Clinical trial NCT03979313
Conditions: Respiratory Syncytial Virus Infections
Keywords: Respiratory Syncytial Virus RSV Late Preterm Infants Healthy Infants Lower Respiratory Tract Infection
Sponsor: AstraZeneca
Start date: 2019-07-23; Completion date: 2023-03-21
Enrollment: 3012 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics (PK), and antidrug antibody (ADA) response for MEDI8897 in healthy late preterm and term infants who are 35 weeks or greater gestational age and entering their first RSV season.

Detailed description:
This pivotal Phase 3 study will determine if MEDI8897 will prevent medically attended RSV-confirmed lower respiratory tract infections (LRTI) in healthy infants entering their first RSV season. The population to be enrolled is healthy late preterm and term infants born 35 weeks 0 days or greater gestational age (GA) who would not be eligible to receive RSV prophylaxis. A total of approximately 3,000 infants will be randomized 2:1 to receive either MEDI8897 or placebo. All subjects will be followed for approximately 510 days after dosing. Enrollment is planned at approximately 350 sites across the USA, Canada, Europe, Asia, and Southern Hemisphere.

Arms: arm 1: Anti-RSV monoclonal antibody with an extended half-life arm 2: Commercially available 0.9% (w/v) saline
Interventions: intervention 1: MEDI8897 intervention 2: Placebo
Intervention descriptions: intervention 1: Anti-RSV monoclonal antibody with an extended half-life intervention 2: Commercially available 0.9% (w/v) saline

Protocol documents:
Prot_000.pdf: 
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A Phase 3 Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Safety and Efficacy of MEDI8897, a Monoclonal 
Antibody With an Extended Half-life Against Respiratory 
Syncytial Virus, in Healthy Late Preterm and Term Infants
(MELODY)
Sponsor Protocol Number:
D5290C00004
Application Number:
IND number 118524
Investigational Product:
MEDI8897
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC, 
, Gaithersburg, 
Maryland, 20878, USA
Medical Monitor:
 AstraZeneca
Contract Research Organization: IQVIA
Protocol History, Date:
Original Protocol, 05Apr2019
Protocol Amendment 1, 01Feb2021
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Amendment 1 (01Feb2021)
Overall Rationale for the Amendment
The principal reason for this amendment was to introduce a complementary safety cohort 
(which will be referred to as the safety cohort throughout the protocol) and clarify the number 
of subjects to be enrolled and the analysis populations for the efficacy and safety analyses. 
The safety cohort will serve the purpose of providing additional safety assessment. Although 
efficacy data will be collected for the safety cohort, only descriptive summaries will be 
provided and there is no intent to pool the efficacy data from the safety cohort with that from 
the primary cohort. These changes were made to reflect mitigation of the low RSV circulation 
and impact on efficacy data due to the COVID-19 pandemic related measures. 
Section
Description of Change
Brief Rationale
Title Page
Updated the medical monitor 
information 
Due to the change in medical 
monitor for this study
Synopsis,
3.1.1 Overview
Added text and revised the study flow 
diagram (Figure 1) to indicate that the 
study will comprise 2 cohorts: a primary 
cohort and safety cohort
To reflect mitigation of the low 
RSV circulation and impact on 
efficacy data due to the COVID-19 
pandemic related measures
Synopsis,
3.2.3 Rationale for 
endpoints,
4.3.1.1 Lower Respiratory 
Tract Infection
Revised the RSV resistance monitoring 
language 
To improve clarity of exploratory 
endpoint analysis and to align with 
clinical virology analysis plan
Synopsis, 
4.8.1 General 
Considerations
Added the definition of the primary 
cohort and safety cohort
Added the definition of ITT1, ITT2, 
AT1, and AT2
Updated the planned analyses, and when 
and what data will be analyzed for each 
analysis
To reflect mitigation of the low 
RSV circulation and impact on 
efficacy data due to the COVID-19 
pandemic related measures, and 
provide clarification of the analysis 
populations
Synopsis, 
4.8.2 Sample Size
Updated the sample size and power 
information
Updated study power based on the 
sample size of the primary cohort, 
on which the primary efficacy 
analysis will be based 


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Section
Description of Change
Brief Rationale
Synopsis, 
4.8.3 Efficacy,
4.8.4 Safety, 
4.8.6 Exploratory Analysis
Specified cohorts/populations that will 
be analyzed for the primary, secondary, 
and exploratory endpoint analyses
Clarified that subjects randomized from 
the primary cohort (ITT1) will be 
analyzed in the primary and secondary 
efficacy analyses, and subjects 
randomized from the safety cohort 
(ITT2) will be summarized descriptively
Clarified that safety analyses will be 
conducted on the overall As-treated 
Population, AT1, and AT2
Clarified that the summaries of the 
magnitude of HRU and caregiver burden 
will be conducted on ITT1 and ITT2
To provide clarification of the 
cohorts/populations to be analyzed
Synopsis,
4.8.3 Efficacy
Removed the stratification factor 
“hemisphere” from the analyses for the 
primary efficacy endpoint 
To update the analyses due to 
known convergence or estimation 
issue during blinded data review 
prior to the database lock for 
primary analysis
4.8.3.4 Subgroup Analyses 
of the Primary Endpoint
Updated subgroup “weight at birth 
(weight ≤ 2.5 kg, weight > 2.5 kg to 
< 5 kg, weight ≥ 5 kg)” to “weight at 
birth (weight ≤ 2.5 kg, weight > 2.5 kg)”
To update based on data availability 
4.2.2 Treatment and 
Follow-up Periods 
(Table 5)
Added a concomitant medications 
assessment for the D362-511 period and 
corresponding footnote to specify that it 
applies only to subjects with LRTIs 
diagnosed during this period
To collect concomitant medications 
for subjects with LRTIs diagnosed 
during this period
4.3.1.1 Lower Respiratory 
Tract Infection 
(Respiratory Secretions for 
RSV Detection)
Changed “Testing may include other 
respiratory pathogens” to “Testing of all 
samples may include other respiratory 
pathogens”
For clarity
4.5.1.5 Reporting Product 
Complaints
Removed the fax number and the 
 
phone number
The deleted numbers are no longer 
in use
4.6.2 Methods to Ensure 
Blinding, 
4.8.1 General 
Considerations
Added a description of the unblinding 
strategy 
To ensure the double-blind setting 
and trial integrity will be maintained 
with the newly added safety cohort 
and the updated analysis strategy
4.8.3.2 Additional 
Analyses of the Primary 
Endpoint
Added sensitivity analyses 
To assess the impact of the 
COVID-19 pandemic on the 
robustness of the efficacy results 


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Section
Description of Change
Brief Rationale
5.3.1 Hypersensitivity, 
Including Anaphylaxis,
5.7.3.1 Hypersensitivity, 
Including Anaphylaxis
Clarified hypersensitivity by adding 
immediate (type I)
For clarity
Throughout
Minor editorial revisions
Minor, therefore, were not 
summarized
AT1 = As-treated Population 1; AT2 = As-treated Population 2; COVID-19 = coronavirus disease 2019; 
D = Day; HRU = healthcare resource utilization; ITT1 = Intent-to-treat Population 1; ITT2 = Intent-to-treat 
Population 2; LRTI = lower respiratory tract infection; RSV = respiratory syncytial virus.


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PROTOCOL SYNOPSIS
TITLE
A Phase 3 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of 
MEDI8897, a Monoclonal Antibody With an Extended Half-life Against Respiratory Syncytial Virus, in 
Healthy Late Preterm and Term Infants (MELODY)
HYPOTHESES
Primary Hypothesis
Compared to placebo, a single intramuscular (IM) MEDI8897 dose, 50 mg if weight < 5 kg or 100 mg if 
weight ≥ 5 kg, will be efficacious in reducing medically attended lower respiratory tract infection (LRTI) 
caused by real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed respiratory 
syncytial virus (RSV) in healthy late preterm and term infants born ≥ 35 weeks 0 days gestational age (GA)
and entering their first RSV season, and the safety profile will be acceptable.
Secondary Hypotheses
•
There will be a reduction in the incidence of hospitalizations attributable to RT-PCR-confirmed RSV
•
The predicted serum exposures of MEDI8897 will be adequate for the duration of the RSV season
•
Anti-drug antibody (ADA) to MEDI8897 will not impact the serum concentrations or safety of 
MEDI8897 through 150 days post dosing (ie, during a 5-month RSV season)
OBJECTIVES and ASSOCIATED ENDPOINTS
Type
Objective
Endpoint
Primary
Efficacy
To assess the efficacy of MEDI8897 
when administered as a single fixed 
IM dose to infants ≥35 weeks 0 
days GA and entering their first 
RSV season, in reducing medically 
attended LRTI due to RT-PCR-
confirmed RSV, compared to 
placebo
Incidence of medically attended LRTI (inpatient 
and outpatient) due to RT-PCR-confirmed RSV 
through 150 days after dosing (ie, during a typical 
5-month RSV season)
Secondary
Efficacy
To assess the efficacy of MEDI8897 
in reducing hospitalizations due to 
RT-PCR-confirmed RSV, compared 
to placebo
Incidence of hospitalizations due to RT-PCR-
confirmed RSV through 150 days after dosing (ie, 
during a typical 5-month RSV season)
Safety
To evaluate the safety and 
tolerability of MEDI8897 when 
administered as a single fixed IM 
dose, compared to placebo
Safety and tolerability of MEDI8897 as assessed by 
the occurrence of treatment-emergent adverse 
events (TEAEs), treatment-emergent serious 
adverse events (TESAEs), adverse events of special 
interest (AESIs), and new onset chronic diseases 
(NOCDs)
PK
To evaluate single-dose serum 
concentrations of MEDI8897
Summary of MEDI8897 serum concentrations and 
estimated PK parameters: apparent clearance, 
AUC0-∞, if data permit
ADA
To evaluate ADA responses to 
MEDI8897 in serum
Incidence of ADA to MEDI8897 in serum


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Type
Objective
Endpoint
Exploratory
Healthcare 
resource 
utilization and 
caregiver 
burden
To assess healthcare resource 
utilization and caregiver burden for 
MEDI8897 recipients compared to 
placebo recipients
• Magnitude of healthcare resource utilization 
(HRU; eg, number of admissions to hospitals and 
intensive care units and duration of stay; number 
of subjects who require respiratory support and 
supplemental oxygen and the duration of use; 
number and type of outpatient visits, eg, 
emergency room [ER], urgent care, outpatient 
clinic; and number of prescription and over-the-
counter medications and duration of use) 
• Caregiver burden (eg, caregiver missed work 
days, subject absence from day care) for subjects 
with medically attended LRTI caused by 
RT-PCR-confirmed RSV
RSV 
neutralizing 
antibody
To determine anti-RSV neutralizing 
antibody levels in serum afforded 
by a single dose of MEDI8897 
compared to maternally derived 
RSV neutralizing antibody levels 
and those elicited by RSV infection 
in the placebo group
Anti-RSV neutralizing antibody levels (IU/mL) in 
serum for MEDI8897 recipients compared to 
placebo recipients
RSV serology
To evaluate exposure to RSV by 
measuring seroresponse to different 
RSV proteins
• Antibody levels to RSV pre-F, post-F, Ga, Gb,
and N at different time points
• Changes in antibody levels (seroresponse) 
indicating exposure to RSV
RSV 
resistance 
monitoring
To characterize resistance to 
MEDI8897 through genotypic and 
phenotypic analyses
Genotypic analysis and susceptibility of RSV 
variants to neutralization by MEDI8897
RSV LRTI 
after Day 151
To assess the incidence of medically 
attended LRTI due to RT-PCR-
confirmed RSV, compared to 
placebo after Day 151
Incidence of medically attended LRTI (inpatient and 
outpatient) due to RT-PCR-confirmed RSV from 
Day 152 to Day 361
STUDY DESIGN
Study D5290C00004 (MELODY) is a pivotal Phase 3 randomized, double-blind, placebo-controlled, 
single-dose study to determine if MEDI8897 will prevent medically attended RSV-confirmed LRTI in healthy 
infants entering their first RSV season. The population to be enrolled is healthy late preterm and term infants 
born ≥ 35 weeks 0 days GA who would not receive RSV prophylaxis based on the American Academy of 
Pediatrics (AAP) or other local or national guidelines. A total of approximately 3,000 infants will be 
randomized 2:1 to receive a 50-mg (if weight < 5 kg) or 100-mg (if weight ≥5 kg) IM dose of MEDI8897 
(N = 2,000) or placebo (N = 1,000). Randomization will be stratified by hemisphere (northern hemisphere 
[NH], southern hemisphere [SH]) and by subject age at the time of randomization (≤ 3 months, > 3 to 
≤6 months, > 6 months). Enrollment of infants > 6 months of age will be limited to approximately 500. The 
study will comprise 2 cohorts: a primary cohort (N = ~1,500) and a complementary safety cohort (hereafter 
referred to as the safety cohort; N = ~1,500) for a total of approximately 3,000 subjects. The primary cohort 
will include subjects from the NH2019, SH2020, and NH2020 enrollment seasons. The safety cohort will 
include subjects enrolled after the NH2020 enrollment season. Given the largely reduced circulation of RSV 
due to the coronavirus disease 2019 (COVID-19) pandemic related measures, the efficacy analyses performed 
in the primary analysis for the primary cohort will serve the purpose of evaluating the efficacy of MEDI8897 
in the study population. Although efficacy data will also be collected for the safety cohort, only descriptive 


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summaries will be provided and there is no intent to pool the efficacy data from the safety cohort with that 
from the primary cohort. Both the primary and safety cohorts, individually and combined, will serve the 
purpose of evaluating the safety of MEDI8897.
All subjects will be followed for approximately 510 days after dosing. An independent data monitoring 
committee will review safety data regularly and make recommendations regarding further study conduct.
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical attention for a 
respiratory illness (in either the inpatient or outpatient setting) will be evaluated for the occurrence of LRTI. 
All subjects found to have an LRTI and all subjects who require hospitalization for a respiratory infection, 
even if there is not a diagnosis of LRTI, should have respiratory samples obtained and respiratory assessment 
forms completed. Samples should be collected for all of these events (even those not meeting the protocol 
definition of LRTI). Subjects who have a primary hospitalization for a respiratory infection (ie, upper or lower 
tract) or a respiratory deterioration during a hospitalization, or who seek outpatient medical attention 
(including ER visits) for a lower respiratory illness, will be assessed clinically for the presence of LRTI and 
for RSV by central laboratory diagnostic testing of respiratory secretions. 
In addition to the clinical assessment of LRTI, there is a protocol definition using objective criteria for the 
determination of a medically attended protocol-defined LRTI. To meet the protocol-defined endpoint of 
medically attended LRTI, subjects with signs of LRTI must have documented at least one physical exam 
finding of rhonchi, rales, crackles, or wheeze AND at least one of the following clinical signs:
•
Increased respiratory rate at rest (age < 2 months, ≥ 60 breaths/min; age 2 to 6 months, ≥50 breaths/min; 
age > 6 months, ≥ 40 breaths/min) OR
•
Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1,800 meters or < 92% at altitudes 
> 1,800 meters), OR
•
Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new onset apnea, 
nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting) or dehydration secondary to 
inadequate oral intake due to respiratory distress (need for intravenous fluid)
Testing for RSV will be performed centrally using the United States Food and Drug Administration-cleared
and Conformité Européenne or European Conformity-marked in vitro diagnostic real-time RT-PCR assay 
(Lyra RSV + human metapneumovirus [hMPV] assay; Quidel Corporation, San Diego, CA). A diagnosis of 
RSV LRTI requires having a respiratory sample positive for RSV by the central laboratory RT-PCR.
TARGET SUBJECT POPULATION
Healthy late preterm and term infants > 35 weeks 0 days GA entering their first RSV season
TREATMENT GROUPS AND REGIMENS
Subjects will be randomly assigned in a 2:1 ratio to receive a single IM dose of MEDI8897 (N = 2,000) or 
placebo (N = 1,000). The MEDI8897 dose level will be stratified by body weight at time of dosing: 50 mg 
MEDI8897 for infants < 5 kg or 100 mg MEDI8897 for infants ≥5 kg.
STATISTICAL METHODS
General Considerations:
Tabular summaries will be presented by treatment group. Categorical data will be summarized by the number 
and percentage of subjects in each category. Continuous variables will be summarized by descriptive statistics. 
Additional details of statistical analyses will be described in the Statistical Analysis Plan (SAP). 
There will be 2 study cohorts: a primary cohort and a safety cohort. The primary cohort will include subjects 
from the NH2019, SH2020, and NH2020 enrollment seasons (enrollment was paused after one subject from 
NH2020 was enrolled due to the impact of the COVID-19 pandemic). The safety cohort will include subjects 
enrolled after the NH2020 enrollment season.
The Intent-to-treat (ITT) Population is defined as all subjects who are randomized. Subjects will be included 
in the treatment group corresponding to their randomized treatment. All analyses, with the exception of safety, 


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will be performed on the ITT Population unless otherwise specified. Subjects in the ITT Population and from 
the primary cohort will be ITT Population 1 (ITT1). Subjects in the ITT Population and from the safety cohort 
will be ITT Population 2 (ITT2).
The As-treated Population will include all subjects who are randomized and who receive any amount of 
investigational product. Subjects will be included in the treatment group corresponding to the treatment 
actually received. All safety analyses will be performed on the As-treated Population. Subjects in the As-
treated Population and from the primary cohort will be As-treated Population 1 (AT1). Subjects in the As-
treated Population and from the safety cohort will be As-treated Population 2 (AT2).
Sample Size:
This Phase 3 study will enroll approximately 3,000 subjects of whom approximately 2,000 will receive 
MEDI8897 and 1,000 will receive placebo. The 2,000 subjects to be dosed with MEDI8897 in this study, 
together with the 968 subjects dosed with MEDI8897 in the Phase 2b Study D5290C00003 and at least
600 subjects dosed with MEDI8897 in the palivizumab-controlled Phase 2/3 Study D5290C00005, will 
contribute to a safety database of at least approximately 3,600 subjects exposed to MEDI8897. 
For this Phase 3 study, the original sample size of 3,000 was driven by the safety database requirement, and 
the study had at least 99% power for the primary efficacy endpoint. Reducing the sample size to 1,500 still 
allows the study to be sufficiently powered. More specifically, the sample size of approximately 1,500 
subjects in the primary cohort has at least 99% power to detect 70% relative risk reduction (RRR), assuming a 
placebo group medically attended RSV LRTI incidence of 8% with a 2-sided α = 0.05.
The 70% RRR assumption is based on the Phase 2b Study D5290C00003 in which there was 70% RRR in the 
incidence of medically attended RSV LRTI (9.5% placebo, 2.6% MEDI8897; p < 0.001) and 79% RRR in the 
incidence of RSV hospitalization (4.1% placebo, 0.8% MEDI8897; p < 0.001) in subjects who received 
MEDI8897 prophylaxis. In addition, the assumption is supported by a placebo-controlled study in Native 
American term infants in which there was a 
 
 in infants who received motavizumab 
prophylaxis. In the event that the incidence rate in the placebo group drops due to the impact of the COVID-
19 pandemic (eg, social distancing), the sample size of 1,500 still provides at least 90% power to detect 70% 
RRR if the placebo incidence rate is 4% or higher.
To evaluate risk, a sample size of 2,000 subjects exposed to MEDI8897 in this Phase 3 study will provide a
> 99% probability of observing at least one adverse event (AE) if the true event rate is 0.3%; if no AEs are 
observed, this study provides 98% confidence that the true event rate is < 0.2%.
Statistical Analyses:
There are 3 planned analyses for this study: the primary analysis, safety analysis, and final analysis. The 
primary analysis will be conducted after all randomized subjects (except for one subject enrolled in the 
NH2020 season) from the primary cohort have been followed through Day 361 and will be the primary 
analysis for which the study is designed to assess efficacy. For the primary analysis, all efficacy, 
pharmacokinetics (PK), ADA, and safety data collected for the primary cohort through at least Day 361 will 
be analyzed. The safety analysis will be conducted when all subjects from the safety cohort have been 
followed through Day 151. For the safety analysis, in addition to the analyses conducted during the primary 
analysis based on the primary cohort, all available efficacy, PK, ADA, RSV neutralizing antibody, RSV 
serology, and safety data collected for the safety cohort will be analyzed (only descriptive summaries will be 
provided for the efficacy data collected for the safety cohort). The final analysis will be conducted when all 
subjects have completed the last visit of the study (ie, Day 511). Given the largely reduced circulation of RSV 
due to the COVID-19 pandemic related measures, the efficacy analyses performed in the primary analysis for 
the primary cohort will serve the purpose of evaluating the efficacy of MEDI8897 in the study population.
Although efficacy data will also be collected for the safety cohort, only descriptive summaries will be 


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provided and there is no intent to pool the efficacy data from the safety cohort with that from the primary 
cohort. Both the primary and the safety cohorts, individually and combined, will serve the purpose of 
evaluating the safety of MEDI8897.
The primary and secondary efficacy hypotheses will be assessed in the primary analysis for the primary cohort 
by a hierarchical order. That is, the secondary hypothesis will be tested at a significance level of 0.05 only if 
the treatment effect on the primary efficacy endpoint is demonstrated at the significance level of 2-sided 0.05. 
With that, the overall Type I error is controlled at 0.05. Therefore, no further multiplicity adjustment is 
necessary.
Primary Endpoint Analysis:
Primary Efficacy Analysis
The incidence of RSV LRTI (inpatient and outpatient) during 5 months of the RSV season will be based on 
RSV test results (performed centrally via RT-PCR) and objective clinical LRTI criteria and will be presented 
by treatment group. For subjects with multiple medically attended RSV LRTI events, only the first occurrence 
will be used in the primary analysis.
The primary efficacy analysis of the primary endpoint will be conducted on ITT1. RSV LRTI that occurs 
through 150 days post dose will contribute to the primary efficacy analysis. For subjects who do not have a 
medically attended RSV LRTI and are not followed through 150 days post dose, their event status will be 
imputed assuming the observed placebo RSV LRTI rate conditional on stratification factors using multiple 
imputation techniques and will be described in the SAP. A Poisson regression model with robust variance will 
be used as the primary efficacy analysis model to compare the incidence of medically attended RSV LRTI 
between MEDI8897 and placebo, including treatment group, age at the time of randomization (ie, ≤ 3 months, 
> 3 to ≤6 months, > 6 months), and dichotomous temperate hemispheres (NH and SH) as covariates. In 
addition, the 2-sided p-value and corresponding 2-sided 95% confidence interval on the relative risk will be 
provided from the model. RRR is defined as (1 - Pn/Ps) where Pn is the incidence of RSV LRTI through 
150 days post dose in the MEDI8897 group and Ps is the incidence of RSV LRTI through 150 days post dose 
in the placebo group generated by the model. Statistical significance will be achieved if the 2-sided p-value is 
≤0.05. 
During blinded data review prior to database lock for the primary analysis, it was decided to drop the 
stratification factor hemisphere from the full model due to no incidence of medically attended RSV LRTI 
events through 150 days post dose for SH in the primary cohort, which would cause a known convergence or 
estimation issue. Similar consideration also applies to other analyses for the primary efficacy endpoint, where 
hemisphere will be dropped from the corresponding models.
Additional Analyses of the Primary Endpoint
A Cochran-Mantel-Haenszel approach stratified by age group at the time of randomization (ie, ≤ 3 months, 
> 3 to ≤ 6 months, > 6 months) will be used to compare the incidence of RSV LRTI through 150 days post 
dose between treatment groups as a secondary analysis for the primary endpoint. The additional analyses will 
be conducted on ITT1. In addition, a time-to-event analysis assessing time to first RSV LRTI may be 
performed as a supplementary analysis.
An analysis may also include all RSV positive LRTI endpoints, using results from either the central laboratory 
or local laboratory.
Different approaches to handle missing data (ie, early discontinuation and no RSV LRTI prior to 
discontinuation) may be considered for supplementary analyses. Additional analyses may be performed to 
adjust duration of efficacy follow-up and to assess the efficacy within subgroups. These analyses will be 
described in the SAP.
The incidence of medically attended RSV LRTI through 150 days post dose will also be summarized by 
treatment group on ITT2.


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Secondary Endpoint Analyses:
Efficacy
The incidence of RSV LRTI hospitalization through 150 days post dose will be presented by treatment group. 
Similar methods as described above for the primary efficacy endpoint will be used to assess efficacy on RSV 
LRTI hospitalization on ITT1. 
The incidence of RSV LRTI hospitalization through 150 days post dose will also be summarized by treatment 
group on ITT2.
Safety
The safety analyses will be conducted on the overall As-treated Population, AT1, and AT2. Safety of 
MEDI8897 will primarily be assessed by the occurrence of TEAEs and TESAEs. Adverse events will be 
graded according to the current version of the National Cancer Institute Common Terminology Criteria for 
Adverse Events where applicable for pediatric assessments. Adverse events will be coded by Medical 
Dictionary for Regulatory Activities and the type, incidence, severity, and relationship to investigational 
product will be summarized by treatment group. Other safety assessments will include:
•
Occurrence of AESIs to include targeted AEs of hypersensitivity (including anaphylaxis), 
thrombocytopenia, and immune complex disease (eg, vasculitis, endocarditis, neuritis, 
glomerulonephritis) following investigational product administration.
•
Occurrence of NOCDs following investigational product administration
Pharmacokinetics Analysis
Following a single dose of MEDI8897, individual MEDI8897 serum concentration data will be tabulated by 
treatment group along with descriptive statistics. PK parameters, eg, Cmax, AUC, apparent clearance, and 
terminal half-life, will be estimated using non-compartmental analysis, if data permit.
Anti-drug Antibody Analysis
The incidence of ADA to MEDI8897 will be assessed and summarized by number and percentage of subjects 
that are ADA positive by treatment group. The ADA titer will be listed by subject at different time points. The 
impact of ADA on PK, efficacy, and association with TEAEs and TESAEs will be assessed. These summaries 
will be conducted on the overall As-treated Population, AT1, and AT2, unless specified otherwise.
Exploratory Endpoint Analyses:
HRU and Caregiver Burden
The magnitude of HRU (eg, number of admissions to hospitals and ICUs and duration of stay; number of 
subjects who require respiratory support and supplemental oxygen and the duration of use; number and types 
of outpatient visits, eg, ER, urgent care, outpatient clinic; and number of prescription and over-the-counter
medications and duration of use) will be summarized overall by treatment group, and for the following 
subgroups: subjects with at least one medically attended LRTI caused by RT-PCR-confirmed RSV, subjects 
with medically attended LRTI not caused by RSV, and subjects with non-protocol defined LRTIs, which may 
be further broken down by RSV status. These summaries will be conducted on ITT1 and ITT2 (if data permit).
Caregiver burden (eg, caregiver missed work days, subject absence from day care) for subjects with medically 
attended LRTI caused by RT-PCR-confirmed RSV will be summarized by treatment group on ITT1 and ITT2 
(if data permit).
RSV Neutralizing Antibody and RSV Serology
RSV neutralizing antibody levels afforded by MEDI8897 will be compared to maternal RSV neutralizing 
antibody levels and those elicited following infection in the placebo group.
RSV seroresponses will be evaluated as a measure of RSV exposure in the placebo and MEDI8897 groups.


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Monitoring RSV Resistance to MEDI8897
Genotypic analysis of the full-length mature F protein will be conducted on all RSV-positive isolates 
confirmed centrally using the Lyra RSV + hMPV real-time RT-PCR assay manufactured by Quidel 
Corporation. RSV genotypic analysis will report amino acid changes in the mature F protein sequence 
compared to contemporary RSV A and RSV B reference strains. Phenotypic analyses will report changes in 
susceptibility of engineered recombinant RSV variants to MEDI8897 and palivizumab neutralization 
compared to laboratory-derived reference viruses.
RSV LRTI Occurring From Day 152 to Day 361
The incidence of medically attended RSV LRTI (inpatient and outpatient) from Day 152 to Day 361 will be 
based on RSV test results (performed centrally via RT-PCR) and objective clinical LRTI criteria and will be 
summarized by treatment group on ITT1 and ITT2.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 2
PROTOCOL SYNOPSIS...................................................................................................... 5
LIST OF ABBREVIATIONS ............................................................................................. 16
1
INTRODUCTION............................................................................................ 18
1.1
Disease Background ......................................................................................... 18
1.2
MEDI8897 Background.................................................................................... 19
1.3
Summary of Nonclinical Experience................................................................. 20
1.4
Summary of Clinical Experience....................................................................... 21
1.4.1
Study D5290C00001......................................................................................... 21
1.4.2
Study D5290C00002......................................................................................... 21
1.4.3
Study D5290C00003......................................................................................... 23
1.5
Rationale for Conducting the Study .................................................................. 25
1.6
Benefit-Risk and Ethical Assessment................................................................ 25
1.7
Research Hypotheses ........................................................................................ 26
1.7.1
Primary Hypothesis .......................................................................................... 26
1.7.2
Secondary Hypotheses...................................................................................... 26
2
OBJECTIVES AND ENDPOINTS................................................................... 27
2.1
Primary Objective and Associated Endpoint ..................................................... 27
2.1.1
Secondary Objectives and Associated Endpoints............................................... 27
2.1.2
Exploratory Objectives and Associated Endpoints ............................................ 28
3
STUDY DESIGN ............................................................................................. 28
3.1
Description of the Study ................................................................................... 28
3.1.1
Overview.......................................................................................................... 28
3.1.2
Treatment Regimen........................................................................................... 32
3.2
Rationale for Dose, Population, and Endpoints ................................................. 32
3.2.1
Dose Rationale.................................................................................................. 32
3.2.2
Rationale for Study Population ......................................................................... 32
3.2.3
Rationale for Endpoints .................................................................................... 33
4
MATERIALS AND METHODS ...................................................................... 34
4.1
Subjects ............................................................................................................ 34
4.1.1
Number of Subjects .......................................................................................... 34
4.1.2
Inclusion Criteria .............................................................................................. 34
4.1.3
Exclusion Criteria ............................................................................................. 34
4.1.4
Subject Enrollment and Randomization ............................................................ 35
4.1.5
Withdrawal from the Study............................................................................... 36
4.1.6
Discontinuation of Investigational Product........................................................ 36
4.1.7
Withdrawal of Informed Consent for Data and Biological Samples................... 36
4.2
Schedule of Study Procedures........................................................................... 37
4.2.1
Enrollment/Screening Period ............................................................................ 37


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4.2.2
Treatment and Follow-up Periods ..................................................................... 37
4.3
Description of Study Procedures....................................................................... 40
4.3.1
Efficacy. ........................................................................................................... 40
4.3.1.1
Lower Respiratory Tract Infection .................................................................... 40
4.3.2
Medical History and Physical Examination, Weight, and Vital Signs................ 43
4.3.3
Pharmacokinetics, Anti-drug Antibody, and RSV Serology .............................. 43
4.3.3.1
Pharmacokinetic Evaluation.............................................................................. 43
4.3.3.2
Anti-drug Antibody Evaluation......................................................................... 44
4.3.3.3
RSV Neutralizing Antibody Evaluation ............................................................ 44
4.3.3.4
RSV Serology Evaluation ................................................................................. 44
4.3.4
Healthcare Resource Utilization and Caregiver Burden..................................... 44
4.3.5
Skin Reactions.................................................................................................. 44
4.3.6
Estimate of Volume of Blood to be Collected ................................................... 45
4.4
Study Suspension or Termination...................................................................... 45
4.5
Investigational Products.................................................................................... 46
4.5.1
Identity of Investigational Products................................................................... 46
4.5.1.1
Investigational Product Inspection .................................................................... 46
4.5.1.2
Dose Administration Steps................................................................................ 47
4.5.1.3
Treatment Administration................................................................................. 47
4.5.1.4
Monitoring of Dose Administration .................................................................. 47
4.5.1.5
Reporting Product Complaints .......................................................................... 48
4.5.2
Additional Study Medications........................................................................... 48
4.5.3
Labeling ........................................................................................................... 48
4.5.4
Storage ............................................................................................................. 48
4.5.5
Treatment Compliance...................................................................................... 48
4.5.6
Accountability .................................................................................................. 48
4.6
Treatment Assignment and Blinding ................................................................. 49
4.6.1
Methods for Assigning Treatment Groups......................................................... 49
4.6.2
Methods to Ensure Blinding.............................................................................. 49
4.6.3
Methods for Unblinding.................................................................................... 50
4.6.3.1
Unblinding in the Event of a Medical Emergency ............................................. 50
4.7
Restrictions During the Study and Concomitant Treatment(s) ........................... 50
4.7.1
Permitted Concomitant Medications ................................................................. 50
4.7.2
Prohibited Concomitant Medications ................................................................ 50
4.8
Statistical Evaluation ........................................................................................ 51
4.8.1
General Considerations..................................................................................... 51
4.8.2
Sample Size...................................................................................................... 52
4.8.3
Efficacy ............................................................................................................ 53
4.8.3.1
Primary Efficacy Analysis ................................................................................ 53
4.8.3.2
Additional Analyses of the Primary Endpoint ................................................... 54
4.8.3.3
Supplementary Analyses of the Primary Endpoint............................................. 55
4.8.3.4
Subgroup Analyses of the Primary Endpoint..................................................... 55
4.8.3.5
Secondary Efficacy Analyses............................................................................ 56
4.8.3.6
Additional Efficacy Analyses for the Safety Cohort .......................................... 57
4.8.4
Safety ............................................................................................................... 57


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4.8.5
Analysis of Pharmacokinetics and Anti-drug Antibody..................................... 58
4.8.5.1
Pharmacokinetic Analysis................................................................................. 58
4.8.5.2
Anti-drug Antibody Analysis ............................................................................ 58
4.8.6
Exploratory Analysis ........................................................................................ 58
4.8.7
Data Monitoring Committee ............................................................................. 59
4.8.8
Interim Analysis ............................................................................................... 59
5
ASSESSMENT OF SAFETY ........................................................................... 59
5.1
Definition of Adverse Events............................................................................ 59
5.2
Definition of Serious Adverse Events ............................................................... 60
5.3
Definition of Adverse Events of Special Interest............................................... 60
5.3.1
Hypersensitivity, Including Anaphylaxis........................................................... 60
5.3.2
Immune Complex Disease ................................................................................ 61
5.3.3
Thrombocytopenia............................................................................................ 61
5.4
Definition of New Onset Chronic Disease......................................................... 62
5.5
Recording of Adverse Events............................................................................ 62
5.5.1
Time Period for Collection of Adverse Events .................................................. 62
5.5.2
Follow-up of Unresolved Adverse Events......................................................... 62
5.5.3
Deaths .............................................................................................................. 62
5.6
Reporting of Serious Adverse Events................................................................ 63
5.7
Other Events Requiring Immediate Reporting................................................... 63
5.7.1
Overdose .......................................................................................................... 63
5.7.2
Medication Error............................................................................................... 64
5.7.3
Adverse Events of Special Interest.................................................................... 65
5.7.3.1
Hypersensitivity, Including Anaphylaxis........................................................... 65
5.7.3.2
Immune Complex Disease ................................................................................ 65
5.7.3.3
Thrombocytopenia............................................................................................ 65
5.7.4
New Onset Chronic Disease.............................................................................. 66
6
STUDY AND DATA MANAGEMENT........................................................... 66
6.1
Training of Study Site Personnel....................................................................... 66
6.2
Monitoring of the Study.................................................................................... 66
6.2.1
Source Data ...................................................................................................... 67
6.2.2
Study Agreements............................................................................................. 67
6.2.3
Archiving of Study Documents......................................................................... 67
6.3
Study Timetable and End of Study.................................................................... 67
6.4
Data Management............................................................................................. 67
6.5
Medical Monitor Coverage ............................................................................... 68
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 68
7.1
Subject Data Protection..................................................................................... 68
7.2
Ethics and Regulatory Review .......................................................................... 68
7.3
Informed Consent ............................................................................................. 69
7.4
Changes to the Protocol and Informed Consent Form........................................ 69


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7.5
Audits and Inspections...................................................................................... 70
8
REFERENCES................................................................................................. 70
LIST OF TABLES
Table 1
Primary Objective and Associated Endpoint ............................................ 27
Table 2
Secondary Objectives and Associated Endpoints...................................... 27
Table 3
Exploratory Objectives and Endpoints ..................................................... 28
Table 4
Schedule of Screening Procedures ........................................................... 37
Table 5
Schedule of Treatment Period and Follow-up Period Study Procedures.... 38
Table 6
Criteria for Meeting the Protocol-defined Endpoint of Medically 
Attended RSV LRTI................................................................................ 41
Table 7
Volume of Blood to be Collected............................................................. 45
Table 8
Identification of Investigational Products................................................. 46
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 31
LIST OF APPENDICES
Appendix A
Additional Safety Guidance ..................................................................... 73
Appendix B
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.............. 76


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
aa
amino acid
AAP
American Academy of Pediatrics
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
AT1
As-treated Population 1
AT2
As-treated Population 2
AUC
area under the concentration time-curve
AUC0-∞
area under the concentration-time curve from time 0 to infinity
CHD
congenital heart disease
CI
confidence interval
CLD
chronic lung disease
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease 2019
eCRF
electronic case report form
EDC
electronic data capture
ER
emergency room
EU
European Union
F
fusion
Fc
fragment cystallizable
FcRn
neonatal Fc receptor
GA
gestational age
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
hMPV
human metapneumovirus
HRU
healthcare resource utilization
IC50
half-maximal inhibitory concentration
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgG1κ
immunoglobulin G1 kappa 
IM
intramuscular


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Abbreviation or 
Specialized Term
Definition
IRB
Institutional Review Board
ITT
Intent-to-treat
ITT1
Intent-to-treat Population 1
ITT2
Intent-to-treat Population 2
IV
intravenous
IWRS
interactive web response system
JCVI
Joint Committee on Vaccination and Immunisation
LRTI
lower respiratory tract infection
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MELODY
Study D5290C00004
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NH
northern hemisphere
NOCD
new onset chronic disease
OTC
over-the-counter
PK
pharmacokinetic(s)
RRR
relative risk reduction
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SH
southern hemisphere
SID
subject identification
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
TK
toxicokinetic(s)
TESAE
treatment-emergent serious adverse event
UK
United Kingdom
URTI
upper respiratory tract infection
US FDA
United States Food and Drug Administration
USA
United States of America
YTE
M257Y/S259T/T261E triple amino acid substitution


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1
INTRODUCTION
Prevention of respiratory syncytial virus (RSV) illnesses in all infants is a major public health 
priority. However, despite more than 50 years of attempted vaccine development, there are no 
licensed vaccines. As there is no approved RSV prophylaxis for the broader population of 
healthy infants and no treatment for RSV, the current management for these patients when 
they acquire serious RSV illness is supportive care. 
The only currently approved prophylaxis for RSV, palivizumab (Synagis®), was developed by
MedImmune and is only indicated for use in high-risk children: preterm infants ≤35 weeks 
gestational age (GA), children with chronic lung disease (CLD) of prematurity, and children 
with haemodynamically significant congenital heart disease (CHD). In addition, further 
restrictions have been implemented by local or national recommending bodies on the use of 
palivizumab. For example, in the United States of America (USA) per the American Academy 
of Pediatrics (AAP) guidelines, palivizumab is not recommended for healthy preterm infants 
≥29 weeks GA (American Academy of Pediatrics, 2014). In the United Kingdom (UK), 
palivizumab is recommended by the Joint Committee on Vaccination and Immunisation 
(JCVI) for preterm infants with CLD or haemodynamically significant, acyanotic CHD 
based on the GA at birth and chronological age at the start of the RSV season (JCVI, 2010a, 
2010b).
1.1
Disease Background
Respiratory syncytial virus is the most common cause of lower respiratory tract infection 
(LRTI) among infants and young children, resulting in annual epidemics worldwide (Hall et 
al, 2009; Hall, 2012; Madhi et al, 2006; Shay et al, 1999; Shi et al, 2017; Stockman et al, 
2012). All children, including healthy term infants, are at risk for severe RSV LRTI with 
primary RSV infection during infancy. Ninety percent of children are infected with RSV in 
the first 2 years of life and up to 40% of those will have LRTI with the initial episode 
(American Academy of Pediatrics, 2014; Greenough et al, 2001; Meissner, 2003; Parrott et al, 
1973). RSV LRTI, characterized predominantly as bronchiolitis or pneumonia, represents a 
serious illness with acute and perhaps long-term consequences to the developing lungs in 
these young children (Blanken et al, 2013). It is estimated that RSV causes up to 90% of 
childhood bronchiolitis and up to 40% of pediatric pneumonias (Hall, 2001). In 2015, an 
estimated 33.1 million (uncertainty range, 21.6 to 50.3 million) new episodes of 
RSV-associated LRTI occurred worldwide in children younger than 5 years (28% of LRTI 
episodes), with approximately 3.2 million (range, 2.7 to 3.8 million) episodes necessitating 
hospitalizations, leading to 59,600 (range, 48,000 to 74,500) in-hospital deaths (Shi et al, 
2017). Children younger than 1 year of age had an estimated 2.3 million hospital admissions. 
The overall mortality due to RSV LRTI was estimated to be as high as 118,200 (uncertainty 
range, 94,600 to 149,400 (Shi et al, 2017).


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Although hospitalization is well recognized as an important consequence of RSV illness, a 
large percentage of the healthcare burden from RSV occurs outside the hospital (Carroll et al, 
2008; Hall et al, 2009; Hall, 2012; Paramore et al, 2010) as office visits and emergency 
department visits, especially in healthy infants. In children < 5 years of age in the USA, RSV 
is estimated to cause 1 in 13 private practice visits, 1 in 38 emergency department visits, and 
1 in 334 hospitalizations (Hall, 2012). Another study demonstrated that in otherwise healthy 
term infants < 12 months of age in a Medicaid program (1995 - 2003), 13.3% had an 
outpatient visit, 6.2% had an emergency department visit, and 5.5% were hospitalized for 
bronchiolitis (Carroll et al, 2008). Paramore and colleagues reported high rates of outpatient 
RSV LRTI among infants and young children, ranging from 157.5 to 252.0 per 1,000 children 
< 1 year of age (Paramore et al, 2010). This study also showed that outpatient RSV LRTI rates 
for late preterm (33 to 36 weeks GA) infants ranged from 183.3 to 245.7 per 1,000 infants, 
with rates for full-term infants ranging from 128.8 to 171.3 per 1,000 infants.
Hospitalization rates among young children in European countries appear to be similar to 
those in the US; the rates for infants within the first year of life were invariably the highest, 
19 to 22 per 1,000 children, consistent with the USA and Canadian data (Jansen et al, 2007; 
van Gageldonk-Lafeber et al, 2005; Weigl et al, 2001). In addition, RSV hospitalization rates 
among German children 0 to 3 years of age were found to be 4 and 9 times greater than the 
hospitalization rates associated with parainfluenza and influenza viral infections, respectively
(König et al, 2004).
Similarly, high rates of RSV hospitalization are evident in South Africa. For infants 
< 6 months of age, the incidence (95% confidence interval [CI]) of severe LRTI was 
26.2 (range, 23.6 to 29.0) per 1,000 in those born at ≥36 weeks GA, 125.0 (range, 95.3 to 
159.9) per 1,000 in those born at 32 to 35 weeks GA, and 142.3 (range, 89.50 to 212.0) per 
1,000 in those born at < 32 weeks GA (Madhi et al, 2006).
1.2
MEDI8897 Background
MEDI8897 is briefly described below. Refer to the current Investigator’s Brochure for details. 
MEDI8897 is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody 
(mAb) directed against the prefusion conformation of the RSV F protein. The antibody has 
been engineered with a triple amino acid substitution (YTE; M257Y/S259T/T261E
[M252Y/S254T/T256E, according to the European Union (EU) numbering system]) in the 
fragment crystallizable (Fc) region to prolong the terminal half-life (t1/2), which is expected to 
provide protection from serious RSV disease for the duration of the RSV season. MEDI8897
neutralizes RSV by binding the prefusion conformation of the RSV F protein at a site distinct 
from that bound by palivizumab. In preclinical studies, MEDI8897 was > 150-fold more 
potent than palivizumab in vitro and approximately 9-fold more potent than palivizumab in 
vivo in the cotton rat model (Zhu et al, 2017). MEDI8897 is currently under development by 


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MedImmune for the passive immunization of all infants entering their first RSV season and 
children with CLD or CHD entering their first and second RSV season for the prevention of 
LRTI caused by RSV. MEDI8897 may provide a cost-effective opportunity to protect all 
infants from RSV disease based on an improvement in potency and the extended t1/2 that is 
expected to support once-per-RSV-season dosing.
1.3
Summary of Nonclinical Experience
The potential clinical utility of MEDI8897 and dose predictions of the antibody were 
evaluated in the cotton rat model of RSV infection. The pharmacokinetics (PK) of 1G7, the 
non-YTE version of MEDI8897, was evaluated in cotton rats following a single intramuscular 
(IM) dose of 0.25 to 3.0 mg/kg. Serum concentrations increased dose proportionally across the 
entire dose range with a terminal-phase elimination t1/2 of approximately 1 day. In cotton rats, 
a serum concentration of 6.8 μg/mL resulted in a 3-log reduction in lung RSV titers and for 
Phase 2b was identified as the target serum concentration to maintain in children to provide 
antiviral activity against RSV over a typical 5-month RSV season.
The YTE amino acid substitutions introduced into MEDI8897 do not impact RSV neutralizing 
activity when compared to the parental mAb, 1G7. MEDI8897/1G7 showed potent antiviral 
activity in vitro against RSV A and B laboratory strains, clinical isolates, as well as 
palivizumab-resistant viruses. MEDI8897/1G7 was > 150-fold more potent than 
palivizumab in vitro against the laboratory strains and > 50-fold more potent than 
palivizumab against clinical isolates based on the median half-maximal inhibitory 
concentration (IC50) (Zhu et al, 2017). 
Toxicity, toxicokinetics (TK), and immunogenicity of MEDI8897 were evaluated in a Good 
Laboratory Practice-compliant repeat-dose intravenous (IV) and IM toxicology study 
conducted in cynomolgus monkeys. Cynomolgus monkeys represent a pharmacologically 
relevant model for nonclinical safety assessment based on similar binding of MEDI8897 to 
cynomolgus monkey neonatal Fc receptor (FcRn) compared to human FcRn. Toxicology 
studies in cynomolgus monkeys indicate that there is no evidence of MEDI8897 toxicity in 
these animal models. 
 
 
 
 
 
 
Overall, data from nonclinical studies do not reveal any MEDI8897-related 
safety concerns.


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Details of these studies are included in the current Investigator’s Brochure.
1.4
Summary of Clinical Experience
MEDI8897 has been investigated in 3 completed clinical studies.
1.4.1
Study D5290C00001
The first-time-in-human Study D5290C00001 (Griffin et al, 2017) was a Phase 1a, 
randomized, double-blind, placebo-controlled, dose-escalation study to evaluate the safety, 
tolerability, and PK of MEDI8897 compared to placebo. A total of 136 subjects were 
randomized and received a single dose of MEDI8897 (6 subjects each at doses of 300 mg IV, 
1,000 mg IV, 3,000 mg IV, and 100 mg IM; 78 subjects at 300 mg IM) or placebo 
(34 subjects). The mean t1/2 of MEDI8897 ranged from 85 to 117 days across the IV and IM 
dose groups confirming the predicted 3- to 4-fold increase in the t1/2 of MEDI8897 compared 
to a standard immunoglobulin G (IgG) antibody. The safety profile of MEDI8897 was 
favorable, with similar proportions of treatment-emergent adverse events (TEAEs) reported in 
placebo (61.8%) and MEDI8897 recipients (62.7%). Two treatment-emergent serious adverse 
events (TESAEs; gunshot wound and appendicitis) were reported in 2 MEDI8897 recipients. 
TEAEs judged to be related to investigational product were reported in 29.4% of placebo 
recipients and 17.6% of MEDI8897 recipients. The most frequent TEAEs in the MEDI8897 
total group included upper respiratory tract infection (URTI; 18.6%), headache (8.8%), 
urinary tract infection (5.9%), dermatitis contact (4.9%), musculoskeletal pain (4.9%), nausea 
(4.9%), and vomiting (4.9%). The most frequent TEAEs in the placebo group were headache 
(17.6%), URTI (8.8%), nausea (5.9%), increased blood creatine phosphokinase level (5.9%), 
and paresthesia (5.9%). There were no events designated as an adverse event of special 
interest (AESI) or new onset chronic disease (NOCD). There were no deaths. No safety 
signals in this healthy adult population were observed. Post-baseline ADA was detected in 
13.7% of adults receiving MEDI8897 and 15.2% of adults in the placebo group. On Day 361, 
ADA was detected in 5.3% of subjects in the MEDI8897 total group and 10.7% of subjects in 
the placebo group. The highest titer at Day 361 was 1:200 for both the MEDI8897 total and 
placebo groups. The presence and titer of ADA had no effect on the PK or safety profile. 
These results confirmed the extended half-life and demonstrated an acceptable safety profile 
for MEDI8897, including no observed hypersensitivity reactions, thus supporting further 
clinical studies of IM administration of 1 dose of MEDI8897 in the target population of 
infants to provide protection for the duration of the RSV season.
1.4.2
Study D5290C00002
The first-time-in-infant Study D5290C00002 (Domachowske et al, 2018) was a Phase 1b/2a, 
randomized, double-blind, placebo-controlled, single ascending-dose study to evaluate safety,
PK, and ADA in healthy preterm infants. The population enrolled was healthy preterm infants 
born between 32 weeks 0 days and 34 weeks 6 days gestation who would not receive RSV 


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prophylaxis based on the AAP or other national or local guidelines. These subjects would not 
be receiving palivizumab, allowing for a placebo comparator group. A total of 89 infants from 
sites in the USA, Chile, and South Africa were randomized and received a single IM dose of 
MEDI8897 (10, 25, or 50 mg; N = 71) or placebo (N = 18) and were followed for 
approximately 360 days after dosing. 
A total of 66 subjects (93%) in the MEDI8897 group and 17 subjects (94.4%) in the placebo 
group reported at least 1 TEAE. No safety signals were observed with ascending dose levels. 
The majority of the events were mild or moderate in severity; only 2 TEAEs were assessed as 
≥ Grade 3 severity, and neither was considered to be related to investigational product by the 
investigator. There were no deaths, AESIs, or NOCDs in any dose group. 
Three MEDI8897 subjects (4.2%) had a total of 5 TESAEs, none of which were considered 
related to investigational product by the investigator; no subjects in the placebo group had a 
TESAE. One infant who received 25 mg of MEDI8897 was hospitalized for LRTI. Real-time 
reverse transcriptase-polymerase chain reaction (RT-PCR) testing from the central laboratory 
was negative for RSV (but positive for human metapneumovirus [hMPV]); the illness 
resolved.
 
 
 
 
The most frequently reported TEAEs for the MEDI8897 group were URTI (69.0%), 
gastroenteritis (29.6%), cough (25.4%), pyrexia (22.5%), and otitis media (21.1%). There 
were no trends by dose of MEDI8897 for these events. The most frequently reported TEAEs 
in the placebo group were URTI (66.7%), anemia (33.3%), gastroenteritis (22.2%), cough 
(22.2%), and otitis media (22.2%). Skin rashes (defined as adverse events [AEs] that coded to 
the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms of dermatitis, 
dermatitis allergic, dermatitis atopic, dermatitis contact, dermatitis diaper, dry skin, eczema, 
rash, and rash papular) were reported for 38.9% of subjects in the placebo group and 47.9% of 
subjects in the MEDI8897 group. No skin events were consistent with hypersensitivity. 
MEDI8897 exhibited a less-than-dose-proportional exposure increase between the 10 and 
25 mg doses; however, exposure increase was dose proportional between 25 and 50 mg doses. 
Following a single IM dose of 10, 25, or 50 mg, the estimated t½ of MEDI8897 ranged from 
62.5 to 72.9 days. On Day 151, 87% of the MEDI8897 serum concentrations following the 
50 mg IM dose were above the EC90 threshold of 6.8 μg/mL.
ADA was not detected in any subject at Day 151. Post-baseline ADA was detected at Day 361 
only in 18/68 (26.5%) subjects, and there were 2 subjects with transient ADA positive titers at 
Day 50 only who were ADA negative at Day 361. Overall, post-baseline ADA was detected in 


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20/71 subjects (28.2%) in the MEDI8897 group and 0/17 subjects (0%) in the placebo group. 
None of the post-baseline MEDI8897 ADA-positive subjects were ADA positive at baseline; 
only one subject (in the placebo group) was ADA-positive at baseline. The highest titer 
detected was 1:25,600 (observed in 2 subjects [2.8%]). The 20 subjects in the MEDI8897 
group who had ADA detected were positive for the presence of ADA targeting the YTE 
domain and 4 of the 20 subjects with samples available had neutralizing ADA antibody. 
There was no impact of the presence of ADA on safety. ADAs did not appear to impact PK 
for 150 days after dosing, but there may have been an impact between Day 151 and Day 361. 
Serum anti-RSV neutralizing antibody titers increased dose-dependently following 
administration of MEDI8897 and were higher than placebo by Day 8 and through Day 151. 
Serum MEDI8897 concentrations were correlated with serum anti-RSV neutralizing antibody 
across all the dose levels, confirming anti-RSV activity of MEDI8897.
1.4.3
Study D5290C00003
The Phase 2b Study D5290C00003 was a randomized, double-blind, placebo-controlled 
single-dose study that evaluated the safety, efficacy, PK, and ADA response of MEDI8897 in 
healthy preterm infants. Subjects were 29 to < 35 weeks GA entering their first RSV season 
who would not receive RSV prophylaxis based on the JCVI, AAP, or other local or national 
guidelines. Overall, 1,453 subjects were randomized 2:1 to receive a single dose of 50 mg IM 
MEDI8897 (n = 969) or placebo (n = 484). A total of 1,447 subjects were dosed, including 
966 subjects in the MEDI8897 group and 481 subjects in the placebo group. Subjects were 
followed for approximately 360 days after dosing. The study was completed on 06Dec2018 
(last subject last visit). 
Results from the planned primary analysis conducted after all randomized subjects who 
remained in the study completed the Day 151 visit demonstrated a statistically significant 
relative risk reduction (RRR) in the incidence of the primary endpoint of RSV-confirmed 
LRTI (inpatient and outpatient) and the secondary endpoint of RSV hospitalization. 
 
 
 
 
 
Based on the primary analysis, the safety profile for the MEDI8897 group was comparable to 
the placebo group, with no identified risks. Overall, 
 of subjects in the MEDI8897 
group and 
 of subjects in the placebo group had at least 1 TEAE. The majority of the 
TEAEs were mild or moderate in severity. TEAEs ≤1 day post dose occurred in 2.5% of 
subjects in both groups. In comparison to the placebo group, the MEDI8897 group had a 


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lower incidence of TEAEs occurring ≤7 days post dose (15.2% vs 12.5%, respectively), 
TEAEs ≥Grade 3 in severity (12.3% vs 7.4%, respectively), and TESAEs (16.7% vs 10.4%, 
respectively). The most common TESAEs, based on the MEDI8897 group, were bronchiolitis 
(2.1% MEDI8897, 4.2% placebo), LRTI (1.4% MEDI8897, 2.7% placebo), pneumonia 
(1.4% MEDI8897, 2.1% placebo), and bronchitis (1.2% MEDI8897, 2.3% placebo). None of 
the TESAEs were considered related to study treatment by the investigator. Five deaths were 
reported during the study through Day 361, including 2 subjects (0.2%) in the MEDI8897 
group and 3 subjects (0.6%) in the placebo group. None of the deaths were related to study 
drug according to the investigator.
Overall, the incidence of investigational product-related TEAEs (MEDI8897 2.3%, placebo 
2.1%); AESIs, including hypersensitivity, immune complex disease, and thrombocytopenia 
(MEDI8897 0.5%, placebo 0.6%); and NOCDs (MEDI8897 0.3%, placebo 0.8%) was low 
and generally comparable between the placebo and MEDI8897 groups. AESIs were reported 
in 5 subjects (4 subjects with rash or rash macular and 1 subject with petechiae) in the 
MEDI8897 group and 3 subjects (rash or rash papular) in the placebo group. All events were 
Grade 1 in severity. The TEAE of petechiae that was reported as an AESI was 1-day duration 
and was reported by the site investigator based on description by the parent. There were no 
laboratory assessments for the petechiae.
TEAEs that involved the skin and subcutaneous tissues (including diaper rash) were collected 
as skin reactions, with a few exceptions for skin reactions that could be definitively diagnosed 
such as impetigo, varicella, and scabies. 
 
Following a single fixed 50 mg IM dose of MEDI8897, over 95% of measurable Day 151 
concentrations were greater than the nonclinical EC90 target of 6.8 μg/mL. The median area 
under the concentration-time curve from time 0 to infinity (AUC0-∞) and estimated apparent 
t½ were 5.3 day.mg/mL (range, 3.2 to 10.2 day.mg/mL) and 56.5 days (range, 46.8 to 
81.1 days), respectively. 
Overall, the rate and titers of ADA were low, and in ADA-positive subjects there was no 
effect on PK or safety. Of the subjects who had serum samples available for testing, ADA was 
detected post baseline in 4.3% (40/921) of subjects in the MEDI8897 group and 
2.8% (13/466) of subjects in the placebo group; with less than 5% of subjects in either group 
being ADA positive at any visit. ADA titers ranged from 1:50 to 1:3,200 in the MEDI8897 
group and 1:50 to 1:200 in the placebo group. Of the MEDI8897 subjects who were 
post-baseline ADA positive, ADA targeting the YTE domain was observed in 4/17 subjects 
on Day 151 and 10/15 on Day 361. Two MEDI8897 subjects had neutralizing ADA antibody 
on Day 361.


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1.5
Rationale for Conducting the Study
Prevention of RSV illnesses in all infants is a major public health priority but, despite almost 
50 years of attempted vaccine development and extensive ongoing work 
(www.clinicaltrials.gov), there is not yet a safe and effective vaccine. While RSV prevention 
exists in the form of a specific RSV IgG (Synagis®, palivizumab) requiring 5 monthly 
injections, it is licensed only for infants who experience the greatest morbidity and mortality 
from RSV: preterm infants born ≤ 35 weeks GA, children with CLD of prematurity, and
children with hemodynamically significant CHD. In addition, due to the cost of prophylaxis, 
further restrictions have been implemented by local or national recommending bodies. For 
example, the USA national guidelines provided by the AAP (American Academy of 
Pediatrics, 2014) limit the recommendation for palivizumab to (a) preterm infants born before 
29 weeks GA who are younger than 12 months of age at the start of the RSV season, 
(b) preterm infants with a GA of < 32 weeks and CLD for the first year of life with 
consideration of prophylaxis during the second year if continued medical support is required, 
and (c) infants with hemodynamically significant CHD who are 12 months of age or younger. 
In the UK, palivizumab is recommended by the JCVI for preterm infants with CLD or 
hemodynamically significant, acyanotic CHD based on the GA at birth and chronological age 
at the start of the RSV season (JCVI, 2010a, 2010b). Currently, there is no approved RSV 
prophylaxis for the broader population of healthy infants, and there is no treatment for active 
RSV infection. The current standard of care for these patients with serious RSV illness is 
supportive care. Thus, there is a significant unmet medical need in healthy infants. MEDI8897 
is being developed as a cost-effective opportunity to protect all infants from RSV disease 
based on improved potency and an extended t1/2, which is expected to support once-per-RSV-
season dosing.
Based on advice from the United States Food and Drug Administration (US FDA), a pivotal 
Phase 2b study was conducted in healthy preterm infants born 29 to 35 weeks GA to 
demonstrate efficacy and safety of MEDI8897 in healthy preterm infants who are not eligible 
to receive palivizumab according to AAP or other local guidelines. Based on favorable 
benefit-risk results following the primary analysis, this Phase 3 study in healthy infants
≥35 weeks GA will be initiated.
1.6
Benefit-Risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
Prevention of RSV illness in all infants is a major public health priority. However, despite 
many years of attempted vaccine development, there is no safe and effective vaccine for these 
children. As there is no approved RSV prophylaxis for the broader population of healthy 


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infants once they acquire serious RSV illness, the medical management for these patients is 
supportive care. 
Based on the risk of serious RSV disease in younger infants and in high-risk children, there is 
an established unmet medical need for the use of MEDI8897 as a prophylactic mAb in all 
infants entering their first RSV season and in high-risk preterm infants and children up to 
2 years of age with CLD or CHD. Infants in this study who receive MEDI8897 may 
potentially benefit by being protected against serious RSV disease; however, this has not yet 
been proven in this population.
MEDI8897 has no endogenous targets, and no safety concerns were identified in nonclinical 
studies. The potential risks are based primarily on common safety risks observed with any 
immunoglobulin, including mAbs such as palivizumab. These potential risks include, but are 
not limited to, hypersensitivity (including anaphylaxis), immune complex disease, 
thrombocytopenia, and injection site reactions. To date, there have been no observed events of 
anaphylaxis, significant hypersensitivity reactions, immune complex disease, or 
thrombocytopenia attributable to MEDI8897 in the clinical studies. Nonetheless, subjects in 
MEDI8897 clinical studies will be monitored for important potential risks, and routine 
pharmacovigilance and risk minimization activities will be performed accordingly.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
Compared to placebo, a single IM MEDI8897 dose, 50 mg if weight < 5 kg or 100 mg if 
weight ≥ 5 kg, will be efficacious in reducing medically attended LRTI caused by RT-PCR-
confirmed RSV in healthy late preterm and term infants born ≥ 35 weeks 0 days GA and
entering their first RSV season, and the safety profile will be acceptable.
1.7.2
Secondary Hypotheses
!
There will be a reduction in the incidence of hospitalizations attributable to RT-PCR-
confirmed RSV
!
The predicted serum exposure of MEDI8897 will be adequate for the duration of the RSV 
season
!
ADA to MEDI8897 will not significantly impact the serum concentrations or safety of 
MEDI8897 through 150 days post dosing (ie, during a 5-month RSV season)


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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 1
Primary Objective and Associated Endpoint
Type
Objective
Endpoint
Efficacy
To assess the efficacy of MEDI8897 when 
administered as a single fixed IM dose to 
infants ≥ 35 weeks 0 days GA and entering 
their first RSV season, in reducing medically 
attended LRTI due to RT-PCR-confirmed 
RSV, compared to placebo
Incidence of medically attended LRTI 
(inpatient and outpatient) due to RT-PCR-
confirmed RSV through 150 days after 
dosing (ie, during a typical 5-month RSV 
season)
GA = gestational age; IM = intramuscular; LRTI = lower respiratory tract infection; RSV = respiratory 
syncytial virus; RT-PCR = reverse transcriptase-polymerase chain reaction.
2.1.1
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Efficacy
To assess the efficacy of MEDI8897 in 
reducing hospitalizations due to RT-PCR-
confirmed RSV, compared to placebo
Incidence of hospitalizations due to RT-
PCR-confirmed RSV through 150 days after 
dosing (ie, during a typical 5-month RSV 
season)
Safety
To evaluate the safety and tolerability of 
MEDI8897 when administered as a single 
fixed IM dose, compared to placebo
Safety and tolerability of MEDI8897 as 
assessed by the occurrence of TEAEs, 
TESAEs, AESIs, and NOCDs
PK
To evaluate single-dose serum 
concentrations of MEDI8897
Summary of MEDI8897 serum 
concentrations and estimated PK parameters 
(apparent clearance and AUC, if data permit) 
ADA
To evaluate ADA responses to MEDI8897 
in serum
Incidence of ADA to MEDI8897 in serum
ADA = anti-drug antibody; AESI = adverse event of special interest; AUC = area under the concentration time-
curve; IM = intramuscular; NOCD = new onset chronic diseases; PK = pharmacokinetic; RSV = respiratory 
syncytial virus; RT-PCR = reverse transcriptase-polymerase chain reaction; TEAE = treatment-emergent 
adverse event; TESAE = treatment-emergent serious adverse event.


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2.1.2
Exploratory Objectives and Associated Endpoints
Table 3
Exploratory Objectives and Endpoints
Type
Objective
Endpoint
Healthcare 
resource 
utilization
To assess healthcare resource utilization
and caregiver burden for MEDI8897 
recipients compared to placebo recipients
• Magnitude of healthcare resource utilization 
(eg, number of admissions to hospitals and 
intensive care units and duration of stay; 
number of subjects who require respiratory 
support and supplemental oxygen and the 
duration of use; number and type of 
outpatient visits, eg, emergency room,
urgent care, outpatient clinic; and number 
of prescription and over-the-counter 
medications and duration of use) 
• Caregiver burden (eg, caregiver missed 
work days, subject absence from day care) 
for subjects with medically attended LRTI 
caused by RT-PCR-confirmed RSV
RSV neutralizing 
antibody
To determine anti-RSV neutralizing 
antibody levels in serum afforded by a 
single dose of MEDI8897 compared to 
maternal RSV neutralizing antibody 
levels and those elicited following 
infection in the placebo group 
Anti-RSV neutralizing antibody levels 
(IU/mL) in serum for MEDI8897 recipients 
compared to placebo recipients
RSV serology
To evaluate exposure to RSV by 
measuring seroresponses to different RSV 
proteins
• Antibody levels to RSV pre-F, post-F, Ga, 
Gb, and N at different time points
• Changes in antibody levels (seroresponse)
indicating exposure to RSV
RSV resistance 
monitoring
To characterize resistance to MEDI8897 
through genotypic and phenotypic 
analyses
Genotypic analysis and susceptibility of RSV 
variants to neutralization by MEDI8897
RSV LRTI after 
Day 151
To assess the incidence of medically 
attended LRTI due to RT-PCR-confirmed 
RSV, compared to placebo after Day 151
Incidence of medically attended LRTI 
(inpatient and outpatient) due to RT-PCR-
confirmed RSV from Day 152 to Day 361
LRTI = lower respiratory tract infection; RSV = respiratory syncytial virus; RT-PCR = reverse transcriptase-
polymerase chain reaction.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
Study D5290C00004 (MELODY) is a pivotal Phase 3 randomized, double-blind, 
placebo-controlled, single-dose study to determine if MEDI8897 will prevent medically 
attended RSV-confirmed LRTI in healthy infants entering their first RSV season (Figure 1). 
The population to be enrolled is healthy late preterm and term infants born ≥ 35 weeks 0 days 
GA who would not receive RSV prophylaxis based on the AAP or other local or national 
guidelines. The study will be conducted over 5 respiratory virus seasons (3 northern 


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hemisphere [NH] and 2 southern hemisphere [SH] seasons) to better characterize RSV cases 
over multiple seasons. A total of approximately 3,000 infants will be randomized in a 2:1 ratio 
to receive a single 50-mg (if < 5 kg weight at the time of dosing) or 100-mg (if ≥ 5 kg weight 
at the time of dosing) IM dose of MEDI8897 (N = 2,000) or placebo (N = 1,000). The study 
may continue to enroll through 5 enrollment seasons even if the target of 3,000 subjects is 
met. Randomization will be stratified by hemisphere (NH, SH) and by subject age at the time 
of randomization (≤ 3 months, > 3 to ≤6 months, > 6 months). Enrollment of infants 
> 6 months of age will be limited to approximately 500. The study will comprise 2 cohorts: a 
primary cohort (N = ~1,500) and a complementary safety cohort (hereafter referred to as the 
safety cohort; N = ~1,500) for a total of approximately 3,000 subjects. Given the largely 
reduced circulation of RSV due to the coronavirus disease 2019 (COVID-19) pandemic
related measures, the primary cohort will include subjects from the NH2019, SH2020, and 
NH2020 enrollment seasons. The safety cohort will include subjects enrolled after the 
NH2020 enrollment season. The efficacy analyses performed in the primary analysis for the 
primary cohort will serve the purpose of evaluating the efficacy of MEDI8897 in the study 
population. Although efficacy data will also be collected for the safety cohort, only descriptive 
summaries will be provided and there is no intent to pool the efficacy data from the safety 
cohort with that from the primary cohort. Both the primary and the safety cohorts, individually 
and combined, will serve the purpose of evaluating the safety of MEDI8897. All subjects will 
be followed for approximately 510 days after dosing. An independent data monitoring 
committee will review safety data regularly and make recommendations regarding further 
study conduct.
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical 
attention for a respiratory illness (in either the inpatient or outpatient setting) will be evaluated 
for the occurrence of LRTI. All subjects found to have an LRTI and all subjects who require 
hospitalization for a respiratory infection, even if there is not a diagnosis of LRTI, should have 
respiratory samples obtained and respiratory assessment forms completed. Samples should be 
collected for all of these events (even those not meeting the protocol definition of LRTI). 
Subjects who have a primary hospitalization for a respiratory infection (ie, upper or lower 
tract) or a respiratory deterioration during a hospitalization, or who seek outpatient medical 
attention (including emergency room [ER] visits) for a lower respiratory illness, will be 
assessed clinically for the presence of LRTI and for RSV by central laboratory diagnostic 
testing of respiratory secretions. 
In addition to the clinical assessment of LRTI, there is a protocol definition using objective 
criteria for the determination of a medically attended protocol-defined LRTI. To meet the 
protocol-defined endpoint of medically attended LRTI, subjects with signs of LRTI must have 
documented at least one physical exam finding of rhonchi, rales, crackles, or wheeze AND at 
least one of the following clinical signs:


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!
Increased respiratory rate at rest (age < 2 months, ≥ 60 breaths/min; age 2 to 6 months, 
≥50 breaths/min; age > 6 months, ≥ 40 breaths/min) OR
!
Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1,800 meters or < 92% at 
altitudes > 1,800 meters), OR
!
Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new 
onset apnea, nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting) 
or dehydration secondary to inadequate oral intake due to respiratory distress (need for 
IV fluid)
Testing for RSV will be performed centrally using the US FDA-cleared and Conformité 
Européenne or European Conformity-marked in vitro diagnostic real-time RT-PCR assay 
(Lyra RSV + hMPV assay; Quidel Corporation, San Diego, CA, www.quidel.com). A 
diagnosis of RSV LRTI requires having a respiratory sample positive for RSV by the central 
laboratory RT-PCR.


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Figure 1
Study Flow Diagram
ADA = anti-drug antibody; IM = intramuscular; LRTI = lower respiratory tract infection; PK = pharmacokinetic.
Blood samples for PK and ADA will be collected at screening or Day 1 predose, on Days 31, 151, and 361, and 
from subjects hospitalized for a respiratory infection through Day 361. 
Safety assessments will be performed through Day 361. 
a
Dose level will be stratified by body weight at time of dosing. In the MEDI8897 group, subjects will 
receive 50 mg (0.5 mL) MEDI8897 if < 5 kg or 100 mg (1.0 mL) MEDI8897 if ≥ 5 kg. Subjects in the 
placebo group will receive a corresponding volume of normal saline, ie, 0.5 mL if < 5 kg or 1.0 mL if 
≥5 kg.
The endpoints to be measured in this study are described in Section 2.


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3.1.2
Treatment Regimen
Subjects will be randomly assigned in a 2:1 ratio to receive a single IM dose of MEDI8897 
(N = 2,000) or placebo (N = 1,000). The MEDI8897 dose level will be stratified by body 
weight at time of dosing: 50 mg MEDI8897 for infants < 5 kg or 100 mg MEDI8897 for 
infants ≥5 kg.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
A single fixed 50-mg IM dose was shown to be efficacious in the Phase 2b Study 
D5290C00003 in preterm infants (29 to < 35 weeks GA) in their first RSV season (see 
Section 1.4). Model-based analyses of the Phase 2b clinical PK and efficacy data identified a 
projected serum AUC0-∞of 
 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. 
 
 
 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.
3.2.2
Rationale for Study Population
MEDI8897 has the potential to address a serious unmet medical need by protecting all infants 
from RSV disease with once per season dosing. A dose of 50 mg MEDI8897 was first 
evaluated in healthy preterm infants 29 to < 35 weeks GA (per US FDA advice) in the pivotal 
Phase 2b Study D5290C00003 with favorable benefit-risk results following the primary 
analysis (see Section 1.4). This study proposes to further extend the population to healthy late 
preterm and term infants (≥35 weeks GA) to meet the overall goal of evaluating MEDI8897 
for prevention of RSV disease in all infants entering their first RSV season.


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3.2.3
Rationale for Endpoints
The endpoints for this Phase 3 pivotal study are the same as the endpoints used in the 
completed Phase 2b pivotal study. The primary endpoint is the incidence of medically 
attended LRTI (inpatient and outpatient) due to RT-PCR-confirmed RSV through 150 days 
after dosing (ie, during a typical 5-month RSV season). This endpoint will examine the 
efficacy of MEDI8897 compared to placebo in preventing LRTI due to RSV. RSV results in a 
significant burden of disease consisting of hospitalization, visits to the ER, and visits to 
outpatient clinics. This primary endpoint is designed to allow the capture of the total burden of 
RSV disease and the efficacy of MEDI8897 in reducing that burden. A separate secondary 
endpoint of RSV hospitalization will also be evaluated. 
Safety endpoints include TEAEs, TESAEs, AESIs (defined as hypersensitivity including 
anaphylaxis, immune complex disease, and thrombocytopenia), NOCDs, and concomitant 
medications. 
Serum concentration of MEDI8897 at selected time points will be evaluated as a secondary 
endpoint to confirm that adequate serum exposures are maintained for at least 5 months after 
dosing. Additionally, serum concentration data will be used to characterize the PK of 
MEDI8897 in infants using a population PK approach separately. For infants who require 
hospitalization for LRTI or any respiratory infection, an additional serum sample for 
measurement of MEDI8897 concentration and ADA will be obtained contemporaneous with 
time of hospitalization. Exposure-response analysis will be performed to relate MEDI8897 
serum concentrations and efficacy endpoints (LRTI including RSV-associated 
hospitalization).
To determine MEDI8897 serum levels post dosing and correlation with the development of 
ADA, serum concentrations will be measured up to 360 days post dosing. ADA will be 
measured at selected time points throughout the study and at 360 days post dosing, when 
MEDI8897 levels are expected to be low. 
Exploratory endpoints will examine magnitude of healthcare resource utilization (HRU) and 
caregiver burden due to RSV illness in the studied population. This will allow the 
determination of social and economic resources that are required for infants who have 
RSV-confirmed LRTI. Serum anti-RSV neutralizing antibody levels will be evaluated for 
correlation with serum MEDI8897 levels and maternally-derived RSV neutralizing antibody 
levels in the placebo group. RSV serology will be performed to identify potential exposure to 
RSV. To monitor for RSV resistance, the F protein from collected RSV isolates will be 
genetically characterized and novel variants will be phenotypically characterized for 
susceptibility to MEDI8897 and palivizumab neutralization. The incidence of medically 
attended LRTI (inpatient and outpatient) due to RT-PCR-confirmed RSV from Day 152 to
Day 361 will be assessed to determine if there is a possible effect of MEDI8897 past Day 151.


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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of approximately 3,000 infants will be enrolled and randomized in a 2:1 ratio to 
receive a single IM dose of MEDI8897 (N = 2,000) or placebo (N = 1,000).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Healthy infants in their first year of life and born ≥ 35 weeks 0 days GA (infants who 
have an underlying illness such as cystic fibrosis or Down syndrome with no other risk 
factors are eligible)
2
Infants who are entering their first RSV season at the time of screening
3
Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act in the USA, EU Data Privacy Directive in the EU) 
obtained from the subject's parent(s)/legal representative prior to performing any 
protocol-related procedures, including screening evaluations
4
Subject's parent(s)/legal representative is able to understand and comply with the 
requirements of the protocol including follow-up and illness visits as judged by the 
investigator
5
Subject is available to complete the follow-up period, which will be 17 months after 
receipt of study drug
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
Meets national or other local criteria to receive commercial palivizumab
2
Any fever (≥ 100.4°F [≥ 38.0°C], regardless of route) or acute illness within 7 days prior 
to randomization
3
Any history of LRTI or active LRTI prior to, or at the time of, randomization
4
Known history of RSV infection or active RSV infection prior to, or at the time of,
randomization
5
Any drug therapy (chronic or other) within 7 days prior to randomization or expected 
receipt during the study with the exception of: a) multivitamins and iron; b) infrequent 
use of over-the-counter (OTC) medications for the systemic treatment of common 
childhood symptoms (eg, pain relievers) that may be permitted according to the judgment 
of the investigator
6
Any current or expected receipt of immunosuppressive agents including steroids (except 
for the use of topical steroids according to the judgment of the investigator)


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7
History of receipt of blood, blood products, or immunoglobulin products, or expected 
receipt through the duration of the study
8
Receipt of any investigational drug
9
Known renal impairment
10 Known hepatic dysfunction including known or suspected active or chronic hepatitis 
infection
11 History of CLD/bronchopulmonary dysplasia
12 Clinically significant congenital anomaly of the respiratory tract
13 Chronic seizure or evolving or unstable neurologic disorder
14 CHD, except for children with uncomplicated CHD (eg, patent ductus arteriosus, small 
septal defect)
15 Prior history of a suspected or actual acute life-threatening event
16 Known immunodeficiency, including human immunodeficiency virus (HIV)
17 Mother with HIV infection (unless the child has been proven to be not infected)
18 Any known allergy, including to immunoglobulin products, or history of allergic reaction
19 Receipt of palivizumab or other RSV mAb or any RSV vaccine, including maternal RSV 
vaccination
20 Receipt of any monoclonal or polyclonal antibody (for example, hepatitis B immune 
globulin, IV immunoglobulin)
21 Any condition that, in the opinion of the investigator, would interfere with evaluation of 
the investigational product or interpretation of subject safety or study results
22 Concurrent enrollment in another interventional study
23 Children of employees of the sponsor, clinical study site, or any other individuals 
involved with the conduct of the study, or immediate family members of such individuals
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive web response system [IWRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not be
randomized or administered investigational product. The investigator must consult with the 
sponsor before a subject who has failed screening may be considered for rescreening.


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4.1.5
Withdrawal from the Study
Subjects may at any time be withdrawn from the study without prejudice to further treatment
(withdrawal of consent). The caregivers of such subjects will always be asked about the 
reason(s) for withdrawal and the presence of any AEs. If possible, the subject will be seen and 
assessed by the investigator. AEs will be followed up. If a subject withdraws from further 
participation in the study, then no further study visits or data collection should take place.
4.1.6
Discontinuation of Investigational Product
Each subject in this study will receive a single IM dose of investigational product. An 
individual subject will not receive investigational product if any of the following occur in the 
subject in question:
1
Withdrawal of consent
2
Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation
Subjects who have received investigational product will be followed for protocol-specified 
assessments including follow-up of any AEs unless consent is withdrawn from further study 
participation (Section 4.1.5) or the subject is lost to follow-up. Subjects who have not received 
investigational product, regardless of reason, will not be followed.
4.1.7
Withdrawal of Informed Consent for Data and Biological Samples
MedImmune ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
MedImmune is not obliged to destroy the results of this research.
The Principal Investigator:
!
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to MedImmune.
!
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.
!
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site.
!
Ensures that the subject and MedImmune are informed about the sample disposal.


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MedImmune ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
4.2
Schedule of Study Procedures
Whenever vital signs and blood draws are scheduled for the same nominal time, vital signs 
should occur prior to blood draws.
4.2.1
Enrollment/Screening Period
Table 4 shows all procedures to be conducted at the screening visit. 
Table 4
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -30 to Day 1
Written informed consent/ assignment of SID number
X
Medical history
X
Physical examination 
X
Weight
X
Vital signs
X
Blood sample for PK, ADA, RSV neut Ab, and RSV serology a
X
Assessment of AEs/SAEs
X
Concomitant medications
X
Verify eligibility criteria
X
ADA = anti-drug antibody; AEs = adverse events; neut Ab = neutralizing antibody; PK = pharmacokinetic; 
RSV = respiratory syncytial virus; SAEs = serious adverse events; SID = subject identification; V = visit.
Visit 1/Screening and Visit 2/Day 1 may occur on the same day.
a
If Visit 1/Screening and Visit 2/Day 1 do not occur on the same day, blood sample for PK, ADA, RSV 
neut Ab, and RSV serology can be collected at either Visit 1/Screening or Visit 2/Day 1 predose.
4.2.2
Treatment and Follow-up Periods
Study drug is administered on Day 1. Table 5 shows all procedures to be conducted during the 
treatment and follow-up periods.


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Table 5
Schedule of Treatment Period and Follow-up Period Study Procedures
Study Period
Treatment 
Period
Follow-up Period
Visit Number
V2 a
TC
V3
V4
V5
V6
V7
TC
LRTI
Skin 
Reaction
Procedure / 
Study Day
D1
D8 
(± 2 
days)
D15 
(± 2 
days)
D31 
(± 5 
days)
D91 
(± 7 
days)
D151 
(± 7 
days)
D361
(± 7 
days)
D1-151 
Q2W
(± 5 
days)
D152-361
monthly 
(± 5 
days)
D362-511 
Q2W 
(± 5 
days)
D1-361 
as 
needed
D362-511
as 
needed
D1-361 
as 
needed
Medical history update
X
X
X
X
X
X
Physical examination 
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs 
X b
X
X
X
X
X
Blood sample for PK, 
ADA, RSV neut Ab, and 
RSV serology
X c
X
X
X
X d
Assessment of 
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
Assessment of AESIs 
and NOCDs
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X i
X
Verify eligibility criteria
X
Randomization
X
Investigational product 
administration
X
Assessment of LRTI 
(inpatient or outpatient) 
or any respiratory 
infection that requires 
hospitalization
X d, e
X e
Nasal swab collection
X e
X e
Assessment of skin 
reaction
X f


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Table 5
Schedule of Treatment Period and Follow-up Period Study Procedures
Study Period
Treatment 
Period
Follow-up Period
Visit Number
V2 a
TC
V3
V4
V5
V6
V7
TC
LRTI
Skin 
Reaction
Procedure / 
Study Day
D1
D8 
(± 2 
days)
D15 
(± 2 
days)
D31 
(± 5 
days)
D91 
(± 7 
days)
D151 
(± 7 
days)
D361
(± 7 
days)
D1-151 
Q2W
(± 5 
days)
D152-361
monthly 
(± 5 
days)
D362-511 
Q2W 
(± 5 
days)
D1-361 
as 
needed
D362-511
as 
needed
D1-361 
as 
needed
Telephone contact g
X
X
X
X
(respiratory 
illness
inquiry only)
HRU and caregiver 
burden h
X
ADA = anti-drug antibody; AEs = adverse events; AESIs = adverse events of special interest; D = study day; ER = emergency room; HRU = healthcare resource utilization; 
ICU = intensive care unit; LRTI = lower respiratory tract infection; neut Ab = neutralizing antibody; NOCDs = new onset chronic diseases; OTC = over-the-counter; 
PK = pharmacokinetic; Q2W = once every two weeks; RSV = respiratory syncytial virus; SAEs = serious adverse events; TC = telephone call; V = visit.
a
Visit 2/Day 1 and Visit 1/Screening can occur on the same day. 
b
All vital signs (temperature, blood pressure, heart rate, and respiratory rate) should be obtained within 60 minutes prior to dosing, and at 30 minutes (± 5 minutes) and 
60 minutes (± 5 minutes) post dose.
c
If Visit 1/Screening and Visit 2/Day 1 do not occur on the same day, blood sample for PK, ADA, RSV neut Ab, and RSV serology can be collected at either 
Visit 1/Screening or Visit 2/Day 1 predose.
d
Blood samples will be collected from all subjects hospitalized with LRTI or any respiratory infection within approximately 2 days following hospital admission.
e
Nasal samples will be collected from all subjects with LRTIs (inpatient or outpatient) and from all subjects hospitalized with any respiratory infection (upper or lower) 
within approximately 2 days after the initial healthcare provider assessment and diagnosis.
f
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction regardless of severity, duration, time of onset post dosing, or relationship to 
investigational product.
g
Telephone contact must be verbal communication. Written communication via text, email, or other written form is not acceptable.
Telephone contact from Days 362 to 511 is only to determine whether there were any respiratory illnesses that required a medical visit.
h
HRU includes admission and duration of hospital and ICU stay, number of subjects who require respiratory support and supplemental oxygen use, duration of respiratory 
support and supplemental oxygen use, number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and number and days of prescription and OTC 
medication. Caregiver burden includes days of worked missed by the parent(s)/legal representative or other household member as a result of the subject’s illness, and days 
of day care/babysitting missed by the subject as a result of illness.
i
Only for subjects with LRTIs diagnosed during this period.


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4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Lower Respiratory Tract Infection
Subjects will be monitored throughout the study for LRTI (see Table 5). All subjects seeking 
medical attention for a respiratory illness (in either the inpatient or outpatient setting) will be 
evaluated for the occurrence of LRTI (Table 6). All subjects found to have an LRTI and all 
subjects who require hospitalization for a respiratory infection, even if there is not a diagnosis 
of LRTI, should have respiratory samples obtained and respiratory assessment forms 
completed. Samples should be collected for all of these respiratory events even those not 
meeting the protocol definition of LRTI. Subjects who have a primary hospitalization for a 
respiratory infection (ie, upper or lower tract) or a respiratory deterioration during a 
hospitalization, or who seek outpatient medical attention (including ER visits) for a lower 
respiratory illness, will be assessed clinically for the presence of LRTI and for RSV by central 
laboratory diagnostic testing of respiratory secretions. Testing for RSV will be performed 
using the US FDA-cleared and CE-marked in vitro diagnostic real-time RT-PCR assay (Lyra 
RSV + hMPV assay; Quidel Corporation, San Diego, CA, www.quidel.com). A diagnosis of 
RSV LRTI requires having a respiratory sample positive for RSV by the central laboratory 
RT-PCR assay.
In addition to the clinical assessment of LRTI, there is a protocol definition using objective 
criteria for the determination of a medically attended protocol-defined RSV LRTI. To meet 
the protocol-defined endpoint of medically attended RSV LRTI, subjects with signs of LRTI 
must have documented at least one physical exam finding of rhonchi, rales, crackles, or 
wheeze AND at least one of the following clinical signs:
•
Increased respiratory rate at rest (age: < 2 months, ≥ 60 breaths/min; 2 to 6 months, 
≥50 breaths/min; > 6 months, ≥40 breaths/min), OR
•
Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1,800 meters or < 92% at 
altitudes > 1,800 meters), OR
•
Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new 
onset apnea, nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting) or 
dehydration secondary to inadequate oral intake due to respiratory distress (need for IV
fluid).


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Table 6
Criteria for Meeting the Protocol-defined Endpoint of Medically 
Attended RSV LRTI 
RSV
Lower Respiratory Tract
Medical Significance
RSV Confirmed: 
•
Positive by central 
laboratory RT-PCR assay
Documented PE findings 
localizing to lower respiratory 
tract: 
•
Rhonchi
•
Rales
•
Crackles
•
Wheeze
Objective measures of clinical severity: 
•
Increased respiratory rate
•
Hypoxemia
•
Acute hypoxic or ventilatory failure
•
New onset apnea
•
Nasal flaring
•
Retractions
•
Grunting
•
Dehydration due to respiratory 
distress
LRTI = lower respiratory tract infection; PE = physical examination; RSV = respiratory syncytial virus; 
RT-PCR = reverse transcriptase-polymerase chain reaction. 
Note: One item from each column is required to meet the protocol-defined endpoint of RSV LRTI.
RSV Hospitalization
An RSV hospitalization is defined as either (1) a respiratory hospitalization with a positive 
RSV test within approximately 2 days of hospital admission (primary) or (2) a new onset of 
respiratory symptoms in an already hospitalized subject, with an objective measure of 
worsening respiratory status and positive RSV test (nosocomial). Primary and nosocomial 
RSV hospitalization are further defined below.
Primary RSV Hospitalization
RSV diagnostic testing will be performed on respiratory secretions obtained within 
approximately 2 days before or after admission for subjects hospitalized for respiratory 
infection (upper or lower respiratory tract). If the RSV diagnostic test (performed centrally via 
RT-PCR) is positive, the hospitalization will be classified as a primary RSV hospitalization. 
Deaths that can be demonstrated as caused by RSV (by autopsy or clinical history and 
virologic evidence) will also be considered as primary RSV hospitalization endpoints.
Nosocomial RSV Hospitalization
Subjects hospitalized for a respiratory illness or non-respiratory illness whose RSV diagnostic 
test is negative may develop nosocomial RSV illness during the study.
If signs (such as retractions, rhonchi, wheezing, crackles or rales) of a new lower respiratory 
illness occur during a hospitalization, whatever the reason for hospitalization, and there is an 
objective measure of worsening respiratory status (that is, new requirement for supplemental 
oxygen, increase in supplemental oxygen requirement from prior to the onset of symptoms, or 


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need for new or additional mechanical ventilation), a specimen will be collected within 
approximately 2 days from worsening of respiratory status for RSV diagnostic testing by the 
central laboratory. For any subject who is hospitalized for a respiratory infection (upper or 
lower respiratory tract), the subject must return to his/her baseline respiratory status or be 
clearly resolving the preceding respiratory illness before a subsequent respiratory deterioration 
for a nosocomial RSV hospitalization event can be determined.
If the RSV diagnostic test (performed centrally via RT-PCR) is positive, the subsequent 
hospital days will count as a nosocomial RSV hospitalization. The days of RSV 
hospitalization will be counted beginning with the start of the respiratory deterioration that 
resulted in the RSV diagnostic test.
RSV LRTI Outpatient Events
Subjects who seek outpatient medical attention, including ER and urgent care visits, for an 
LRTI should have respiratory secretions obtained within approximately 2 days after the initial 
healthcare provider assessment.
Respiratory Secretions for RSV Detection
Respiratory secretions for RSV testing must be collected from all subjects with LRTIs 
(inpatient or outpatient) and from all hospitalized subjects with any new respiratory infection 
(upper or lower) within approximately 2 days after the initial healthcare provider assessment 
and diagnosis. Nasal secretions will be obtained unless the subject is intubated, and then 
tracheal secretions may be obtained.
Respiratory secretions will be tested in a central laboratory for RSV using the US FDA-
cleared and CE-marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV + hMPV 
assay; Quidel Corporation, San Diego, CA, www.quidel.com). Testing of all samples may 
include other respiratory pathogens.
Monitoring for RSV Resistance
As an exploratory endpoint, novel RSV F variants identified in RSV positive nasal specimens
collected from study subjects will be evaluated by genotypic and phenotypic methods to 
monitor potential susceptibility changes to MEDI8897 neutralization. The subtype and 
genotypic determination of RSV will be performed directly on the nasal specimens that are 
collected from all subjects who are confirmed RSV-positive using the Lyra RSV + hMPV 
real-time RT-PCR assay manufactured by Quidel Corporation (Lyra RSV + hMPV assay;
Quidel Corporation, San Diego CA, www.quidel.com).The full-length F gene will be 
amplified using a standard, single-tube population-based RT-PCR method and sequenced by 
Sanger sequencing methodology. Amino acid substitution(s) within the MEDI8897 binding 


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site (amino acid [aa] 62-69 and aa 196-212) and outside the binding site in the extracellular 
regions of mature F protein (aa 24-109 and aa 137-524), including the palivizumab binding 
site (aa 267-275), will be reported and compared to F protein sequences of contemporary 
reference RSV strains. In vitro phenotypic analysis (susceptibility to MEDI8897 and 
palivizumab neutralization) will be attempted using an RSV neutralization assay with either 
RSV viruses constructed through site-directed mutagenesis of the F gene and reverse 
genetics..
4.3.2
Medical History and Physical Examination, Weight, and Vital Signs
A complete medical history will be obtained at screening and a medical history update will be 
obtained on the day of dosing and during the follow-up period as defined in Section 4.2. 
Assessment will include history and current medical conditions, past or present cardiovascular 
disorders, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, 
hematologic, immunologic, dermatological, psychiatric, genitourinary, drug and surgical 
history, or any other diseases or disorders.
A physical examination will be performed at screening, on the day of dosing, and during the 
follow-up period as defined in Section 4.2. The physical examination will include assessment 
of weight at screening and at each study visit mentioned above.
Vital signs (temperature, blood pressure, respiratory rate, and heart rate measurements) will be 
collected at screening, on the day of dosing, and during the follow-up period as defined in 
Section 4.2. On Day 1, vital signs will be monitored before and after administration of 
investigational product. 
Baseline information will be collected on breastfeeding, smoking in the household, and if the 
infant attends day care.
4.3.3
Pharmacokinetics, Anti-drug Antibody, and RSV Serology
A blood sample for assessment of PK, ADA, RSV neutralizing antibody, and RSV serology
will be collected through Day 361 according to the schedule defined in Section 4.2. A 
Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.
4.3.3.1
Pharmacokinetic Evaluation
Blood samples to evaluate the PK of MEDI8897 in serum will be collected according to 
scheduled time points. Blood samples for PK evaluation will also be collected from subjects 
hospitalized with LRTI or any respiratory infection within approximately 2 days following 
hospitalization. See the collection schedule in Section 4.2. The concentration of MEDI8897 in 
serum will be measured using validated assays.


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4.3.3.2
Anti-drug Antibody Evaluation 
Blood samples to evaluate ADA responses to MEDI8897 in serum will be collected according 
to scheduled time points. Blood samples will also be collected for ADA response from
subjects hospitalized with LRTI or any respiratory infection within approximately 2 days 
following hospitalization. See the collection schedule in Section 4.2. Evaluations will be 
performed using validated immunoassays. 
4.3.3.3
RSV Neutralizing Antibody Evaluation
Blood samples to measure RSV neutralizing antibody levels in serum will be collected 
according to scheduled time points. Blood samples will also be collected for measuring RSV 
neutralizing antibody levels from subjects hospitalized with LRTI or any respiratory infection
within approximately 2 days following hospitalization. See the collection schedule in 
Section 4.2. Analyses will be performed using an RSV neutralizing antibody assay previously 
described (Shambaugh et al, 2017).
4.3.3.4
RSV Serology Evaluation
Blood samples to measure RSV antigen-specific antibody levels in serum will be collected 
according to scheduled time points. Blood samples will also be collected for measuring RSV 
antigen-specific antibody levels from subjects hospitalized with LRTI or any respiratory 
infection within approximately 2 days following hospitalization. See the collection schedule in 
Section 4.2. Analyses will be performed using an updated version of an assay previously 
described (Maifeld et al, 2016).
4.3.4
Healthcare Resource Utilization and Caregiver Burden
Information on HRU and caregiver burden will be collected for all events of medically 
attended LRTI through Day 361 (see Table 5). This will include admission to and duration of 
hospital and intensive care unit stay, number of subjects who require respiratory support and 
supplemental oxygen use, duration of respiratory support and supplemental oxygen use, 
number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and the number of 
prescription and OTC medications and their duration of use. Caregiver burden will be 
assessed through, for example, caregiver missed work days and the subject’s absence from 
day care.
4.3.5
Skin Reactions
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction 
through Day 361 to assist in determination of the etiology of the reaction (see Table 5). 
Information will be collected regardless of event severity, duration, time of onset post dosing, 
or relationship to investigational product. Parents/legal representatives of study subjects will 
be given a hypersensitivity card and instructed to call the study site immediately for signs of 
hypersensitivity or allergic reaction. Sites must notify MedImmune within 24 hours of 
knowledge of such events. For any skin or skin-related reactions, including all rashes that 


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occur within 7 days after dosing, the infant will be brought to the study site as soon as possible 
for evaluation.
4.3.6
Estimate of Volume of Blood to be Collected
Blood volume estimates are provided in Table 7 by visit/study day.
Table 7
Volume of Blood to be Collected
Visit/Study Day
Estimated Blood Volume (mL)
Visit 1/Screening or Visit 2/Day 1
1.5 mL
Visit 4/Day 31
1.5 mL
Visit 6/Day 151
1.5 mL
Visit 7/Day 361
1.5 mL
Total
6.0 mL
4.4
Study Suspension or Termination
MedImmune reserves the right to temporarily suspend or permanently terminate this study at 
any time. The reasons for temporarily suspending or permanently terminating the study may 
include but are not limited to the following: 
1
Death in any subject in which the cause of death is assessed as related to investigational 
product (in this case the study will be paused for the MedImmune safety review 
committee to evaluate the events)
2
Anaphylactic reaction that is related to investigational product (see Appendix B for a
definition of anaphylaxis; in this case the study will be paused for the MedImmune safety 
review committee to evaluate the events)
3
Grade 3 and/or 4 hypersensitivity AEs based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) grading scale that are assessed 
as related to MEDI8897 in 2 or more subjects
4
Two serious adverse events (SAEs) of the same type that are assessed as related to
MEDI8897 
5
Other events that, in the judgment of the sponsor or site investigator, are deemed serious 
enough to warrant immediate review by the MedImmune safety review committee
6
Subject enrollment is unsatisfactory
7
Sponsor decision to terminate development
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating investigators 
(or head of the medical institution, where applicable). When feasible, MedImmune will 
provide advance notice to all participating investigators (or head of the medical institution, 
where applicable) of the impending action.




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If there are any defects noted with the investigational product, the investigator and Site 
Monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.5) for further instructions.
4.5.1.2
Dose Administration Steps
No incompatibilities between MEDI8897 and polycarbonate or polypropylene syringes have 
been observed.
MEDI8897 does not contain preservatives and any unused portion must be discarded. Total 
in-use storage time from needle puncture of the investigational product vial to administration 
should not exceed 4 hours at room temperature. If storage time exceeds these limits, a new 
vial should be used.
The dose administration steps are as follows:
1
A dose of 50 mg (ie, 0.5 mL) of MEDI8897 will be obtained by withdrawing the entire 
contents of 1 investigational vial with an appropriately sized syringe.
2
A dose of 100 mg (ie, 1.0 mL) of MEDI8897 will be obtained by withdrawing the entire 
contents of 2 investigational vials with an appropriately sized syringe.
3
For subjects randomized to placebo, a corresponding volume of placebo (0.5 mL for 
infants < 5 kg or 1.0 mL for infants ≥ 5 kg) should be administered. 
4
Switch the needle prior to administration.
5
Administer investigational product using the appropriate size needle ranging from 22 to 
25 gauge and 5/8 to 1.0 inches based on muscle size and weight of the subject.
4.5.1.3
Treatment Administration
The first day of dosing is considered Day 1.
Investigational product (MEDI8897 or placebo) will be supplied by an unblinded 
investigational product manager. Blinding will be performed at the site level to ensure that 
MEDI8897 and placebo are indistinguishable in appearance and are not labeled to reveal
treatment identity. 
Investigational product (MEDI8897 or placebo) should be administered in the anterolateral 
aspect of the thigh according to standard practice procedures for IM injections.
4.5.1.4
Monitoring of Dose Administration
Subjects will be monitored before and after investigational product administration through 
assessment of vital signs (temperature, blood pressure, heart rate, and respiratory rate). All 
vital signs should be obtained within 60 minutes prior to dosing, and at 30 minutes 
(± 5 minutes) and at 60 minutes (± 5 minutes) post dose. 


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As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
4.5.1.5
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email:
Phone:
Mail:
MedImmune
Attn: Product Complaint Department
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into local 
languages, as required.
4.5.4
Storage
Store investigational product at 2°C to 8°C.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 


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of investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of 
upon authorization by MedImmune.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IWRS will be used for randomization to a treatment group and assignment of blinded
investigational product kit numbers. A subject is considered randomized into the study when 
the investigator notifies the IWRS that the subject meets eligibility criteria and the IWRS 
provides the assignment of blinded investigational product kit numbers to the subject.
Subjects will be randomized at a 2:1 ratio to receive MEDI8897 (N = 2,000) or placebo 
(N = 1,000). Randomization will be stratified by hemisphere (NH and SH) and by subject age 
at the time of randomization (ie, ≤3 months, > 3 to ≤ 6 months, > 6 months). Enrollment of 
infants > 6 months of age will be limited to approximately 500.
The procedure for using IWRS is as follows:
!
The investigator or designee contacts the IWRS and provides the SID number and 
subject’s baseline characteristic(s) used to verify that it is the same subject
!
Placebo (provided by site) or a vial from a MEDI8897 kit will be assigned to the subject
!
Confirmation of this information is sent to the unblinded investigational product manager 
who prepares the investigational product to be dispensed to the subject per the response 
system and records the appropriate information in the investigational product 
accountability log
Investigational product (MEDI8897 or placebo) must be administered the same day the 
investigational product is assigned. Total in-use storage time from needle puncture of the 
investigational product vial to administration should not exceed 4 hours at room temperature. 
If storage time exceeds these limits, a new vial should be used. If there is a delay in the 
administration of investigational product such that it will not be administered within the 
specified timeframe, the unblinded investigational product manager must be notified 
immediately.
4.6.2
Methods to Ensure Blinding
This is a double-blind study in which sites are using commercially available saline as the 
placebo. MEDI8897 and placebo are visually indistinguishable once in syringes. Neither the 
subject/legal representative nor the investigator or any of the site staff who are involved in the 
treatment or clinical evaluation of the subjects will be aware of the treatment received 
(ICH E9). In the event that treatment allocation for a subject becomes known to the 
investigator or other blinded study staff involved in the management of study subjects, the 
sponsor must be notified immediately. If the treatment allocation for a subject needs to be 


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known to treat an individual subject for an AE, the investigator must notify the sponsor 
immediately. The site will maintain a written plan detailing which staff members are 
blinded/unblinded and the process of investigational product administration used to maintain 
the blind.
Details of maintaining the double-blind setting until database lock for the primary and safety 
analyses are provided in Section 4.8.1.
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IWRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In the majority of cases, the management of a 
medical emergency would be the same whether or not investigational product was received by 
the subject. If this was the case, the investigational product allocation should not be unblinded.
MedImmune retains the right to unblind the treatment allocation for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the electronic case report form (eCRF).
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care including routine vitamins and iron.
4.7.2
Prohibited Concomitant Medications
Use of concomitant medications including OTC medications (except for routine vitamins and 
iron), herbal supplements, etc from Day 1 through Day 15 post dose is discouraged. Subjects’ 
legal representatives must be instructed not to administer any medications, including OTC
products, without first consulting with the investigator.


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4.8
Statistical Evaluation
4.8.1
General Considerations
There will be 2 study cohorts: a primary cohort and a safety cohort. The primary cohort will 
include subjects from the NH2019, SH2020, and NH2020 enrollment seasons (enrollment was 
paused after one subject from the NH2020 was enrolled due to the impact of the COVID-19 
pandemic). The safety cohort will include subjects enrolled after the NH2020 enrollment 
season.
There are 3 planned analyses for this study: the primary analysis, safety analysis, and final 
analysis. The primary analysis will be conducted after all randomized subjects (except for 
one subject enrolled in the NH2020 season) from the primary cohort have been followed 
through Day 361 and will be the primary analysis for which the study is designed to assess 
efficacy. For the primary analysis, all efficacy, PK, ADA, and safety data collected for the 
primary cohort through at least Day 361 will be analyzed. The safety analysis will be 
conducted when all subjects from the safety cohort have been followed through Day 151. For 
the safety analysis, in addition to the analyses conducted during the primary analysis based on 
the primary cohort, all available efficacy, PK, ADA, RSV neutralizing antibody, RSV 
serology, and safety data collected for the safety cohort will be analyzed (only descriptive 
summaries will be provided for the efficacy data collected for the safety cohort). The final 
analysis will be conducted when all subjects have completed the last visit of the study (ie, 
Day 511). Given the largely reduced circulation of RSV due to the COVID-19 pandemic
related measures, the efficacy analyses performed in the primary analysis for the primary 
cohort will serve the purpose of evaluating the efficacy of MEDI8897 in the study population. 
Although efficacy data will also be collected for the safety cohort, only descriptive summaries 
will be provided and there is no intent to pool the efficacy data from the safety cohort with 
that from the primary cohort. Both the primary and the safety cohorts, individually and 
combined, will serve the purpose of evaluating the safety of MEDI8897.
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. Additional details of statistical analyses will be 
described in the Statistical Analysis Plan (SAP). 
The Intent-to-treat (ITT) Population will include all subjects who are randomized. In this 
population, data will be analyzed according to the randomized treatment. All analyses, with 
the exception of safety, will be performed on the ITT Population unless otherwise specified.
Subjects in the ITT Population and from the primary cohort will be ITT Population 1 (ITT1). 
Subjects in the ITT Population and from the safety cohort will be ITT Population 2 (ITT2).
The As-treated Population will include all subjects who are randomized and who receive any 
amount of investigational product. In this population, data will be analyzed according to the 


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treatment actually received. All safety analyses will be performed on the As-treated 
Population. Subjects in the As-treated Population and from the primary cohort will be 
As-treated Population 1 (AT1). Subjects in the As-treated Population and from the safety 
cohort will be As-treated Population 2 (AT2).
The Per-protocol Population will include subjects in the ITT Population who receive the 
correct dose of randomized treatment and who do not have a serious protocol violation. 
Detailed criteria defining this population will be determined and documented prior to 
performing the primary analysis.
The study will maintain a double-blind setting (ie, blind for subjects, Investigators/site staff, 
and Sponsor/designated clinical research organization) until database lock for the primary and 
safety analyses. More specifically, at the time of the primary analysis (where the analyses will 
be based only on the primary cohort), the data from the primary cohort will be unblinded to 
the Sponsor/designated clinical research organization associated with the analysis, write-up,
and submission. To maintain the double-blind setting for the safety cohort until the safety 
analysis, any data with potential unblinding risk will be split by primary cohort and safety 
cohort by the corresponding third party data vendors and when the primary database lock
occurs, no potential unblinded information will be transferred from subjects not in the primary 
cohort. The unblinded data from the safety cohort will not be transferred to the Sponsor until 
the database lock for safety analysis occurs. The site personnel, subjects, and the study team 
members involved in advice or decisions involving study subjects and/or day-to-day 
interactions with the site will remain blinded until the end of the study (ie, all subjects have 
completed the Day 511 visit) to ensure the trial integrity is maintained. Further details will be 
specified in the unblinding plan prior to unblinding of the primary cohort data.
4.8.2
Sample Size
This Phase 3 study will enroll approximately 3,000 subjects of whom approximately 
2,000 will receive MEDI8897 and 1,000 will receive placebo. The 2,000 subjects to be dosed 
with MEDI8897 in this study, together with the 968 subjects dosed with MEDI8897 in the 
Phase 2b Study D5290C00003 and at least 600 subjects dosed with MEDI8897 in the 
palivizumab-controlled Phase 2/3 Study D5290C00005, will contribute to a safety database of 
at least approximately 3,600 subjects exposed to MEDI8897.
For this Phase 3 study, the original sample size of 3,000 was driven by the safety database 
requirement, and the study had at least 99% power for the primary endpoint. Reducing the 
sample size to 1,500 still allows the study to be sufficiently powered. More specifically, the
sample size of approximately 1,500 subjects in the primary cohort has at least 99% power to 
detect 70% RRR, assuming a placebo group medically attended RSV LRTI incidence of 8%,
with a 2-sided α = 0.05. The assumption of 8% incidence is supported both by literature 


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(Paramore et al, 2010) and the observed placebo incidence rate (9.6%) in the Phase 2b Study 
D5290C00003.
The 70% RRR assumption is based on the Phase 2b Study D5290C00003 in which there was 
70% RRR in the incidence of medically attended RSV LRTI (9.5% placebo, 
2.6% MEDI8897; p < 0.001) and 
RRR in the incidence of RSV hospitalization 
(4.1% placebo, 0.8% MEDI8897; p < 0.001) in subjects who received MEDI8897 prophylaxis 
(see Section 1.4.3). In addition, the assumption is supported by a placebo-controlled study in 
Native American term infants in which there was a
 
 
in infants who received motavizumab prophylaxis (O'Brien et al, 2015). In the 
event that the incidence rate in the placebo group drops due to the impact of the COVID-19 
pandemic (eg, social distancing), the sample size of 1,500 still provides at least 90% power to 
detect 70% RRR if the placebo incidence rate is 4% or higher.
To evaluate risk, a sample size of 2,000 subjects exposed to MEDI8897 in this Phase 3 study 
will provide a > 99% probability of observing at least one AE if the true event rate is 0.3%; if 
no AEs are observed, this study provides 98% confidence that the true event rate is < 0.2%.
4.8.3
Efficacy
The primary and secondary efficacy hypotheses will be assessed in the primary analysis for 
the primary cohort by a hierarchical order. That is, the secondary hypothesis will be tested at a 
significance level of 0.05 only if the treatment effect on the primary efficacy endpoint is 
demonstrated at the significance level of 2-sided 0.05. More specifically, after the significance 
of the primary efficacy endpoint is demonstrated, the secondary efficacy endpoint will first be 
tested from pooling all ITT subjects from the Phase 2b Study D5290C00003 and ITT1 in the 
Phase 3 Study D5290C00004. If the significance of the pooled efficacy based on pooling all 
subjects from Phase 2b and Phase 3 is demonstrated (at 2-sided 0.05), the secondary efficacy 
endpoint will be further tested from pooling the 860 subjects weighing < 5 kg on Day 1 (ie, 
290 subjects randomized to placebo and 570 subjects randomized to MEDI8897) in the 
Phase 2b Study D5290C00003 and ITT1 subjects in the Phase 3 Study D5290C00004. If the 
significance of the pooled efficacy based on pooling the subjects weighing < 5 kg from 
Phase 2b and Phase 3 ITT1 subjects is again demonstrated (at 2-sided 0.05), the secondary 
efficacy endpoint will be tested using ITT1 subjects from this Phase 3 study alone. With that, 
the overall Type I error is controlled at 0.05. Therefore, no further multiplicity adjustment is 
necessary.
4.8.3.1
Primary Efficacy Analysis
The primary endpoint is the incidence of medically attended RSV LRTI (inpatient and 
outpatient) through 150 days post dose. For subjects with multiple events, only the first 


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occurrence will be used in the primary analysis. The determination of medically attended RSV 
LRTI will be based on RSV test results (performed centrally using RT-PCR) and objective 
clinical LRTI criteria.
The primary efficacy analysis of the primary endpoint will be performed on ITT1 using a
Poisson regression model with robust variance (Zou, 2004). The model contains the term of 
treatment group and age group at randomization (ie, age ≤3 months, age > 3 to ≤ 6 months, 
age > 6 months) and dichotomous temperate hemispheres (NH and SH) as covariates. The
RRR, defined as 1- Relative Risk, and its corresponding 2-sided 95% CI, will be estimated 
from the model. In addition, the 2-sided p-value testing null hypothesis that the incidence of 
medically attended RSV LRTI between MEDI8897 and placebo groups are the same will be 
obtained from the model. Statistical significance will be achieved if the 2-sided p-value is 
≤0.05.
During blinded data review prior to database lock for the primary analysis, it was revealed that 
there was no incidence of medically attended RSV LRTI events through 150 days post dose 
for SH in the primary cohort, which would cause a known convergence or estimation issue. 
Therefore, it was decided to drop the stratification factor hemisphere from the full model and 
a reduced model (including the term of treatment group and age at randomization stratum as 
covariate) will be used instead. Similar consideration also applies to other analyses for the 
primary efficacy endpoint, where hemisphere will be dropped from the corresponding models. 
RSV LRTI that occurs through 150 days post dose will contribute to the primary efficacy 
analysis. For subjects who do not have a medically attended RSV LRTI and are not followed 
through 150 days post dose, their event status will be imputed assuming the observed placebo 
RSV LRTI rate conditional on stratification factor (age at randomization) using multiple 
imputation techniques and will be described in the SAP.
If convergence cannot be achieved using the Poisson regression analysis model, the stratified 
Cochran-Mantel-Haenszel (CMH) test (detailed in Section 4.8.3.2) will be used as the primary 
analysis model.
The above described analysis on the primary efficacy endpoint will also be conducted on the 
Per-protocol Population.
4.8.3.2
Additional Analyses of the Primary Endpoint
The additional analyses of the primary endpoint will be conducted on ITT1. To allow for 
differences in follow-up time, the primary analysis using a Poisson Regression with robust 
variance will be repeated, adjusting for the same covariates as well as log (follow-up time) as 
an offset. Since the follow-up time is adjusted in the model, there is no missing imputation for 
this analysis.


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A CMH test stratified by age at randomization (ie, ≤3 months, > 3 to ≤6 months, > 6 months) 
will be used to compare between treatment groups through 150 days post dose as the key 
secondary analysis for the primary endpoint. The RRR and its associated 95% CI will be 
provided. This analysis will be performed without imputation. The Breslow-Day test and 
Zelen’s exact test will be used to test the homogeneity of the odds ratios across strata and the 
corresponding p-values will be presented.
In addition, a Kaplan-Meier curve for time to first medically attended RSV LRTI will be
generated based on observed events. Treatment group differences in time-to-first medically 
attended RSV LRTI will be compared using the stratified log-rank test with the stratification 
factor (age at randomization) as the strata.
Additional analyses, including summaries for age at onset of the first medically attended RSV 
LRTI, inpatient/outpatient visit settings, and RSV subtypes associated with the primary 
endpoint will be provided.
An analysis may also include all RSV positive LRTI endpoints, using results from either the 
central laboratory or local laboratory.
Additional sensitivity analyses will be conducted on ITT1 to assess the robustness of the 
efficacy results with regard to the impact of the COVID-19 pandemic. 
4.8.3.3
Supplementary Analyses of the Primary Endpoint
The supplementary analyses of the primary endpoint will be conducted on ITT1. To evaluate 
the impact of the missing data on the primary analyses, the following supplementary analyses 
will be conducted. For subjects who do not have an RSV LRTI and are not followed through 
150 days post dose:
1
Count these subjects as having not met the RSV LRTI endpoint within each treatment 
group 
2
Perform multiple imputation using the observed event rate per treatment group for their 
event status
3
Perform single imputation using observed placebo rate for both groups
The details of the supplementary analyses will be described in the Statistical Analysis Plan.
4.8.3.4
Subgroup Analyses of the Primary Endpoint
Subgroup analysis will be performed for the primary efficacy endpoint, the incidence of 
medically attended RSV LRTI. Treatment-by-subgroup interaction will be tested using the 
Poisson regression with robust variance model with the terms of treatment, age group, 
subgroup, and treatment-by-subgroup interaction. If this full model does not achieve 
convergence, a reduced model of treatment, subgroup, and treatment-by-subgroup interaction 


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will be used. Significant treatment-by-subgroup interaction is judged at the significance level 
of 0.10. Within each level of a subgroup, the RRR and its corresponding 95% CI will be 
estimated using a Poisson regression model with robust variance with the term of treatment. A 
forest plot of the RRR and the 95% CI will be presented. In the event that the Poisson 
regression model does not converge for any stratum of a subgroup, the exact conditional 
method based on the number of RSV LRTIs (Breslow and Day, 1987) will be used as the 
analytical model to generate the RRR and its corresponding CI for all subgroup strata.
The subgroup analysis will be conducted for the following subgroups on ITT1:
!
Hemisphere
!
Age at randomization stratum (age ≤ 3 months, age > 3 to ≤ 6 months, age > 6 months)
!
Gender
!
Race (Caucasian, non-Caucasian)
!
Weight at birth (weight ≤2.5 kg, weight > 2.5 kg )
!
Weight on Day 1 (weight < 5 kg, weight ≥ 5 kg)
!
Sibling also participating in the study (yes/no)
In addition, incidence of medically attended RSV LRTI will be summarized by country on 
ITT1.
4.8.3.5
Secondary Efficacy Analyses
The secondary efficacy endpoint is the incidence of RSV LRTI hospitalization through 
150 days post dose. For subjects with multiple RSV LRTI hospitalizations, only the first 
occurrence will be used in the analysis.
For the pooled analysis, a Poisson regression model with robust variance (Zou, 2004) will be 
used to assess the treatment effect on the incidence of RSV LRTI hospitalization between 
MEDI8897 and placebo groups in the pooled ITT population, which includes all ITT subjects 
from Study D5290C00003 and ITT1 subjects from Study D52090C00004. In addition to the 
treatment arm, the variable “Study” (which identifies the enrolled study for each subject) will 
be used as a covariate to adjust for differences between the 2 studies. RRR and its 
corresponding 95% CI will be estimated from the model. RSV LRTI hospitalization that 
occurs through 150 days post dose will contribute to the analysis. For subjects who do not 
have an RSV LRTI and were not followed through 150 days post dose, their event status will 
be imputed using the observed placebo RSV LRTI hospitalization rate following the repeated 
imputation procedure conditional on study.
For the analysis using the primary cohort of Phase 3 data alone, a Poisson regression model 
with robust variance (Zou, 2004) using only the treatment term will be used to assess the 
treatment effect on the incidence of RSV LRTI hospitalization between MEDI8897 and 


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placebo groups in ITT1. RRR and its corresponding 95% CI will be estimated from the model. 
RSV LRTI hospitalization that occurs through 150 days post dose will contribute to the 
analysis. For subjects who do not have an RSV LRTI and were not followed through 150 days 
post dose, their event status will be imputed using the observed placebo RSV LRTI 
hospitalization rate following the repeated imputation procedure without involvement of 
stratification factors.
The additional analyses, including the CMH test stratified by study (for the pooled population) 
or the CMH test with the only term of treatment (for subjects from Phase 3 alone) for the 
incidence of RSV LRTI hospitalization, and the Kaplan-Meier for time-to-first RSV LRTI 
hospitalization will be conducted on ITT1. Treatment group differences in time-to-first RSV 
LRTI hospitalization will be compared using log-rank test. 
In addition, age at onset of the first medically attended RSV LRTI hospitalization through 
150 days post dose will be analyzed similar to that for the primary endpoint. Summary of 
incidence of RSV LRTI hospitalization by subgroup will also be provided. These analyses 
will be conducted on ITT1.
4.8.3.6
Additional Efficacy Analyses for the Safety Cohort
Additional efficacy summaries on ITT2 will be produced.
The incidence of medically attended RSV LRTI (inpatient and outpatient) through 150 days 
post dose will be summarized by treatment group using ITT2. For subjects with multiple 
medically attended RSV LRTI events, only the first occurrence will be used in the summary.
The incidence of RSV hospitalization through 150 days after dosing will be summarized by 
treatment group using ITT2.
Additional analyses, including summaries for age at onset of the first medically attended RSV
LRTI, inpatient/outpatient visit settings, and RSV subtypes associated with the incidence of 
medically attended RSV LRTI through 150 days post dose will be provided.
Details of the efficacy analyses for the safety cohort will be provided in the SAP.
4.8.4
Safety
Safety analyses will be conducted for the overall As-treated Population, AT1, and AT2. Safety 
of MEDI8897 will primarily be assessed and measured by the occurrence of all TEAEs and 
TESAEs. AEs will be graded according to the current version of the NCI CTCAE where 
applicable for pediatric assessments. AEs will be coded by MedDRA system organ class and 
preferred term. Specific AEs will be counted once for each subject for calculating rates, but 
will be presented in total in subject listings. In addition, if the same AE occurs multiple times 
within a particular subject, the highest severity and level of causality will be reported. The 


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type, incidence, severity, and relationship to study investigational product will be summarized 
by treatment group. In addition, summaries of deaths and SAEs will be provided. Other safety 
assessments will include:
!
Occurrence of AESIs to include targeted AEs of hypersensitivity (including anaphylaxis), 
thrombocytopenia, and immune complex disease (eg, vasculitis, endocarditis, neuritis, 
glomerulonephritis) following investigational product administration 
!
Occurrence of NOCDs following investigational product administration
4.8.5
Analysis of Pharmacokinetics and Anti-drug Antibody
4.8.5.1
Pharmacokinetic Analysis
Following a single dose of MEDI8897, individual MEDI8897 serum concentration data will 
be tabulated by treatment group along with descriptive statistics. PK parameters, eg, Cmax, 
AUC, apparent clearance, and t1/2, will be estimated using non-compartmental analysis, if data 
permit.
4.8.5.2
Anti-drug Antibody Analysis
The incidence of ADA to MEDI8897 will be assessed and summarized by number and 
percentage of subjects who are ADA positive by treatment group. The ADA titer will be listed 
by subject at different time points. The impact of ADA on PK, efficacy, and association with 
TEAEs and TESAEs, will be assessed. The summaries will be conducted on the overall 
As-treated Population, AT1, and AT2, unless specified otherwise. 
4.8.6
Exploratory Analysis
The magnitude of HRU (eg, number of admissions to hospitals and ICUs and duration of stay; 
number of subjects who require respiratory support and supplemental oxygen and the duration 
of use; number and types of outpatient visits, eg, ER, urgent care, outpatient clinic; and 
number of prescription and OTC medications and duration of use) will be summarized overall 
by treatment group, and for the following subgroups: subjects with at least one medically 
attended LRTI caused by RT-PCR-confirmed RSV, subjects with medically attended LRTI 
not caused by RSV, and subjects with non-protocol defined LRTIs, which may be further 
broken down by RSV status. Summaries of the magnitude of HRU will be conducted on ITT1
and ITT2 (if data permit).
Caregiver burden (eg, caregiver missed work days, subject absence from day care) for subjects 
with medically attended LRTI caused by RT-PCR-confirmed RSV will be summarized by 
treatment group on ITT1 and ITT2 (if data permit).
RSV seroresponses will be evaluated as a measure of “RSV exposure” in the placebo and 
MEDI8897 groups.  


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RSV neutralizing antibody levels afforded by MEDI8897 will be compared to maternal RSV 
neutralizing antibody levels and those elicited following infection in the placebo group.
RSV genotypic analysis will report the sequence changes in the mature F protein from all 
RSV positive isolates compared to contemporary RSV A and RSV B reference strains.  
Susceptibility of novel RSV variants to MEDI8897 will be tested and compared to control 
viruses.
The incidence of medically attended RSV LRTI (inpatient and outpatient) from Day 152 to 
Day 361 will be based on RSV test results (performed centrally via RT-PCR) and objective 
clinical LRTI criteria and will be summarized by treatment group on ITT1 and ITT2.
4.8.7
Data Monitoring Committee
An independent data monitoring committee will review safety data regularly and make 
recommendations regarding further study conduct.
4.8.8
Interim Analysis
No interim analyses are planned.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time even if no 
study treatment has been administered.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment
should be recorded as an AE or SAE.


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5.2
Definition of Serious Adverse Events
An SAE is any AE that:
!
Results in death
!
Is immediately life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
∀
Hospital admissions and/or surgical operations planned before or during a study are
not considered AEs if the illness or disease existed before the subject was enrolled in 
the study, provided that it did not deteriorate in an unexpected way during the study.
!
Results in persistent or significant disability/incapacity 
!
Is a congenital anomaly/birth defect in offspring of the subject
!
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
∀
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an ER or at home for allergic bronchospasm, blood dyscrasias, 
or convulsions that do not result in hospitalizations
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
investigator to MedImmune. An AESI may be serious or nonserious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
5.3.1
Hypersensitivity, Including Anaphylaxis
Administration of polyclonal immunoglobulin preparations and mAbs has been associated 
with immediate (type I) hypersensitivity (including anaphylaxis) that occurs during or after 
dosing. An immediate hypersensitivity reaction is defined as an acute onset of an illness with 
involvement of the skin, mucosal tissue, or both during administration of investigational 
product (but does not meet the definition of anaphylaxis). Anaphylaxis is a rare event, usually 
occurring after subsequent exposure to antigen, and it is most commonly accompanied by 
severe systemic skin and or mucosal reactions. It is potentially a fatal, systemic allergic 
reaction that is distinct from simple allergic reactions (eg, rash, pruritus) because of the 
simultaneous involvement of several organ systems (Sampson et al, 2006). A full definition of 
anaphylaxis is provided in Appendix B. See Section 5.5 for recording AEs.


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5.3.2
Immune Complex Disease
Immune complex disease can manifest in the form of a number of conditions such as 
vasculitis, endocarditis, neuritis, glomerulonephritis, serum sickness, and arthralgias. 
Drug-induced immune complex (type III) hypersensitivity reactions can occur when host 
immune system generates antibodies to drug resulting in soluble circulating antigen-antibody 
complexes formation and their deposition in blood vessels. Subsequently this initiates tissue 
damaging inflammatory reactions mediated by complement and/or leukocytes and mast cells. 
The pathology and clinical manifestations are dependent on the tissues/organs involved, with 
vascular, skin and renal tissues being common sites of injury. Common examples of immune 
complex hypersensitivity reactions are serum sickness (systemic) and Arthus reactions (local). 
The clinical manifestations of serum sickness include skin rash, fever, malaise, and 
polyarthralgias or polyarthritis. Symptoms typically develop 1 to 2 weeks after first exposure 
to antigen and usually resolve in several weeks after withdrawal of the causative agent. Serum 
sickness needs to be differentiated from other ‘serum-sickness-like’ reactions that have a 
similar clinical presentation (eg, viral infections, anti-seizure drugs), but are believed to have 
different pathogenic mechanisms. Both serum sickness and serum sickness-like reactions have 
been reported with mAbs (eg, rituximab, infliximab). Clinical presentation and time to onset 
should be taken into account for the diagnosis and differentiation of these reactions. Diagnosis 
of these suspected reactions is best confirmed via biopsy of the affected tissues. See 
Section 5.5 for recording AEs.
5.3.3
Thrombocytopenia
Thrombocytopenia is a disorder in which there is an abnormally low platelet count; a normal 
platelet count ranges from 150,000 to 450,000 platelets per μL. The 3 major causes of low 
platelet counts include: 1) insufficient platelet synthesis in the bone marrow; 2) increased 
breakdown of platelets in the bloodstream; and 3) increased breakdown of platelets in the 
spleen or liver. General symptoms of thrombocytopenia include bleeding in the mouth and 
gums, bruising, nosebleeds, and petechiae (pinpoint red spots/rash). Severe bleeding is the 
major complication, which may occur in the brain or gastrointestinal tract. Drug-induced 
thrombocytopenia is a reversible form of thrombocytopenia that should be suspected in a 
subject who presents with new onset thrombocytopenia or recurrent episodes of acute 
thrombocytopenia, without an obvious alternative etiology. It is commonly induced by 
drug-dependent antibodies that cause platelet destruction or clearance by the 
reticuloendothelial system (drug-induced immune thrombocytopenia), and less commonly by 
drug-induced bone marrow suppression or autoimmune thrombocytopenia that is initiated by 
exposure to the offending drug but persists in its absence. The initial approach to the subject 
with suspected drug-induced thrombocytopenia involves confirming thrombocytopenia, 
establishing a temporal relationship to a drug, and eliminating other causes of 
thrombocytopenia. The diagnosis is made clinically by documenting prompt resolution of 
thrombocytopenia after discontinuation of the suspected drug (typically within 1 week). Most 


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subjects with drug-induced thrombocytopenia require no specific treatment, as their platelet 
counts will recover promptly following withdrawal of the causative agent. See Section 5.5 for 
recording AEs.
5.4
Definition of New Onset Chronic Disease
An NOCD is a newly diagnosed medical condition that is of a chronic, ongoing nature. It is 
observed after receiving the investigational product and is assessed by the investigator as 
medically significant. Examples of NOCDs include, but are not limited to diabetes, 
autoimmune disease (eg, lupus, rheumatoid arthritis), and neurological disease (eg, epilepsy). 
Events that would not be considered as NOCDs are mild eczema, diagnosis of a congenital 
anomaly present at study entry, or acute illness (eg, upper respiratory infection, otitis media, 
bronchitis). See Section 5.5 for recording AEs.
5.5
Recording of Adverse Events
AEs, including SAEs, AESIs, and NOCDs, will be recorded on the eCRF using a recognized 
medical term or diagnosis that accurately reflects the event. These events will be assessed by 
the investigator for severity, relationship to the investigational product and study procedure(s), 
possible etiologies, and whether the event meets criteria of an SAE (see Sections 5.2 and 5.6), 
or is an AESI or NOCD (see Sections 5.3, 5.4, and 5.7) and therefore requires immediate 
notification to the sponsor. See Appendix A for guidelines for assessment of AE severity and 
relationship to investigational product. If an AE evolves into a condition that meets the 
definition of “serious,” it will be reported on the AE form in the eCRF as an SAE.
5.5.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from the time of signature of informed consent through 
Day 361. 
All AESIs and NOCDs will be collected from the time of dosing through Day 361.
5.5.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit are followed up by the investigator for 
as long as medically indicated but without further recording in the eCRF. MedImmune retains 
the right to request additional information for any subject with ongoing AE(s)/SAE(s) at the 
end of the study, if judged necessary.
5.5.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:
!
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy 


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of the post-mortem results should be forwarded to MedImmune representative(s) within 
the usual timeframes (refer to Section 5.6 for additional information).
5.6
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate sponsor study representative(s) within one day ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated sponsor study representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel must inform 
sponsor study representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
study representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor study representative by telephone. The sponsor study 
representative will advise the investigator/study site personnel how to proceed.
5.7
Other Events Requiring Immediate Reporting
5.7.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Investigator’s Brochure, unless otherwise specified in this protocol.
•
An overdose with associated AEs is recorded as the AE diagnosis on the relevant AE 
modules in the eCRF and on the overdose eCRF module.
•
An overdose associated with an SAE must be recorded as an SAE.
•
An overdose without associated symptoms is only reported on the overdose eCRF module.


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If an overdose on a MedImmune study drug occurs in the course of the study, then the 
investigator or other site personnel must inform appropriate sponsor study representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. The 
designated sponsor study representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site. For all overdoses, 
reporting to the data entry site must occur within 24 hours.
5.7.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for a MedImmune study drug that either causes harm to the subject or 
has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error: 
!
Occurred
!
Was identified and intercepted before the subject received the drug
!
Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject
!
Drug not administered as indicated, eg, wrong route or wrong site of administration
!
Drug not stored as instructed, eg, kept at room temperature when it should be in the 
refrigerator 
!
Wrong subject received the medication (excluding IWRS errors)
!
Wrong drug administered to subject (excluding IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IWRS - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
!
Accidental overdose (will be captured as an overdose)
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  


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If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate MedImmune representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated MedImmune representative works with the investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 5.6) and within 30 days for all other medication errors. 
Medication errors should be reported using a Medication Error Report Form.
5.7.3
Adverse Events of Special Interest
5.7.3.1
Hypersensitivity, Including Anaphylaxis
Events of immediate (type I) hypersensitivity, including anaphylaxis (as defined in 
Appendix B), require that the investigator or other site personnel inform appropriate sponsor 
study representatives immediately, or no later than 24 hours of when he or she becomes 
aware of the event. The designated sponsor study representative works with the investigator to 
ensure that all relevant information is provided and entered in EDC. If the event is considered 
serious it must be reported as an SAE (see Section 5.6).
Signs of immediate hypersensitivity include urticaria, pruritus, angioedema, skin rash, 
difficulty breathing, and wheezing. Parent(s)/legal representatives will be provided a card with 
this information to aid in prompt identification and reporting of these signs. Parent(s)/legal 
representatives will be instructed to immediately report the occurrence of any of these findings 
to the site investigator who should then report the events to appropriate sponsor study 
representatives immediately, or no later than 24 hours of when he or she becomes aware of 
the event.
5.7.3.2
Immune Complex Disease
Events of immune complex disease (as defined in Section 5.3.2) require that the investigator 
or other site personnel inform appropriate sponsor study representatives immediately, or no 
later than 24 hours of when he or she becomes aware of the event. The designated sponsor 
study representative works with the investigator to ensure that all relevant information is 
provided and entered into EDC. If the event is considered serious it must be reported as an 
SAE (see Section 5.6).
5.7.3.3
Thrombocytopenia
Events of thrombocytopenia (platelet count < 120,000 per μL) require that the investigator or 
other site personnel inform appropriate sponsor study representatives immediately, or no later 
than 24 hours of when he or she becomes aware of the event. The designated sponsor study 
representative works with the investigator to ensure that all relevant information is provided 
and entered into EDC. If the event is considered serious it must be reported as an SAE (see 
Section 5.6).


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5.7.4
New Onset Chronic Disease
If a case of NOCD occurs in the course of this study, the investigator or other site personnel 
must inform appropriate sponsor representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. The designated sponsor study representative works with 
the investigator to ensure that all relevant information is provided and entered into EDC. If the 
event is considered serious it must be reported as an SAE (see Section 5.6).
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review and 
discuss the requirements of the protocol and related documents with the investigational staff 
and also train them in any study-specific procedures and system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
!
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts)
!
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.


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6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment (including telephone contact).
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Sections 4.1.5 and 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study.
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff or other party
according to the Data Management Plan.
An EDC system will be used for data collection and query handling. The investigator will 
ensure that data are recorded in the eCRFs as specified in the study protocol and in accordance 
with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.


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6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The informed consent 
form will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that describes how subject data will be collected, used, and distributed 
in compliance with relevant data protection and privacy legislation.
7.2
Ethics and Regulatory Review
The IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the informed consent form and any other written information 
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising 
used to recruit subjects for the study. The investigator is responsible for submitting these 
documents to the applicable IRB/IEC, and distributing them to the study site staff.
The opinion of the IRB/IEC must be given in writing. The investigator must provide a copy of 
the written approval to MedImmune before enrollment of any subject into the study. 
MedImmune should approve any substantive modifications to the informed consent form that 
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.
Before the study is initiated, MedImmune will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. MedImmune 
will provide safety updates/reports according to local requirements, including suspected 


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unexpected serious adverse reactions where relevant, to regulatory authorities, IRB/IEC, and 
principal investigators.
Each Principal Investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product to the 
IRB/IEC. MedImmune will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
informed consent form for use by all investigators in the clinical study. MedImmune must 
approve any modifications to the informed consent form that are needed to meet local 
requirements.
The Principal Investigator(s) at each center will:
!
Ensure each subject’s legal guardian is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study
!
Ensure each subject’s legal guardian is notified that they are free to discontinue from the 
study at any time
!
Ensure that each subject’s legal guardian is given the opportunity to ask questions and 
allowed time to consider the information provided
!
Ensure each subject’s legal guardian provides signed and dated informed consent before 
conducting any procedure specifically for the study
!
Ensure the original, signed informed consent form(s) is/are stored in the Investigator’s 
Study File
!
Ensure a copy of the signed informed consent form is given to the subject’s legal guardian
!
Ensure that any incentives for subjects and/or their legal guardians who participate in the 
study as well as any provisions for subjects harmed as a consequence of study 
participation are described in the informed consent form that is approved by an IRB/IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the investigators and 
MedImmune. Any changes must be documented in a study protocol amendment. 
For a substantial change to the protocol, MedImmune will distribute amended versions of the 
protocol to the Principle Investigator(s). Before implementation, amended protocols must be 
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the informed consent form, 


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advertising, and any other written information and/or materials resulting from the change to 
the protocol.
Any non-substantial changes will be communicated to or approved by each IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site.
8
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Appendix A
Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an ER is not in itself a serious AE, although the reasons for it may be 
(eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations planned 
before or during a study are not considered AEs if the illness or disease existed before the 
subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:
!
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an ER or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below.


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Grade 1
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living.
Grade 2
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death.
Grade 5
Death as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
A guide to Interpreting the Causality Question
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product.
!
Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?
!
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties? 
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?


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


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


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5290c00004-csp-version-2
Document Title:
D5290C00004 Clinical Study Protocol Version 2
Document ID:
Doc ID-003711908
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
02-Feb-2021 01:11 UTC
Author Approval
01-Feb-2021 17:40 UTC
Content Approval
01-Feb-2021 20:28 UTC
Content Approval
02-Feb-2021 00:03 UTC
Content Approval
01-Feb-2021 20:51 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
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Statistical Analysis Plan
A Phase 3 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and 
Efficacy of MEDI8897, a Monoclonal Antibody With an Extended Half-life Against 
Respiratory Syncytial Virus, in Healthy Late Preterm and Term Infants (MELODY)
Protocol Number: D5290C00004


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TABLE OF CONTENTS
1
INTRODUCTION.............................................................................................. 5
2
STUDY OVERVIEW......................................................................................... 6
2.1
Study Objectives.................................................................................................6
2.1.1
Primary Study Objective..................................................................................... 6
2.1.2
Secondary Study Objectives................................................................................ 6
2.1.3
Exploratory Study Objectives ............................................................................. 6
2.2
Study Design ...................................................................................................... 6
2.3
Treatment Assignment and Blinding ................................................................... 7
2.3.1
Methods for Assigning Treatment Groups........................................................... 7
2.3.2
Methods to Ensure Blinding................................................................................ 8
2.3.3
Methods for Unblinding...................................................................................... 8
2.3.3.1
Unblinding in the Event of a Medical Emergency ............................................... 8
2.4
Sample Size........................................................................................................ 9
3
STATISTICAL METHODS ............................................................................. 10
3.1
General Considerations..................................................................................... 10
3.2
Study Cohorts, Analysis Populations, and Datasets........................................... 12
3.3
Stratification Factors......................................................................................... 13
3.4
Study Subjects .................................................................................................. 14
3.4.1
Subject Disposition and Completion Status....................................................... 14
3.4.2
Demographics and Baseline Characteristics ...................................................... 14
3.4.3
Study Drug Exposure........................................................................................ 15
3.4.4
Violations and Deviations................................................................................. 15
3.5
Efficacy Analyses............................................................................................. 16
3.5.1
Primary Efficacy Endpoint and Analyses .......................................................... 16
3.5.1.1
Primary Efficacy Endpoint................................................................................ 16
3.5.1.2
Primary Efficacy Analysis ................................................................................ 17
3.5.1.3
Secondary Analyses of the Primary Efficacy Endpoint...................................... 19
3.5.1.4
Supplementary Analyses of the Primary Efficacy Endpoint............................... 19
3.5.1.5
Analyses for Medically Attended RSV LRTI Beyond the Primary Endpoint ..... 23
3.5.2
Secondary Efficacy Endpoint and Analyses ...................................................... 24
3.5.2.1
Secondary Efficacy Endpoint............................................................................ 24
3.5.2.2
Secondary Efficacy Analyses............................................................................ 24
3.5.2.3
Supplementary Analyses of the Secondary Efficacy Endpoint........................... 26
3.5.3
Other Efficacy Analyses ................................................................................... 27
3.5.4
Additional Efficacy Analyses for the Safety Cohort .......................................... 30
3.5.4.1
Analyses of Incidence of Medically Attended RSV LRTI ................................. 30
3.5.4.2
Analyses of Incidence of RSV LRTI Hospitalization ........................................ 30
3.5.4.3
Other Efficacy Analyses ................................................................................... 31
3.6
Exploratory Analyses........................................................................................ 32
3.6.1
Healthcare Resource Utilization (HRU) ............................................................ 32
3.6.2
Caregiver Burden.............................................................................................. 34


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3.6.3
Anti-RSV Neutralizing Antibody...................................................................... 34
3.6.4
RSV serology ................................................................................................... 35
3.6.5
RSV resistance monitoring ............................................................................... 35
3.6.6
Incidence of Medically Attended LRTI Due to RT-PCR-confirmed RSV After 
Day 151 (Between Day 152 and Day 361) ........................................................ 36
3.7
Safety Analyses ................................................................................................ 36
3.7.1
Adverse Events and Serious Adverse Events..................................................... 36
3.7.2
Adverse Events of Special Interest.................................................................... 37
3.7.3
Skin and Hypersensitivity Reactions................................................................. 37
3.7.4
New Onset Chronic Disease.............................................................................. 37
3.7.5
Subgroup Analyses ........................................................................................... 37
3.7.6
Clinical Laboratory Parameters......................................................................... 37
3.7.7
Other Safety Evaluations .................................................................................. 38
3.8
Anti-drug Antibodies ........................................................................................ 39
3.9
Pharmacokinetics.............................................................................................. 40
3.10
Impact on Analyses due to COVID-19 Pandemic.............................................. 40
3.10.1
Sensitivity Analyses.......................................................................................... 40
4
REFERENCES................................................................................................. 41
5
VERSION HISTORY....................................................................................... 43
LIST OF IN-TEXT TABLES
Table 1
Analysis Populations ............................................................................... 12
Table 2
Definition for New Onset of Events......................................................... 29
LIST OF APPENDICES
Appendix 1
Elements to Evaluate for Case Definition of Medically Attended RSV 
LRTI (Protocol defined) .......................................................................... 48
Appendix 2
Analysis Window for ADA/RSV Neutralizing Antibody/RSV Serology.. 49
Appendix 3
Analysis Window for Clinical Lab Data................................................... 50
Appendix 4
Imputation Rule for Partial Dates............................................................. 51


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
AAP
American Academy of Pediatrics
ADA
Anti-drug antibody (ies)
AE(s)
adverse event(s)
AESI
adverse event of special interest
CE
Conformité Européenne or European Conformity
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPAP
Continuous Positive Airway Pressure 
CSR
Clinical Study Report 
DBL
database lock
DOB
date of birth
eCRF
electronic case report form
ED
emergency department
EU
European Union
GA
gestational age
HRU
healthcare resource utilization
ICU
intensive care unit
IDMC
independent data monitoring committee
IM
intramuscular
IP
Investigational Product
ITT
intent-to-treat
IWRS
interactive web response system
LRTI
lower respiratory tract infection
MedDRA
Medical Dictionary for Regulatory Activities
NH
Northern Hemisphere
OTC
over-the-counter
PK
pharmacokinetic(s)
PT
Preferred Term
RR
relative risk
RRR
relative risk reduction
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction


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Abbreviation or 
Specialized Term
Definition
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SH
Southern Hemisphere
SID
subject identification
SOC
System Organ Class
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
US FDA
United States Food and Drug Administration
USA
United States of America
1
INTRODUCTION
This document describes the statistical analysis plan (SAP) for protocol D5290C00004, a
pivotal Phase 3 study to determine if MEDI8897 is safe and efficacious in reducing medically 
attended respiratory syncytial virus (RSV)-confirmed lower respiratory tract infection (LRTI)
in healthy late preterm and term infants entering their first RSV season. The primary efficacy 
hypothesis of this study is that, compared to placebo, a single intramuscular (IM) MEDI8897 
dose, 50 mg if weight < 5 kg or 100 mg if weight ≥ 5 kg, will be efficacious in reducing
medically attended LRTI caused by real-time reverse transcriptase-polymerase chain reaction 
(RT-PCR)-confirmed RSV in healthy late preterm and term infants born ≥ 35 weeks 0 days 
gestational age (GA) and entering their first RSV season, and the safety profile will be 
acceptable. The secondary hypotheses are that (1) there will be a reduction in the incidence of 
hospitalizations attributable to RT-PCR confirmed RSV, (2) the predicted serum exposure will 
be adequate for the duration of the RSV season, and (3) anti-drug antibodies (ADA) to 
MEDI8897 will not significantly impact the serum concentrations or safety of MEDI8897 
through 150 days post dosing (i.e. over the 5-month RSV season). These hypotheses will be 
assessed by the incidence of RSV LRTI, RSV hospitalization, ADA, pharmacokinetic (PK) 
data, and descriptive statistics from safety data. This document details the statistical 
summaries relating to each study objective and describes the general conventions and 
definitions that will be used.
In addition, a set of table templates and specifications is planned to be created in a statistical 
programming plan to complement this document.


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2
STUDY OVERVIEW
2.1
Study Objectives
2.1.1
Primary Study Objective
To assess the efficacy of MEDI8897 when administered as a single fixed IM dose to infants ≥ 
35 weeks 0 days GA and entering their first RSV season, in reducing medically attended LRTI 
due to RT-PCR-confirmed RSV, compared to placebo.
2.1.2
Secondary Study Objectives
1
To assess the efficacy of MEDI8897 for the reduction of hospitalizations due to RT-PCR-
confirmed RSV, compared to placebo
2
To evaluate the safety and tolerability of MEDI8897 when administered as a single fixed 
IM dose, compared to placebo
3
To evaluate single-dose serum concentrations of MEDI8897
4
To evaluate ADA responses to MEDI8897 in serum
2.1.3
Exploratory Study Objectives
1
To assess healthcare resource utilization (HRU) and caregiver burden for MEDI8897 
recipients compared with placebo recipients.
2
To determine anti-RSV neutralizing antibody levels in serum afforded by a single dose of 
MEDI8897 compared to maternal RSV neutralizing antibody levels and those elicited 
following infection in the placebo group
3
To evaluate exposure to RSV by measuring seroresponses to different RSV proteins
4
To characterize resistance to MEDI8897 through genotypic and phenotypic analyses
5
To assess the incidence of medically attended LRTI due to RT-PCR-confirmed RSV, 
compared to placebo after Day 151 (between Day 152 and Day 361)
2.2
Study Design
The population to be enrolled is healthy late preterm and term infants born ≥ 35 weeks 0 days 
GA who would not receive RSV prophylaxis based on the AAP or other local or national 
guidelines. These infants will not be receiving palivizumab, allowing for a placebo 
comparator group for the determination of efficacy and the safety profile. A total of 
approximately 3,000 infants will be randomized in a 2:1 ratio to receive a single 50-mg (if < 5 
kg weight at the time of dosing) or 100-mg (if ≥ 5 kg weight at the time of dosing) IM dose of 
MEDI8897 (N = 2,000) or placebo (N = 1,000). Randomization will be stratified by temperate 
zones in the northern and southern hemisphere and by subject age group at randomization
(ie, ≤3.0 months, > 3.0 to ≤6.0 months, > 6.0 months). Enrollment of infants > 6.0 months of 


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age will be limited to approximately 500. All infants will be followed for approximately 510
days after dosing. 
The study will comprise 2 cohorts: a primary cohort (N = ~ 1,500) and a safety cohort 
(N = ~1,500) for a total of ~ 3000 subjects. The primary cohort will include subjects enrolled 
from the NH2019, SH2020, and NH2020 enrolment seasons (enrolment was paused after one 
subject from NH2020 was enrolled due to the impact of the coronavirus disease 2019
[COVID-19] pandemic). The safety cohort will include subjects enrolled after NH2020 
enrollment season. Given the largely reduced circulation of RSV due to COVID-19-related 
measures, the efficacy analyses performed in the primary analysis for the primary cohort will 
serve the purpose of evaluating the efficacy of MEDI8897 in the study population. Although 
efficacy data will also be collected for the safety cohort, only descriptive summaries will be 
provided and there is no intent to pool the efficacy data from safety cohort with that from the 
primary cohort. Both the primary and the safety cohorts, individually and combined, will 
serve the purpose of evaluating the safety of MEDI8897. All subjects will be followed for 
approximately 510 days after dosing. An independent data monitoring committee will review 
safety data regularly and make recommendations regarding further study conduct.
2.3
Treatment Assignment and Blinding
2.3.1
Methods for Assigning Treatment Groups
An interactive web response system (IWRS) will be used for randomization to a treatment 
group and assignment of blinded investigational product kit numbers. A subject is considered 
randomized into the study when the investigator notifies the IWRS that the subject meets
eligibility criteria and the IWRS provides the assignment of blinded investigational product kit 
numbers to the subject.
Subjects will be randomized at a 2:1 ratio to receive a single fixed IM dose of MEDI8897 
(N = 2,000) or placebo (N = 1000). Randomization will be stratified by temperate zones in the 
northern and southern hemisphere and by subject age group at randomization 
(ie, ≤3.0 months, > 3.0 to ≤ 6.0 months, > 6.0 months). Enrollment of infants > 6.0 months of 
age will be limited to approximately 500.
The procedure for using IWRS is as follows:
•
The investigator or designee contacts the IWRS and provides the subject identification 
(SID) number and subject’s baseline characteristic(s) used to verify that it is the same 
subject
•
Placebo (provided by site) or a vial from a MEDI8897 kit will be assigned to the subject
•
Confirmation of this information is sent to the unblinded investigational product manager 
who prepares the investigational product to be dispensed to the subject per the response 


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system and records the appropriate information in the investigational product 
accountability log
Investigational product (MEDI8897 or placebo) must be administered the same day the 
investigational product is assigned. Total in-use storage time from needle puncture of the 
investigational product vial to administration should not exceed 4 hours at room temperature. 
If storage time exceeds these limits, a new vial should be used. If there is a delay in the 
administration of investigational product such that it will not be administered within the 
specified time frame, the unblinded investigational product monitor must be notified 
immediately.
2.3.2
Methods to Ensure Blinding
This is a double-blind study in which sites are using commercially available saline as the 
placebo. MEDI8897 and placebo are visually indistinguishable once in syringes. Neither the 
subject/legal representative nor the investigator or any of the site staff who are involved in the 
treatment or clinical evaluation of the subjects will be aware of the treatment received 
(ICH E9). In the event that treatment allocation for a subject becomes known to the 
investigator or other blinded study staff involved in the management of study subjects, the 
sponsor must be notified immediately. If the treatment allocation for a subject needs to be 
known to treat an individual subject for an AE, the investigator must notify the sponsor 
immediately. The site will maintain a written plan detailing which staff members are 
blinded/unblinded and the process of investigational product administration used to maintain 
the blind.
Details of maintaining the double-blind setting until database lock for the primary and safety 
analyses are provided in Section 3.1.
2.3.3
Methods for Unblinding
2.3.3.1
Unblinding in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IWRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In the majority of cases, the management of a 
medical emergency would be the same whether or not investigational product was received by 
the subject. If this was the case, the investigational product allocation should not be unblinded.
MedImmune retains the right to unblind the treatment allocation for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities.


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Site personnel and parents/guardians of the subjects will remain blinded to the treatment 
assignment until the end of the study.
2.4
Sample Size
This Phase 3 study will enroll approximately 3,000 subjects of whom 2,000 will receive 
MEDI8897 and 1,000 will receive placebo. The proposed sample size is to ensure a sufficient 
expected safety database at the time of marketing application submission. The 2,000 subjects 
to be dosed with MEDI8897 in this Phase 3 study, together with the 968 subjects dosed with 
MEDI8897 in the Phase 2b study (D5290C00003) and at least 600 subjects to be dosed with 
MEDI8897 in the palivizumab-controlled Phase 2/3 study (D5290C00005), will contribute to
a safety database of at least approximately 3,600 infants exposed to MEDI8897. 
For this Phase 3 study, the original sample size of 3,000 was driven by the safety database 
requirement, and the study had at least 99% power for the primary efficacy endpoint.
Reducing the sample size to 1,500 still allows the study to be sufficiently powered. More 
specifically, the sample size of approximately 1,500 subjects in the primary cohort has at 
least 99% power to detect 70% relative risk reduction (RRR), assuming a placebo group 
medically attended RSV LRTI incidence of 8%. Power calculations are based on a Poisson 
regression model with robust variance (Zou, 2004) comparing MEDI8897 versus placebo, 
with 2-sided, α = 0.05.
•
The assumption of 8% incidence is supported both by literature (Paramore et al, 2010) and 
the observed placebo incidence rate 
 in the Phase 2b Study D5290C00003.
•
The 70% RRR assumption is based on the Phase 2b Study D5290C00003 in which there 
was 70% RRR in the incidence of medically attended RSV LRTI (9.5% placebo, 
2.6% MEDI8897; p < 0.001) and 
RRR in the incidence of RSV hospitalization 
(4.1% placebo, 0.8% MEDI8897; p < 0.001) in subjects who received MEDI8897 
prophylaxis. In addition, the assumption is supported by a placebo-controlled study in 
Native American term infants in which there was a
 
 
in infants who received motavizumab prophylaxis (O'Brien et al, 
2015O'BrienO'BrienO'BrienO'BrienO'Brien).
•
In the event that the incidence rate in the placebo group drops due to the impact of the 
COVID-19 pandemic (eg, social distancing), the sample size still provides at least 90% 
power to detect 70% RRR if the placebo incidence rate is 4% or higher.
To evaluate risk, a sample size of 2,000 subjects exposed to MEDI8897 will provide a 
> 99% probability of observing at least one AE if the true event rate is 0.3%; if no AEs are 
observed, this study provides 98% confidence that the true event rate is < 0.2%.


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3
STATISTICAL METHODS
3.1
General Considerations
There are three planned analyses for this study: the Primary Analysis, Safety Analysis, and 
Final Analysis. The Primary Analysis will be conducted after all randomized subjects (except 
for the one subject enrolled in the NH2020 season) from the primary cohort have been 
followed through Day 361. The subjects enrolled in the NH2020 season will have completed 
the Day 151 visit. The efficacy of MEDI8897 will be evaluated in the Primary Analysis as 
intended by the study design. For the Primary Analysis, all efficacy, PK, ADA, and safety 
data collected for the primary cohort through Day 361 will be analyzed and unless specified 
otherwise, data collected after Day 361 will only be listed. The Safety Analysis will be 
conducted when all subjects for the safety cohort have been followed through Day 151. For 
the Safety Analysis, in addition to the analyses conducted during the Primary Analysis based 
on the primary cohort, summaries based on data collected for the primary cohort after Day 
361 will be generated; all available efficacy, PK, ADA, RSV neutralizing antibody, RSV 
serology, and safety data collected for the safety cohort will be analyzed (only descriptive 
summaries will be provided for the efficacy data collected for the safety cohort); unless 
specified otherwise, data collected for the safety cohort after Day 361 will only be listed. The 
Final Analysis will be conducted when all subjects have completed the last visit of the study 
(Day 511) and include all data and planned analyses (including applicable summaries based 
on data collected for the safety cohort after Day 361). Given the largely reduced circulation of 
RSV due to COVID-19-related measures, the efficacy analyses performed in the primary 
analysis for the primary cohort will serve the purpose of evaluating the efficacy of MEDI8897 
in the study population. Although efficacy data will also be collected for the safety cohort, 
only descriptive summaries will be provided and there is no intent to pool the efficacy data 
from safety cohort with that from the primary cohort. Both the primary and the safety cohorts, 
individually and combined, will serve the purpose of evaluating the safety of MEDI8897.
The study will maintain a double-blind setting (ie, blind for subjects, Investigators/site staff, 
and Sponsor/designated clinical research organization) until database lock (DBL) for the 
primary and safety analyses. More specifically, at the time of the Primary Analysis (where the 
analyses will be based only on the primary cohort), the data from the primary cohort will be 
unblinded to Sponsor/designated clinical research organization associated with the analysis, 
write-up, and regulatory submission. To maintain the double-blind setting for the safety cohort 
until the Safety Analysis, any data with potential unblinding risk will be split by primary 
cohort and safety cohort by the corresponding third party data vendors and when the primary 
DBL occurs, only unblinding data from the primary cohort will be transferred to the Sponsor 
for analysis. The unblinding data from the safety cohort will not be transferred to the Sponsor 
until the DBL for Safety Analysis. The site personnel, participants, and the study team 
members who participate in the advice or decisions involving study subjects and/or day-to-day 
interactions with the site, will remain blinded until the end of the study (ie, all subjects have 


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completed Day 511 visit) to ensure the study integrity is maintained. Further details will be 
specified in the unblinding plan prior to unblinding of the primary cohort data. 
For the visit-based summaries for ADA, RSV neutralizing antibody, RSV serology and 
clinical laboratory data, the summaries will be based on the scheduled days with adjusted 
analysis-defined visit windows. The adjusted analysis-defined windows will be based on the 
collection schedule listed in the protocol and summaries will be windowed to the closest 
scheduled visit for those data. Visit windows have been constructed so that every observation 
collected can be allocated to a particular visit. However, all data will be included in the 
listings. If multiple readings are recorded within a single analysis-defined visit window, the 
following rules will apply:
!
If there are 2 or more valid, non-missing observations within the same visit window, and
-
if they are on different days, then the non-missing one which is closest to the 
scheduled visit day will be used in the analysis. 
-
if they are on the same day which is closest to the scheduled visit day, then the non-
missing one with the later collection time will be used in the analysis. 
!
If 2 or more valid observations are equidistant from the scheduled visit, and 
-
if they are on different days, then the non-missing post-dose observation with the 
earlier collection date will be used in the analysis for the post-baseline observations, 
and the non-missing pre-dose observation with the later collection date will be used in 
the analysis for the screening observations.
-
if they are on the same day, then the non-missing observation with the later collection 
time will be used in the analysis.
!
For LRTI visits or unscheduled visits, if 2 or more valid observations are collected on the 
same day, then the non-missing observation with the later collection time will be included 
in the analysis.  
!
If a visit window does not contain any observations, then the data will remain missing.
!
For the visit-based summaries for ADA, if both ADA positive and negative samples are 
available within a subject’s visit, ADA positive will be reported. 
For assignment of data to adjusted analysis-defined visit windows, study day will be defined 
as:
•
Screening period: Study day = Date of assessment – date of randomization
•
After randomization: Study day = Date of assessment – date of randomization + 1
The adjusted analysis-defined windows for ADA, RSV neutralizing antibody, RSV serology 
are defined in Appendix 2, and for clinical laboratory data are defined in Appendix 3.


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The partial dates imputation are described in Appendix 4.
Summary statistics will be tabulated by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by mean, median, standard deviation, minimum, and maximum. In general, 
unless stated otherwise, baseline will be defined as the last non-missing value prior to dosing.
Data analyses will be conducted using the SAS® System Version 9.4 or higher (SAS Institute 
Inc., Cary, NC).
3.2
Study Cohorts, Analysis Populations, and Datasets
There are two study cohorts, primary cohort and safety cohort. 
!
Primary cohort includes all subjects enrolled in the NH2019, SH2020, and NH2020 
enrollment seasons.
!
Safety cohort includes subjects enrolled after the NH2020 enrollment season.
The primary cohort will serve the purpose of evaluating the efficacy of MEDI8897. Both the 
primary and the safety cohorts, individually and combined, will serve the purpose of 
evaluating the safety of MEDI8897.
The analysis populations are defined in Table 1.
Table 1
Analysis Populations
Population
Description
Intent-to-treat (ITT) population
Subjects who are randomized will be included in the ITT population; 
in this population data will be analyzed according to their randomized
treatment group.
Intent-to-treat population 1 (ITT1)
Subjects in the ITT population and from the primary cohort. 
Intent-to-treat population 2 (ITT2)
Subjects in the ITT population and from the safety cohort. 
As-treated population
Subjects who are randomized and receive any investigational product 
will be included in the as-treated population; in this population, data 
will be analyzed according to the treatment they actually receive.
As-treated population 1 (AT1)
Subjects in the as-treated population and from the primary cohort.
As-treated population 2 (AT2)
Subjects in the as-treated population and from the safety cohort. 
Per-protocol population
The per-protocol population includes subjects in the ITT1 population 
who receive the correct dose of randomized treatment and who do not 
have a serious protocol deviation. Detailed criteria defining this 
population will be determined and documented prior to performing the 
Primary Analysis. 
Analysis Datasets  


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•
The Primary Dataset contains all efficacy, safety, ADA, and PK data from all randomized 
subjects from the primary cohort through Day 361, except for the one subject enrolled in 
the NH2020 enrollment season, for whom the data will be through at least Day 151. The 
Primary Analysis will be performed on the Primary Dataset.
•
The Safety Dataset contains all data (efficacy, safety, ADA, PK, RSV serology and RSV 
neutralizing antibody) from all randomized subjects from the primary cohort, including 
data in the Primary Dataset and data from the subjects who were ongoing at the time when 
the Primary Dataset was locked. The Safety Dataset also contains subjects from the safety 
cohort that have been followed through Day 151, and all available data as of the data 
cutoff date. The Safety Analysis will be performed on the Safety Dataset.  
•
The Final Dataset contains all data collected in this study, including data in the Primary 
Dataset, Safety Dataset and data from the subjects who were ongoing at the time when the 
Primary Dataset and Safety Dataset were locked. The Final Analysis will be performed on 
the Final Dataset.
3.3
Stratification Factors
Two stratification factors are used in study design as well as in data analysis, and these are: 
age group at randomization (age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0 months) 
and hemisphere (northern hemisphere, southern hemisphere). For subjects who were assigned 
to an incorrect age stratum at randomization, the age stratum as calculated from the electronic 
case report form (eCRF) will differ from the stratum recorded for the subject in the IWRS
database. Unless stated otherwise, the age stratum based on the CRF calculation will be used.
CRF calculation for age when full date of birth (DOB) is available: 
•
Age at randomization (months) = (randomization date – DOB) / (365.25/12)
When full DOB is unavailable, age at screening will be used. Since screening may be 
collected in terms of days, weeks, or months, it will be first converted in terms of months as 
follows: 
•
Age at screening (days) / (365.25/12) = Age at screening (months)
•
Age at screening (weeks) / (52/12) = Age at screening (months)
Once age at screening is converted to months, 
•
Age at randomization (months) = Age at screening (months) + [(randomization date –
screening date) / (365.25/12)]
Determination of hemisphere in stratification and analysis is as follows: The sites have been 
grouped together by country into the following two hemispheres: Northern Hemisphere 


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(Austria, Belgium, Bulgaria, Canada, Czech Republic, Estonia, Finland, France, Germany, 
Hungary, Israel, Italy, Japan, Latvia, Lithuania, Mexico, Poland, Republic of Korea, Russia, 
Spain, Sweden, Turkey, Ukraine, United Kingdom, and United States of America [USA]) and 
Southern Hemisphere (Argentina, Australia, Brazil, Chile, Colombia, New Zealand, Panama, 
and South Africa).
3.4
Study Subjects
3.4.1
Subject Disposition and Completion Status
A summary of subject eligibility and randomization as well as treatment received (including 
summary of subjects randomized but not treated) will be provided for each cohort. In addition, 
disposition of subjects throughout the study and by milestone visit (ie, Day 151, Day 361) will 
be provided for all screened subjects, screened subjects from the primary cohort, and screened 
subjects from the safety cohort. These summaries will be presented by treatment group and for 
all subjects combined. The denominators for these summaries will include all subjects who 
were randomized into the study or in the corresponding cohorts unless specified otherwise.
3.4.2
Demographics and Baseline Characteristics
Enrolment will be summarized by hemisphere, country, site, and by hemisphere, country, and 
age at randomization stratum for each treatment group and for all subjects combined. The total 
number of subjects randomized into each treatment group will be used as the denominator. For 
the summary of hemisphere, country, and age at randomization stratum, the number of mis-
stratified subjects (ie, age stratum as calculated from the eCRF does not match the IWRS
database) will be summarized. These summaries will be provided overall and by cohort.
Demographic information related to gender, age at randomization stratum (months) calculated 
from the CRF, age at randomization stratum determined using the CRF age calculation 
(age ≤3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0 months), age at randomization 
category (age < 9.0 months, age ≥9.0 months), GA (weeks), ethnicity, race, weight (kg) on 
Day 1, weight on Day 1 category (weight < 5 kg, weight ≥ 5 kg), birth weight (kg), birth 
weight category (weight ≤ 2.5 kg, weight > 2.5 kg), multiple birth (yes/no), siblings enrolled 
in the study (yes/no), ever breastfed (yes/no), currently breastfed (yes/no), smoking in the 
household (yes/no), currently in daycare (yes/no), Down syndrome (yes/no), and cystic 
fibrosis (yes/no) will be summarized by treatment group and for all subjects combined using 
the overall ITT population, ITT1 and ITT2. Subjects will be excluded from the summary (eg, 
means and percentages) of an individual parameter if data are missing. This will be done for 
all subjects, each age at randomization stratum, and by hemisphere.
In addition, family history of atopy (including asthma, hay fever, eczema, wheezing) will be 
summarized for each treatment group and for all subjects combined overall and by cohort.


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3.4.3
Study Drug Exposure
Due to the simplicity of dosing for this study, exposure is summarized in the Subject 
Disposition and Completion Status table under “Randomized and dosed.” No other summary 
will be reported.
3.4.4
Violations and Deviations
Important protocol deviations are a subset of protocol deviations that may significantly impact 
the completeness, accuracy, and/or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being.
The final list of important protocol deviations will be documented prior to unblinding the 
study data, and will include but may not be limited to:
!
Subjects who did not meet inclusion criteria or met exclusion criteria according to protocol 
but were enrolled in the study, except for one violation of the exclusion criterion that 
children of employees of the sponsors, clinical study site, or any other individuals 
involved with the conduct of the study, or immediate family members of such individuals 
will not be considered as an important protocol deviation. 
!
Subjects who reported investigational product (IP) compliance-related deviations. This can 
be further categorized into IP administration, IP assignment-, and/or IP handling-related 
deviations. 
-
IP administration-related deviations include but are not limited to:  
-
Subjects receive incorrect dose, including subjects do not receive full 
planned dose or are not treated; 
-
Subjects receive IP despite withdrawal of consent or not meeting eligibility 
prior to IP dosing; 
-
Subject was administered IP but was not observed for at least 1 hour post 
dose
-
IP assignment-related deviations include but are not limited to:  
-
Inappropriate use of study IP (e.g. giving IP to non-study subjects);
-
Kit dispensed without IWRS transaction
-
Subjects who reported the following IP handling-related deviations: 
-
Dispensing of IP that has had an unapproved temperature excursion or is 
not suitable for use upon inspection for whatever reason to a subject;
-
IP was administered to the subject after 4 hours post preparation. 
!
Subjects who had no central RT-PCR nasal samples collected at any of the LRTI visits.
!
Subjects who received approved or investigational product for RSV prophylaxis prior to 
Day 151.


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!
Subjects who reported safety-related deviations:
-
Severe violation in safety follow-up for subject;
-
Serious adverse event not reported in eCRF.
Only important protocol deviations will be tabulated in the clinical study report (CSR). The 
important protocol deviations will be reviewed and documented by the medical advisors and 
statisticians prior to the DBL.
Protocol deviations associated with the COVID-19 pandemic will also be summarized and 
listed separately (see Section 3.10). 
In addition, the per-protocol population includes subjects in the ITT1 population who receive 
the correct dose of randomized treatment and who do not have a serious protocol deviation. 
The final list of serious protocol deviations will be documented in a separate file reviewed by 
medical monitor prior to unblinding the study data.
3.5
Efficacy Analyses
The analyses of the primary efficacy endpoint, the protocol-defined medically attended RSV 
LRTI (also described as the medically attended RSV LRTI) through 150 days post dose, and 
the secondary efficacy endpoint, the protocol-defined RSV hospitalization (also described as 
the RSV LRTI hospitalization) through 150 days post dose, will be performed on the Primary 
Dataset.  
Efficacy analyses performed on the Primary Dataset will be refreshed in the primary cohort 
data in Safety Dataset and Final Dataset to make sure statistical inferences on MEDI8897 
efficacy made from the Primary Analysis are consistent with those from the Safety and Final 
Analyses. Although efficacy data will also be collected for the safety cohort, only descriptive 
summaries will be provided and there is no intent to pool the efficacy data from safety cohort 
with that from the primary cohort.
3.5.1
Primary Efficacy Endpoint and Analyses
3.5.1.1
Primary Efficacy Endpoint
The primary endpoint is the incidence of medically attended RSV LRTI (inpatient and 
outpatient) through 150 days post dose. For subjects with multiple medically attended RSV 
LRTI events (inpatient or outpatient), only the first occurrence will be used in the primary 
analysis.
The determination of medically attended RSV LRTI will be based on objective clinical LRTI 
criteria (described in the Protocol Section 4.3.1.1 and SAP Appendix 1) and RSV test results 
obtained from analyzing the respiratory secretions using a validated RSV RT-PCR assay for 


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the detection of RSV A or RSV B performed in a central laboratory. These LRTI events may 
occur in the inpatient or outpatient visit setting. 
Prior to DBL for the Primary Analysis, a blinded review of data will be undertaken to 
determine an analysis window such that all positive results will be counted as a medically 
attended RSV LRTI if they occurred in a respiratory sample collected within -7 to 14 days
relative to the initial date seen by the healthcare provider (eg, admission/deterioration date 
associated with the event, urgent care visit, outpatient emergency department [ED] visit, or 
outpatient clinic visit). The actual window used will be documented prior to unblinding. In 
addition, deaths that can be demonstrated as caused by RSV (by autopsy or clinical history 
and virologic evidence) will also be considered as primary medically attended RSV LRTI 
events.
3.5.1.2
Primary Efficacy Analysis
The primary efficacy analysis of the primary endpoint will be performed on ITT1. A Poisson 
regression model with robust variance (Zou, 2004) will be used as the primary efficacy 
analysis model to estimate the relative risk (RR) on the incidence of medically attended RSV 
LRTI between the MEDI8897 and the placebo groups. The full model contains the term of 
treatment group and age group at randomization based on the calculation detailed in Section 
3.3. (ie, age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0 months) and dichotomous 
temperate (northern and southern) hemispheres as covariates. The RRR, defined as 1 - RR, 
and its corresponding 2-sided 95% CI, will be estimated from the model. In addition, the 2-
sided p-value testing null hypothesis that the incidence of medically attended RSV LRTI 
between MEDI8897 and placebo groups are the same will be obtained from the model. 
Statistical significance will be achieved if the 2-sided p-value is ≤0.05.
During blinded data review prior to the DBL for Primary Analysis, it was revealed that there 
was no incidence of medically attended RSV LRTI events through 150 days post dose for SH
in primary cohort, which would cause known convergence or estimation issue. Therefore it 
was decided to drop the stratification factor hemisphere from the full model and a reduced 
model (including the term of treatment group and age at randomization stratum as covariate)
will be used instead. Similar consideration also applies to other analyses for primary efficacy 
endpoint, where hemisphere will be dropped from the corresponding models.
The Poisson regression with robust variance analysis will be implemented by using the SAS 
PROC GENMOD procedure with the REPEATED statement for subject ID and logarithm 
link. The estimated parameter  [ie, log(
 )], 2-sided 95% confidence interval (CI) for , and 
the 2-sided p-value will be obtained from the SAS outputs. The estimated RR and 
corresponding CI for the RR is given by exponentiating  and its confidence limits. Therefore, 
the percent of RRR is given by [(1 – exp()) * 100%]. The CI for the percent of RRR is given 


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by ([1 – exp(upper confidence limit for ) * 100%], [1 – exp(lower confidence limit for ) * 
100%]). 
If the number of subjects in any stratum is too small and/or convergence cannot be achieved
with the Poisson regression analysis model, the stratified Cochran-Mantel-Haenszel (CMH) 
test (detailed in Section 3.5.1.3) will be used as the primary analysis model to test the 
treatment effect on medically attended RSV LRTI between MEDI8897 and placebo groups.  
The above described analysis on the primary efficacy endpoint will also be conducted on the 
Per-protocol population. 
Handling of Dropouts and Missing Data
Medically attended RSV LRTI that occurs through 150 days post dose will contribute to the 
primary efficacy analysis. For subjects who do not have a medically attended RSV LRTI and 
are not followed through 150 days post dose, their event status will be imputed assuming the 
observed placebo medically attended RSV LRTI rate conditional on stratification factor (age 
at randomization stratum) using multiple imputation techniques as described in the following 
paragraphs.
The primary analysis uses Poisson regression with robust variance requires a subject-level 
dataset. A repeated imputation approach is introduced to impute medically attended RSV 
LRTI status for missing observations at the subject-level for the model fitting. By 
incorporating the between-imputation variance, a reliable statistical inference in both 
hypothesis testing and CI estimation of the treatment effect is expected through the repeated 
imputation (Little and Rubin, 2002). In the primary analysis the missing outcome for subjects 
who drop out (eg, withdrawal by parent/legal representative, lost to follow-up, death not 
caused by RSV, etc) prior to reaching Day 150 post dose without a medically attended RSV 
LRTI event will be imputed per stratum determined by the stratification factor (age at 
randomization stratum) using placebo event rate. The imputation and subsequent analysis will 
be carried out using SAS PROC MI (Monotone Logistic Regression Method) and SAS PROC 
MIANALYZE. The detailed imputation steps are described as follows. 
!
Step 1: For the subjects in the MEDI8897 arm who do not have an RSV LRTI and are not 
followed through 150 days post dose, their treatment code of “MEDI8897” will be 
substituted with “placebo” to ensure the placebo RSV LRTI rate is applied in the 
imputation for the MEDI8897 dropouts adjusted for their stratification values. The 
imputation will be executed using SAS Proc MI (eg, logistic regression with the recoded 
treatment term and stratification factor [age at randomization stratum]).
!
Step 2: The original treatment code will be restored after the RSV LRTI event statuses 
have been imputed. A complete dataset comprises the imputed RSV LRTI status and 
observed RSV LRTI status.


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!
Step 3: Analyze the complete dataset using a Poisson regression model with robust 
variance to estimate the RR on the incidence of medically attended RSV LRTI between 
MEDI8897 and placebo, with the term of treatment group and stratification factor (age at 
randomization stratum). The point estimate of log-transformed RR and its variance will 
be extracted from the model. 
!
Steps 2-3 will be repeated 20 times. SAS procedure PROC MIANALYZE will be used to 
combine inferences from the 20 completed datasets, that will result in a combined point 
estimate of log-transformed RR and the variance. The random seed is 12345. 
3.5.1.3
Secondary Analyses of the Primary Efficacy Endpoint
The secondary efficacy analysis of the primary endpoint will be performed on ITT1. A CMH 
test stratified by age group at randomization (ie, age ≤ 3.0 months, age > 3.0 to ≤6.0 months, 
age > 6.0 months) will be used to compare between treatment groups through 150 days post 
dose as the key secondary analysis for the primary endpoint. SAS procedure of PROC FREQ 
with CMH option will be used to perform the analysis. The RR of MEDI8897 over placebo 
for the incidence of medically attended RSV LRTI events and the 95% CI will be obtained 
from the SAS procedure. The percent of RRR and the 95% CI will be reported following the 
relationship of RRR (%) = (1- RR) * 100%. This analysis will be performed without any 
imputation of event for subjects who dropped out the study prior to Day 150 post dose and did 
not have a medically attended RSV event. The Breslow-Day test and Zelen’s exact test will be 
used to test the homogeneity of the odds ratios across strata and the corresponding p-values 
will be judged at the significance level of 0.05.
3.5.1.4
Supplementary Analyses of the Primary Efficacy Endpoint
The following analyses will be conducted on ITT1 as supplementary analyses.  
Poisson Regression with Robust Variance Adjusting for Follow-up Time
To allow for differences in follow-up time, the primary analysis using a Poisson Regression 
with robust variance will be repeated, adjusting for the same covariates as well as log (follow-
up time) as an offset. Since the follow-up time is adjusted in the model, there is no missing 
imputation for this analysis. Calculation of follow-up are detailed as follows:
!
For subjects who meet the medically attended RSV LRTI endpoint within 150 days post 
dose, the follow-up time will be calculated as (Date of Onset of RSV LRTI) – (Date of 
Dosing) + 1. Date of Onset of RSV LRTI is defined as the initial date seen by the 
healthcare provider for the corresponding AE. 
!
For subjects who do not experience a medically attended RSV LRTI event within 
150 days post dose, the efficacy follow-up will be determined based on the following: 
∀
If an end of study date occurs within 150 days post dose (or end of study date is 
missing and last assessment date occurs within 150 days post dose), the efficacy 


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follow-up will be calculated as (Date of End of Study or Date of Last Assessment, 
whichever is later) – (Date of Dosing) + 1. 
∀
If an end of study date occurs after 150 days post dose (or end of study date is 
missing and last assessment date is after 150 days post dose), the efficacy follow-up 
will be censored (at 151 days). 
For subjects who are ongoing at the time of Primary Analysis, the data cut-off date will be 
used as their last assessment date.
Kaplan-Meier Analysis 
A Kaplan-Meier curve for time to first medically attended RSV LRTI will be generated based 
on observed events. The algorithm for time-to-event calculation is the same as that for follow-
up time (see the section right above). Treatment group differences in time-to-first medically 
attended RSV LRTI will be compared using the stratified log-rank test with the stratification 
factor (age at randomization) as the strata. In addition, hazard ratio and the corresponding 
95% confidence interval will be obtained from the stratified proportional hazard model with 
the stratification factor (age at randomization stratum) as the strata. 
Primary Endpoint by Visit Setting
In addition, all observed medically attended RSV LRTI events through 150 days post dose and 
the corresponding incidence rates will be tabulated by Inpatient (primary hospitalization, 
nosocomial hospitalization) and Outpatient, for the latter category, further presentation will be 
made by different medical settings: outpatient clinic, urgent care clinic, and ED visits for 
subjects who did not have a hospitalization due to RSV.
Missing Data Imputation 
Five supplementary analyses for RSV LRTI through 150 days post dose will be performed to 
address subjects who do not have an RSV LRTI and are not followed through 150 days post 
dose through various approaches of missing data imputation are described as follows: 
1. Count these subjects as having not met the RSV LRTI endpoint within each treatment 
group 
2. Perform multiple imputation using the observed event rate per treatment group for their 
event status
3. Perform single imputation using observed placebo rate for both groups
4. Impute missing data in MEDI8897 group as an event and missing data in the placebo 
group as no event
5. Impute missing data in MEDI8897 group as no event and missing data in the placebo 
group as an event


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For supplementary analysis 1, all subjects who do not have an RSV LRTI event and are not 
followed through 150 days post dose will be assumed having no event. The subjects with 
imputed values of RSV LRTI status will be combined with the remaining subjects who either 
have an RSV LRTI prior to 150 days post dose or who were followed through 150 days post 
dose without the event to form a complete dataset. The primary efficacy analysis model will 
be used to analyse the completed datasets via the specified imputation method.
For supplementary analysis 2, the medically attended RST LRTI event status for the subjects 
who do not have an RSV LRTI and are not followed through 150 days post dose will be 
imputed by the observed event rate per treatment group. That is, following the standard 
Multiple Imputation procedure and carried by PROC MI (Monotone Logistic Regression 
Method) and PROC MIANALYZE.  
For supplementary analysis 3, the number of medically attended RSV LRTI events for 
subjects who dropped out prior to Day 150 post dose without the event will be generated using 
the observed placebo event rates for both treatment groups. With the imputed number of 
events, the RRR and the 95% CI will be constructed using an exact conditional method
without stratum based on the number of RSV LRTIs (Breslow and Day, 1987). The number of 
events for each treatment group will be used as the response variable and the logarithm of 
total number of participants for treatment group will be used as an offset variable in the 
model. This analysis will be implemented using PROC GENMOD with the EXACT 
statement.
For supplementary analysis 4, for subjects who do not have an RSV LRTI event and are not 
followed through 150 days post dose, if they are in the placebo group, they will be assumed 
having no events; if they are in the MEDI8897 group, they will be assumed having events. 
The remaining part will be the same as that described in supplementary analysis 1.
For supplementary analysis 5, for subjects who do not have an RSV LRTI event and are not 
followed through 150 days post dose, if they are in the MEDI8897 group, they will be 
assumed having no events; if they are in the placebo group, they will be assumed having 
events. The remaining part will be the same as that described in supplementary analysis 1.
In addition, a tipping point analysis will be conducted to assess the robustness of efficacy 
under a series of assumed event rates for the missing data in both treatment groups, ranging 
from 10% to 100%, increment by 10%. For the assumed event rates of 10%-90%, the tipping 
point analysis will be conducted following the steps below:
!
Step 1: Impute the event status for subjects who do not have an RSV LRTI and are not 
followed through 150 days post dose in each treatment arm using the Bernoulli 
distribution with assumed event rate without involvement of stratification factors.


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!
Step 2: The subjects with imputed values of RSV LRTI status (yes/no) will be combined 
with the remaining subjects who either have an RSV LRTI prior to 150 days post dose or 
who were followed through 150 days post dose without an RSV LRTI, to form a 
complete dataset. 
!
Step 3: Analyze the complete dataset using a Poisson regression model with robust 
variance to compare the incidence of medically attended RSV LRTI between MEDI8897 
and placebo, including treatment group, and the stratification factor (age at randomization 
stratum) as covariates. The point estimate of log-transformed RR and its variance will be 
produced from the model. 
!
The steps 1-3 will be repeated 20 times with seed 1-20, respectively. SAS procedure 
PROC MIANALYZE will be used to combine inferences from the 20 completed datasets, 
which will result in a combined point estimate of log-transformed RR and the variance. 
The random seed is 12345.
For the assumed event rate of 100%, all subjects who do not have an RSV LRTI and are not 
followed through 150 days post dose will be imputed as having an event. The subjects with 
imputed values of RSV LRTI status will be combined with the remaining subjects who either 
have an RSV LRTI prior to 150 days post dose or who were followed through 150 days post 
dose without the event to form a complete dataset. The primary efficacy analysis model will 
be used to analyse the completed datasets via the specified imputation method.
Subgroup Analyses
Subgroup analysis will be performed for the primary efficacy endpoint, the incidence of 
medically attended RSV LRTI. Treatment-by-subgroup interaction will be tested using the 
Poisson regression with robust variance model with the terms of treatment, age group, 
subgroup, and treatment-by-subgroup interaction, which will be implemented using PROC 
GENMOD procedure. If this full model does not achieve convergence, a reduced model of 
treatment, subgroup, and treatment-by-subgroup interaction will be used. Significant 
treatment-by-subgroup interaction is judged at the significance level of 0.10. Within each 
level of a subgroup, the RRR and its corresponding 95% CI will be estimated using a Poisson 
regression model with robust variance with the term of treatment. A forest plot of the RRR 
and the 95% CI will be presented. In the event that the Poisson regression model does not 
converge for any stratum of a subgroup, the exact conditional method based on the number of 
RSV LRTIs (Breslow and Day, 1987) will be used as the analytical model to generate the 
RRR and its corresponding CI for all subgroup strata. This model will be implemented by 
StatXact PROC Poisson procedure and the point estimate and mid-p adjusted 95% CI will be 
reported.
The subgroup analysis will be conducted for the following subgroups on ITT1:
!
Hemisphere


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!
Age at randomization stratum (age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0
months)
!
Gender
!
Race (Caucasian, non-Caucasian)
!
Weight at birth (weight ≤2.5 kg, weight > 2.5 kg)
!
Weight on Day 1 (weight < 5 kg, weight ≥ 5 kg)
!
GA (≥ 35 weeks to < 37 weeks, ≥ 37 weeks)
!
Sibling also participating in the study (yes/no)
In addition, incidence of medically attended RSV LRTI will be summarized by Country.
3.5.1.5
Analyses for Medically Attended RSV LRTI Beyond the Primary Endpoint
The following analyses will be conducted on ITT1 and based on observed events, unless 
stated otherwise. 
The incidence of medically attended RSV LRTI that occurred through 360 days post dose and 
> 360 days post dose will be summarized by treatment group. ITT1 will be used for the 
summary of the incidence through 360 days post dose, and ITT1 subjects who remained in the 
study after the Day 361 visit will be used as the denominator to calculate the incidence rate for 
the summary of the incidence > 360 days post dose.
Age at onset of the first medically attended RSV LRTI through 150 days post dose will be 
tabulated by age group used for randomization stratification by treatment group. In addition, 
time-to-first medically attended RSV LRTI will be plotted at subject’s level along the axis of 
age at birth. 
The incidence of medically attended RSV LRTI by subtype (RSV A, RSV B) through 
150 days post dose, through 360 days post dose, and > 360 days post dose will be summarized 
by treatment group. The populations that the summary will be based on will be similar to what 
had been used for the analysis of medically attended RSV LRTI at each corresponding time 
period. 
To capture and summarize multiple medically attended RSV LRTIs through 150 days post 
dose, the total number of new onset medically attended RSV LRTIs since the previous 
medically attended RSV LRTI will be calculated for each subject. A new onset medically 
attended RSV LRTI is defined as an adverse event (AE) meeting protocol specified medically 
attended RSV LRTI that occurred at least 14 days after the resolution date of the previous AE 
for a medically attended RSV LRTI. Similar definition is applied with a 30 days interval 
between the resolution of the previous event and a new onset of event (see Table 2 for details). 
A listing will be generated to provide the following information: age at randomization
stratum, hemisphere, total number of events (at least 14 days apart), total number of events (at 


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least 30 days apart), days to event, adverse event (AE) verbatim term, date of AE onset/stop, 
days from previous event, visit setting, and RSV subtype. 
AEs associated with medically attended RSV LRTI will be summarized overall, as well as 
categorized by MedDRA system organ class (SOC) and preferred term (PT). Summaries will 
be presented through 150 days post dose, through 360 days post dose, and after 360 days post 
dose.
3.5.2
Secondary Efficacy Endpoint and Analyses
3.5.2.1
Secondary Efficacy Endpoint
The secondary efficacy endpoint is the incidence of RSV LRTI hospitalization through 150 days 
post dose. For subjects with multiple RSV LRTI hospitalizations, only the first occurrence will 
be used in the analysis.
The events of “RSV hospitalization” are a subset of “medically attended RSV LRTI,” which 
are determined based on objective clinical LRTI criteria (described in the Protocol 
Section 4.3.1.1 and SAP Appendix 1) and RSV test results obtained from central laboratory 
analysis respiratory secretions using a validated RSV RT-PCR assay for the detection of RSV 
A or RSV B. 
Prior to analysis, a blinded review of data will be undertaken to determine an analysis window 
such that all positive results will be counted as an RSV LRTI hospitalization if they occurred 
in a respiratory sample collected within this window relative to the admission/deterioration 
date. The actual window used will be documented prior to unblinding. In addition, deaths that
can be demonstrated as caused by RSV (by autopsy or clinical history and virologic evidence) 
will also be considered as RSV LRTI hospitalization endpoints.
3.5.2.2
Secondary Efficacy Analyses
Providing information to physicians and parents/legal representatives on the effect of 
MEDI8897 in reducing the risk of RSV hospitalization is considered important and was the 
primary endpoint for the approval of palivizumab. Due to its importance, RSV hospitalization 
was pre-specified as a key secondary endpoint in the Phase 2b Study D5290C00003 and will 
be again pre-specified as a key secondary endpoint in this Phase 3 study. However, as the 
management of more serious RSV disease has been shifting to the outpatient setting, there is a 
risk that the incidence of RSV hospitalization in this Phase 3 study population of healthy late 
preterm and term infants may be too low (expected to be approximately 1% in the placebo 
group) for this secondary efficacy analysis to reach statistical significance (p ≤ 0.05) within 
this Phase 3 study alone. 
The rationale of a pooled analysis, which consists of all ITT subjects from the Phase 2b Study 
D5290C00003 and ITT1 subjects from the Phase 3 study, is to assess the overall efficacy of 


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RSV hospitalization in the target population (pre-term and term infants). The pooled analysis 
consisting of the 860 ITT subjects weighing < 5 kg in the Phase 2b Study D5290C00003 and 
ITT1 subjects in this Phase 3 study, will be conducted to assess the efficacy in all subjects 
under the clinically efficacious exposure suggested by PK analysis. Combining these subjects 
for analysis is justified based on the similar study designs and disease similarity between the 
infant pediatric study populations. 
Given the importance of controlling for multiplicity, a hierarchical testing strategy is proposed 
as follows. Statistical testing of the null hypothesis that the incidence of RSV LRTI 
hospitalization between MEDI8897 and placebo groups is the same will only be performed if 
the primary efficacy analysis has achieved a p-value that is ≤ 0.05. More specifically, after the 
significance of the primary efficacy endpoint is demonstrated, the secondary efficacy endpoint 
will first be tested from pooling all ITT subjects from the Phase 2b Study D5290C00003 and 
ITT1 subjects from the Phase 3 study. If the significance of the pooled efficacy based on 
pooling all subjects from Phase 2b and ITT1 subjects from Phase 3 is demonstrated (at 2-sided 
0.05), the secondary efficacy endpoint will be further tested from pooling the 860 subjects 
weighing < 5 kg on Day 1 (ie, 290 subjects randomized to placebo and 570 subjects 
randomized to MEDI8897) in the Phase 2b Study D5290C00003 and ITT1 subjects in this 
Phase 3 study. If the significance of the pooled efficacy based on pooling the subjects 
weighing < 5 kg from Phase 2b and Phase 3 ITT1 subjects is again demonstrated (at 2-sided 
0.05), the secondary efficacy endpoint will be tested using ITT1 subjects from this Phase 3 
study alone. We would test the secondary endpoint in the pooled population before that in this
Phase 3 study alone for the reason that the pooling strategy will mimic the efficacy we can 
expect to see with the dosing scheme we plan to ultimately register and deploy for use in the 
target population and therefore has a higher importance.
For the pooled analyses, a Poisson regression model with robust variance (Zou, 2004) will be 
used to assess the treatment effect on the incidence of RSV LRTI hospitalization between 
MEDI8897 and placebo groups in the pooled ITT population. In addition to the treatment arm, 
the variable “Study” (which identifies the enrolled study for each subject) will be used as a 
covariate to adjust for potential differences between the 2 studies. RRR and its corresponding 
95% CI will be estimated from the model implemented by PROC GENMOD as detailed in 
Section 3.5.1.2.
For the analysis using Phase 3 data alone, a Poisson regression model with robust variance 
(Zou, 2004) using only the treatment term will be used to assess the treatment effect on the 
incidence of RSV LRTI hospitalization between MEDI8897 and placebo groups in the ITT1
population. RRR and its corresponding 95% CI will be estimated from the model.
Above stated analyses on RSV LRTI hospitalization will also be conducted on the 
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Handling of Dropouts and Missing Data
RSV LRTI hospitalization that occurs through 150 days post dose will contribute to the 
analysis. Subjects who only have outpatient RSV LRTI through 150 days post dose will be 
regarded as not meeting the RSV LRTI hospitalization endpoint. For subjects who do not have 
an RSV LRTI and were not followed through 150 days post dose, their event status will be 
imputed. Due to the expected low event rate, and correspondingly high likelihood of empty 
cells by strata, the stratification factors will not be used during the repeated imputation step to 
avoid potential convergence issue.
For the pooled analyses, the event status for subjects requiring imputation will be imputed 
using the observed placebo RSV LRTI hospitalization rate following the repeated imputation 
procedure conditional on study, similar to what has been described for imputing missing data 
for primary endpoint (Section 3.5.1.2) with the exception of using the variable “Study” instead 
of the stratification factors in SAS PROC MI and the Poisson regression model with robust 
variance.  
For the analysis using Phase 3 data alone, the event status for subjects requiring imputation
will be imputed using the observed placebo RSV LRTI hospitalization rate following the 
repeated imputation procedure without involvement of stratification factors. The computation 
steps will be conducted following the steps below:
!
Step 1: Determine the observed placebo RSV LRTI hospitalization rate through 150 days 
post dose, which is calculated as the proportion of all randomized placebo subjects with 
observed RSV LRTI hospitalization.
!
Step 2: Impute the event status for subjects who do not have an RSV LRTI and are not 
followed through 150 days post dose in each treatment group using the Bernoulli 
distribution with the observed placebo RSV LRTI hospitalization rate.
!
Step 3: The subjects with imputed values of RSV LRTI hospitalization status (yes/no) 
will be combined with the remaining subjects to form a complete dataset. 
!
Step 4: Analyze the complete dataset using a Poisson regression model with robust 
variance to compare the incidence of RSV LRTI hospitalization between MEDI8897 and 
placebo, including the treatment group only. The point estimate of log-transformed RR 
and its variance will be produced from the model. 
!
The steps 2-4 will be repeated 20 times with seed 1-20, respectively. SAS procedure 
PROC MIANALYZE will be used to combine inferences from the 20 completed datasets, 
which will result in a combined point estimate of log-transformed RR and the variance. 
The random seed is 12345.
3.5.2.3
Supplementary Analyses of the Secondary Efficacy Endpoint
The supplementary analyses will be conducted on ITT1.


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These analyses including the CMH test stratified by study (for the pooled population) or the 
CMH test with the only term of treatment (for ITT1 subjects from Phase 3) for the incidence 
of RSV LRTI hospitalization, and the Kaplan-Meier for time-to-first RSV LRTI 
hospitalization will be conducted. Treatment group differences in time-to-first RSV LRTI 
hospitalization will be compared using log-rank test. In addition, hazard ratio and the 
corresponding 95% confidence interval will be obtained from the proportional hazard model.
For each treatment group, age at onset of the first medically attended RSV LRTI 
hospitalization will be tabulated by age group used for randomization stratification by 
treatment group. In addition, time-to-first medically attended RSV LRTI hospitalization will 
be plotted at subject’s level along the axis of age at birth. RSV LRTI hospitalization will also 
be summarized by RSV subtype (A or B).  
The incidence of RSV LRTI hospitalization will also be summarized by the following 
subgroups. 
!
Hemisphere
!
Age at randomization stratum (age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0
months)
!
Gender
!
Race (Caucasian, non-Caucasian)
!
Weight at birth (weight ≤2.5 kg, weight > 2.5 kg)
!
Weight on Day 1 (weight < 5 kg, weight ≥ 5 kg)
!
GA (≥ 35 weeks to < 37 weeks, ≥ 37 weeks)
!
Sibling also participating in the study (yes/no)
In addition, incidence of RSV LRTI hospitalization will be summarized by Country.
3.5.3
Other Efficacy Analyses
The following analyses will be conducted on ITT1. 
An overall summary of subjects with any medically attended LRTI (protocol-defined or not) 
or hospitalization due to any respiratory illness will be presented by treatment group. In this 
summary, a subject is reported only once even though he or she might have multiple events in 
the time interval of reporting. In that occasion, the event with the highest severity level will be 
reported. The rules to define severity among multiple LRTI events for a subject are as follows: 
protocol-defined > non-protocol defined, RSV > non-RSV, and hospitalization > non-
hospitalization. The rules to define severity among multiple hospitalizations due to any 
respiratory illness are as follows: LRTI > non-LRTI, RSV > non-RSV. Incidence of all 
medically attended LRTI will be summarized by protocol-defined LRTI (RSV or non-RSV) 
and non-protocol defined LRTI (RSV or non-RSV) with each further breaking done by 


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hospitalization status. For subjects who were hospitalized due to any respiratory illness, LRTI
and non-LRTI cases will be further reported and broken down by RSV status. In addition, a 
summary for subjects with at least one medically attended LRTI event (categorized by RSV, 
non-RSV, hospitalization, outpatient only), regardless of severity, will be presented. In this 
summary, a subject can be reported in multiple event categories as long as the subject has at 
least one corresponding event. Correspondingly, a side-by-side bar plot for incidence of all 
medically attended LRTIs regardless of severity through 150 days post dose will be presented 
by RSV status (RSV, non-RSV) per treatment group, with the visit setting category
(hospitalization, outpatient only) stacked.
Summaries for subjects who met primary efficacy endpoint (ie, protocol-defined medically 
attended RSV LRTI) will be presented by treatment group for each of the elements used to 
evaluate for the case definition of medically attended RSV LRTI (Appendix 1). These 
elements include the following: rhonchi, rales, crackles, wheeze, increased respiratory rate, 
hypoxemia, acute hypoxic or ventilatory failure, new onset apnea, retractions, grunting, 
dehydration due to respiratory distress requiring IV hydration. In this summary, a subject is 
reported once even though he or she might have the element multiple times during the 
reporting period.
For all medically attended LRTI events, RSV status (positive, negative or not done) will be 
summarized by central RT-PCR or local testing results by treatment group. The proportion of 
each category will be calculated based on the total number of LRTI events for the respective 
treatment group. In addition, incidence of positive RSV LRTI either by RT-PCR or by local 
testing results will also be summarized by LRTI categories (protocol-defined, non-protocol 
defined) and treatment group. The same analysis window as described in above sections for 
the RT-PCR central tests will be used for the local tests. In this summary, if a subject has 
multiple LRTI events, the one with the highest severity will be reported (in the order of 
protocol-defined > non-protocol defined) and the incidence of the event will be calculated 
based on the number of randomized subjects for the respective treatment group.
In addition, for each treatment group, all medically attended LRTI events will be tabulated by 
Inpatient (primary hospitalization, nosocomial hospitalization) and Outpatient, for the latter 
category, further presentation will be made by different medical settings: outpatient clinic, 
urgent care clinic, and ED visits. The proportion of each category will be calculated based on 
the total number of LRTI events for the respective treatment group.
All above stated summaries will be based on observed events and data summary will be 
presented by through Day 150 post dose (on ITT1), after 150 days post dose (on ITT1 with 
Day 151 visit), through 360 days post dose (on ITT1), and after 360 days post dose (on ITT1 
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For various LRTI events, including the primary endpoint, detailed definitions of new onset of 
events are defined in the following table, Table 2. For all medically attended LRTI (RSV, 
non-RSV, protocol-defined, non-protocol defined), the total number of events for each subject 
and the percentage of each outcome will be summarized by treatment group on 4 time-
intervals: Day 150 post dose (on the ITT1), after 150 days post dose (on ITT1 with Day 151 
visit), through 360 days post dose (on ITT1), after 360 days post dose (on ITT1 with Day 361 
visit). In addition, a listing that provides relevant information for subjects with more than one 
medically attended LRTI event throughout the study will be generated. The listing contains 
the following information: Age at randomization stratum, Hemisphere, Total number of 
events, Days post dose, AE verbatim term, Date of AE onset/stop, Days from previous event, 
Visit setting, Protocol-defined (Y/N), RSV (Y/N), and RSV subtype (when applicable). A 
similar listing for subjects with more than one medically attended RSV LRTI event 
(regardless protocol-defined or not) will also be presented. 
Table 2
Definition for New Onset of Events
Event
Description
New onset 
medically attended 
RSV LRTI
A new onset medically attended RSV LRTI will be defined as an adverse event (AE) (for 
which at least one healthcare visit is associated with RSV LRTI) and occurs at least 14 
days (and similarly using 30 days) after the resolution date of the previous AE for a 
medically attended RSV LRTI.
New onset RSV 
LRTI
hospitalization
A new onset medically attended RSV LRTI hospitalization will be defined as an AE (for 
which at least one hospitalization is associated with RSV LRTI) and occurs at least 14 
days (and similarly using 30 days) after the resolution date of the previous AE for a 
medically attended RSV LRTI hospitalization.
New onset 
medically attended 
RSV outpatient
LRTI
A new onset medically attended RSV outpatient LRTI will be defined as an AE (for 
which at least one healthcare outpatient visit is associated with RSV LRTI) and occurs at 
least 14 days (and similarly using 30 days) after the resolution date of the previous AE for 
a medically attended RSV outpatient LRTI.
New onset 
medically attended 
LRTI
A new onset medically attended LRTI will be defined as an AE of LRTI that occurs after 
the resolution date of the previous AE for a medically attended LRTI.
New onset LRTI 
hospitalization
A new onset medically attended LRTI hospitalization will be defined as an AE (with at 
least one hospitalization associated with LRTI) that occurs after the resolution date of the 
previous AE for a medically attended LRTI hospitalization.
New onset 
medically attended 
outpatient LRTI
A new onset medically attended outpatient LRTI will be defined as an AE (with at least 
one outpatient healthcare visit associated with LRTI) that occurs after the resolution date 
of the previous AE for a medically attended outpatient LRTI.
AEs associated with all medically attended LRTI will be summarized overall, as well as 
categorized by the Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class (SOC) and preferred term (PT). Summaries will be presented through 150 days, after 


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150 days, through 360 days, and after 360 days post dose on the following populations: ITT1, 
ITT1 with Day 151 visit, ITT1, and ITT1 with Day 361 visit, respectively.
3.5.4
Additional Efficacy Analyses for the Safety Cohort
The following descriptive analyses will be conducted on ITT2 and based on observed events, 
unless stated otherwise.  
3.5.4.1
Analyses of Incidence of Medically Attended RSV LRTI 
The incidence of medically attended RSV LRTI (inpatient and outpatient) through 150 days 
post dose will also be summarized by treatment group using ITT2. For subjects with multiple 
medically attended RSV LRTI events, only the first occurrence will be used in the summary.  
In addition, the same analyses of all observed medically attended RSV LRTI events through 
150 days post dose by visit setting as described in Section 3.5.1.4 will be repeated for ITT2.
The incidence of medically attended RSV LRTI will also be summarized by the subgroups 
and countries as defined in Section 3.5.1.4 for ITT2.
In addition, the incidence of medically attended RSV LRTI that occurred through 360 days 
post dose and after 360 days post dose will be summarized as described in Section 3.5.1.5 for 
ITT2.
Age at onset of the first medically attended RSV LRTI through 150 days post dose will be 
summarized as described in Section 3.5.1.5 for ITT2. In addition, time-to-first medically 
attended RSV LRTI will be plotted at subject’s level along the axis of age at birth. 
The incidence of medically attended RSV LRTI by subtype (RSV A, RSV B) will be 
summarized as described in Section 3.5.1.5 for ITT2.
For multiple medically attended RSV LRTIs, the total number of new onset medically
attended RSV LRTIs will be summarized as described in Section 3.5.1.5 for ITT2. A listing 
will be generated similarly.
AEs associated with medically attended RSV LRTI will be summarized overall, as well as 
categorized by MedDRA system organ class (SOC) and preferred term (PT). Summaries will 
be presented as described in Section 3.5.1.5 for ITT2.
3.5.4.2
Analyses of Incidence of RSV LRTI Hospitalization
The incidence of RSV hospitalization through 150 post dose days will be summarized by 
treatment group for each cohort as well as for the ITT2. For subjects with multiple RSV LRTI 
hospitalizations, only the first occurrence will be used in the analysis.


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For each treatment group, age at onset of the first medically attended RSV LRTI 
hospitalization will be summarized as described in Section 3.5.2.3 for ITT2. In addition, time-
to-first medically attended RSV LRTI hospitalization will be plotted at subject’s level along 
the axis of age at birth. RSV LRTI hospitalization will also be summarized by RSV subtype 
(A or B).
The incidence of RSV LRTI hospitalization will also be summarized by subgroups and 
country as described in Section 3.5.2.3 for the ITT2. 
3.5.4.3
Other Efficacy Analyses 
An overall summary of subjects with any medically attended LRTI (protocol-defined or not) 
or hospitalization due to any respiratory illness will be presented by treatment group as 
described in Section 3.5.3 for ITT2. 
Summaries will be presented by treatment group for each of the elements used to evaluate for 
the case definition of medically attended RSV LRTI (Appendix 1) as described in Section 
3.5.3 for ITT2. 
For all medically attended LRTI events, RSV status (positive, negative or not done) will be 
summarized by central RT-PCR or local testing results by treatment group as described in 
Section 3.5.3. In addition, incidence of positive RSV LRTI either by RT-PCR or by local 
testing results will also be summarized by LRTI categories (protocol-defined, non-protocol 
defined) and treatment group as described in Section 3.5.3 for ITT2. 
In addition, for each treatment group, all medically attended LRTI events will be tabulated by 
Inpatient (primary hospitalization, nosocomial hospitalization) and Outpatient as described in 
Section 3.5.3for ITT2. 
All above stated summaries will be presented by through Day 150 post dose (on ITT2), after 
150 days post dose (on ITT2 with Day 151 visit), through 360 days post dose (on the ITT2), 
and after 360 days post dose (on ITT2 with Day 361 visit). 
For all medically attended LRTI (RSV, non-RSV, protocol-defined, non-protocol defined), the 
total number of events for each subject and the percentage of each outcome will be 
summarized by treatment group on 4 time-intervals: Day 150 post dose (on ITT2), after 150 
days post dose (on ITT2 with Day 151 visit), through 360 days post dose (on ITT2), and after 
360 days post dose (on ITT2 with Day 361 visit). In addition, a listing that provides relevant 
information for subjects with more than one medically attended LRTI event throughout the 
study will be generated. The listing contains the information as described in Section 3.5.3.
AEs associated with all medically attended LRTI will be summarized overall, as well as 
categorized by the Medical Dictionary for Regulatory Activities (MedDRA) system organ 


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class (SOC) and preferred term (PT). Summaries will be presented through 150 days, after 
150 days, and through 360 days post dose and after 360 days post dose on the following 
populations: ITT2, ITT2 with Day 151 visit, ITT2, ITT2 with Day 361 visit, respectively.
3.6
Exploratory Analyses
3.6.1
Healthcare Resource Utilization (HRU)
The magnitude of Healthcare Resource Utilization (HRU; measured by number of admissions
to hospitals and duration of stay; number of admissions to the intensive care unit [ICU] and 
duration of stay, number requiring respiratory support [using Continuous Positive Airway 
Pressure (CPAP) or mechanical ventilation] and the duration of use, and the number of 
supplemental oxygen and the duration of use; number of visiting out-patient facilities 
[outpatient ED, urgent care, outpatient clinic]; will be summarized by treatment group and 
reported in 3 time periods: through 150 days post dose (on ITT1), after 150 days post dose (on 
ITT1 with Day 151 visit), and through 360 days post dose (on ITT1). 
Specifically, the following summary tables by treatment group will be used to report the 
magnitudes of overall HRU for all medically-attended LRTI (protocol defined, non-protocol 
defined, RSV, non-RSV).
!
The number and percent of subjects who have had at least one of the following: 
hospitalization, ICU admission, requiring respiratory support, requiring supplemental 
oxygen, or visiting an outpatient facility (for any type of the outpatient facility). Similar 
summaries will also be provided by respiratory support subtype (CPAP or mechanical 
ventilation) and the type of outpatient facility. The percentage will be calculated based on 
ITT1 for time interval through 150 days post dose, on ITT1 with Day 151 visit for time 
interval after 150 days post dose, and on ITT1 for time interval through 360 days post 
dose. 
!
For each of the medical activities listed above, the total number of the activity for a 
subject who has had at least one respective event in the reporting time-period will be 
calculated and summarized by treatment group using descriptive statistics (mean, median, 
standard deviation [SD], minimum, and maximum).  
!
The total duration of each of the following (in days) will be calculated accumulatively 
throughout the reporting time-period and summarized by descriptive statistics (mean, 
median, SD, minimum, and maximum): hospital stay, ICU stay, use of respiratory 
support, or use of supplemental oxygen for the subjects who has had at least one of the 
corresponding activities.
Duration of each hospitalization will be calculated from the admission or deterioration date to 
discharge date. If the discharge date is missing because of the reason that the subject died in 
the hospital, the duration of that hospital stay will be calculated by from admission to the 
minimum of {Death Date, End-of-Study Date, Data Cutoff Date at the time of Analysis}. 


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Total duration of hospitalization is the cumulated days of each hospital stay throughout the 
reporting time-period.  
Similarly, duration of each ICU admission, use of respiratory support, or use of supplemental 
oxygen will be calculated from start date to stop date or the end date, and the total duration of 
each medical intervention for a subject is calculated by summing the duration of all
occurrences in the time interval of interest. 
In addition to the overall HRU summary, the HRU for medically attended RSV LRTI
(Protocol-defined), will be summarized through 150 days post dose, after 150 days post dose, 
and through 360 days post dose. The same conventions used for the overall summary (eg, 
patient population included in a specific summary) will be applied for the respective events 
and the HRU must occur during the event being summarized. Only the subjects with protocol-
defined medically attended RSV LRTI will be included in the summary.
In addition, the number of pre-specified OTC medication (analgesics/antipyretics) use; the 
number of pre-specified prescription medication (systemic antibacterial agents) use; and the 
number of anti-wheezing medication use will be summarized by treatment group and reported 
through 150 days post dose, except for the analgesics/antipyretics use, which will be 
summarized through one week after dosing. The ATC codes for these medications will be 
provided in a separate file by the medical monitor prior to the DBL for the Primary Analysis.
The number and percentage of subjects with pre-specified prescription medications (systemic 
antibacterial agents) use through 150 days post dose will be provided. The number of use per 
subject (for those with the medication use) will be summarized through 150 days post dose 
using descriptive statistics (mean, median, SD, minimum, and maximum) by treatment group 
and for all subjects combined.
The number and percentage of subjects with pre-specified OTC medications 
(analgesics/antipyretics) use within one week after dosing will be provided. The number of 
use per subject (for those with the medication use) will be summarized using descriptive 
statistics (mean, median, SD, minimum, and maximum) by treatment group and for all 
subjects combined. The same summaries will be repeated for subjects with any 
co-administered routine childhood vaccination (J07) within one week of dosing.
The number and percentage of subjects with anti-wheezing medications use through 150 days 
post dose will be provided. The number of use per subject (for those with the medication use) 
will be summarized through 150 days post dose using descriptive statistics (mean, median, 
SD, minimum, and maximum) by treatment group and for all subjects combined. 
Above summaries will be repeated for ITT2, if data permit.


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3.6.2
Caregiver Burden
Caregiver burden (measured by days of work the caregiver missed, days of 
daycare/babysitting the subject missed) will be summarized for subjects with medically 
attended RSV LRTI (Protocol-defined) by treatment group for subjects who have had at least 
one event in the time-period of reporting. These summaries will be presented through 150 
days post dose, after 150 days post dose, and through 360 days post dose using similar 
reporting convention as described previously. 
For each of the events mentioned above and each time-period of reporting, the accumulated 
total days of work the caregiver missed and the accumulated total days of daycare/babysitting 
the subject missed will be calculated for each subject and presented using descriptive statistics 
(mean, median, SD, minimum, and maximum) by treatment group. For each treatment group, 
the average caregiver burden (ie, the average number of days of work the caregiver missed, 
the average number of days of daycare/babysitting the subject missed) for a respective event 
will be calculated as the total caregiver burden across subjects who has had at least one of the 
events divided by the total number of the events among these subjects in the time interval of 
interest. Similar summary will also be provided by the status of hospitalization (at least one or 
none) that is caused by a respective event mentioned above. The summaries for the caregiver 
burden will be based on ITT1 and ITT2.
3.6.3
Anti-RSV Neutralizing Antibody
RSV neutralizing antibody levels afforded by MEDI8897 will be compared to maternal RSV 
neutralizing antibody levels and those elicited following infection in the placebo group. RSV 
exposure as measured by increasing concentrations of serum RSV neutralizing antibody, is 
defined as ≥ 4-fold rise in concentration of serum RSV neutralizing antibody from the 
previous timepoint. A subject shows “evidence of exposure” if this criterion is met for any set 
of consecutive timepoints. The summary will be provided for Placebo at scheduled visits 
when the serum samples were collected. The summary will be cumulative; that is, if subjects 
show exposure in a previous timepoint, they should be included in later timepoints as well. At 
each scheduled timepoint, the denominator will be the number of subjects with a result. The 
exposure will be examined by results based on serum RSV neutralizing antibodies.These 
analyses will be conducted for all subjects, as well as subjects with and without RT-PCR 
confirmed RSV through 360 days post dose.
Individual MEDI8897 and placebo serum RSV neutralizing antibody levels will be tabulated 
by treatment group along with descriptive statistics. RSV neutralizing antibody levels in 
serum will be summarized by geometric mean concentration and geometric mean-fold rise 
from baseline and corresponding 95% Clopper-Pearson exact CIs of the proportion for each 
treatment group at each visit for all subjects, as well as for subjects with and without RT-PCR 
confirmed RSV through 360 days post dose. In addition, summaries of geometric mean 


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concentration will also be provided for all subjects combined at baseline. Box plots of RSV 
neutralizing antibody levels in logarithm scale with base 10 will be provided by treatment 
group and by visit.
Anti-RSV neutralizing antibody level t1/2 will be estimated using non-compartmental analysis
(if data permit), and will be reported outside the CSR. The analysis for the RSV neutralizing 
antibody will be based on the overall as-treated population, AT1, and AT2. The analysis based 
on the overall as-treated population will only be conducted at the Final analysis.
3.6.4
RSV serology
RSV seroresponses will be evaluated as a measure of “RSV exposure” in the placebo and 
MEDI8897 groups. RSV exposure (defined as ≥ 4-fold rise in serum antibody levels to RSV 
antigens from the previous timepoint) will be examined by results based on anti-RSV pre-F, 
post-F, Ga, Gb, N, or any of these antigens except Pre-F. Similar summary (as described for
anti-RSV neutralizing antibodies in Section 3.6.3) will be provided by treatment group at 
scheduled visits when the serum samples were collected. As MEDI8897 will interfere with the 
pre-F result, the exposure based on pre-F will not be examined for the MEDI8897 group. 
These analyses will be conducted for all subjects, as well as subjects with and without RT-
PCR confirmed RSV through 360 days post dose.
Analysis of serum antibody levels to RSV antigens in MEDI8897 and placebo subjects will be 
summarized by geometric mean concentration and geometric mean-fold rise from baseline for 
each of the anti-RSV antigens (RSV pre-F, post-F, Ga, Gb and N antigens) and corresponding 
95% Clopper-Pearson exact CIs for each treatment group at each visit for all subjects, as well 
as subjects with and without RT-PCR confirmed RSV through 360 days post dose. In 
addition, summaries of geometric mean concentration will also be provided for all subjects 
combined at baseline. Seroresponses in MEDI8897 and placebo subjects will be determined 
by examining the fold-rise in antibodies to pre-F, post-F, Ga, Gb, and N antigens. By 
measuring antibodies to pre-F, post-F, Ga, Gb, and N: 1) baseline maternal antibodies and 
their decay can be measured over time; 2) the exposure to RSV (infection) that results in an 
increase in RSV-specific antibodies for the infants own immune system can be determined. 
Box plots of serum antibody levels to RSV antigens in logarithm scale with base 10 will be 
provided by treatment group and by visit.
The analysis for RSV serology will be based on the overall as-treated population, AT1, and 
AT2. The analysis based on the overall as-treated population will only be conducted at the 
Final analysis.
3.6.5
RSV resistance monitoring
Nasal samples collected from study subjects with RT-PCR confirmed RSV will be subtyped, 
genotyped, and evaluated by genotypic and phenotypic resistance analyses. Genotypic 


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analyses will report amino acid changes in the mature RSV F protein sequence compared to 
contemporary reference strains. Phenotypic analyses will report changes in susceptibility of 
engineered recombinant RSV variants to MEDI8897 and palivizumab neutralization compared 
to laboratory-derived reference viruses. A detailed description of subjects/samples analyzed, 
sample collection and testing workflow, performance characteristics of assays and 
methodologies, analysis plans, and reporting plans have been included in a separate clinical
virology analysis plan. The details of genotypic and phenotypic analyses and presentation of 
these data will be included in a separate virology study report.
3.6.6
Incidence of Medically Attended LRTI Due to RT-PCR-confirmed RSV 
After Day 151 (Between Day 152 and Day 361)
For summary of this exploratory endpoint, the analysis population will be ITT1 and ITT2, for
subjects, who remained in the study at the Day 151 visit. For subjects with multiple medically 
attended RSV LRTI events after Day 151, only the first occurrence will be used in the 
summary.
The incidence of medically attended RSV LRTI that occurred > 150 days (from Day 152 to 
Day 361) post dose will be based on RSV test results (performed centrally via RT-PCR) and 
objective clinical LRTI criteria and will be summarized by treatment group. This endpoint 
will be further summarized by RSV subtype (RSV A, RSV B) and by treatment group. In 
addition, AEs associated with this endpoint will be summarized overall, as well as categorized 
by MedDRA SOC and PT.
3.7
Safety Analyses
All safety analyses will be conducted on overall as-treated population, AT1, and AT2.
3.7.1
Adverse Events and Serious Adverse Events
Adverse events and serious adverse events will be coded by MedDRA version 22 or higher 
and the type, incidence, severity and relationship to study investigational product will be 
summarized by treatment group. Specific AEs will be counted once for each subject for 
calculating percentages. In addition, the total number of AEs will also be provided. In 
addition, if the same AE occurs multiple times within a particular subject, the highest severity 
and level of relationship observed will be reported. All treatment-emergent AEs (TEAEs) and 
treatment-emergent SAEs (TESAEs) occurring through Day 361 will be summarized overall, 
as well as categorized by MedDRA SOC and PT. In addition, the TEAEs occurring at 1% or 
higher in either treatment group will be reported by PT.
Nontreatment-emergent AEs/serious adverse events (SAEs), defined as AEs/SAEs that occur 
prior to the administration of investigational product or after Day 361, will be presented in the 
listings.  


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3.7.2
Adverse Events of Special Interest
Adverse events of special interest (AESI) will include targeted AEs of anaphylaxis and other 
serious hypersensitivity reactions including immune complex disease and AEs of
thrombocytopenia. The number and percentage of subjects with AESIs will be summarized by 
treatment group and by SOC and PT.
Of note, investigators have been requested to identify the AESI in reporting. The primary 
interpretation of data will be made upon those events with investigator assessment. In 
addition, a supplementary analysis is conducted which runs the narrow Standardised 
MedDRA Queries (SMQs) for hypersensitivity, the narrow and broad SMQS for anaphylactic 
reactions, and a study specific query based on compatible PTs for thrombocytopenia and 
immune complex disease occurring in the database. Narrow hypersensitivity SMQs include 
some PTs of immune complex disease. These SMQs and PTs will be provided by the medical 
monitor in a separate document before DBL for Primary Analysis.
3.7.3
Skin and Hypersensitivity Reactions
The number and percentage of subjects with any skin reactions (including skin 
hypersensitivity reactions) which are reported on the dedicated eCRF page and judged to be 
related to IP by the investigator will be summarized by treatment group and by SOC and PT.
3.7.4
New Onset Chronic Disease
New onset chronic diseases include, but are not limited to diabetes, autoimmune disease (eg, 
lupus, rheumatoid arthritis), and neurological disease (eg, epilepsy) and the type, incidence, 
and relationship to study investigational product will be summarized by treatment group and 
by SOC and PT based on MedDRA.
3.7.5
Subgroup Analyses
All AEs (including TEAEs, TESAEs, AESIs, IP-related skin reactions [including skin 
hypersensitivity reactions], NOCDs) will be summarized by age group used as randomization 
stratum (age ≤ 3.0 months, age > 3.0 to ≤ 6.0 months, age > 6.0 months), and weight on Day 1 
(weight < 2.5kg, weight ≥2.5 kg and < 5 kg, weight ≥ 5 kg). TEAEs, AESIs, IP-related skin 
reactions (including skin hypersensitivity reactions), and NOCDs will also be summarized by 
timing relative to dosing (‘within 1 day,’ ‘within 3 days’, ‘within 7 days’, ‘within 14 days’). In 
addition, TEAEs occurring within 1 day, 3 days, 7 days, and 14 days post dose by age group
at randomization stratum (≤3.0 months, > 3.0 to ≤ 6.0 months, > 6.0 months), weight on Day 
1 (weight < 2.5kg, weight ≥2.5 kg and < 5 kg, weight ≥ 5 kg) will also be summarized. 
3.7.6
Clinical Laboratory Parameters
Laboratory parameters (collected for Japanese subjects only) will be summarized at each visit 
by treatment group. Frequencies of worst observed Grade 3-4 toxicity, as defined by the 


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Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events (available at  https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables), will be presented for each laboratory parameter below by treatment group:
-
CBC: hemoglobin, platelets
-
WBC with differential: white blood cell count
-
Liver function: bilirubin, AST/ALT
-
Chemistry – general: creatinine. 
Also, laboratory parameters will be assessed by presenting tables containing information 
associated with 2-grade (or greater) laboratory shifts from baseline. All other serum chemistry 
and hematology parameters not listed above will be presented in the data listings.
For laboratory values reported as lower than the lower limit of quantification (LLOQ), a value 
equal to half of the limit of quantification will be imputed in the summaries. However, 
< LLOQ will be reported in the listings.
3.7.7
Other Safety Evaluations
Additional data collected throughout the study include screen failure data, significant findings 
in medical history and physical exam, vital signs, and concomitant medications through Day 
361. 
Medical history findings and those that are ongoing at the time of signed informed consent 
will be summarized by treatment group and for all subjects combined using the overall ITT 
population, ITT1 and ITT2. Data listings will be provided for these data. 
In addition, vaccines exposure, including the number of subjects receiving vaccine dose of the
six pre-specified vaccine groups (Tuberculosis vaccine; Influenza vaccine; 
Measles/Mumps/Rubella/Varicella; Rotavirus vaccine; Polyvalent diphtheria-poliomyelitis-
tetanus containing vaccine, Pneumococcal vaccine) and the total number of vaccine doses 
received within ±7 days of IP dosing, will be summarized for each vaccine group. The 
summaries will be conducted by treatment group and for all subjects combined using the 
overall as-treated population, AT1 and AT2. The same summary will be repeated within ±14 
days of IP dosing for the overall as-treated population, AT1 and AT2, and on the same day of 
IP dosing for AT2 only. 
For subjects with co-administered vaccines doses (on the same day, within ±7 days or ±14 
days of IP dosing), TEAEs that occur within 7 or 28 days following vaccine administration
will be summarized by SOC and PT and by treatment group. The percentage will be 


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calculated using subjects who received co-administered vaccine doses (on the same day, 
within ±7 days or ±14 days of IP dosing) as the denominator. These summaries will be 
provided for each of the six pre-specified vaccine groups individually. These summaries will 
only be conducted on AT2. The ATC codes for these vaccines will be provided in a separate 
file by the medical monitor prior to the DBL for the Primary Analysis. 
Subjects flagged as having wheeze during their respiratory illness assessment after Day 361 
will be listed. 
Upon review of the listings, additional summary tables may be generated as appropriate.
3.8
Anti-drug Antibodies
The number and percentage of subjects who develop anti-MEDI8897 antibodies will be 
summarized at each visit by treatment group on the overall as-treated population, AT1 and 
AT2. For those with a positive assessment, the ADA titer results will also be summarized. The 
number and percentage of ADA positive samples with specificity to the YTE or RSV-
neutralizing regions of MEDI8897 will also be summarized.
An additional table will summarize the number and percentage of subjects positive for ADA 
at baseline and positive at any post-baseline time point. The percentage who were persistent 
positive and transient positive will also be presented.
1
Persistent positive is defined as negative at baseline and positive at ≥ 2 post-baseline 
assessments (with ≥16 weeks between first and last positive) or positive at last post-
baseline assessment
2
Transient positive is defined as negative at baseline and at the last one post-baseline 
assessment, and positive at only ≥ 1 post-baseline assessment and not fulfilling the 
conditions for persistent positive.
To evaluate the impact of ADA on efficacy and safety, the primary and the secondary efficacy 
endpoints, as well as TEAE and SAE by SOC and PT based on MedDRA will be summarized 
by ADA post-baseline status (ie, at least one post-baseline ADA positive or not through 360 
days post dose). The primary and secondary efficacy endpoints will also be summarized by 
ADA post-baseline status through 150 days post dose. The safety summaries will be based on 
overall as-treated population, AT1, and AT2. The efficacy summaries will be based on ITT1 
and ITT2.
The impact of ADA on PK will be evaluated as described in Section 3.9.


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3.9
Pharmacokinetics
Individual MEDI8897 serum concentrations for each nominal sampling time will be listed and 
summary descriptive statistics will be presented and plotted versus time. Individual 
MEDI8897 serum concentrations will be graphically illustrated, and summarized, by ADA 
status. The PK summaries will be based on the as-treated population.
Further, model-based evaluation of PK will be detailed in a separate PK analysis plan and 
reported outside the CSR.
3.10
Impact on Analyses due to COVID-19 Pandemic
The COVID-19 pandemic has posed challenges in study conduction (including performing 
scheduled visits, and sample collections etc.). 
Efforts are ongoing to collect outstanding data via alternative means where possible, when on-
site visits cannot be performed. The following analyses have been added to assess the impact 
of the pandemic:  
!
Three sensitivity analyses of primary endpoint will be conducted for ITT1. Details are 
described in Section 3.10.1. 
!
Protocol deviations, including sample collections or visits missed due to COVID-19 
related protocol deviations will be described separately in the CSR. These deviations will 
be identifiable in the database with a ‘COVID’ prefix. This summary will be repeated for 
ITT1 and ITT2. 
!
Confirmed or suspected cases of COVID-19 will be summarized and included as AEs as 
appropriate. This summary will be repeated for the overall as-treated population, AT1, and 
AT2. 
3.10.1
Sensitivity Analyses
Sensitivity analyses 1 and 2 are to assess the robustness of the primary efficacy by exploring 
different estimands in handling the intercurrent events, defined as COVID-19 related protocol 
deviations or disruptions which occurs prior to having met the primary efficacy endpoint (and 
prior to Day 151). 
-
For sensitivity analysis 1, intercurrent events will be handled using principal stratum 
strategy. That is, subjects with intercurrent events will be excluded from the analysis. 
The remaining subjects will be analyzed using the same primary analysis model as 
described in Section 3.5.1.2. 


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-
For sensitivity analysis 2, intercurrent events will be handled using hypothetical 
strategy. That is, for subjects with intercurrent events, their event status will be 
imputed using the standard multiple imputation approach (based on the observed event 
rate per treatment group). Other than that, the analysis will be conducted using the 
same primary analysis model as described in Section 3.5.1.2. 
Sensitivity analysis 3 is to employ all available positive RT-PCR results (regardless from local 
or central lab) considering the challenge of obtaining nasal sample for central lab RT-PCR 
during the pandemic. More specifically, for subjects with intercurrent events, central lab 
RT-PCR results or local lab results (only if central lab results are not available) obtained after 
intercurrent events will be evaluated to determine RSV status (subjects will be considered 
RSV positive with either local or central lab positive RT-PCR result using the same analysis 
window as described in Section 3.5.1.1). Other than that, the analysis will be conducted using 
the same analysis model as described in Section 3.5.1.2. 
4
REFERENCES
Paramore LC, Mahadevia PJ, Piedra PA. Outpatient RSV lower respiratory infections among 
high-risk infants and other pediatric populations. Pediatr Pulmonol. 2010;45(6):578-84.
Zou, G. A Modified Poisson Regression Approach to Prospective Studies with Binary Data. 
Am J Epidemiol 2004; 159:702–706.
Little, R. J. A. and Rubin, D. B. Statistical Analysis with Missing Data, 2nd Edition, Hoboken, 
NJ: John Wiley & Sons 2002; 257.
O'Brien KL, Chandran A, Weatherholtz R, Jafri HS, Griffin MP, Bellamy T, et al. Respiratory 
Syncytial Virus Prevention study group. Efficacy of motavizumab for the prevention of 
respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomized 
double-blind placebo-controlled trial. Lancet Infect Dis. 2015;15(12):1398-408.
Breslow NE, Day NE. Statistical methods in cancer research. Volume II -- the design and 
analysis of cohort studies. IARC Sci Publ. 1987; (82):1-406.
O'Kelly, M, Bohdana, R. Clinical trials with missing data: A guide for practitioners. John 
Wiley & Sons, 2014.
Wilson, EB, Hilferty, MM. (1931). The distribution of chi-square. Proceedings of the National 
Academy of Sciences of the United States of America, 17, 684-688.
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. 
[July 2017].


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5
VERSION HISTORY
Version
Date
Description of Change
1.0
22JUL2019
Initial version
2.0
29Jan2021
•
Editorial changes for clarification.
•
Section 2.2 Study Design: added description of the primary 
and safety cohorts.
•
Section 2.4 Sample Size: updated study power based on the 
sample size of the primary cohort, on which the primary 
efficacy analysis will be based.
•
Section 3.1 Generation Considerations: updated planned 
analyses to Primary Analysis, Safety Analysis and Final 
Analysis; added description of the planned analyses; added 
general description of unblinding strategy; added visit 
window definitions. 
•
Section 3.2 Study Cohorts, Analysis Populations and 
Datasets: added “Study Cohorts” in the section name; added 
definitions of study cohorts; added the definitions ITT1, 
ITT2, AT1 and AT2 in Table 1 Analysis Populations; 
modified the definition of the primary dataset and final 
dataset, and added the definition of the safety dataset.
•
Added section 3.4.4 Violations and Deviations
•
Section 3.5.1.2 Primary Efficacy Analysis: provided the 
rational of using a reduced model when evaluating the 
primary endpoint. Dropped hemisphere from the analysis 
model. 
•
Section 3.5.1.2 Secondary Analyse of the Primary Efficacy
Endpoint: dropped hemisphere from the analysis model. 
•
Section 3.5.1.4 Supplementary Analyses of the Primary 
Efficacy Endpoint: added stratified proportional hazard model 
to generate hazard ratio and the corresponding 95% 


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confidence interval in Kaplan-Meier Analysis. Dropped 
hemisphere from the analysis model. Used the standard SAS 
procedure PROC GENMOD with the EXACT statement 
(rather than StatXact PROC Poisson procedure) in 
implementing the exact conditional method. Updated 
subgroup “weight at birth (weight ≤ 2.5 kg, weight > 2.5 kg to 
< 5 kg, weight ≥ 5 kg)” to “weight at birth (weight ≤ 2.5 kg, 
weight > 2.5 kg)”
•
Section 3.5.3 Other Efficacy Analyses: in the first paragraph, 
the summary for subjects who were hospitalized due to any 
respiratory illness, non-LRTI cases, with at least one 
medically attended LRTI event will only be categorized by 
RSV, non-RSV, hospitalization, outpatient only. 
Categorization by protocol-defined and non-protocol defined 
were removed. 
•
Added section 3.5.4 Additional Efficacy Analyses for the 
Safety Cohort. Added descriptive summaries for the safety 
cohort. 
•
Section 3.6.5 RSV resistance monitoring: revised the RSV 
resistance monitoring language to improve clarify and to align 
with clinical virology analysis plan
•
Section 3.7 Safety Analyses: updated safety summaries by as-
treated subjects from the primary and safety cohorts, and the 
overall as-treated subjects. 
•
Added age at randomization category by ≤8 months or > 8 
months as a subgroup in Section 3.4.2 Demographics and 
Baseline Characteristics, and for all AEs summaries in section 
3.7.5 Subgroup Analyses
•
Section 3.7.6 Clinical Laboratory Parameters: removed 
summary for BUN. 
•
Added section 3.10 Impacted on Analyses due to COVID-19 
Pandemic


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•
Appendix 2: added analysis window for ADA/RSV 
Neutralizing Antibody/RSV Serology.
•
Appendix 3: added analysis window for clinical lab data.
3.0
11Apr2021
•
Editorial change for clarity, including updating “3 months”,
“6 months” to “3.0 months” , “6.0 months”, respectively.
•
Section 3.1 General Considerations: clarified that all efficacy, 
PK, ADA and safety data collected for the primary cohort will 
be analyzed through Day 361, and data collected after Day 
361 will only be listed at Primary Analysis; similarly, data 
collected after Day 361 for safety cohort will only be listed at
the time of the Safety Analysis.
•
Section 3.4.2 Demographics and Baseline Characteristics: 
updated age at randomization category from ≤ 8.0 months 
or > 8.0 months, to < 9.0 months or ≥9.0 months. 
•
Section 3.4.4 Violations and Deviations: updated criteria for 
IPDs and added criteria for serious PDs.
•
Section 3.5.1.1 Primary Efficacy Endpoint: defined a RSV 
sample analysis window [-7, 14] days for medically attended 
RSV LRTI based on blinded data review.
•
Section 3.5.2.3 Supplementary Analyses of the Secondary 
Efficacy Endpoint Point: added hazard ratio and the 
corresponding 95% CI for time-to-first RSV LRTI 
hospitalization analysis.
•
Section 3.5.3 Other Efficacy Analyses: clarified rules to 
define severity among multiple LRTI events, and among 
multiple hospitalizations due to any respiratory illness, 
separately; added a bar plot for incidence of all medically 
attended LRTI regardless of severity through 150 days post 
dose; updated summaries for case definition elements to 
subjects who have at least one medically attended RSV LRIT 
(protocol-defined).


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•
Section 3.6.1 Healthcare Resource Utilization (HRU): 
updated summaries for pre-specified prescription (systemic 
antibacterial agents) and over the counter medications
(analgesics/antipyretics); added summaries for anti-wheezing 
medication use; removed medically attended non-RSV LRTI 
(protocol-defined), medically attended RSV LRTI (non-
protocol defined), and medically attended non-RSV LRTI 
(non-protocol defined) from the HRU summaries.
•
Section 3.6.2 Caregiver Burden: removed medically attended 
non-RSV LRTI (protocol-defined), medically attended RSV 
LRTI (non-protocol defined), and medically attended non-
RSV LRTI (non-protocol defined) from the caregiver burden
summaries.
•
Section 3.6.3 Anti-RSV Neutralizing Antibody and Section 
3.6.4 RSV Serology: added definition for RSV exposure and 
summaries for RSV exposure; added summaries of RSV 
exposure, geometric mean concentration, and geometric mean 
fold-rise for subjects with and without central RT-PCR 
positive results through 360 days post dose; added box plot 
for serum antibody levels for all subjects by treatment group 
and by visit. Clarified that the analysis based on overall as-
treated population will only be conducted during Final 
Analysis.
•
Section 3.7.2 Adverse Events of Special Interest: modified 
wording in summarizing AESIs; added summaries of AESIs 
based on SMQs and selected MedDRA preferred terms codes. 
•
Section 3.7.3 Skin and Hypersensitivity Reactions: updated 
the wording to summarize IP-related skin reactions only. 
•
Section 3.7.5 Subgroup Analyses: modified wording for 
clarification; added “within 3 days” as timing relative to 
dosing; removed summaries by age at randomization group ≤ 
8.0 months or > 8.0 months; added additional summaries 
examining dose relative to dosing combined with other 
subgroups of interest.


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•
Section 3.7.7 Other Safety Evaluation: added summaries for 
medical history findings (overall and ongoing); added 
summaries for vaccines exposure; added summaries for
treatment-emergent adverse events onset within 7 or 28 days
post co-administered vaccine doses (within ±7 days or ±14 
days of IP dosing).
•
Section 3.8 Anti-drug Antibodies: modified the definition of 
persistent positive and transient positive.
•
Section 3.9, serum concentrations and ADA influence on PK 
will be summarized within the CSR (not in PK report). 
Removed reference to PK parameters as PK will be evaluated 
using a model-based approach (described and reported outside 
the CSR). This change has been made prior to DBL for 
Primary Analysis. 
•
Added Appendix 4 Imputation Rule of Partial Dates


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Appendix 1
Elements to Evaluate for Case Definition of Medically 
Attended RSV LRTI (Protocol defined)
Specificity 
Sensitivity
Medical Significance
RSV Confirmed: 
•
Positive by central laboratory 
RT-PCR assay 
Documented PE findings 
localizing to lower respiratory 
tract: 
•
Rhonchi
•
Rales
•
Crackles
•
Wheeze
Objective measures of clinical 
severity: 
•
Increased respiratory rate
•
Hypoxemia
•
Acute hypoxic or ventilatory 
failure
•
New onset apnea
•
Nasal flaring
•
Retractions
•
Grunting
•
Dehydration due to 
respiratory distress requiring 
IV hydration
LRTI = lower respiratory tract infection; PE = physical examination; RSV = respiratory syncytial virus; RT-PCR 
= real time reverse transcriptase-polymerase chain reaction; 
Note: One item from each column is required to meet the case definition of RSV LRTI.


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Statistical Analysis Plan for Protocol D5290C00004
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Appendix 2
Analysis Window for ADA/RSV Neutralizing Antibody/RSV 
Serology
Protocol 
Scheduled Study Day
Analysis Windows
Global/Japan
Day 1
≤ 1
Global/Japan
Day 31
2 - 91
Global/Japan
Day 151
92 - 255
Global/Japan
Day 361
≥ 256
EU
Day 1
≤ 1
EU
Day 151
2 - 255
EU
Day 361
≥ 256


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Statistical Analysis Plan for Protocol D5290C00004
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Appendix 3
Analysis Window for Clinical Lab Data
Protocol
Scheduled Study Day
Analysis Windows
Japan
Day 1
≤ 1
Japan
Day 8
2 - 20
Japan
Day 31
21 - 91
Japan
Day 151
≥ 92


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Statistical Analysis Plan for Protocol D5290C00004
MEDI8897
11 Apr 2021; Final v3.0
CONFIDENTIAL AND PROPRIETARY
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Appendix 4
Imputation Rule for Partial Dates
If only a partial date is available is required for imputation, the following rules will be applied. 
General Imputation Rule for Partial Date
•
Partial dates where only the year is known: 
-
For start dates assume January 1st. 
-
For stop dates assume December 31st. 
•
Partial dates where only the month and year are known: 
-
For start dates assume the first of the month. 
-
For stop dates assume the end of the month.
Imputation Rule for Partial AE Start Date
•
When AE range is available:
Step 1: For partial AE start dates, regardless if only the year is known, or only the 
month and year are known, first use the following rule to impute an AE start date:
-
Assume (dose date + 1 day) if AE started <= 7 days after dosing;
-
Assume (dose date + 7 days) if AE started 8 - 14 days after dosing;
-
Assume (dose date + 14 days) if AE started >14 days after dosing.
Step 2: After getting an imputed AE start date from Step 1, compare the imputed AE 
start date with the partial AE start date:
-
If partial AE start date where only the year is known:
o
If the year of partial AE start date is the same as imputed AE start date 
from Step 1, then use imputed AE start date from Step 1;
o
If the year of partial AE start date is different from the year of imputed 
AE start date from Step 1, assume partial AE start date as January 1st;
o
If the imputed AE start date is after AE end date, then set AE start date 
the same as AE end date.
-
If partial AE start date where only the year and month are known:
o
If the year and month of partial AE start date are the same as imputed AE 
start date from Step 1, then use imputed AE start date from Step 1;
o
Otherwise, assume partial AE start date as the first day of the month.
o
If the imputed AE start date is after AE end date, then set AE start date 
the same as AE end date.
•
When AE range is not available, for any treatment-emergent AEs,
-
If partial AE start date where only the year is known,
o
If the same year as dosing date, and if AE does not occur on the same 
day of dosing, then AE start date is one day after dosing date; otherwise, 
AE start date is the same as dosing date.
o
If different year from dosing date, assume January 1st.
-
If partial AE start date where only the year and month are known,
o
If the same year and month as dosing date, and if AE does not occur on 
the same day of dosing, then AE start date is one day after dosing date;
otherwise, AE start date is the same as dosing date.
o
Otherwise, assume the first day of that month.


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11 Apr 2021; Final v3.0
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Imputation Rule for Partial Concomitant Medications Dates
•
If a ConMed is not associated with an AE:
-
Apply the general imputation rule wherever fits.
•
If a ConMed is associated with an AE:
-
The ConMed start date will be imputed with either observed or imputed AE start 
date. If there are multiple associated AEs, the earliest AE start date either observed 
or imputed will be used for imputation. 
-
The ConMed end date will be imputed by the general imputation rule for end date 
whenever fits. 


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Document Name: d5290c00004-sap-ed-3
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Statistical Analysis Plan Edition 3
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