent can take place before Visit 1 but 
inclusion/exclusion criteria verification and all other procedures must take place 
immediately before dosing/randomization. 
• It was stated in the protocol that only infants born at ≥ 29 weeks gestational age would be 
included in the study. This requirement is now part of inclusion criterion I01 for more 
clarity.  
Amendment 1 – Version 3.0 (19 July 2023) 
Overall Rationale for the Amendment: 
As a result of a post-marketing commitment to the United States Food and Drug Administration 
(FDA) to collect data for the evaluation of antibody-dependent enhancement of RSV disease in 
the second RSV season of neonates and infants who received nirsevimab prior to or during their 
first RSV season, the follow-up of HARMONIE participants is being extended to 24 months. 
To address this commitment, the HARMONIE study design was updated with the addition of a 
12-month follow-up period, including 2 phone calls at D546 and D731 
post-dosing/randomization, in United Kingdom (UK) participants only. At the end of the first-year 
follow-up, all UK participants’ parents/LARs still in the study will be informed of the study 
extension and their consent will be asked.  

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In order to minimize the burden on sites, families and participants while still answering the 
objectives of this protocol amendment, it was decided to invite in this study extension only the 
UK participants, who represent 50% of the study population. Only UK participants whose 
parents/LARs have given consent (called reconsented participants hereafter) will participate in the 
study extension.  
The 12-month extension period is also used as the opportunity to retrospectively collect 
information on wheeze at D366 and D731 post-dosing/randomization in UK reconsented 
participants only. 
 
 

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Kramer R, Duclos A, Lina B, Casalegno JS. Cost and burden of RSV related
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Murray J, Bottle A, Sharland M, Modi N, Aylin P, Majeed A, et al. Risk factors for
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Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, et al. Single-
Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020;383(5):415-25.
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Stollar F, Glangetas A, Luterbacher F, Gervaix A, Barazzone-Argiroffo C, Galetto-Lacour
A. Frequency, Timing, Risk Factors, and Outcomes of Desaturation in Infants With Acute
Bronchiolitis and Initially Normal Oxygen Saturation. JAMA network open.
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Young M, Smitherman L. Socioeconomic Impact of RSV Hospitalization. Infectious
diseases and therapy. 2021;10(Suppl 1):35-45.
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van Houten CB, Naaktgeboren C, Buiteman BJM, van der Lee M, Klein A, Srugo I, et al.
Antibiotic Overuse in Children with Respiratory Syncytial Virus Lower Respiratory Tract
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