Conditions: Respiratory Syncytial Virus Infections
Keywords: Respiratory Syncytial Virus, RSV Preterm Infants Lower Respiratory Tract Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1453
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics (PK), and antidrug antibody (ADA) response for MEDI8897 in healthy preterm infants who are between 29 and 35 weeks gestational age (GA) and entering their first Respiratory Syncytial Virus (RSV) season.

Detailed description:
This pivotal Phase 2b study will determine if MEDI8897 will be efficacious in reducing medically attended RSV-confirmed lower respiratory tract infections (LRTI) in healthy preterm infants entering their first RSV season. The population to be enrolled is healthy preterm infants born between 29 weeks 0 days and 34 weeks 6 days GA who would not receive RSV prophylaxis. A total of 1500 infants will be randomized 2:1 to receive either MEDI8897 or placebo. Participants will be followed for 360 days after dosing. Enrollment is planned at approximately 197 sites across the USA, Canada, Europe, and the Southern Hemisphere.

Arms:
arm 1: Participants will receive a single intramuscular (IM) dose of placebo matched to MEDI8897 on Day 1 of the study. arm 2: Participants will receive a single IM dose of MEDI8897 50 milligrams (mg) on Day 1 of the study.

Interventions: intervention 1: MEDI8897 intervention 2: Placebo
Intervention descriptions: intervention 1: A single IM dose of 50 mg on Day 1 of the study. intervention 2: A single IM dose of placebo matched to MEDI8897 on Day 1 of the study.

Protocol document:
Prot_000.pdf: 
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A Phase 2b 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 Preterm Infants
Sponsor Protocol Number: D5290C00003
Application Number:
Investigational Product:
MEDI8897
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca 
PLC, One MedImmune Way, Gaithersburg, Maryland, 20878, 
USA 
Medical Monitor:
Senior Director, Clinical Development, MedImmune
Contract Research Organization:
Protocol History, Date:
Original Protocol, 02Jun2016
Protocol Amendment 1, 25Jan2018


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PROTOCOL SYNOPSIS
TITLE  
A Phase 2b 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 Preterm Infants
HYPOTHESES  
Primary Hypothesis:
Compared to placebo, a single 
mg intramuscular (IM) dose of MEDI8897 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 preterm infants 
born between 29 weeks 0 days and 34 weeks 6 days gestational age (GA) and entering their first RSV season, 
and the safety profile will be acceptable.
Secondary Hypotheses: 
1.
There will be a reduction in the incidence of hospitalizations attributable to RSV 
2.
The predicted extended terminal half-life (t1/2) will be adequate for the duration of the RSV season
3.
Anti-drug antibody (ADA) to MEDI8897 will not significantly impact the serum concentrations or 
safety of MEDI8897 over the 5-month RSV season
OBJECTIVES
Primary Objective:
To assess the efficacy of MEDI8897 when administered as a single 
mg IM dose to healthy preterm infants 
born between 29 weeks 0 days and 34 weeks 6 days GA and entering their first RSV season for the reduction 
of medically attended LRTI due to RT-PCR-confirmed RSV, compared to placebo
Secondary 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
Exploratory Objective:
To assess healthcare resource utilization (HRU) and caregiver burden for MEDI8897 recipients compared to 
placebo recipients
STUDY ENDPOINTS  
Primary Endpoint: 
Incidence of medically attended LRTI (inpatient and outpatient) due to RT-PCR-confirmed RSV over the 
duration of the 5-month RSV season
Secondary Endpoints: 
1.
Incidence of hospitalizations due to RT-PCR-confirmed RSV over the duration of the 5-month RSV 
season  
2.
Safety and tolerability of MEDI8897 as assessed by the occurrence of all treatment-emergent adverse 
events (TEAEs), treatment-emergent serious adverse events (TESAEs), adverse events of special interest 
(AESIs), and new onset chronic diseases (NOCDs)
3.
Single-dose MEDI8897 serum concentrations
4.
Incidence of ADA to MEDI8897 in serum
Exploratory Endpoints:
1.
Magnitude of HRU (eg, number of admissions to hospitals and intensive care units [ICUs] and duration 
of stay; number of subjects who require respiratory support and supplemental oxygen and the duration of 


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use; number and type of outpatient visits, eg, emergency room [ER], urgent care, outpatient clinic; and 
number of prescription and over-the-counter [OTC] medications and duration of use) for MEDI8897 
recipients compared to placebo recipients.
2.
Caregiver burden (eg, caregiver missed work days, subject absence from day care) for subjects with 
medically attended LRTI caused by RT-PCR-confirmed RSV
STUDY DESIGN  
This pivotal Phase 2b study is a randomized, double-blind, placebo-controlled, single-dose study to 
determine if MEDI8897 will be efficacious in reducing medically attended RSV-confirmed LRTI in healthy 
preterm infants entering their first RSV season. The population to be enrolled is healthy preterm infants born 
between 29 weeks 0 days and 34 weeks 6 days GA who would not receive RSV prophylaxis based on the 
American Academy of Pediatrics (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 1,500 infants will be randomized 2:1 to receive a 
 mg IM dose of MEDI8897 (N = 
1000) or placebo (N = 500). Randomization will be stratified by temperate zones in the northern and 
southern hemisphere and by subject age at the time of randomization (ie, ≤3 months, > 3 – ≤6 months, > 6 
months). Enrollment of infants > 6 months of age will be limited to approximately 500. All infants will be 
followed for approximately 360 days after dosing.
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical attention for a 
respiratory illness (inpatient or outpatient setting) will be evaluated for the occurrence of LRTI. Subjects who 
have a primary hospitalization for a respiratory illness, a respiratory deterioration during a hospitalization, or 
who seek outpatient medical attention, including ER visits for a respiratory illness, will be assessed for RSV 
by diagnostic testing of respiratory secretions and clinical assessment for the presence of LRTI. Testing for 
RSV will be performed centrally using the United States Food and Drug Administration (US FDA)-approved 
and Conformité Européenne or European Conformity (CE) - marked in vitro diagnostic real-time RT-PCR 
assay (Lyra RSV + human metapneumovirus [hMPV] Assay, Quidel, San Diego, CA www.quidel.com). A 
diagnosis of RSV LRTI requires having a respiratory sample positive for RSV by RT-PCR.
Subjects with signs of LRTI must have documented physical exam findings of rhonchi, rales, crackles, or 
wheeze AND any of the following:
•
Increased respiratory rate at rest (age < 2 months, ≥ 60 breaths/min; age 2–6 months, ≥50 breaths/min; 
age > 6 months – 2 years, ≥40 breaths/min) OR
•
Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1800 meters or < 92% at altitudes 
> 1800 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).
TARGET SUBJECT POPULATION  
This study will be conducted in healthy preterm infants born between 29 weeks 0 days and 34 weeks 6 days 
GA who would not be recommended to receive palivizumab per AAP or local or national guidelines, and 
who are entering their first RSV season at the time of screening.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION  
Subjects will be randomly assigned to receive a single dose of MEDI8897
 mg IM) or placebo.
STATISTICAL ANALYSIS PLAN
General Considerations:
Tabular summaries will be presented by treatment group. Categorical data will be summarized by the number 
and percentage of subjects in each category. Continuous variables will be summarized by descriptive 
statistics. Additional details of statistical analyses will be described in the statistical analysis plan.
The 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, will be performed on the ITT Population.


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The As-treated Population will include all subjects who are randomized into the study and who receive any 
amount of investigational product. Subjects will be included in the treatment group corresponding to the 
treatment actually received. All safety analyses will be performed on the As-treated Population.
Sample size:
The sample size of 1,500 is necessary based on advice from the US FDA requesting that 1,000 preterm 
infants be exposed to MEDI8897 in this Phase 2b study. This sample size has approximately 99% power to 
detect 70% relative risk reduction, assuming a placebo group medically attended RSV LRTI incidence of 
8%. Power calculations are based on Poisson regression model with robust variance (Zou, 2004) comparing 
MEDI8897 
 versus placebo, with 2-sided significance level of α = 0.05.
•
The 70% relative risk reduction assumption is based on a placebo-controlled study in Native American 
infants in which there was 87% relative reduction in the incidence of RSV hospitalization (11.3% 
placebo; 1.5% motavizumab; p < 0.001) and 71% relative reduction in the incidence of outpatient RSV 
LRTI (10.0% placebo; 2.9% motavizumab; p < 0.001) in infants who received motavizumab prophylaxis
(O’Brien et al, 2015).
In order to evaluate risk, a sample size of 1,000 subjects exposed to MEDI8897 will provide a 90% 
probability of observing at least one adverse event (AE) if the true event rate is 0.2%; if no AEs are observed, 
this study provides 95% confidence that the true event rate is < 0.3%.
Statistical Analyses:
There are two planned analyses for this study: the primary analysis and the final analysis. The primary 
analysis will be conducted after all randomized subjects have completed follow-up through the 5-month RSV 
season (ie, Day 151 visit) 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 through at 
least Day 151 will be analyzed. The final analysis for safety follow-up will be conducted when all subjects 
have completed the last visit of the study (ie, Day 361). Since efficacy endpoints are collected in the time 
interval from randomization up to Day 151, the efficacy analyses performed in the primary analysis will 
serve the purpose of evaluating the efficacy of MEDI8897 in the study population. 
The primary and secondary efficacy hypotheses will be assessed in the primary analysis 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 will be summarized 
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 will be conducted on the ITT Population. LRTI caused by RSV that occurs 
prior to discontinuation from participation in the study will contribute to the primary efficacy analysis. For 
subjects who do not have an RSV LRTI prior to discontinuation from participation, their event status will be 
imputed assuming the observed placebo RSV LRTI rate. This will be implemented by imputations based on 
repeated simulations and will be described in the Statistical Analysis Plan. 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 – ≤ 6 months, > 6 months), and dichotomous temperate (northern and 
southern) hemispheres as covariates. In addition, the 2-sided p-value and corresponding 2-sided 95% CI on 
the relative risk will be provided from the model. Relative risk reduction is defined as (1 - Pn/Ps) where Pn is 
the incidence of RSV LRTI during 5 months of the RSV season in the MEDI8897 group and Ps is the 
incidence of RSV LRTI during 5 months of the RSV season in the placebo group generated by the model.
Statistical significance will be achieved if the 2-sided p-value is ≤0.05.
Additional Analyses of the Primary Endpoint


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A CMH (Cochran-Mantel-Haenszel) approach stratified by hemisphere and age group at the time of 
randomization (ie, ≤ 3 months, > 3 – ≤ 6 months, > 6 months) will be used to compare the incidence of RSV 
LRTI during 5 months of the RSV season between treatment groups as a sensitivity analysis for the primary 
endpoint. 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 lab or 
local lab.
Different approaches to handle missing data (ie, early discontinuation and no RSV LRTI prior to 
discontinuation) may be considered for sensitivity analyses. Additional analyses or subgroup summaries may 
be performed to adjust duration of efficacy follow-up and/or other possible confounding factors. These 
analyses will be described in the Statistical Analysis Plan.
Secondary Endpoint Analyses:
Efficacy
The incidence of RSV hospitalization during 5 months of the RSV season will be summarized by treatment 
group. The same methods described above for the primary efficacy endpoint will be used to assess treatment 
effect on RSV hospitalization. Following a hierarchical testing procedure, the secondary efficacy endpoint is 
tested at the significance level of 2-sided 0.05 if the primary analysis on the primary efficacy endpoint has 
achieved statistical significance at the level of 2-sided 0.05.
Safety
Safety of MEDI8897 will primarily be assessed by the occurrence of treatment-emergent AEs and SAEs. 
Adverse events will be graded according to the current version of the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) where applicable for pediatric assessments. Adverse 
events will be coded by Medical Dictionary for Regulatory Activities (MedDRA) and the type, incidence, 
severity and relationship to study 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. Terminal phase half-life (t1/2) 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 and association with TEAEs and TESAEs will be assessed.
Exploratory Endpoint Analyses:
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 without medically attended LRTI.
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.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................2
LIST OF ABBREVIATIONS........................................................................................10
1
INTRODUCTION ..............................................................................................12
1.1
Disease Background..................................................................................12
1.2
MEDI8897 Background............................................................................13
1.3
Summary of Nonclinical Experience .........................................................14
1.4
Summary of Clinical Experience...............................................................15
1.5
Rationale for Conducting the Study...........................................................17
1.6
Research Hypotheses ................................................................................17
1.6.1 Primary Hypothesis.........................................................................17
1.6.2 Secondary Hypotheses ....................................................................17
2
OBJECTIVES.....................................................................................................18
2.1
Objectives.................................................................................................18
2.1.1 Primary Objective...........................................................................18
2.1.2 Secondary Objectives......................................................................18
2.1.3 Exploratory Objective.....................................................................18
2.1.4 18
2.2
Study Endpoints........................................................................................18
2.2.1 Primary Endpoint............................................................................18
2.2.2 Secondary Endpoints ......................................................................18
2.2.3 Exploratory Endpoints ....................................................................19
3
STUDY DESIGN................................................................................................19
3.1
Description of the Study............................................................................19
3.1.1 Overview……….............................................................................19
3.1.2 Treatment Regimen.........................................................................21
3.2
Study Design and Dose Rationale .............................................................22
3.2.1 Dose Rationale................................................................................22
3.2.2 Rationale for Study Population .......................................................22
3.2.3 Rationale for Endpoints ..................................................................22
4
MATERIALS AND METHODS.........................................................................23
4.1
Subjects ....................................................................................................23
4.1.1 Number of Subjects ........................................................................23
4.1.2 Inclusion Criteria ............................................................................23
4.1.3 Exclusion Criteria ...........................................................................24
4.1.4 Subject Enrollment and Randomization ..........................................25
4.1.5 Withdrawal from the Study.............................................................25


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4.1.6 Criteria for Discontinuation of Investigational Product for Individual 
Subjects ...........................................................................25
4.1.7 Replacement of Subjects.................................................................26
4.1.8 Withdrawal of Informed Consent for Data and Biological Samples.26
4.2
Schedule of Study Procedures...................................................................27
4.2.1 Enrollment/Screening Period ..........................................................27
4.2.2 Treatment and Follow-up Period.....................................................28
4.3
Description of Study Procedures ...............................................................31
4.3.1 Efficacy………...............................................................................31
4.3.1.1
Lower Respiratory Tract Infection....................................31
4.3.2 Medical History and Physical Examination, Weight, and Vital 
Signs................................................................................34
4.3.3 Pharmacokinetic and Anti-drug Antibody Samples .........................34
4.3.4 Pharmacokinetic Evaluation and Methods.......................................34
4.3.5 Anti-drug Antibody Response Evaluation and Methods ..................35
4.3.6 Healthcare Resource Utilization and Caregiver Burden Evaluation .35
4.3.7 Estimates of Blood Volume to be Collected ....................................35
4.4
Study Suspension or Termination..............................................................35
4.5
Investigational Products............................................................................36
4.5.1 Identity of Investigational Product(s) ..............................................36
4.5.1.1
Investigational Product Dose Administration....................37
4.5.1.2
Treatment Administration ................................................38
4.5.1.3
Monitoring of Dose Administration..................................38
4.5.1.4
Reporting Product Complaints .........................................38
4.5.2 Additional Study Medications.........................................................39
4.5.3 Labeling………..............................................................................39
4.5.4 Storage………................................................................................39
4.5.5 Treatment Compliance....................................................................39
4.5.6 Accountability ................................................................................39
4.6
Treatment Assignment and Blinding .........................................................40
4.6.1 Methods for Assigning Treatment Groups.......................................40
4.6.2 Methods for Ensuring Blinding .......................................................40
4.6.3 Methods for Unblinding..................................................................41
4.6.3.1
Unblinding in the Event of a Medical Emergency.............41
4.6.3.2
Unblinding for Primary Analysis Purposes.......................41
4.7
Restrictions During the Study and Concomitant Treatment(s) ...................41
4.7.1 Permitted Concomitant Medications ...............................................42
4.7.2 Prohibited Concomitant Medications ..............................................42
4.8
Statistical Evaluation.................................................................................42


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4.8.1 General Considerations...................................................................42
4.8.2 Sample Size and Power Calculations...............................................42
4.8.3 Efficacy Analysis............................................................................43
4.8.3.1
Primary Efficacy Analysis................................................43
4.8.3.2
Additional Analyses of the Primary Endpoint...................44
4.8.3.3
Secondary Efficacy Analyses ...........................................44
4.8.4 Safety Analysis………. ..................................................................44
4.8.5 Analysis of Pharmacokinetics and Anti-drug Antibody...................45
4.8.5.1
Analysis of Pharmacokinetics...........................................45
4.8.5.2
Analysis of Anti-drug Antibodies.....................................45
4.8.6 Exploratory Analyses......................................................................45
4.8.7 Data Monitoring Committee ...........................................................45
5
ASSESSMENT OF SAFETY..............................................................................46
5.1
Definition of Adverse Events ....................................................................46
5.2
Definition of Serious Adverse Events........................................................46
5.3
Definition of Adverse Events of Special Interest .......................................47
5.3.1 Hypersensitivity, Including Anaphylaxis.........................................47
5.3.2 Immune Complex Disease ..............................................................47
5.3.3 Thrombocytopenia..........................................................................48
5.4
Definition of New Onset Chronic Disease.................................................49
5.5
Recording of Adverse Events....................................................................49
5.5.1 Time Period for Collection of Adverse Events ................................49
5.5.2 Follow-up of Unresolved Adverse Events .......................................49
5.6
Reporting of Serious Adverse Events ........................................................49
5.7
Other Events Requiring Immediate Reporting ...........................................50
5.7.1 Overdose……….............................................................................50
5.7.2 Adverse Events of Special Interest..................................................51
5.7.2.1
Hypersensitivity, Including Anaphylaxis..........................51
5.7.2.2
Immune Complex Disease................................................51
5.7.2.3
Thrombocytopenia ...........................................................51
5.7.3 New Onset Chronic Disease............................................................52
6
STUDY AND DATA MANAGEMENT .............................................................52
6.1
Training of Study Site Personnel...............................................................52
6.2
Monitoring of the Study............................................................................52
6.2.1 Source Data ....................................................................................53
6.2.2 Study Agreements...........................................................................53
6.2.3 Archiving of Study Documents.......................................................53
6.3
Study Timetable and End of Study............................................................53


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6.4
Data Management .....................................................................................53
6.5
Medical Monitor Coverage........................................................................54
7
ETHICAL AND REGULATORY REQUIREMENTS........................................54
7.1
Ethical Conduct of the Study.....................................................................54
7.2
Subject Data Protection.............................................................................54
7.3
Ethics and Regulatory Review...................................................................54
7.4
Informed Consent......................................................................................55
7.5
Changes to the Protocol and Informed Consent Form................................56
7.6
Audits and Inspections ..............................................................................56
8
REFERENCES ...................................................................................................57
9
CHANGES TO THE PROTOCOL......................................................................59
9.1
Protocol Amendment 1, 25Jan2018...........................................................59
LIST OF IN-TEXT TABLES
Table 4.2.1-1
Schedule of Screening Procedures ....................................................27
Table 4.2.2-1
Schedule of Treatment Period and Follow-up Period Study 
Procedures........................................................................................29
Table 4.3.1.1-1
Elements to Evaluate for Case Definition of RSV LRTI....................32
Table 4.3.7-1
Volume of Blood to be Collected......................................................35
Table 4.5.1-1
Identification of Investigational Products..........................................37
LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................21
LIST OF APPENDICES
Appendix 1
Signatures.........................................................................................60
Appendix 2
Additional Safety Guidance ..............................................................63
Appendix 3
National Institute of Allergy and Infectious Diseases (NIAID) and 
Food and Allergy Anaphylaxis Network (FAAN) Guidance for 
Anaphylaxis Diagnosis .....................................................................66


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
AAP
American Academy of Pediatrics
AE
adverse event
AESI
adverse event of special interest
BP
blood pressure
CE
Conformité Européenne or European Conformity
CHD
congenital heart disease
CI
confidence interval
CLD
chronic lung disease
DMC
data monitoring committee
eCRF
electronic case report form
EDC
electronic data capture
ER
emergency room
EU
European Union
Fc
fragment cystallizable
FcRn
neonatal Fc receptor
FTIH
first-time-in-human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HIV
human immunodeficiency virus
hMPV
human metapneumovirus
HRU
healthcare resource utilization
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee
IgG1κ
immunoglobulin G1 kappa 
IM
intramuscular
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
LRTI
lower respiratory tract infection
mAb
monoclonal antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID
National Institute of Allergy and Infectious Diseases
NOCD
new onset chronic disease
OTC
over-the-counter


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Abbreviation or 
Specialized Term
Definition
PEF
peak expiratory flow
PK
pharmacokinetics
RSV
respiratory syncytial virus
RT-PCR
real time reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SID
subject identification
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
TK
toxicokinetics
TESAE
treatment-emergent serious adverse event
URTI
upper respiratory tract infection
US FDA
United States Food and Drug Administration
USA
United States of America
UTI
urinary tract infection 
wGA
weeks gestational age
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 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 infants and no treatment for RSV, the current management for 
these patients when they acquire serious RSV illness is supportive care. 
Palivizumab (Synagis®) is the only approved agent for RSV prophylaxis, and its use is 
restricted to high-risk children (preterm infants ≤ 35 weeks gestational age [wGA], children 
with chronic lung disease [CLD] of prematurity, and children with hemodynamically 
significant congenital heart disease [CHD]). As its terminal half-life (t1/2) is approximately 1 
month, palivizumab must be administered monthly (as an intramuscular [IM] injection) 
throughout the RSV season, making its use in a broader infant population unfeasible. In 
addition, due to the cost, further restrictions have been implemented by local or national 
recommending bodies. 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 wGA (American Academy of Pediatrics Committee on 
Infectious Diseases, 2014).
1.1
Disease Background
Respiratory syncytial virus is the most common cause of lower respiratory illness among 
infants and young children, resulting in annual epidemics worldwide (Hall et al, 2009; Hall, 
2012; Nair et al, 2010; Shay et al, 1999; Stockman et al, 2012). All children, including 
healthy term infants, are at risk for severe RSV lower respiratory illness with primary 
infection during infancy. Ninety percent of children are infected with RSV in the first 2 years 
of life and up to 40% will have lower respiratory tract infection (LRTI) (Greenough et al, 
2001; Meissner, 2003; Parrott et al, 1973). Respiratory syncytial virus 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). Respiratory syncytial virus bronchiolitis was the 
leading cause of hospital admissions for infants < 1 year of age for any reason in the years 
between 1997 and 1999 (Leader et al, 2002).
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) such that office visits and 


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emergency department visits are more frequent than subsequent hospitalization, 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). Additionally, Paramore and colleagues reported high rates of outpatient RSV LRTI 
among infants and young children, ranging from 157.5 to 252.0 per 1000 children < 1 year of 
age (Paramore et al, 2010). This study also showed that outpatient RSV LRTI rates for late 
preterm (33 to 36 wGA) infants ranged from 183.3 to 245.7 per 1000 infants, with rates for 
full-term infants ranging from 128.8 to 171.3 per 1000 infants.
Hospitalization rates among young children in European countries appear to be similar to 
those in the USA; 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.
Similarly, high rates of RSV hospitalization are evident in South Africa for infants < 6 
months of age, in which the incidence (95% confidence interval [CI]) of severe LRTI was 26.2
(23.6-29.0) per 1000 in those born at ≥ 36 wGA, 125.0 (95.3-159.9) per 1000 in those born at
32 - 35 wGA, and 142.3 (89.5-212.0) per 1000 in those born at < 32 wGA (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 numbering 
system]) in the fragment crystallizable (Fc) region to prolong the t1/2, which is expected to 
provide protection from serious RSV disease for the duration of the RSV season. 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 


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potent than palivizumab in vitro and approximately 9-fold more potent than palivizumab in 
vivo in the cotton rat model. MEDI8897 is currently under development by 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 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 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). 
Toxicity, toxicokinetics (TK) and immunogenicity of MEDI8897 were evaluated in a Good 
Laboratory Practice (GLP)-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. Once weekly IV or IM administration (5 doses total) of MEDI8897 to 
monkeys, up to and including 300 mg/kg IV or 300 mg IM dose levels, was not associated 
with any treatment-related adverse effects locally or systemically. The no-observed-adverse-
effect-level (NOAEL) was considered to be 300 mg/kg IV and 300 mg IM. No anti-drug 
antibody (ADA) was detected in any of the monkeys during the treatment phase. During the 
recovery phase, 4 of 12 animals treated with MEDI8897 and 0 of 6 control animals were 


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ADA positive with variable impact on TK. In addition, tissue cross-reactivity against 
cryosections of a full panel of adult and a selected panel of juvenile, neonatal, and fetal 
human tissues showed no staining of any tissues, as expected, given the target for MEDI8897 
is a non-endogenous viral-specific target. Overall, data from nonclinical studies do not reveal 
any MEDI8897-related safety concerns.
Details of these studies are included in the current Investigator’s Brochure.
1.4
Summary of Clinical Experience
Two clinical studies of MEDI8897 have been conducted so far. The Phase 1a, first-time-in 
human (FTIH) study (Study D5290C00001; ClinicalTrials.gov Identifier NCT02114268) in 
healthy adult volunteers was completed in June 2015, and the second study, a Phase 1b/2a 
study (D5290C00002; ClinicalTrials.gov Identifier NCT02290340), in healthy preterm 
infants of 32-35 wGA has completed enrollment and dosing; follow-up is ongoing.
The FTIH study, D5290C00001, was a Phase 1a, randomized, double-blind, placebo-
controlled, dose-escalation study to evaluate the safety and tolerability, PK, and ADA for 
MEDI8897 when administered as a single fixed dose of 300, 1000, or 3000 mg IV, or 100 or 
300 mg IM to healthy adult subjects. Subjects completed 1 year of follow-up in June 2015. A 
total of 136 subjects were randomly assigned to receive 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, and model-estimated systemic bioavailability after 
IM administration was 87%. The predicted 3- to 4-fold increase in the t1/2 of MEDI8897 
compared to a standard immunoglobulin G (IgG) antibody was confirmed. In healthy adults, 
the safety profile of MEDI8897 was favorable, with similar proportions of adverse events 
(AEs) reported in placebo (21/34; 61.8%) and MEDI8897 recipients (64/102; 62.7%). Two 
SAEs (gunshot wound and appendicitis) were reported in 2 MEDI8897 recipients. AEs 
judged to be related to study drug were reported in 29.4% (10/34) of placebo recipients and 
17.6% (18/102) of MEDI8897 recipients. The most frequently reported AEs in the 
MEDI8897 cohorts were upper respiratory tract infection (URTI; 19/102; 18.6%), headache 
(9/102; 8.8%), urinary tract infection (UTI; 6/102; 5.9%); and dermatitis contact,
musculoskeletal pain, nausea and vomiting (5/102, 4.9% each). All other AEs occurred in 4
or fewer subjects. There were no events designated as adverse events of special interest
(AESI). One event of Type 2 diabetes was reported as a new onset chronic disease (NOCD)
in the placebo group. There were no deaths. No safety signals in this healthy adult population 
were observed. Post-baseline ADA was detected in a similar proportion of placebo recipients 
(5/33, 15.2%) and MEDI8897 recipients (14/102, 13.7%), and the presence and titer of ADA 


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had no effect on PK or the safety profile. These results demonstrated an acceptable safety 
profile for MEDI8897.
The Phase 1b/2a first-in-pediatric study (D5290C00002) is an ongoing, randomized, double-
blind, placebo-controlled, dose-escalation study designed to evaluate the safety and 
tolerability, PK and ADA for MEDI8897 in healthy preterm infants of 32 - 35 wGA who
would not receive RSV prophylaxis based on the AAP (American Academy of Pediatrics 
Committee on Infectious Diseases, 2014) or any other local or national recommending 
bodies’ guidelines. This study population was selected based on advice from the United 
States Food and Drug Administration (US FDA) to perform initial clinical evaluations of 
MEDI8897 in a population where the benefit of RSV prophylaxis has been proven.
Enrolment and dosing have been completed in 89 infants from sites in the United States, Chile, 
and South Africa. Infants were randomized and received a single IM dose of 10 mg, 25 mg, or
50 mg MEDI8897 (N = 71) or placebo (N = 18). All subjects are being followed for 1 year. 
The first interim analysis was conducted 30 days (October 2015) after the last subject was 
dosed to evaluate MEDI8897 serum concentrations, ADA, and safety. At the interim 
analysis, 1 infant in the placebo group had been withdrawn from the study because the 
mother could no longer bring the infant in for follow-up visits. At study entry, infants had a 
mean age (± SD) and mean weight (± SD) of 6.95 (± 2.63) months and 7.31 (± 1.84) kg in 
the placebo group and 6.50 (± 2.64) months and 6.82 (± 1.90) kg in the MEDI8897 group. 
MEDI8897 serum concentrations were consistent with the expected extended t1/2 in infants. 
Model-based simulations predict the MEDI8897 median t½ to range from 83 to 94 days for 
the 50 mg dose in infants with normal clearance. In healthy preterm infants the safety profile 
of MEDI8897 was favorable with similar proportions of AEs reported in the placebo (12/18, 
66.7%) and MEDI8897 (51/71, 71.8%) recipients. No safety signals were observed with the 
ascending dose levels. There was 1 serious adverse event (SAE) that occurred in an infant 
who received 25 mg of MEDI8897. The infant was hospitalized for LRTI and, upon 
subsequent testing, was found to be negative for RSV by the real time reverse transcriptase-
polymerase chain reaction (RT-PCR) assay. The illness resolved. All of the AEs were Grade 
1 or 2 in severity. The most frequently reported AEs were URTI (placebo, 7/18, 38.9%; 
MEDI8897 27/71, 38%), anemia (placebo 5/18, 27.8%; MEDI8897, 9/71, 12.7%), cough 
(placebo 2/18, 11.1%; MEDI8897, 9/71, 12.7%), pyrexia (placebo 0, MEDI8897, 8/71,
11.3%), bronchiolitis (placebo 5.6%, MEDI8897 7/71, 9.9%), and rhinorrhea (placebo, 1/18, 
5.6%; MEDI8897 7/71, 9.9%). There were no AESIs, NOCDs, or deaths. ADA levels at the 
30-day interim analysis were similar for placebo and MEDI8897 recipients, with rates of 
12.5% (2/18) and 4.4% (3/71) for placebo and MEDI8897 recipients, respectively. A second 
interim analysis is planned for 6 months after the last subject was dosed (March 2016) to 
evaluate MEDI8897 serum concentrations, ADA, and safety.


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Additional data from these studies is available in the Investigator’s Brochure.
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 ≤ 35 wGA, 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, 
in the USA, per the AAP guidelines, palivizumab is not recommended for healthy preterm
infants ≥ 29 wGA. Currently, there is no approved RSV prophylaxis for the broader 
population of healthy newborns and 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 US FDA, this initial pivotal study to demonstrate efficacy and 
safety of MEDI8897 will be conducted in healthy preterm infants who are not eligible to 
receive palivizumab according to AAP or other local guidelines. After 500 preterm infants 
are dosed with MEDI8897, a benefit: risk assessment will be conducted, and if favorable, a 
Phase 3 study in healthy infants > 35 wGA can be initiated.
1.6
Research Hypotheses
1.6.1
Primary Hypothesis
Compared to placebo, a single 
mg IM dose of MEDI8897 will be efficacious in reducing 
medically attended LRTI caused by RT-PCR-confirmed RSV in healthy preterm infants born 
between 29 weeks 0 days and 34 weeks 6 days gestational age (GA) and entering their first 
RSV season, and the safety profile will be acceptable.
1.6.2
Secondary Hypotheses
1. There will be a reduction in the incidence of hospitalizations attributable to RSV 
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3. ADA to MEDI8897 will not significantly impact the serum concentrations or safety of 
MEDI8897 over the 5-month RSV season.
2
OBJECTIVES
2.1
Objectives
2.1.1
Primary Objective
To assess the efficacy of MEDI8897 when administered as a single 
mg IM dose to healthy 
preterm infants born between 29 weeks 0 days and 34 weeks 6 days GA and entering their 
first RSV season for the reduction of medically attended LRTI due to RT-PCR-confirmed 
RSV, compared to placebo.
2.1.2
Secondary 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 Objective
To assess healthcare resource utilization (HRU) and caregiver burden for MEDI8897 
recipients compared to placebo recipients
2.1.4
2.2
Study Endpoints
2.2.1
Primary Endpoint
Incidence of medically attended LRTI (inpatient and outpatient) due to RT-PCR-confirmed 
RSV over the duration of the 5-month RSV season
2.2.2
Secondary Endpoints
1. Incidence of hospitalizations due to RT-PCR-confirmed RSV over the duration of the 5-
month RSV season 
2. Safety and tolerability of MEDI8897 as assessed by the occurrence of all treatment-
emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), 
AESIs, and NOCDs
3. Single-dose MEDI8897 serum concentrations


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4. Incidence of ADA to MEDI8897 in serum
2.2.3
Exploratory Endpoints
1. Magnitude of HRU (eg, number of admissions to hospitals and intensive care units
[ICUs] and duration of stay; number of subjects who require respiratory support and 
supplemental oxygen and the duration of use; number and types of outpatient visits, eg, 
emergency room [ER], urgent care, outpatient clinic; and number of prescription and 
over-the-counter [OTC] medications and the duration of use) for MEDI8897 recipients 
compared to placebo recipients.
2. Caregiver burden (eg, caregiver missed work days, subject absence from day care) for 
subjects with medically attended LRTI caused by RT-PCR-confirmed RSV.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview……….
This pivotal Phase 2b study is a randomized, double-blind, placebo-controlled, single-dose 
study to determine if MEDI8897 will be efficacious in reducing medically attended 
RSV-confirmed LRTI in healthy preterm infants entering their first RSV season. The 
population to be enrolled is healthy preterm infants born between 29 weeks 0 days and 
34 weeks 6 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 
1,500 infants will be randomized 2:1 to receive a 
 mg IM dose of MEDI8897 (N = 1000) 
or placebo (N = 500; see Figure 3.1.1-1). Randomization will be stratified by temperate 
zones in the northern and southern hemisphere and by subject age at the time of 
randomization (ie, ≤ 3 months, > 3 – ≤6 months, > 6 months). Enrollment of infants > 
6 months of age will be limited to approximately 500. Based on preclinical efficacy results in 
the cotton rat and pharmacokinetic (PK) modeling and simulation, the predicted efficacious 
dose in infants is a single fixed IM dose of 
 mg. All infants will be followed for 
approximately 360 days after dosing. 
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical
attention for a respiratory illness (inpatient or outpatient setting) will be evaluated for the 
occurrence of LRTI. Subjects who have a primary hospitalization for a respiratory illness, a
respiratory deterioration during a hospitalization, or who seek outpatient medical attention,
including ER visits for a respiratory illness, will be assessed for RSV by diagnostic testing of
respiratory secretions and clinical assessment of the presence of LRTI. Testing for RSV will


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be performed centrally using the FDA-approved and Conformité Européenne or European 
Conformity (CE) - marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV + human 
metapneumovirus [hMPV] Assay, Quidel, San Diego, CA www.quidel.com). A diagnosis of
RSV LRTI requires having a respiratory sample positive for RSV by RT-PCR.
Subjects with signs of LRTI must have documented physical exam findings of rhonchi, rales, 
crackles, or wheeze AND any of the following:
•
Increased respiratory rate at rest (age < 2 months, ≥ 60 breaths/min; age 2–6 months, ≥50
breaths/min; age > 6 months – 2 years, ≥40 breaths/min) OR
•
Hypoxemia (in room air - oxygen saturation < 95% at altitudes ≤ 1800 meters or < 92% 
at altitudes > 1800 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).
A study schematic is presented in Figure 3.1.1-1.


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Figure 3.1.1-1
Study Flow Diagram
ADA = anti-drug antibody; IM = intramuscular; N = number; PK = pharmacokinetic
The endpoints to be measured in this study are described in Section 2.2.  
3.1.2
Treatment Regimen
Subjects will be randomly assigned in a 2:1 ratio to receive a single dose of either 
 mg
MEDI8897 (1000 subjects) or placebo (500 subjects) by IM injection on Day 1.


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3.2
Study Design and Dose Rationale
3.2.1
Dose Rationale
In preclinical cotton rat efficacy studies, MEDI8897 serum concentrations of 6.8 μg/mL were 
shown to result in a 3-log decrease in RSV titers in cotton rat lungs. A population PK model 
developed using PK data from the Phase 1a study in healthy adults and Day 30 interim data 
from the Phase 1b/2a study in healthy preterm infants was used to simulate PK profiles in the 
Phase 2b population. PK profiles were simulated in 1,000 infants for each of the following 
populations: preterm infants (29-35 weeks GA) at birth, full-term infants at birth, and full-
term infants at 12 months of age. A single 
mg fixed IM dose of MEDI8897 is predicted to
be the likely efficacious dose that will sustain serum concentrations above the target level of 
6.8 μg/mL in the majority of infants over the entire RSV season and provide complete 
protection for infants entering their first RSV season.
3.2.2
Rationale for Study Population
The population of healthy preterm infants born between 29 weeks 0 days and 34 weeks 6 
days GA and who do not meet AAP criteria (American Academy of Pediatrics Committee on 
Infectious Diseases, 2014) to receive palivizumab was selected based on advice from the US 
FDA. The US FDA made the recommendation based on the higher risk of serious RSV 
disease in this population compared to older GA infants and the proven benefit shown in 
previous studies of RSV prophylaxis in this preterm population. In addition, since this 
population would not be eligible to receive palivizumab (per AAP or other local or national 
guidelines), a study conducted with a placebo control group is acceptable and protective 
efficacy can be directly evaluated.
3.2.3
Rationale for Endpoints
MEDI8897 is being developed to provide RSV immunoprophylaxis for all infants entering 
their first RSV season. The primary endpoint will examine the efficacy of MEDI8897 
compared to placebo in preventing LRTI due to RSV. Respiratory syncytial virus 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 this total burden 
of disease and the efficacy of MEDI8897 in reducing that burden.
A separate secondary endpoint of RSV hospitalization, which would indicate the most 
serious illnesses, will also be evaluated. Additionally, descriptive statistics of the serum 
concentrations of MEDI8897 at selected time points will be evaluated as a secondary 
endpoint and to confirm that serum concentrations are maintained above the target value of 


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6.8 μg/mL for 5 months. The serum concentration data will be used to characterize the PK of 
MEDI8897 in infants using a population PK approach. For infants who require 
hospitalization for LRTI, an additional serum sample for measurement of MEDI8897 
concentration and ADA will be obtained around the time of hospitalization. Exposure-
response analysis will be performed to relate MEDI8897 serum concentrations and efficacy 
endpoints (LRTI including RSV-associated hospitalization). 
To determine the duration of MEDI8897 serum levels post dosing and to correlate with the 
development of ADA, serum concentrations will be measured at 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 and to not interfere with detection of ADA, if 
present.
Exploratory endpoints will examine magnitude of healthcare resource utilization and 
caregiver burden due to RSV illness in the current population. This will allow the 
determination of social and economic resources that are required for infants who have LRTI.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of 1,500 infants will be enrolled and randomized in a 2:1 ratio to receive a single IM 
dose of 
 mg MEDI8897 (N = 1000) or placebo (N = 500).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Healthy infants born between 29 weeks 0 days and 34 weeks 6 days GA
2. Infants who are entering their first full RSV season at the time of screening
3. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act [HIPAA] in the USA, European Union [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 1 year after receipt of 
the dose of study drug


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4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Meets AAP or other local criteria to receive commercial palivizumab
2. Any fever (≥ 100.4°F [≥ 38.0°C], regardless of route) or lower respiratory illness within 
7 days prior to randomization
3. Acute illness (defined as the presence of moderate or severe signs and symptoms) at the 
time of randomization
4. Active RSV infection (a child with signs/symptoms of respiratory infection must have 
negative RSV testing) or known prior history of RSV infection
5. Any drug therapy (chronic or other) within 7 days prior to randomization or expected 
receipt during the study with the exception of: 1) multivitamins and iron; 2) infrequent 
use of over the counter medications for the systemic treatment of common childhood 
symptoms (eg, pain relievers, decongestants or cough suppressants) 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)
7. History of receipt of blood transfusion 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. Congenital heart disease, 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 monoclonal antibody or any RSV vaccine, 
including maternal RSV vaccination
20. Receipt of any monoclonal or polyclonal antibody (for example, Hepatitis B immune 
globulin, intravenous 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


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Note: An individual who initially is excluded from study participation based on one or more 
of the above time-limited criteria (eg, acute illness) may be reconsidered for enrollment once 
the condition has resolved as long as the subject continues to meet all other entry criteria.
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.
4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). The caregivers 
of such subjects will always be asked about the reason(s) and the presence of any AEs. If 
possible, the subject will be seen and assessed by an investigator. Adverse events 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
Criteria for Discontinuation of Investigational Product for Individual 
Subjects
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


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Subjects who have received investigational product will be followed for protocol-specified 
assessments including follow-up of any AEs unless consent is withdrawn specifically from 
further study participation or the subject is lost to follow-up. Subjects who have not received 
investigational product, regardless of reason, will not be followed.
4.1.7
Replacement of Subjects
Subjects who are randomized but not dosed or who are randomized but do not complete any 
study evaluation after dosing may be replaced. At the discretion of the sponsor, subjects who 
prematurely discontinue study participation at any time through Day 91 may also be 
replaced. The replacement subject will receive the same treatment assignment as the 
corresponding subject being replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
Samples Obtained for Future Research
Samples obtained, which may be used for future research, will be labeled with a sample 
identification number. If the subject withdraws consent for participating in the future 
research, the sponsor will locate the subject’s sample and destroy it after protocol specified 
analyses are completed. 
If the subject consents to have his/her samples used for future research, this additional 
research may not start immediately and may start at any time during the storage period. The 
subject’s sample(s) will be stored by the sponsor with similar samples from other subjects at 
a secure central laboratory. The subject’s samples will not be kept for more than 25 years 
after the end of the study in which they were collected. If the subject chooses not to allow 
his/her study samples to be used for future research, the samples will be destroyed by the 
sponsor once they are no longer required for the main study.


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If consent is withdrawn, the sponsor and the investigator will ensure that these sample(s) are 
destroyed unless the identification number has been removed and the subject can no longer 
be linked to any sample(s). However, if the subject’s samples have already been used for 
research, the sponsor is not required to destroy results of this research. In this case, only the 
remaining sample(s) will be destroyed.
The sites must keep a log of all subjects who sign the informed consent form for the main 
study and the informed consent form for future use, this log contains subject SID and must be 
supplied to the sponsor at the end of the study, or closure of the site whichever is sooner.
4.2
Schedule of Study Procedures
4.2.1
Enrollment/Screening Period
Table 4.2.1-1 shows all procedures to be conducted at the screening visit. 
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws.
Table 4.2.1-1
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
PK blood sample
X
ADA blood sample
X
Assessment of AEs/SAEs
X
Concomitant medications
X
Verify eligibility criteria
X
ADA = anti-drug antibody; AEs = adverse events; PK = pharmacokinetic; SAEs = serious adverse events; 
SID = subject identification; V = visit.
Screening and Day 1 visits may occur on the same day.


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4.2.2
Treatment and Follow-up Period
The day of dosing is Day 1 of the study. Table 4.2.2-1 shows all procedures to be conducted 
on day of dosing and during the follow-up period. Assessments should be performed in the 
order shown in the table.


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Table 4.2.2-1
Schedule of Treatment Period and Follow-up Period Study Procedures
Study Period
Treatment
Period
Follow-up Period
Visit Number
V2
V3
V4
V5
V6
V7
Telephone 
Call
Telephone 
Call
LRTI
Procedure / 
Study Day
Day 1
Day 8 (±
2 days)
Day 31
(± 5
days)
Day 91
(± 7 days)
Day 151
(± 7 days)
Day 361
(± 7
days)
Q2W from 
Day 1 to 
Day 151 (± 
5 days)
Monthly after 
Day 151 to 
Day 361 (± 5
days)
As 
needed
Medical history update
X
X
X
X
X
X
Physical examination (abbreviated)
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs
X a
X
X
X
X
X
PK blood sample
X
X
X
Xb
ADA blood sample
X
X
X
Xb
Assessment of AEs/SAEs
X
X
X
X
X
X
Assessment of AESI and NOCDs
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Verify eligibility criteria
X
Randomization
X
Investigational product 
administration
X
Assessment of LRTI
Xb
Nasal swab collection
Xb
Telephone contact
X
X
HRU c
X


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Table 4.2.2-1
Schedule of Treatment Period and Follow-up Period Study Procedures
Study Period
Treatment
Period
Follow-up Period
Visit Number
V2
V3
V4
V5
V6
V7
Telephone 
Call
Telephone 
Call
LRTI
Procedure / 
Study Day
Day 1
Day 8 (±
2 days)
Day 31
(± 5
days)
Day 91
(± 7 days)
Day 151
(± 7 days)
Day 361
(± 7
days)
Q2W from 
Day 1 to 
Day 151 (± 
5 days)
Monthly after 
Day 151 to 
Day 361 (± 5
days)
As 
needed
ADA = anti-drug antibody; AEs = adverse events; AESI = adverse event of special interest; ER = emergency room; HRU = healthcare resource utilization; 
ICU = intensive care unit; LRTI = lower respiratory tract infection; NOCDs = new onset of chronic disease; OTC = over-the-counter; PK = pharmacokinetic; 
Q2W = once every two weeks; RSV = respiratory syncytial virus; SAEs = serious adverse events; SID = subject identification; V = visit.
a
All vital signs (temperature, blood pressure, heart rate, and respiratory rate) should be obtained within 60 minutes prior to dosing, at 30 minutes 
(± 5 minutes) and at 60 minutes (± 5 minutes) post dose
b
Nasal samples will be collected for all LRTI within 2 days and up to 14 days after the diagnosis. PK and ADA samples will be collected only for subjects 
hospitalized with LRTI within 2 days and up to 14 days following hospitalization. 
c
HRU includes admission and duration of hospital and ICU stay, number of subjects who require respiratory support and supplemental oxygen use, 
duration of respiratory support and supplemental oxygen use, number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and number and 
days of prescription and OTC medication


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4.3
Description of Study Procedures
4.3.1
Efficacy……….
4.3.1.1
Lower Respiratory Tract Infection
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical 
attention for a respiratory illness (defined as new onset events indicating a change from the 
child’s baseline medical status referable to the lower respiratory tract) will be evaluated for 
the occurrence of LRTI (Table 4.3.1.1-1). These events may occur in the inpatient or 
outpatient setting. Subjects who have a primary hospitalization for a respiratory illness, or 
who have a respiratory deterioration during a hospitalization, or who seek outpatient medical 
attention, including ER visits, for a respiratory illness will be assessed for RSV by diagnostic 
testing of respiratory secretions. Testing for RSV will be performed centrally using the FDA-
approved and CE-marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV + hMPV 
Assay, Quidel, San Diego, CA www.quidel.com). A diagnosis of RSV LRTI requires having 
a respiratory sample positive for RSV by RT-PCR.
To meet the protocol-specified criteria for LRTI, subjects with signs of LRTI must have 
documented physical exam findings of rhonchi, rales, crackles, or wheeze AND any of the 
following:
•
Increased respiratory rate at rest (age: < 2 months, ≥ 60 breaths/min; 2–6 months, ≥ 50 
breaths/min; > 6 months – 2 years, ≥40 breaths/min), OR
•
Hypoxemia (in room air - oxygen saturation < 95% at altitudes ≤ 1800 meters or < 92% 
at altitudes > 1800 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).


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Table 4.3.1.1-1
Elements to Evaluate for Case Definition of RSV LRTI 
Specificity 
Sensitivity
Medical Significance
RSV Confirmed: 
•
Positive RT-PCR
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
•
Prescription medications 
(only for children with 
underlying lung disease)
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.
Respiratory Syncytial Virus Hospitalization
A RSV hospitalization is defined as either 1) a respiratory hospitalization with a positive 
RSV test within 2 days of hospitalization (primary) or 2) new onset of respiratory symptoms 
in an already hospitalized child, 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 2 days 
before or after admission for children who are hospitalized for respiratory illness. If the RSV 
diagnostic test (performed centrally via RT-PCR) is positive, the hospitalization will be 
classified as a primary RSV hospitalization. Deaths which 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
Children hospitalized for a respiratory illness or non-respiratory illness whose RSV 
diagnostic test is negative may develop nosocomial RSV illness during the study.


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If signs (such as retractions, rhonchi, wheezing, crackles or rales) of a new lower respiratory 
illness occur during a hospitalization, whatever the reason for hospitalization, and there is an 
objective measure of worsening respiratory status (that is, new requirement for supplemental 
oxygen, increase in supplemental oxygen requirement from prior to the onset of symptoms, 
or need for new or additional mechanical ventilation), a specimen will be collected within 
2 days from worsening of respiratory status for RSV diagnostic testing by the central 
laboratory. For any child who is hospitalized for a respiratory event, the child 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 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 test.
RSV LRTI Outpatient Events
Children who seek outpatient medical attention, including emergency room and urgent care 
visits, for a respiratory illness should have respiratory secretions obtained within 2 days of 
the visit.
Respiratory Secretions for RSV Detection
Respiratory secretions for RSV testing must be collected within 2 days of diagnosis for 
medically attended outpatient lower respiratory tract infections and hospital admission for, or 
new onset in hospital of, a respiratory illness. Nasal secretions will be obtained unless the 
child is intubated, and then tracheal secretions may be obtained.  
Respiratory secretions in all cases will be tested in a central laboratory for RSV using the 
FDA-approved and CE-marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV +
hMPV Assay, Quidel, San Diego, CA www.quidel.com) and testing may include other 
respiratory pathogens.
Monitoring for RSV Resistance
Nasal samples collected from study subjects that fail MEDI8897 prophylaxis will be 
evaluated by genotypic and phenotypic methods to monitor potential susceptibility changes
to MEDI8897. The subtype and genotypic analysis 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 PCR (RT-PCR) assay manufactured by Quidel Corporation 


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(Lyra RSV + hMPV Assay, Quidel Corporation, San Diego CA, www.quidel.com). The full 
length fusion (F) gene from RSV-positive nasal samples 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 site in F protein will 
be reported. If Sanger sequencing does not detect resistance-associated changes within the 
MEDI8897 binding site in the F gene of virus isolated from individuals who received 
MEDI8897, deep sequencing will be employed to detect minority variants. Recombinant 
viruses containing identified amino acid changes in the MEDI8897 binding region will be 
constructed through reverse genetics, and will be tested for susceptibility to MEDI8897 
neutralization in a cell-based microneutralization assay.  
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 Day 1, Day 8, Day 31, Day 91, Day 151 and Day 361 and 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 complete physical examination will be performed at screening, and an abbreviated 
physical examination will be performed on Day 1, Day 8, Day 31, Day 91, Day 151 and Day 
361. 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 and at each study visit on Day 1, Day 8, Day 31, Day 91, Day 151 
and Day 361. On Day 1, vital signs will be monitored before and after administration of 
investigational product. 
4.3.3
Pharmacokinetic and Anti-drug Antibody Samples
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. 
4.3.4
Pharmacokinetic Evaluation and Methods
Blood will be collected to evaluate the PK of MEDI8897 in serum at screening and on Day 
91, Day 151, Day 361 and as needed (PK samples will be collected for subjects hospitalized 


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with LRTI within 2 days and up to 14 days following hospitalization; see Table 4.2.1-1 and 
Table 4.2.2-1 for schedule of tests). The concentration of MEDI8897 in serum will be 
measured by MedImmune using validated assays. 
4.3.5
Anti-drug Antibody Response Evaluation and Methods
Blood samples will be collected to evaluate ADA responses to MEDI8897 in serum (see 
Table 4.2.1-1and Table 4.2.2-1 for the schedule of tests) at screening and on Day 91,
Day 151 and Day 361 and as needed (ADA samples will be collected for subjects 
hospitalized with LRTI within 2 days and up to 14 days following hospitalization; see 
Table 4.2.1-1 and Table 4.2.2-1 for schedule of tests). Evaluations will be performed by 
MedImmune, using a validated immunoassay.
4.3.6
Healthcare Resource Utilization and Caregiver Burden Evaluation
Information on HRU and caregiver burden will be collected for all events of medically
attended LRTI. This will include admission to and duration of hospital and ICU stay, number 
of subjects who require respiratory support and supplemental oxygen use, duration of 
respiratory support and supplemental oxygen use, number and type of outpatient visits (eg, 
ER, urgent care, outpatient clinic), and the number of prescription and 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.
4.3.7
Estimates of Blood Volume to be Collected
Blood volume estimates are provided in Table 4.3.7-1 by visit.
Table 4.3.7-1
Volume of Blood to be Collected 
Visit
Estimated Blood Volume (mL)
Screening
1.5 mL
Day 91
1.5 mL
Day 151
1.5 mL
Day 361
1.5 mL
Total
6.0 mL
4.4
Study Suspension or Termination
The Sponsor reserves the right to temporarily suspend or terminate this study at any time. 
The reasons for temporarily suspending or terminating the study may include but are not 
limited to the following: 


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1. Death in any subject in which the cause of death is assessed as related to investigational 
product (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 3 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 (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) grading scale that are 
assessed as related to MEDI8897 in 2 or more subjects
4. Two 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. Non-compliance that might significantly jeopardize the validity or integrity of the study
8. 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.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the institutional review board (IRB)/ independent ethics committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product (Table 4.5.1-1) 
using designated distribution centers. 


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Table 4.5.1-1
Identification of Investigational Products 
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
MEDI8897
MedImmune
Liquid formulation at 100 mg/mL in 2R glass 
vials (0.5 mL nominal fill volume) containing 
 
Placebo
To be provided by study sites
Commercially available 0.9% (w/v) saline 
(sterile for human use)
HCl = hydrochloride; w/v = weight/volume
Investigational product should be stored at 2°C to 8°C.
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.
Investigational product will be supplied to the site in open-labeled kits. Each kit has a unique 
number printed on all labels within the kit (ie, the outer carton label and the label of each 
vial).
Refer to Section 4.6.2 for information on coding of the container for blinding purposes.
4.5.1.1
Investigational Product Dose Administration
Investigational Product Inspection
Each vial selected for dose administration should be inspected. MEDI8897 is supplied as a 
sterile liquid formulation with a concentration of 100 mg/mL in 2R glass vials (0.5 mL 
nominal fill volume).
If there are any defects noted with the investigational product, the Investigator and Site 
Monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.4) for further instructions.
Dose Administration Steps
No incompatibilities between MEDI8897 and plastics passing compatibility tests 
(ie, 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 


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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. Each vial of MEDI8897 contains 0.5 mL nominal fill volume of 
mg/mL MEDI8897.
2. The required 0.5 mL volume of MEDI8897 or placebo will be obtained by withdrawing 
the contents of the investigational vial with an appropriately sized syringe. Syringes used 
must be polycarbonate or polypropylene. For ease of preparation, a 1.5 inch 19-gauge 
withdrawal needle should be used.
3. Switch the needle prior to administration.
4. 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.
4.5.1.2
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.
4.5.1.3
Monitoring of Dose Administration
Subjects will be monitored before and after investigational product administration through 
assessment of vital signs (temperature, blood pressure, heart rate, and respiratory rate). All 
vital signs should be obtained within 60 minutes prior to dosing, at 30 minutes (± 5 minutes) 
and at 60 minutes (± 5 minutes) post dose. 
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.
4.5.1.4
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 


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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: productcomplaints@medimmune.com
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 GMP and local 
regulatory guidelines. Label text will be translated into local languages, as required.
4.5.4
Storage……….
Store investigational product at 2°C to 8°C.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel who will monitor compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a MedImmune-
authorized depot or disposed of upon authorization by MedImmune.


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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 a 
 mg IM dose of MEDI8897 (N = 
1,000) or placebo (N = 500). Randomization will be stratified by temperate zones in the 
northern and southern hemisphere and by subject age at the time of randomization (ie, ≤3 
months, > 3 – ≤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 monitor must be notified 
immediately.
4.6.2
Methods for Ensuring 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 any of the investigator or site staff who are involved in the 
treatment or clinical evaluation of the subjects will be aware of the treatment received 
(International Council for Harmonisation [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 


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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.
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.
4.6.3.2
Unblinding for Primary Analysis Purposes 
The primary analysis will be conducted when all randomized subjects have completed the
Day 151 visit and will include all efficacy data for all randomized subjects. All efficacy and 
safety data collected up to the Day 151 visit and available safety data beyond Day 151 at the 
time of that data cut-off date will be included in the primary analysis. Efficacy and safety for 
MEDI8897 will be evaluated in this unblinded analysis. 
Sponsor personnel will be unblinded at this primary analysis. Study site personnel and the 
subjects’ parent(s)/legal guardian will remain blinded to the treatment assignment of 
individual subjects until the last subject completes the study and the final database is locked.
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).


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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 over-the-counter 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 over-the-counter products, without first consulting with the 
investigator.
4.8
Statistical Evaluation
4.8.1
General Considerations
There are two planned analyses for this study: the primary analysis and the final analysis. 
The primary analysis will be conducted after all randomized subjects have completed the 
Day 151 visit, and the final analysis will be conducted when all subjects have completed the 
last visit of the study (Day 361).
Tabular summaries will be presented by treatment group. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics. Additional details of statistical 
analyses will be described in the statistical analysis plan.
The 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, will be performed on the ITT Population.
The As-treated Population will include all subjects who are randomized into the study and 
who receive any amount of investigational product. Subjects will be included in the treatment 
group corresponding to the treatment actually received. All safety analyses will be performed 
on the As-treated Population.
4.8.2
Sample Size and Power Calculations
The sample size of 1,500 is necessary based on advice from the US FDA requesting that
1,000 preterm infants be exposed to MEDI8897 in this Phase 2b study. This sample size has 
approximately 99% power to detect 70% relative risk reduction, assuming a placebo group 
medically attended RSV LRTI incidence of 8%. Power calculations are based on Poisson 


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regression model with robust variance (Zou, 2004) comparing MEDI8897 
mg versus 
placebo, with 2-sided significance level of α = 0.05.
•
The 70% relative risk reduction assumption is based on a placebo-controlled study in 
Native American infants in which there was 87% relative reduction in the incidence of 
RSV hospitalization (11.3% placebo; 1.5% motavizumab; p < 0.001) and 71% relative 
reduction in the incidence of outpatient RSV LRTI (10.0% placebo; 2.9% motavizumab; 
p < 0.001) in infants who received motavizumab prophylaxis (O'Brien et al, 2015)
In order to evaluate risk, a sample size of 1,000 subjects exposed to MEDI8897 will provide a
90% probability of observing at least one AE if the true event rate is 0.2%; if no AEs are
observed, this study provides 95% confidence that the true event rate is < 0.3%.
4.8.3
Efficacy Analysis
The primary analysis will be conducted after all randomized subjects have completed the 
Day 151 visit. At the time of this primary analysis, approximately half of all subjects 
enrolled (722 subjects) will have completed the Day 361 visit. The remaining 731 subjects 
will have completed approximately 8 months of the study. 
The primary and secondary efficacy hypotheses will be assessed in the primary analysis 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.
4.8.3.1
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 summarized 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 with the ITT 
Population. LRTI caused by RSV that occurs prior to discontinuation from participation in 
the study will contribute to the primary efficacy analysis. For subjects who do not have an
RSV LRTI prior to discontinuation from participation, their event status will be imputed 
assuming the observed placebo RSV LRTI rate. This will be implemented by imputations 
based on repeated simulations and will be described in the Statistical Analysis Plan. A 
Poisson regression model with robust variance (Zou, 2004) will be used as the primary 


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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 – ≤ 6 months, > 6 months) and dichotomous temperate (northern and southern)
hemispheres as covariates. In addition, the 2-sided p-value and corresponding 2-sided 95.1% 
CI on the relative risk will be provided from the model. Relative risk reduction is defined as 
(1 - Pn/Ps) where Pn is the incidence of RSV LRTI during 5 months of the RSV season in the 
MEDI8897 group and Ps is the incidence of RSV LRTI during 5 months of the RSV season 
in the placebo group generated from the model. Statistical significance will be achieved if the 
2-sided p-value is ≤0.05.
4.8.3.2
Additional Analyses of the Primary Endpoint
A CMH (Cochran-Mantel-Haenszel) approach stratified by hemisphere and age at the time of 
randomization (ie, ≤ 3 months, > 3 – ≤ 6 months, > 6 months) will be used to compare the 
incidence of RSV LRTI during 5 months of the RSV season between treatment groups as a 
sensitivity analysis for the primary endpoint. 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 lab or local lab.
Different approaches to handle missing data (ie, early discontinuation and no RSV LRTI
prior to discontinuation) may be considered for sensitivity analyses. Additional analyses or 
subgroup summaries may be performed to adjust duration of efficacy follow-up and/or other 
possible confounding factors. These analyses will be described in the Statistical Analysis 
Plan.
4.8.3.3
Secondary Efficacy Analyses
The incidence of RSV hospitalization during 5 months of the RSV season will be 
summarized by treatment group. The same methods described above for the primary efficacy 
endpoint will be used to assess treatment effect on RSV hospitalization. Following a 
hierarchical testing procedure, the secondary efficacy endpoint will be tested at the 
significance level of 2-sided 0.05 if the primary analysis on the primary efficacy endpoint has 
achieved statistical significance at the level of 2-sided 0.05.
4.8.4
Safety Analysis……….
Safety of MEDI8897 will primarily be assessed by the occurrence of treatment-emergent 
AEs and SAEs. Adverse events will be graded according to the current version of the NCI 
CTCAE where applicable for pediatric assessments. Adverse events will be coded by 


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Medical Dictionary for Regulatory Activities (MedDRA) and the type, incidence, severity 
and relationship to study 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, 
and 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
Analysis of Pharmacokinetics
Following a single dose of MEDI8897, individual MEDI8897 serum concentration data will 
be tabulated by treatment group along with descriptive statistics. Terminal-phase half-life 
(t1/2) will be estimated using non-compartmental analysis, if data permit.
4.8.5.2
Analysis of Anti-drug Antibodies
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, and association with 
TEAEs and TESAEs will be assessed.
4.8.6
Exploratory Analyses
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 without medically attended LRTI.
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.
4.8.7
Data Monitoring Committee
An independent DMC will review safety data regularly and make recommendations 
regarding further study conduct.


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5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for Good Clinical Practice E6 (R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (including electrocardiogram [ECG] 
finding) that requires medical intervention by the investigator, or a finding judged by the 
investigator as medically significant should be reported as an AE. If clinical sequelae are 
associated with a laboratory abnormality, the diagnosis or medical condition should be 
reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, 
urine red blood cells [RBC] increased). Abnormal laboratory values that are not, in the 
investigator's opinion, medically significant and do not require intervention should not be 
reported as AEs.
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
A SAE is any AE that:
•
Results in death
•
Is immediately life-threatening


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•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. 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 hypersensitivity (including anaphylaxis) that occurs during or after dosing. A 
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 3. See Section 5.5 for recording AEs.
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 


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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 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.


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5.4
Definition of New Onset Chronic Disease
A 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, asthma, 
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
Adverse events, including SAEs, AESIs and NOCDs, will be recorded on the eCRF using a 
recognized medical term or diagnosis that accurately reflects the event. These events will be 
assessed by the investigator for severity, relationship to the investigational product and study 
procedure(s), possible etiologies, and whether the event meets criteria of an SAE (see Section 
5.2 and 5.6), or is an AESI or NOCD (see Section 5.3, 5.4 and 5.7) and therefore requires 
immediate notification to the sponsor. See Appendix 2 for guidelines for assessment of AE 
severity and relationship to IP. 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 a serious adverse event. 
5.5.1
Time Period for Collection of Adverse Events
Adverse events and SAEs will be collected from the time of signature of informed consent 
through the follow-up period (Day 361 visit). 
All AESIs and NOCDs will be collected from the time of dosing through the follow-up 
period (Day 361 visit).
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.
5.6
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the 
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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 i.e., 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 adverse events 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 
a 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.
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 
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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
Adverse Events of Special Interest
5.7.2.1
Hypersensitivity, Including Anaphylaxis
Events of hypersensitivity, including anaphylaxis (as defined in Appendix 3), 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 hypersensitivity include urticaria, pruritis, 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.
5.7.2.2
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).
5.7.2.3
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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5.7.3
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 Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
6.2
Monitoring of the Study
During the study, a sponsor representative will have regular contacts with the study site, 
including visits to:
•
Provide information and support to the investigator(s)
•
Confirm that facilities remain acceptable
•
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


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The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the study site needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at 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 Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study 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 the 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 according to 
the Data Management Plan.
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.


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The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information 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
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice (GCP), and 
applicable regulatory requirements.
7.2
Subject Data Protection
The Informed Consent Form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
7.3
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the ICF
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff.
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrolment of any subject into the study. 


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The IRB/IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
The Sponsor will handle the distribution of any of these documents to the national regulatory 
authorities.
The Sponsor will provide Regulatory Authorities, IRB/IEC and Principal Investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions (SUSARs), where relevant.
Each Principal Investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
7.4
Informed Consent
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 the 
subject 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 ICF(s) is/are stored in the Investigator’s Study File
•
Ensure a copy of the signed ICF 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 ICF that is approved by an IRB/IEC


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7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the investigators and 
MedImmune.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to IRB/IEC see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
7.6
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the centre, 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.


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8
REFERENCES
American Academy of Pediatrics Committee on Infectious Diseases. American Academy of 
Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab 
prophylaxis among infants and young children at increased risk of hospitalization for 
respiratory syncytial virus infection. Pediatrics. 2014;134(2):e620-38.
Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, et al. 
Dutch, RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy 
preterm infants. N Engl J Med. 2013;368(19):1791-9.
Carroll KN, Gebretsadik T, Griffin MR, Wu P, Dupont WD, Mitchel EF, et al. Increasing 
burden and risk factors for bronchiolitis-related medical visits in infants enrolled in a state 
health care insurance plan. Pediatrics. 2008;122(1):58-64.
Greenough A, Cox S, Alexander J, Lenney W, Turnbull F, Burgess S, et al. Health care 
utilisation of infants with chronic lung disease, related to hospitalisation for RSV infection. 
Arch Dis Child. 2001;85(6):463-8.
Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 
2001;344(25):1917-28.
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The burden 
of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588-
98.
Hall CB. The burgeoning burden of respiratory syncytial virus among children. Infect Disord 
Drug Targets. 2012;12(2):92-7.
Jansen AG, Sanders EA, Hoes AW, van Loon AM, Hak E. Influenza- and respiratory 
syncytial virus-associated mortality and hospitalisations. Eur Respir J. 2007;30(6):1158-66.
Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 
1999. Pediatr Infect Dis J. 2002;21(7):629-32.
Madhi SA, Kuwanda L, Cutland C, Klugman KP. Five-year cohort study of hospitalization 
for respiratory syncytial virus associated lower respiratory tract infection in African children. 
J Clin Virol. 2006;36(3):215-21.
Meissner HC. Selected populations at increased risk from respiratory syncytial virus 
infection. Pediatr Infect Dis J. 2003;22(2 Suppl):S40-5.


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Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global burden of 
acute lower respiratory infections due to respiratory syncytial virus in young children: a 
systematic review and meta-analysis. Lancet. 2010;375(9725):1545-55.
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 randomised double-blind placebo-controlled trial. Lancet Infect Dis. 2015;15(12):1398-
408.
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.
Parrott RH, Kim HW, Arrobio JO, Hodes DS, Murphy BR, Brandt CD, et al. Epidemiology 
of respiratory syncytial virus infection in Washington, D.C. II. Infection and disease with 
respect to age, immunologic status, race and sex. Am J Epidemiol. 1973;98(4):289-300.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-
associated hospitalizations among US children, 1980-1996. JAMA. 1999;282(15):1440-6.
Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virus-
associated hospitalizations among infants and young children in the United States, 1997-
2006. Pediatr Infect Dis J. 2012;31(1):5-9.
van Gageldonk-Lafeber AB, Heijnen ML, Bartelds AI, Peters MF, van der Plas SM, 
Wilbrink B. A case-control study of acute respiratory tract infection in general practice 
patients in The Netherlands. Clin Infect Dis. 2005;41(4):490-7.
Weigl J, Puppe W, Schmitt H. Incidence of respiratory syncytial virus-positive 
hospitalizations in Germany. Eur J Clin Microbiol Infect Dis. 2001;20(7):452-9.
Zou G. A modified poisson regression approach to prospective studies with binary data. Am 
J Epidemiol. 2004;159(7):702-6.


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9
CHANGES TO THE PROTOCOL
All changes below have been incorporated into the current version of the protocol.
9.1
Protocol Amendment 1, 25Jan2018
Major changes to the protocol are summarized below:
1. The interim analysis was removed from the study. (Changes have been made in the 
synopsis and in Section 4.8 [Statistical Evaluation].)
2. As a result of the removal of the interim analysis, no alpha will be spent so the two-sided 
significance level of α = 0.049 has returned to α = 0.05 and the p value required to 
achieve statistical significance of < 0.049 has returned to ≤ 0.05. (Changes have been 
made in the synopsis and in Section 4.8 [Statistical Evaluation].)
3. A decision was made to conduct a primary analysis rather than an interim analysis; 
therefore, text has been added to explain that the primary analysis will now include all 
efficacy data from all randomized subjects through Day 151 and all available safety data 
up to and beyond Day 151 at the time of the final data cut-off date. (Changes have been 
made in the synopsis and in Section 4.8 [Statistical Evaluation].)


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Appendix 1
Signatures


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Sponsor Signature(s)
A Phase 2b 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 Preterm Infants
I agree to the terms of this protocol.
Signature and date: 
(Electronic signature appended)
Clinical Development Therapeutic Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA 
Telephone number: 


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Signature of Principal or Coordinating Investigator
A Phase 2b 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 Preterm Infants
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Appendix 2
Additional Safety Guidance
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the current version of the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) where 
applicable for pediatric assessments. The determination of severity for all other events not 
listed in the CTCAE should be made by the investigator based upon medical judgment and 
the severity categories of Grade 1 to 5 as defined below.
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event 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 (severe)
An 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 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental 
disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, 
etc).
Grade 5 (fatal)
Death (loss of life) 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 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.


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Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)
•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the eCRF (Section 5.6). This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention 
required during the study (eg, blood collection, nasal sample collection). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.


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


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Appendix 3
National Institute of Allergy and Infectious Diseases
(NIAID) and Food and Allergy Anaphylaxis Network 
(FAAN) Guidance for Anaphylaxis Diagnosis
Sampson HA, Munoz-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(2):391-7.
NIAID and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset and 
may cause death. They recognize 3 categories of anaphylaxis, with criteria designated to 
capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 
categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (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. Low systolic blood pressure for children is defined as less than 70 mm 
Hg from 1 month to 1 year, less than (70 mm Hg + [2 × age]) from 1 to 10 years.


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: protocol-d5290c00003-amendment-1
Document Title:
protocol-d5290c00003-amendment-1
Document ID:
Doc ID-003770941
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
25-Jan-2018 21:47 UTC
Author Approval
25-Jan-2018 20:31 UTC
Author Approval
25-Jan-2018 20:28 UTC
Author Approval
25-Jan-2018 21:09 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
1 of 26 
6WDWLVWLFDO$QDO\VLV3ODQ
 
 
 
 
A Phase 2b 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 Preterm Infants 
3URWRFRO1XPEHU D5290C00003 
 
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
2 of 26 
7$%/(2)&217(176
1
INTRODUCTION ...........................................................................................................4
2
STUDY OVERVIEW .....................................................................................................5
2.1
Study Objectives ...................................................................................................5
2.1.1Primary Study Objective(s) ..........................................................................5
2.1.2Secondary Study Objectives .........................................................................5
2.1.3Exploratory Study Objectives .......................................................................5
2.2
Study Design .........................................................................................................6
2.3
Treatment Assignment and Blinding ....................................................................6
2.4
Sample Size...........................................................................................................7
3
STATISTICAL METHODS ...........................................................................................7
3.1
General Considerations .........................................................................................7
3.2
Analysis Populations.............................................................................................8
3.3
Stratification Factors .............................................................................................8
3.4
Study Subjects.......................................................................................................9
3.4.1Subject Disposition and Completion Status..................................................9
3.4.2Demographics and Baseline Characteristics .................................................9
3.4.3Study Drug Exposure ..................................................................................10
3.5
Efficacy Analyses ...............................................................................................10
3.5.1Primary Efficacy Endpoint and Analyses ...................................................10
3.5.1.1
Primary Efficacy Endpoint .......................................................10
3.5.1.2
Handling of Dropouts and Missing Data ..................................11
3.5.1.3
Primary Efficacy Analysis ........................................................12
3.5.1.4
Additional Analyses of the Primary Efficacy Endpoint ...........12
3.5.1.5
Subgroup Analyses ...................................................................15
3.5.2Secondary Efficacy Endpoint and Analyses ...............................................16
3.5.2.1
Secondary Efficacy Endpoint ...................................................16
3.5.2.2
Handling of Dropouts and Missing Data ..................................16
3.5.2.3
Secondary Efficacy Analyses ...................................................17
3.5.2.4
Additional Analyses of the Secondary Efficacy Endpoint .......17
3.5.2.5
Subgroup Analyses ...................................................................17
3.5.3Other Efficacy Analyses .............................................................................18
3.6
Exploratory Analyses ..........................................................................................19
3.6.1Healthcare Resource Utilization .................................................................19
3.6.2Caregiver Burden ........................................................................................21
3.7
Safety Analyses...................................................................................................22
3.7.1Adverse Events and Serious Adverse Events .............................................22
3.7.2Adverse Events of Special Interest .............................................................22
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
3 of 26 
3.7.3Skin and Hypersensitivity Reactions ..........................................................22
3.7.4New Onset Chronic Disease .......................................................................22
3.7.5Subgroup Analyses .....................................................................................22
3.7.6Other Safety Evaluations ............................................................................23
3.8
Anti-drug Antibodies ..........................................................................................23
3.9
Pharmacokinetics ................................................................................................23
4
INTERIM ANALYSIS..................................................................................................24
5
REFERENCES ..............................................................................................................25
 
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Table 3.2-1
Analysis Populations ..............................................................................8
Table 3.5-1
Definition for New Onset of Events ....................................................18
 
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Appendix 1
Elements to Evaluate for Case Definition of Medically Attended RSV 
LRTI .....................................................................................................26
 
 
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
4 of 26 
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AAP 
American Academy of Pediatrics 
AE 
adverse event 
AESI 
adverse event of special interest 
CE 
Conformité Européenne or European Conformity 
CI 
confidence interval 
eCRF 
electronic case report form 
ER 
emergency room 
EU 
European Union 
hMPV 
human metapneumovirus 
HRU 
healthcare resource utilization 
ICU 
intensive care unit 
IDMC 
independent data monitoring committee 
IM 
intramuscular 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
LRTI 
lower respiratory tract infection 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NOCD 
new onset chronic disease 
OTC 
over-the-counter 
PK 
pharmacokinetics 
RSV 
respiratory syncytial virus 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
SAE 
serious adverse event 
SID 
subject identification 
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 
wGA 
weeks gestational age 
 
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This document describes the statistical analysis for protocol D5290C00003, a pivotal 
Phase 2b study to determine if MEDI8897 is efficacious in reducing medically attended 
respiratory syncytial virus (RSV)-confirmed lower respiratory tract infection (LRTI) in 
healthy preterm infants entering their first RSV season. The primary efficacy hypothesis of 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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this study is that, compared to placebo, a single 50-mg intramuscular (IM) dose of 
MEDI8897 will be efficacious in reducing medically attended LRTI caused by RT-PCR-
confirmed RSV in healthy preterm infants born between 29 weeks 0 days and 34 weeks 6 
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 RSV, (2) the predicted extended t1/2 will be adequate for the 
duration of the RSV season, and (3) ADA to MEDI8897 will not significantly impact the 
serum concentrations or safety of MEDI8897 over the 5-month RSV season. These 
hypotheses will be assessed by the incidence of RSV LRTI, RSV hospitalization, ADA, 
pharmacokinetics parameters, 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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To assess the efficacy of MEDI8897 when administered as a single 50 mg IM dose to healthy 
preterm infants born between 29 weeks 0 days and 34 weeks 6 days GA and entering their 
first RSV season for the reduction of medically attended LRTI due to RT-PCR-confirmed 
RSV, compared to placebo. 
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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 
 
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To assess healthcare resource utilization (HRU) and caregiver burden for MEDI8897 
recipients compared to placebo recipients. 
 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
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The population to be enrolled is healthy preterm infants born between 29 weeks 0 days and 
34 weeks 6 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 
1,500 infants will be randomized 2:1 to receive a 50 mg IM dose of MEDI8897 (N = 1000) 
or placebo (N = 500). Randomization will be stratified by temperate zones in the northern 
and southern hemisphere and by subject age at randomization (ie,  3 months, > 3 to  6 
months, > 6 months). Enrollment of infants > 6 months of age will be limited to 
approximately 500. All infants will be followed for approximately 360 days after dosing.  
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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 a 50 mg IM dose of MEDI8897 (N = 
1,000) or placebo (N = 500). Randomization will be stratified by temperate zones in the 
northern and southern hemisphere and by subject age at 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 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
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specified timeframe, the unblinded investigational product monitor must be notified 
immediately. 
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The sample size of 1,500 is necessary based on advice from the US FDA requesting that 
1,000 preterm infants be exposed to MEDI8897 in this Phase 2b study. This sample size has 
approximately > 99% power to detect 70% relative risk reduction, assuming a placebo group 
medically attended RSV LRTI incidence of 8%. Power calculations are based on Poisson 
regression model with robust variance (Zou, 2004) comparing MEDI8897 50 mg versus 
placebo, with 2-sided, Į = 0.049 (due to 0.001 alpha spend at the interim analysis; refer to 
Interim Analysis Section 4). 
•
The 70% relative risk reduction assumption is based on a placebo-controlled study in 
Native American infants in which there was 87% relative reduction in the incidence of 
RSV hospitalization (11.3% placebo; 1.5% motavizumab; p < 0.001) and 71% relative 
reduction in the incidence of outpatient RSV LRTI (10.0% placebo; 2.9% motavizumab; 
p < 0.001) in infants who received motavizumab prophylaxis (O'Brien et al, 2015)  
 
In order to evaluate risk, a sample size of 1,000 subjects exposed to MEDI8897 will provide a 
90% probability of observing at least one AE if the true event rate is 0.2%; if no AEs are 
observed, this study provides 95% confidence that the true event rate is < 0.3%. 
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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. In general, unless stated otherwise, 
baseline will be defined as the last value prior to dosing.  
For the primary efficacy analysis for the primary endpoint of medically attended RSV LRTI 
[and similarly for RSV LRTI hospitalization (Protocol-Defined) and medically attended RSV 
outpatient LRTI (Protocol-Defined)], if a subject does not experience a medically attended 
RSV LRTI prior to discontinuation from participation through 150 days post dose, their event 
status will be imputed assuming the observed placebo medically attended RSV LRTI rate 
conditional on stratification value. For the sensitivity analyses for the primary endpoint, 
similar approaches will be used with various assumed medically attended RSV LRTI event 
rates, with or without stratification adjustment in the imputation.  
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For additional analyses on the primary endpoint, secondary efficacy analyses, and 
exploratory efficacy analyses, if no RSV LRTI occurs prior to discontinuation, the subject 
will be considered as having no RSV LRTI in the analysis, unless stated otherwise.  
All analyses, with the exception of safety, will be performed on the ITT Population. 
Summaries presented for > 150 days post dose will include subjects in the ITT population 
who are still on study after day 150. 
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS Institute 
Inc., Cary, NC) in a UNIX platform. 
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The analysis populations are defined in Table 3.2-1. 
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Intent-to-treat 
(ITT) population 
Subjects who are randomized will be included in the ITT population and subjects will be 
analyzed according to their randomized treatment group. 
As-treated 
population 
Subjects who receive any study investigational product will be included in the as-treated 
population and subjects will be analyzed according to the treatment they actually receive. 
Per-protocol 
population 
The per-protocol population includes all subjects in the as-treated population who are 
either followed through 150 days post dose or not followed through 150 days post dose 
but had medically attended RSV LRTI. 
 
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Many of the planned analyses presented in the following sections include summaries by age 
at randomization [age  3 months (ie, age  91 days), age > 3 to  6 months (ie, age > 91 to 
 183 days), age > 6 months (ie, age > 183 days)] 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 DOB is available:  
•
Age at randomization (months) = (randomization date – date of birth) / (365.25/12) 
 
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MEDI8897 
 
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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)] 
 
Many analyses will also be summarized by hemisphere. The sites have been grouped together 
by country into the following two hemispheres: Northern Hemisphere (Bulgaria, Canada, 
Czech Republic, France, Hungary, Italy, Poland, Russian Federation, Spain, United 
Kingdom, and USA) and Southern Hemisphere (Argentina, Australia, Brazil, Chile, New 
Zealand, and South Africa). 
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A summary of subject eligibility and randomization as well as treatment received (including 
summary of subjects randomized but not treated) will be provided. In addition, disposition of 
subjects throughout the study with respect to follow-up will be provided. This summary will 
be presented by treatment group and for all subjects combined. The denominators for this 
summary will include all subjects who were randomized into the study. 
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Enrollment will be summarised by hemisphere, country and 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.  
Demographic information related to gender, age at randomization (months) calculated from 
the CRF, age at randomization category determined using the CRF age calculation (age  3 
months, age > 3 to  6 months, age > 6 months), gestational age (weeks), gestational age 
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category (29-32 weeks, > 32 weeks), ethnicity, race, weight (kg) on day 1, weight on day 1 
category (weight  2.5 kg, weight > 2.5 to  5 kg, weight > 5 kg), birth weight (kg), birth 
weight category (weight  2.5 kg, weight > 2.5 kg), multiple birth (yes/no), and siblings 
enrolled in the study (yes/no) will be summarized by treatment group and for all subjects 
combined using the ITT population. 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 category at randomization, country, and by hemisphere. 
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Due to the simplicity of dosing for this study, exposure is summarized in the Subject 
Disposition and Completion Status table under the summary “Randomized and dosed.” No 
other summary will be reported. 
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An interim analysis for safety and efficacy will be conducted by an independent data 
monitoring committee (IDMC) after approximately 750 infants have been randomized and 
followed for at least 150 days post dose. There is no provision to stop early due to an efficacy 
claim, however 0.001 alpha will be spent at the interim analysis based on advice from the US 
FDA. The final analysis will be tested at 2-sided alpha 0.049 accordingly. 
For the final analysis, the secondary efficacy hypothesis will be assessed only if the primary 
efficacy hypothesis has been demonstrated. Due to this preplanned sequential testing 
procedure, the overall Type I error is controlled at 0.049. Therefore, no further multiplicity 
adjustment is necessary. 
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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 analysis 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 
the detection of RSV A and RSV B performed in a central laboratory. These LRTI events 
may occur in the inpatient or outpatient visit setting.  
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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 medically attended RSV LRTI if 
they occurred in a respiratory sample collected within this window relative to the initial date 
seen by the healthcare provider (eg, admission/deterioration date associated with the event, 
urgent care visit, outpatient ED visit, or outpatient clinic visit). The actual window used will 
be documented prior to unblinding. In addition, deaths which 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. 
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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 factors as described below.  
The primary analysis uses Poisson regression with robust variance with stratification factors 
as covariates, which 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 confidence interval estimation of 
the treatment effect is expected through the repeated imputation (Little and Rubin, 2002). To 
cope with the primary analysis including stratification factors/covariates, the missing values 
will be imputed at the medically attended RSV LRTI risk level adjusted for subject’s 
stratification value using SAS PROC MI with, e.g., logistic regression method.  
The details for the repeated imputation placebo medically attended RSV LRTI rate adjusted 
for stratification values are provided below. Note that the placebo rate is applied equally to 
both placebo and MEDI8897 groups in the imputation. 
•
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 risk is equally applied in the 
imputation for both the MEDI8897 and placebo subjects adjusted for their stratification 
values. The imputation will be executed using SAS PROC MI (e.g., logistic regression 
with stratification factors). 
•
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 compare the incidence of medically attended RSV LRTI between MEDI8897 
and placebo, including treatment group, categorical age at randomization, and 
dichotomous temperate hemispheres as covariates. The point estimate and variance will 
be extracted from the model.  
•
Steps 2-3 will be repeated multiple times. The set of point estimates and variances for the 
model parameter for each complete dataset will be used to generate statistical inferences 
using the multiple imputation procedure (eg, SAS MIANALYZE procedure). 
 
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The primary (ie, final) efficacy analysis of the primary endpoint will be evaluated using the 
ITT Population. A Poisson regression model with robust variance (Zou, 2004) will be used as 
the primary efficacy analysis to compare the incidence of medically attended RSV LRTI 
between MEDI8897 and placebo groups, including treatment group, age at randomization 
based on CRF calculation (ie, age  3 months, age > 3 to  6 months, age > 6 months) and 
dichotomous temperate (northern and southern) hemispheres as covariates. If the number of 
subjects in any stratum is too small and/or convergence cannot be achieved, the covariate(s) 
may not be included in the model. In addition, the 2-sided p-value and corresponding 2-sided 
95.1% CI on the relative risk will be provided from the model. Relative risk reduction is 
defined as (1 - Pn/Ps) where Pn is the incidence of medically attended 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. Statistical significance will be achieved if the 2-
sided p-value is < 0.049. 
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Additional analyses will be based on observed events and available follow-up through 150 
days, unless stated otherwise.  
To allow for differences in follow-up time, the primary analysis using Poisson Regression 
with robust variance will be repeated, adjusting for the same covariates as well as log(follow-
up time) as an offset.  
•
For subjects who meet the medically attended RSV LRTI endpoint within 150 days 
postdose, the follow-up time will be calculated as (Date of Onset of RSV LRTI) – (Date 
of Dosing) +1. 
•
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 set to 150 days.  
 
Medically attended RSV LRTI will be summarized by treatment group for the per-protocol 
population. Relative risk and 95.1% CI will be constructed using an exact conditional method 
based on the number of RSV LRTIs.  
A CMH (Cochran-Mantel-Haenszel) test stratified by hemisphere and age at randomization (ie, 
age  3 months, age > 3 to  6 months, age > 6 months) will be used to compare between 
treatment groups through 150 days post dose as a sensitivity analysis for the primary endpoint.A 
Kaplan-Meier curve for time to first medically attended RSV LRTI will be used as a 
sensitivity analysis for the primary endpoint. Subjects who have not had a medically attended 
RSV LRTI through 150 days post dose will be considered censored. For these subjects time 
will be defined in days from the date of randomization to date of last follow-up (see above 
for calculation). For subjects experiencing a medically attended RSV LRTI through 150 days 
post dose, time will be defined from randomization to date of first medically attended RSV 
LRTI. A plot presenting the Kaplan-Meier curves will be created. Treatment groups will be 
compared using the stratified log-rank and Wilcoxon tests. 
The incidence of medically attended RSV LRTI by subtype (RSV A, RSV B) through 150 
days post dose will be summarized for each treatment group using the Poisson regression 
approach as described for the primary efficacy analysis (Section 3.5.1.3). The analysis will 
include the relative efficacy, 2-sided p-value and 2-sided 95.1% CI on the relative risk 
reduction from the model. 
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 will be defined as an adverse event (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 adverse event for a medically attended RSV LRTI (see Table 3.5-1). The 
total number of medically attended RSV LRTIs occurring for each subject through 150 days post 
dose will be summarized by numbers and percentages of subjects who have X number of 
medically attended RSV LRTIs (ie, 0, 1, 2, 3... medically attended RSV LRTIs). This summary 
will be repeated for medically attended RSV LRTIs occurring > 150 days post dose and for  360 
days post dose.  
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Additional summaries will present the incidence of medically attended RSV LRTI through 
for  360 days post dose and occurring > 150 days post dose.  
Adverse events 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, after 150 days, and through 360 days. 
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Sensitivity 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. 
The imputed rates of medically attended RSV LRTI through 150 days post dose will be as 
follows: 
1. Subjects who do not have an RSV LRTI and are not followed through 150 days post dose 
will be counted as having not met the RSV LRTI endpoint within each treatment group.  
2. Impute the missing values in each treatment group using 2-times the placebo RSV LRTI 
event rate through 150 days post dose (ie, Bernoulli distribution with expected value 
equal to 2-times placebo RSV LRTI event rate)  
3. Tipping point analysis by imputing the missing values in the MEDI8897 arm using 
2-times the placebo event rate through 150 days post dose and imputing the missing 
values in the placebo arm with the placebo rate (ie, Bernoulli distribution with expected 
value equal to 1 or 2-times placebo RSV LRTI event rate) 
4. Tipping point analysis by imputing the missing values in the MEDI8897 arm using 
3-times the placebo event rate through 150 days post dose and imputing the missing 
values in the placebo arm with the placebo rate (ie, Bernoulli distribution with expected 
value equal to 1 or 3-times placebo RSV LRTI event rate) 
5. Subjects who do not have an RSV LRTI and are not followed through 150 days post dose 
will be counted as having met the RSV LRTI endpoint within each treatment group (ie, 
clinical failures). 
6. Multiple imputation 
 
The sensitivity analyses 2-4 will be carried out following the steps below: 
 
•
Step 1: Determine the observed placebo RSV LRTI rate through 150 days post dose, 
which is calculated as the proportion of all randomized placebo subjects with observed 
RSV.  
•
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 arm or the MEDI8897 arm only 
(depending on the sensitivity analysis assumption above) using the Bernoulli distribution 
with X-times the observed placebo RSV LRTI rate.  
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•
Step 3: 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, to form a complete dataset.  
•
Step 4: 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, categorical age at the time of randomization, and 
dichotomous temperate hemispheres as covariates. The point estimate and variance will 
be provided from the model.  
•
The steps 2-4 will be repeated multiple times. The point estimate and variance for the 
model parameters for each complete dataset will be used to generate statistical inferences 
using the multiple imputation procedure (eg, SAS MIANALYZE procedure). 
 
For sensitivity analyses 1 and 5, all subjects who do not have an RSV LRTI and are not 
followed through 150 days post dose will be assumed to either (1) have an RSV LRTI event 
(sensitivity analysis #5) or (2) not have an RSV LRTI event (sensitivity analysis #1). 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, to form a complete dataset. The primary efficacy analysis using 
the Poisson regression model with robust variance adjusting for the same covariates will be 
run according to this new dataset. 
For sensitivity analysis 6, the same missing data imputation steps described above in Section 
3.5.1.2 for the primary efficacy analysis will be followed, except step 1 (ie, the “MEDI8897” 
treatment code will not be substituted with “placebo” prior to the SAS PROC MI 
imputations); the actual treatment codes will be used.  

6XEJURXS$QDO\VHV
The following subgroups analysis will be provided including the efficacy of MEDI8897 
relative to placebo and corresponding confidence intervals in each subgroup given there are 
sizable numbers of subjects in each level of the subgroups: 
•
Hemisphere/Country 
•
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  2.5 kg, weight > 2.5 to  5 kg, weight > 5 kg) 
•
Gestational age (29-32 weeks, > 32 weeks) 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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•
Sibling also participating in the study (yes/no) 
•
Post-baseline detection of ADA (detected, not detected) – only incidence rates will be 
provided for this summary 
 
Forest plots may be provided showing the relative risk reduction ratio and 95.1% confidence 
interval for each level of the subgroup.  
 
Subgroup analysis will be conducted:  
•
in the ITT population using the same method as for the primary analysis, when 
applicable; 
•
in the per-protocol population using the same method as for the per-protocol analysis 
described in Section 3.5.1.4.  
 

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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 analysis of RSV LRTI hospitalizations 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 central laboratory analysis respiratory secretions using a validated RSV 
RT-PCR assay for the detection of RSV A and 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 which can be demonstrated as caused by RSV (by autopsy or 
clinical history and virologic evidence) will also be considered as RSV LRTI hospitalization 
endpoints. 

+DQGOLQJRI'URSRXWVDQG0LVVLQJ'DWD
RSV LRTI hospitalization that occurs through 150 days post dose will contribute to the 
analysis. For subjects who do not have an RSV LRTI hospitalization and were not followed 
through 150 day post dose, their event status will be imputed assuming the observed placebo 
RSV LRTI hospitalization rate conditional on stratification factors as described below.  
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
17 of 26 
A repeated imputation approach is introduced at the subject-level for the model fitting to 
impute RSV LRTI hospitalization status for missing observations. The same methods 
described above for the primary efficacy endpoint will be used (see Section 3.5.1.2). 
However, the imputation by covariates may not be applicable if the total number of RSV 
LRTI hospitalization events is not adequate (eg, the anticipated number of RSV LRTI 
hospitalizations is < 40% of the primary RSV LRTI endpoints). In this case the imputation 
will be performed using the Bernoulli distribution with the observed placebo RSV LRTI 
hospitalization rate (see Section 3.5.1.4). 

6HFRQGDU\(IILFDF\$QDO\VHV
A Poisson regression model with robust variance (Zou, 2004) will be used to compare the 
incidence of RSV LRTI hospitalization between MEDI8897 and placebo, including treatment 
group, age at randomization stratum based on CRF calculation (ie,  3 months, > 3 to  6 
months, > 6 months) and dichotomous temperate (northern and southern) hemispheres as 
covariates (similar analysis as described above for the primary endpoint of medically 
attended RSV LRTI). In addition, the 2-sided p-value and corresponding 2-sided 95.1% CI 
on the relative risk will be provided from the model. Relative risk reduction is defined as (1 - 
Pn/Ps) where Pn is the incidence of RSV LRTI hospitalization through 150 days post dose in 
the MEDI8897 group and Ps is the incidence of RSV LRTI hospitalization through 150 days 
post dose in the placebo group. Medically attended RSV LRTI hospitalization will be 
summarized by treatment group for the per-protocol population. Relative risk and 95.1% CI 
will be constructed using an exact conditional method based on the number of RSV LRTI 
hospitalization.  
The secondary efficacy hypothesis will be assessed only if the primary efficacy hypothesis 
has been demonstrated. Statistical significance will be achieved if the 2-sided p-value is < 
0.049. 

$GGLWLRQDO$QDO\VHVRIWKH6HFRQGDU\(IILFDF\(QGSRLQW
The additional analyses (except CMH, Kaplan-Meier, and the sensitivity analyses for 
subjects who were not followed through 150 days post dose) as described for the primary 
endpoint will be provided for RSV LRTI hospitalization.  

6XEJURXS$QDO\VHV
The same subgroups analyses as described for the primary endpoint will be provided for RSV 
LRTI hospitalization.  
 
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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
2WKHU(IILFDF\$QDO\VHV
An analysis will also include the incidence of all medically attended LRTI, protocol-defined 
LRTI, non-protocol defined LRTI, and incidence by RSV positive RT-PCR and/or local testing 
results, and RSV negative LRTI by RT-PCR or local testing. This will be repeated for LRTI 
hospitalizations and medically attended outpatient LRTI events. The same analysis window as 
described in above sections for the RT-PCR central tests will be used for the local tests. For 
subjects with multiple events, only the first occurrence will be used in each incidence 
summary, respectively. The observed and imputed counts from the primary and secondary 
endpoint analysis will be presented in this summary. For medically attended RSV outpatient 
LRTI (Protocol-Defined), if a subject does not have an event prior to discontinuation from 
participation, their event status will be imputed assuming the observed placebo event rate 
conditional on stratification value (see Section 3.5.1.2). However, the imputation by 
covariates may not be applicable if the total number of events is not adequate. In this case the 
imputation will be performed using the Bernoulli distribution with the observed placebo 
event rate (see Section 3.5.1.4). All other summaries will be based on observed events and 
available follow-up through 150 days. . This summary will be presented for the ITT 
population through 150 days post dose, after 150 days post dose, and through 360 days post 
dose.  
Similar to the primary endpoint (as described in Section 3.5.1.4), the total number of new 
onset events since previous events will be summarized for the following events: 
7DEOH
'HILQLWLRQIRU1HZ2QVHWRI(YHQWV
(YHQW
'HVFULSWLRQ
New onset 
medically attended 
RSV LRTI 
A new onset medically attended RSV LRTI will be defined as an adverse event (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 adverse event 
for a medically attended RSV LRTI. 
New onset RSV 
LRTI 
KRVSLWDOL]DWLRQ 
A new onset medically attended RSV LRTI hospitalization will be defined as an adverse 
event (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 
adverse event for a medically attended RSV LRTI hospitalization. 
New onset 
medically attended 
RSV RXWSDWLHQW 
LRTI 
A new onset medically attended RSV outpatient LRTI will be defined as an adverse event 
(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 adverse event for a medically attended RSV outpatient LRTI. 
New onset 
medically attended 
LRTI 
A new onset medically attended LRTI will be defined as an adverse event of LRTI that 
occurs after the resolution date of the previous adverse event for a medically attended 
LRTI. 
New onset LRTI 
KRVSLWDOL]DWLRQ 
A new onset medically attended LRTI hospitalization will be defined as an adverse event 
(with at least one hospitalization associated with LRTI) that occurs after the resolution 
date of the previous adverse event for a medically attended LRTI hospitalization. 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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7DEOH
'HILQLWLRQIRU1HZ2QVHWRI(YHQWV
(YHQW
'HVFULSWLRQ
New onset 
medically attended 
RXWSDWLHQW LRTI 
A new onset medically attended outpatient LRTI will be defined as an adverse event (with 
at least one outpatient healthcare visit associated with LRTI) that occurs after the 
resolution date of the previous adverse event for a medically attended outpatient LRTI. 
New onset 
medically attended 
non-RSV LRTI 
A new onset medically attended Non-RSV LRTI will be defined as an adverse event (for 
which at least one healthcare visit is associated with LRTI, but not associated with RSV) 
that occurs after the resolution date of the previous adverse event for a medically attended 
Non-RSV LRTI. 
New onset 
non-RSV LRTI 
KRVSLWDOL]DWLRQ 
A new onset medically attended Non-RSV LRTI hospitalization will be defined as an 
adverse event (for which at least one hospitalization is associated with LRTI, but not 
associated with RSV) that occurs after the resolution date of the previous adverse event 
for a medically attended Non-RSV LRTI hospitalization. 
New onset 
medically attended 
non-RSV 
RXWSDWLHQW LRTI 
A new onset medically attended Non-RSV outpatient LRTI will be defined as an adverse 
event LRTI (for which at least one outpatient healthcare visit is associated with LRTI, but 
not associated with RSV) that occurs after the resolution date of the previous adverse 
event for a medically attended Non-RSV outpatient LRTI. 
 
Adverse events associated with medically attended 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, after 150 days, and through 360 days. 

([SORUDWRU\$QDO\VHV

+HDOWKFDUH5HVRXUFH8WLOL]DWLRQ
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, outpatient ED, urgent care, 
outpatient clinic; and number of prescription and OTC medications and duration of use) will 
be summarized by treatment group for all randomized subjects through 150 days post dose, 
after 150 days post dose, and through 360 days post dose.  
Duration of hospitalization will be calculated from the admission or deterioration date to 
discharge. Durations for the other parameters will be calculated in a similar manner from 
start date to stop date. The subject’s entire experience throughout the study (eg, separate 
occurrences of mechanical ventilation within a hospitalization or across separate 
hospitalizations) will be summed together. All randomized subjects will be included in the 
analysis; therefore, a subject who was not hospitalized or did not utilize the particular 
parameter (CPAP, supplemental oxygen use, ICU stay, or mechanical ventilation) will have a 
duration of 0 days. Unlike the other parameters, supplemental oxygen can also be used in the 
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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outpatient setting, thus the summary of supplemental oxygen will include use in both hospital 
and outpatient settings.  
Durations will be summarized by total days, mean and standard deviation number of days 
(mean calculated as total days divided by total number of randomized subjects per group), 
median days, and minimum/maximum number of days.  
For duration of prescription and OTC medication summaries, missing or partial concomitant 
medication start/stop dates will be imputed as follows: 
•
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. 
 
In addition to the overall HRU summary, the HRU for (1) medically attended RSV LRTI 
(Protocol-Defined), (2) medically attended non-RSV LRTI (Protocol-Defined), and (3) 
medically attended LRTI (Non-Protocol Defined) will be summarized for all randomized 
subjects by treatment group, through 150 days post dose, after 150 days post dose, and 
through 360 days post dose. The same conventions used for the overall summary will apply 
for the respective events; however, the HRU must occur during the event being summarized. 
For example, only supplemental oxygen use during a medically attended RSV LRTI 
(Protocol-Defined) will be counted for the medically attended RSV LRTI summary. A 
concomitant medication will be associated with the adverse event associated with the RSV 
LRTI event if the medication was taken to treat the LRTI (as recorded in the CRF) and the 
medication overlaps the adverse event being summarized. The duration of medications will 
be counted as the days of medication use residing within the adverse event associated with 
the RSV event. 
Additional summaries of HRUs will evaluate HRUs among subjects who have an event. The 
summaries will only include subjects with the event (1) medically attended RSV LRTI 
(Protocol-Defined), (2) medically attended non-RSV LRTI (Protocol-Defined), and (3) 
medically attended LRTI (Non-Protocol Defined). These summaries will provide an estimate 
of the average HRU use among subjects who are experiencing an event. 
The average number of prescriptions (and OTC medications) per medically attended non-
RSV LRTI (Protocol-Defined) per subject will be summarized for each treatment group 
through 150 days post dose. The average number of prescriptions per medically attended 
non-RSV LRTI (Protocol-Defined) will be calculated as the total number of prescriptions 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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provided during the study divided by the total number of medically attended non-RSV LRTI 
(Protocol-Defined) events. Only subjects with a medically attended non-RSV LRTI 
(Protocol-Defined) will be included in the analysis. This summary will be provided for 
subjects with at least one non-RSV LRTI hospitalization and for subjects without any non-
RSV LRTI hospitalizations. Similar summaries will be provided for medically attended LRTI 
(Non-Protocol-Defined). 

&DUHJLYHU%XUGHQ
Caregiver burden (eg, caregiver missed work days, subject absence from day 
care/babysitting) for subjects with medically attended RSV LRTI (Protocol-Defined) will be 
summarized by treatment group for all randomized subjects and among subjects who have an 
event. If at least one healthcare visit occurring during an adverse event is associated with 
RSV, the caregiver burden collected for that adverse event will be counted in this summary. 
For example, consider a subject with an LRTI with three healthcare visits: outpatient ER 
(non-protocol defined LRTI and RSV negative), outpatient clinic (protocol-defined LRTI and 
RSV negative), and hospitalization (protocol-defined LRTI and RSV positive). Since the 
hospitalization for this subject meets the protocol definition for LRTI and is associated with 
RSV, the entire caregiver burden for the adverse event will be included in this summary. 
Similar summaries will be provided for medically attended non-RSV LRTI (Protocol-
Defined) and medically attended LRTI (Non-Protocol-Defined) events. These summaries 
will be presented through 150 days post dose, after 150 days post dose, and through 360 days 
post dose.  
The average caregiver burden (caregiver missed work days, subject absence from day 
care/babysitting) per medically attended non-RSV LRTI (Protocol-Defined) per subject will 
be summarized for each treatment group through 150 days post dose. The average caregiver 
burden (caregiver missed work days, subject absence from day care/babysitting) per 
medically attended non-RSV LRTI (Protocol-Defined) will be calculated as the total 
caregiver burden divided by the total number of medically attended non-RSV LRTI 
(Protocol-Defined). Only subjects with a medically attended non-RSV LRTI (Protocol-
Defined) will be included in the analysis. This summary will be provided for subjects with at 
least one non-RSV LRTI hospitalization and for subjects without any non-RSV LRTI 
hospitalizations. As similar summary will be provided for medically attended LRTI (Non-
Protocol-Defined).  
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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
6DIHW\$QDO\VHV

$GYHUVH(YHQWVDQG6HULRXV$GYHUVH(YHQWV
Adverse events will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
version 19 or higher and the type, incidence, severity and relationship to study investigational 
product will be summarized by treatment group. Specific adverse events (AEs) will be 
counted once for each subject for calculating percentages. 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 will be summarized overall, as well 
as categorized by MedDRA system organ class (SOC) and preferred term (PT).  
Additional summaries will present treatment-emergent AEs by SOC and high-level term and 
by SOC and high-level group term. Nontreatment-emergent AEs/serious adverse events 
(SAEs) will be presented in the listings. 

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Adverse events of special interest will include targeted AEs of hypersensitivity (including 
anaphylaxis), thrombocytopenia, and immune complex disease (eg, vasculitis, endocarditis, 
neuritis, glomerulonephritis), and the type, incidence, and relationship to study 
investigational product will be summarized by treatment group and by SOC and PT based on 
MedDRA. Additional groupings may be added by the Medical Monitor if warranted. 

6NLQDQG+\SHUVHQVLWLYLW\5HDFWLRQV
All skin reactions and skin reactions identified as hypersensitivity/allergic reactions and the 
type, incidence, and relationship to study investigational product will be summarized by 
treatment group and by SOC and PT based on MedDRA.  

1HZ2QVHW&KURQLF'LVHDVH
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.  

6XEJURXS$QDO\VHV
All adverse events will be summarized by age  at randomization stratum (age  3 months, 
age > 3 to  6 months, age > 6 months), and weight on day 1 (weight  2.5 kg, weight > 2.5 
to  5 kg, weight > 5 kg). 
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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
2WKHU6DIHW\(YDOXDWLRQV
Adverse events, adverse events of special interest, skin reactions and skin hypersensitivity 
reactions will also be summarized by timing relative to dosing (‘within 1 day’/‘greater than 1 
day’, ‘within 7 days/greater than 7 days’). 
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. Data listings will be provided and no formal analyses will be conducted on 
these data. Upon review of the listings, additional summary tables may be generated as 
appropriate. 

$QWLGUXJ$QWLERGLHV
The number and percentage of subjects who develop anti-MEDI8897 antibodies will be 
summarized at each visit by treatment group. For those with a positive assessment, the ADA 
titer results will also be summarized. 
An additional table will summarize the number and percentage of subjects positive for ADA 
at baseline (ie, ADA prevalence) and positive at any post-baseline time point (ie, ADA 
incidence). For those with a positive post-baseline assessment, the percentage who were 
persistent positive and transient positive will also be presented. 
1. Persistent positive is defined as 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 last post-baseline assessment and positive at 
only one post-baseline assessment or at 2 post-baseline assessments (with <16 weeks 
between first and last positive) 
 
Adverse events will be summarized by SOC and PT based on MedDRA for subjects with 
ADA to MEDI8897 at any time post-baseline. 
The impact of ADA on PK will be included in the PK report as mentioned in Section 3.9. 

3KDUPDFRNLQHWLFV
Following a single dose of MEDI8897, individual MEDI8897 serum concentrations data will 
be tabulated by treatment group along with description statistics. Terminal-phase half-life 
(t1/2) will be estimated using non-compartmental analysis, if data permit. The details of the 
analyses and presentation of these data will be included in a separate PK report.  
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Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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
,17(5,0$1$/<6,6
An interim analysis for safety and efficacy will be conducted by an IDMC after 
approximately 750 infants have been randomized and followed for 150 days post dose. This 
analysis is being conducted to address the US FDA request that the benefit risk assessment 
should be performed after 500 infants have received MEDI8897 before moving forward into 
Phase 3 in infants > 35 wGA. There is no provision to stop the study early due to an efficacy 
claim; however 0.001 alpha will be spent at this interim analysis based on advice from the 
US FDA. The final analysis will be tested at 2-sided alpha 0.049 accordingly. Additional 
details will be provided in the IDMC charter. 
Given an IDMC recommendation that the risk/benefit is favorable and a Phase 3 study may 
be initiated, a limited and controlled internal review of the unblinded interim results will be 
initiated in order to design the Phase 3 trial and prepare materials for further discussion with 
regulatory agencies. The site investigators, subjects’ parent(s)/legal representative, site 
monitors, and all study team members at MedImmune having direct contact with the site or 
involved in the data collection and cleaning process will remain blinded to individual 
treatment allocation so that blinded follow-up can continue through Day 361. Details will be 
documented in a separate unblinding plan. 
A final analysis is planned after all subjects have completed the 360-day safety follow-up 
period.  
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
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
5()(5(1&(6
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. 
 
 
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MedImmune 
Statistical Analysis Plan for Protocol D5290C00003 
MEDI8897 
 
18Nov2016; Final v1.0 
CONFIDENTIAL AND PROPRIETARY 
26 of 26 
$SSHQGL[
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Positive RT-PCR 
'RFXPHQWHG3(ILQGLQJV
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•
Rhonchi 
•
Rales 
•
Crackles 
•
Wheeze 
2EMHFWLYHPHDVXUHVRIFOLQLFDO
VHYHULW\:  
•
Increased respiratory rate 
•
Hypoxemia 
•
Acute hypoxic or ventilatory 
failure 
•
New onset apnea 
•
Nasal flaring 
•
Retractions 
•
Grunting 
•
Dehydration 
•
Prescription medications (only 
for children with underlying 
lung disease) 
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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MedImmune
Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
14 June 2018; draft v4.0
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Statistical Analysis Plan
A Phase 2b 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 Preterm Infants
Protocol Number: D5290C00003


MedImmune
Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
14 June 2018; draft v4.0
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TABLE OF CONTENTS
1
INTRODUCTION ......................................................................................................5
2
STUDY OVERVIEW .................................................................................................5
2.1
Study Objectives...............................................................................................5
2.1.1Primary Study Objective(s) .......................................................................5
2.1.2Secondary Study Objectives ......................................................................6
2.1.3Exploratory Study Objectives....................................................................6
2.2
Study Design.....................................................................................................6
2.3
Treatment Assignment and Blinding .................................................................6
2.4
Sample Size ......................................................................................................7
3
STATISTICAL METHODS........................................................................................8
3.1
General Considerations .....................................................................................8
3.2
Analysis Populations and Datasets ....................................................................8
Analysis Datasets........................................................................................................9
3.3
Stratification Factors.........................................................................................9
3.4
Study Subjects ................................................................................................10
3.4.1Subject Disposition and Completion Status .............................................10
3.4.2Demographics and Baseline Characteristics.............................................10
3.4.3Study Drug Exposure ..............................................................................10
3.5
Efficacy Analyses ...........................................................................................11
3.5.1Primary Efficacy Endpoint and Analyses.................................................11
3.5.1.1
Primary Efficacy Endpoint.....................................................11
3.5.1.2
Primary Efficacy Analysis......................................................12
3.5.1.3
Handling of Dropouts and Missing Data.................................12
3.5.1.4
Additional Analyses of the Primary Efficacy Endpoint...........13
3.5.1.7. Subgroup Analyses for the Primary Efficacy Endpoint .............18
3.5.2Secondary Efficacy Endpoint and Analyses.............................................19
3.5.2.1
Secondary Efficacy Endpoint .................................................19
3.5.2.2
Secondary Efficacy Analyses .................................................19
3.5.2.3
Handling of Dropouts and Missing Data.................................20
3.5.2.4
Additional Analyses of the Secondary Efficacy Endpoint.......20
3.5.2.5
Subgroup Analyses for the Secondary Efficacy Endpoint .......20
3.5.3Other Efficacy Analyses..........................................................................21
3.6
Exploratory Analyses......................................................................................22
3.6.1Healthcare Resource Utilization (HRU)...................................................22
3.6.2Caregiver Burden ....................................................................................24
3.7
Safety Analyses...............................................................................................25
3.7.1Adverse Events and Serious Adverse Events ...........................................25


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Statistical Analysis Plan for Protocol D5290C00003
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3.7.2Adverse Events of Special Interest...........................................................25
3.7.3Skin and Hypersensitivity Reactions........................................................25
3.7.4New Onset Chronic Disease ....................................................................25
3.7.5Subgroup Analyses..................................................................................26
3.7.6Other Safety Evaluations.........................................................................26
3.8
Anti-drug Antibodies ......................................................................................26
3.9
Pharmacokinetics (PK)....................................................................................27
4
REFERENCES .........................................................................................................27
LIST OF IN-TEXT TABLES
Table 3.2-1
Analysis Populations ..........................................................................8
Table 3.5-1
Definition for New Onset of Events..................................................22
LIST OF APPENDICES
Appendix 1
Elements to Evaluate for Case Definition of Medically Attended RSV 
LRTI (Protocol defined) ...................................................................28


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Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
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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 
DOB
date of birth
eCRF
electronic case report form
ED
Emergency Department
ER
emergency room
EU
European Union
GA
gestational age
HRU
healthcare resource utilization
ICU
intensive care unit
IDMC
independent data monitoring committee
IM
intramuscular
ITT
intent-to-treat
IWRS
interactive web response system
LRTI
lower respiratory tract infection
MedDRA
Medical Dictionary for Regulatory Activities
OTC
over-the-counter
PK
pharmacokinetic(s)
PT
Preferred Term
RR
relative risk
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SID
subject identification
SOC
System Organ Class
t1/2
terminal half-life
TEAE
treatment-emergent adverse event


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Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
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Abbreviation or 
Specialized Term
Definition
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 D5290C00003, a
pivotal Phase 2b study to determine if MEDI8897 is efficacious in reducing medically 
attended respiratory syncytial virus (RSV)-confirmed lower respiratory tract infection (LRTI)
in healthy preterm infants entering their first RSV season. The primary efficacy hypothesis of 
this study is that, compared with placebo, a single 50-mg intramuscular (IM) dose of 
MEDI8897 will be efficacious in reducing medically attended LRTI caused by reverse 
transcriptase-polymerase chain reaction (RT-PCR)-confirmed RSV in healthy preterm infants 
born between 29 weeks 0 days and 34 weeks 6 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 RSV, (2) the 
predicted extended terminal half-life (t1/2) 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 over the 5-month RSV season. These 
hypotheses will be assessed by the incidence of RSV LRTI, RSV hospitalization, ADA, 
pharmacokinetic (PK) parameters, 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.
2
STUDY OVERVIEW
2.1
Study Objectives
2.1.1
Primary Study Objective(s)
To assess the efficacy of MEDI8897 when administered as a single 50 mg IM dose to healthy 
preterm infants born between 29 weeks 0 days and 34 weeks 6 days GA and entering their 
first RSV season for the reduction of medically attended LRTI due to RT-PCR-confirmed 
RSV, compared with placebo.


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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 with placebo
2. To evaluate the safety and tolerability of MEDI8897 when administered as a single fixed 
IM dose, compared with 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
To assess healthcare resource utilization (HRU) and caregiver burden for MEDI8897 
recipients compared with placebo recipients.
2.2
Study Design
The population to be enrolled is healthy preterm infants born between 29 weeks 0 days and 
34 weeks 6 days GA who would not receive RSV prophylaxis based on the American 
Academy of Pediatrics (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 1,500 infants will be randomized in a 2:1 ratio to 
receive a 50 mg IM dose of MEDI8897 (N = 1000) or placebo (N = 500). Randomization 
will be stratified by temperate zones in the northern and southern hemisphere and by subject 
age group at randomization (ie, ≤ 3 months, > 3 to ≤6 months, > 6 months). Enrollment of 
infants > 6 months of age will be limited to approximately 500. All infants will be followed 
for approximately 360 days after dosing. 
2.3
Treatment Assignment and Blinding
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 50 mg IM dose of MEDI8897 
(N = 1,000) or placebo (N = 500). Randomization will be stratified by temperate zones in the 
northern and southern hemisphere and by subject age group at randomization (ie, ≤ 3 months, 
> 3 to ≤ 6 months, > 6 months). Enrollment of infants > 6 months of age will be limited to 
approximately 500.


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Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
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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 
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.
2.4
Sample Size
The sample size of 1,500 subjects is necessary based on advice from the United States Food 
and Drug Administration US FDA requesting that 1,000 preterm infants be exposed to
MEDI8897 in this Phase 2b study. This sample size has approximately > 99% power to 
detect 70% relative-risk reduction, 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 50 mg versus placebo, with 2-sided, α = 0.05.
•
The 70% relative-risk reduction assumption is based on a placebo-controlled study in 
Native American infants in which there was 87% relative reduction in the incidence of 
RSV hospitalization (11.3% placebo; 1.5% motavizumab; p < 0.001) and 71% relative 
reduction in the incidence of outpatient RSV LRTI (10.0% placebo; 2.9% motavizumab; 
p < 0.001) in infants who received motavizumab prophylaxis (O'Brien et al, 2015)
In order to evaluate risk, a sample size of 1,000 subjects exposed to MEDI8897 will provide a
90% probability of observing at least one AE if the true event rate is 0.2%; if no AEs are
observed, this study provides 95% confidence that the true event rate is < 0.3%.


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Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
14 June 2018; draft v4.0
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3
STATISTICAL METHODS
3.1
General Considerations
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. 
There are two planned analyses for this study: the Primary Analysis and the Final Analysis. 
The Primary Analysis will be conducted after all randomized subjects have completed the
Day 151 visit. At the time of this primary analysis, approximately half of all subjects 
enrolled (722 subjects) will have completed the Day 361 visit. The remaining 731 subjects 
will have completed approximately 8 months of the study. MEDI8897’s efficacy will be 
evaluated in the Primary Analysis as intended by the study design. In addition, all available 
PK, ADA, and safety data will be analyzed. The final analysis will be conducted when all 
subjects have completed the last visit of the study.  
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS Institute 
Inc., Cary, NC) in a SAS GRID environment.
3.2
Analysis Populations and Datasets
The analysis populations are defined in Table 3.2-1.
Table 3.2-1
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.
As-treated
population
Subjects who are randomized and receive any study investigational product will be 
included in the as-treated population; in this population, data will be analyzed according 
to the treatment they actually receive.
Per-protocol 
population
The per-protocol population includes 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.  


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Statistical Analysis Plan for Protocol D5290C00003
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Analysis Datasets 
!
The Primary Dataset contains all data (efficacy, safety, ADA, PK) from all 
randomized subjects through the Day 151visit and all available safety data as of the
data cutoff date. The Primary Analysis will be performed on the Primary Dataset.
!
The Final Dataset contains all data collected in this study, including data in the 
Primary Dataset and data from the subjects who were ongoing at the time when the 
Primary Dataset was 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 months (ie, age ≤ 91 days), age > 3 to ≤ 6 months (ie, 
age > 91 to ≤183 days), age > 6 months (ie, age > 183 days)] 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 
(Belgium, Bulgaria, Canada, Czech Republic, Estonia, Finland, France, Hungary, Italy, 


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Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
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Latvia, Lithuania, Poland, Spain, Sweden, Turkey, United Kingdom, and United States of 
America [USA]) and Southern Hemisphere (Argentina, Australia, Brazil, Chile, New 
Zealand, 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. In addition, disposition of 
subjects throughout the study and by visit will be provided. This summary will be presented 
by treatment group and for all subjects combined. The denominators for this summary will 
include all subjects who were randomized into the study.
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. 
Demographic information related to gender, age at randomization (months) calculated from 
the CRF, age at randomization category determined using the CRF age calculation (age ≤ 3 
months, age > 3 to ≤ 6 months, age > 6 months), GA (weeks), GA category (29-32 weeks, 
> 32 weeks), ethnicity, race, weight (kg) on day 1, weight on day 1 category (weight ≤ 2.5 
kg, weight > 2.5 to ≤ 5 kg, weight > 5 kg), birth weight (kg), birth weight category (weight 
≤2.5 kg, weight > 2.5 kg), multiple birth (yes/no), and siblings enrolled in the study (yes/no) 
will be summarized by treatment group and for all subjects combined using the ITT 
population. 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 category
at randomization, country, and by hemisphere.
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.


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Statistical Analysis Plan for Protocol D5290C00003
MEDI8897
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3.5
Efficacy Analyses
The analyses of the primary efficacy endpoint, the protocol-defined medically attended RSV 
LRTI through 150 days post dose (also described as the medically attended RSV LRTI 
through 150 days post dose in Section 3.5.1., Primary Efficacy Endpoint and Analyses), and 
the secondary efficacy endpoint, the protocol-defined RSV hospitalization through 150 days 
post dose (also described as the RSV LRTI hospitalization in Section 3.5.2., Secondary 
Efficacy Endpoint and Analyses), will be performed on the Primary Dataset. 
The Final Dataset will include the events that occurred 150 days post dose, either medically 
attended RSV LRTI or RSV hospitalization, therefore will be used to summarize these events 
that occurred after Day 151 or up to Day 361. Efficacy analyses performed on the Primary 
Dataset will be refreshed in the Final Dataset to make sure statistical inferences on 
MEDI8897 efficacy made from the Primary Analysis are consistent with those from the Final 
Dataset.
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 
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 database lock 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 this window 
relative to the initial date seen by the healthcare provider (eg, admission/deterioration date 
associated with the event, urgent care visit, outpatient 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.


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3.5.1.2
Primary Efficacy Analysis
The primary efficacy analysis of the primary endpoint will be performed on the ITT 
Population. A Poisson regression model with robust variance (Zou, 2004) will be used as the 
primary efficacy analysis model to estimate the relative risk on the incidence of medically 
attended RSV LRTI between the MEDI8897 and the placebo groups. The model contains the 
term of treatment group and age group at randomization based on the calculation detailed in 
Section 3.3. (ie, age ≤ 3 months, age > 3 to ≤ 6 months, age > 6 months) and dichotomous 
temperate (northern and southern) hemispheres as covariates. The relative risk reduction, 
defined as 1- Relative Risk (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.
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 RR reduction is given by [(1 – exp()) * 100%]. The CI for the 
percent of RR reduction is given 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 3.5.1.4) 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. 
3.5.1.3
Handling of Dropouts and Missing Data
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 factors using multiple 
imputation techniques as described in the following paragraphs.


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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 dropped out prior to reaching Day 150 post dose without a medically attended RSV 
LRTI event will be imputed per stratum determined by the two stratification factors 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 factors).
•
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.
•
Step 3: Analyze the complete dataset using a Poisson regression model with robust 
variance to estimate the relative risk on the incidence of medically attended RSV LRTI 
between MEDI8897 and placebo, with the term of treatment group and two stratification 
factors. 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 relative risk and the variance. The random seed is 12345. 
3.5.1.4
Additional Analyses of the Primary Efficacy Endpoint
The following analyses will be conducted on the ITT population. 
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:


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•
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.
•
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 
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). 
A CMH test stratified by hemisphere and age group at randomization (ie, age ≤ 3 months, 
age > 3 to ≤ 6 months, age > 6 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 
relative risk 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 RR 
reduction and the 95% CI will be reported following the relationship of RR reduction (%)
= (1- relative risk)*100%. Similar to the data imputation plan for the Poisson regression 
model with robust variance, repeated imputation algorithm will be applied and placebo event 
rate per stratum will be used to impute the event status for MEDI9987 subjects who dropped 
out the study prior to Day 150 post dose and did not have a medically attended RSV event in 
the stratified CMH test. Detailed steps from data imputation to generate a pooled statistical 
inference from imputed completed datasets for CMH test are described in O'Kelly et al. 
(2014). The key steps are: 1) for each imputed complete dataset, the log-transformed relative 
risk of MEDI8897 over placebo for the incidence of medically attended RSV LRTI events 
and standard error derived from the CMH output will be used as the input for PROC
MIANALYZE to obtain combined relative risk and the 95% CI; 2) for each imputed 
complete dataset, the Wilson-Hilferty transformed CMH statistic will be used as the input for 
PROC MIANALYZE to obtain a combined p-value (Wilson and Hilferty, 1931). 
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 to that 
for follow-up time (see previous). Treatment group differences in time-to-first medically 


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attended RSV LRTI will be compared using the stratified log-rank test and Wilcoxon test 
with two stratification factors as the strata.
In addition, all observed medically attended RSV LRTI events 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 emergency department
visits for subjects who did not have a hospitalization due to RSV.
3.5.1.5. Analyses for Medically Attended RSV LRTI beyond the Primary Endpoint
The following analyses will be conducted on the ITT population and based on observed 
events, unless stated otherwise. 
The incidence of medically attended RSV LRTI that occurred > 150 days post dose and 
≤360 days post dose will be summarized by treatment group. ITT subjects who remained in 
the study at the Day 151 visit will be used as the denominator to calculate the incidence rate
for the summary of the incidence > 150 days post dose, and the ITT population will be used 
for the summary of the incidence ≤360 days post dose.
Age at onset of the first medically attended RSV LRTI 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, > 150 Days and through 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, 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 3.5-1 for details). A listing will be 
generated to provide the following information: age at randomization, hemisphere, total 
number of events (at least 14 days apart), total number of events (at least 30 days apart), days 
to event, adverse event (AE) verbatim term, Date of AE onset/stop, Days from previous 


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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, after 150 days, and 
through 360 days.
3.5.1.6. Sensitivity Analyses for Subjects who are Not Followed through 150 
Days Post Dose
Sensitivity 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. Subjects who do not have an RSV LRTI and are not followed through 150 days post dose
will be counted as having not met the RSV LRTI endpoint. 
2. Impute the missing values in each treatment group using 2-times the placebo RSV LRTI 
event rate through 150 days post dose (ie, Bernoulli distribution with expected value 
equal to 2-times placebo RSV LRTI event rate).
3. Tipping point analysis by imputing the missing values in the MEDI8897 arm using 
2-times the placebo event rate through 150 days post dose and imputing the missing 
values in the placebo arm with the placebo rate (ie, Bernoulli distribution with expected 
value equal to 2 or 1-times placebo RSV LRTI event rate).
4. Tipping point analysis by imputing the missing values in the MEDI8897 arm using 
3-times the placebo event rate through 150 days post dose and imputing the missing 
values in the placebo arm with the placebo rate (ie, Bernoulli distribution with expected 
value equal to 3 or 1-times placebo RSV LRTI event rate)
5. Subjects who do not have an RSV LRTI and are not followed through 150 days post dose
will be counted as having met the RSV LRTI endpoint.
6. Multiple imputations
7. Impute the missing values in each treatment group using 1-time, 2-time, and 3-time the 
overall placebo event rate in single imputation approach. 
The sensitivity analyses 2-4 will be conducted following the steps below:
•
Step 1: Determine the observed placebo RSV LRTI rate through 150 days post dose, 
which is calculated as the proportion of all randomized placebo subjects with observed 
RSV.
•
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 arm or the MEDI8897 arm only 


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(depending on the sensitivity analysis planed above) using the Bernoulli distribution with 
X-times the observed placebo RSV LRTI rate without involvement of stratification 
factors.
•
Step 3: 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 4: 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 two stratification factors (age group and 
hemispheres) as covariates. 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.
For sensitivity analyses 1 and 5, all subjects who do not have an RSV LRTI and are not 
followed through 150 days post dose will be assumed to either (1) have an RSV LRTI event
(sensitivity analysis #5) or (2) not have an RSV LRTI event (sensitivity analysis #1). 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 sensitivity analysis 6, 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 sensitivity analysis 7, the number of medically attended RSV LRTI events for those 
MEDI8897-treated subjects who dropped out prior to Day 150 post dose without the event 
will be generated using a binomial distribution with 1-time, 2-time, or 3-time observed 
placebo event rates, respectively. While placebo-treated subjects who dropped out prior to 
Day 150 post dose without the event will be imputed using a 1-time observed placebo rate. 
With the imputed number of events, the RR reduction and the 95% CI will be constructed using 


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an exact conditional method based on the number of RSV LRTIs (Breslow and Day, 1987). This 
analysis will be carried out by StatXact PROC Poisson procedure.
3.5.1.7. Subgroup Analyses for the Primary Efficacy 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, 
hemisphere, 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 RR reduction 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 RR reduction 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 relative risk reduction 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 the ITT population:
•
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 ≤ 2.5 kg, weight > 2.5 to ≤ 5 kg, weight > 5 kg)
•
GA (29-32 weeks, > 32 weeks)
•
Sibling also participating in the study (yes/no)
In addition, incidence of medically attended RSV LRTI will be summarized by Country.


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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 reverse transcriptase -polymerase chain reaction 
(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
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 ITT population. Relative risk reduction and its 
corresponding 95% CI are estimated from the model implemented by PROC GENMOD as 
detailed in Section 3.5.1.2.
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. In that event, statistically significant 
treatment effect on this secondary efficacy endpoint will be claimed if the 2-sided p-value is 
≤0.05. In this approach, the family-wise Type I error rate of testing the first and the 
secondary efficacy hypotheses is controlled under the significance level of α ≤ 0.05. 
Above stated analysis on RSV LRTI hospitalization will also be conducted on the per-
protocol population. 


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3.5.2.3
Handling of Dropouts and Missing Data
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 computation steps are similar to what has been described in the 
Sensitivity analysis 2 for the primary efficacy endpoint (Section 3.5.1.6).
3.5.2.4
Additional Analyses of the Secondary Efficacy Endpoint
The additional analyses, including the CMH test with the only term of treatment for the 
incidence of RSV LRTI hospitalization, and the Kaplan-Meier for time-to-first RSV LRTI 
hospitalization will be conducted. Treatment effect for time-to-first RSV hospitalization will 
be tested by a log-rank test. For the CHM test, the procedures for missing data imputation 
and the statistical inference from imputed datasets will follow what been described in Section 
3.5.1.4, except for the fact that no stratification factors are involved in the steps.  
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 hospitalization will also be 
summarized by RSV subtype (A or B). 
3.5.2.5
Subgroup Analyses for the Secondary Efficacy Endpoint
The incidence of RSV LRTI hospitalization will be summarized by the following subgroups. 
•
Hemisphere
•
Country
•
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 ≤ 2.5 kg, weight > 2.5 to ≤ 5 kg, weight > 5 kg)
•
GA (29-32 weeks, > 32 weeks)
•
Sibling also participating in the study (yes/no)


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3.5.3
Other Efficacy Analyses
Summary of incidence for all medically attended LRTI, breaking done by protocol-defined 
LRTI (RSV or non-RSV) and non-protocol defined LRTI (RSV or non-RSV) with each 
further breaking done by hospitalization status, will be presented by treatment group. 
For all medically attended LRTI, the incidence of RSV status (positive, negative or not done) 
will be summarized by RT-PCR or local testing results. Incidence of positive RSV either by 
RT-PCR or by local testing results will also be summarized by 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 addition, all LRTI hospitalizations (primary or nosocomial hospitalization) and medically 
attended outpatient LRTI events by different outpatient settings, such as outpatient clinics, 
urgent care clinics, or emergency department visits will be summarized by treatment group. 
All above stated summaries will be based on observed events and data summary will be 
presented by Day 150 post dose (on the ITT population), after 150 days post dose (on the ITT 
population with Day 151 visit), and through 360 days post dose (on ITT population). For 
subjects with multiple events, only the first occurrence will be used in each relevant 
incidence summary.
For various medical events, including the primary endpoint, detailed definitions of new onset 
of events are defined in the following table, Table 3.5-1. For medically attended LRTI 
(regardless RSV Yes or No, or Protocol-defined Yes or No) the total number of event 
occurrences for each subject and the percentage of each outcome will be summarized by 
treatment group on 3 time-intervals: Day 150 post dose (on the ITT population), after 150 
days post dose (on the ITT population with Day 151 visit), and through 360 days post dose
(on ITT population). 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, 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).


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Table 3.5-1
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 150 
days, and through 360 days on the ITT, ITT with Day 151 visit and ITT populations, 
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 Emergency Department [ED], urgent care, outpatient clinic); and 
number of prescription or over the counter [OTC] medications and duration of use) will be 
summarized by treatment group and reported in 3 time period: through 150 days post dose


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(on ITT population), after 150 days post dose (on ITT population with Day 151 visit), and 
through 360 days post dose (on ITT population). 
Specifically, following summary tables by treatment group will be used to report the 
magnitudes of HRU (overall for any reason).
!
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 ITT population for time interval through 150 days post dose, on 
ITT population with Day 151 visit for time interval after 150 days post dose, and on 
ITT population 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 activity.
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}. 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 (1) medically attended RSV LRTI
(Protocol-Defined), (2) medically attended non-RSV LRTI (Protocol-Defined), (3) medically 


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attended RSV LRTI (Non-protocol Defined) and (4) medically attended non-RSV LRTI 
(Non-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 apply for the respective events 
and the HRU must occur during the event being summarized. 
The total number and duration of prescriptions (or OTC medications) related to each of the 4 
previously mentioned events per subject through Day 150 post dose will be summarized 
using descriptive statistics (mean, median, SD, minimum, and maximum) by treatment
group. For each treatment group, the average number of prescriptions and duration per event 
of interest will also be reported. The average number of prescriptions is calculated by 
dividing the total number of prescriptions across subjects who have had at least one 
prescription for the event over the total number of such events over the time interval of 
interest. The average duration will be calculated similarly. Only subjects with the respective 
event will be included in the above analysis. Similar summaries will be provided for subjects 
by RSV hospitalization or non-RSV LRTI hospitalization status (has had at least one or 
none).
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 an event in the time-
period of reporting. Similar summaries will be provided for medically attended non-RSV LRTI 
(Protocol-defined), medically attended RSV LRTI (Non-protocol Defined) and medically 
attended non-RSV LRTI (Non-protocol Defined), respectively. 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 (i.e., 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. 


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3.7
Safety Analyses
All safety analyses will be conducted on As-treated population.
3.7.1
Adverse Events and Serious Adverse Events
Adverse events will be coded by MedDRA version 19 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, 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) will be summarized overall, as well as categorized by MedDRA SOC and PT. 
Additional summaries will present TEAEs by SOC, high-level term, SOC, and high-level 
group term. Nontreatment-emergent AEs/serious adverse events (SAEs) will be presented in 
the listings.
3.7.2
Adverse Events of Special Interest
Adverse events of special interest (AESI) will include targeted AEs of hypersensitivity 
(including anaphylaxis), thrombocytopenia, and immune complex disease (eg, vasculitis, 
endocarditis, neuritis, glomerulonephritis), and the type, incidence, and relationship to study 
investigational product will be summarized by treatment group and by SOC and PT based on 
MedDRA. Additional groupings may be added by the Medical Monitor, if warranted.
3.7.3
Skin and Hypersensitivity Reactions
All skin reactions and skin reactions identified as hypersensitivity/allergic reactions and the 
type, incidence, and relationship to study investigational product will be summarized by 
treatment group, and by SOC and PT based on MedDRA. 
3.7.4
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.


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3.7.5
Subgroup Analyses
All AEs will be summarized by age group used as randomization stratum (age ≤ 3 months, 
age > 3 to ≤ 6 months, age > 6 months), weight on Day 1 (weight ≤ 2.5 kg, weight > 2.5 to 
≤5 kg, weight > 5 kg), and age at randomization by ≤ 8 months or > 8 months.
3.7.6
Other Safety Evaluations
TEAEs, AESIs, skin reactions, and skin hypersensitivity reactions will also be summarized 
by timing relative to dosing (‘within 1 day/greater than 1 day,’ ‘within 7 days/greater than 
7 days’).
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. Data listings will be provided and no formal analyses will be conducted on 
these data. 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. 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 neutralizing regions of MEDI8897 will also be summarized.
An additional table will summarize the number and percentage of subjects positive for ADA 
at baseline (ie, ADA prevalence) and positive at any post-baseline time point (ie, ADA 
incidence). For those with a positive post-baseline assessment, the percentage who were 
persistent positive and transient positive will also be presented.
1. Persistent positive is defined as 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 last one post-baseline assessment, and positive 
at only one post-baseline assessment or at ≥2 post-baseline assessments (with <16 weeks 
between first and last 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 status in three ways: 1) ADA post-baseline status (ie, at least one 
post-baseline ADA positive or not); 2) ADA persistent positive status (Yes or No); 3) ADA 
transient positive status (Yes or No). 


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The impact of ADA on PK will be included in the PK report as mentioned in Section 3.9.
3.9
Pharmacokinetics (PK)
Individual and mean MEDI8897 serum concentrations for each nominal sampling time will 
be listed, summarized and plotted versus time. Pharmacokinetic parameters will be listed for 
each subject and summary descriptive statistics will be presented. Individual and mean 
Tmax, Cmax, C150, AUC0-150, and AUC0-last will be graphically illustrated by ADA status 
and MA-LRTI outcome. The details of the analyses and presentation of these data will be 
included in a separate PK report.
4
REFERENCES
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.


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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 RT-PCR
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
•
Prescription medications 
(only for children with 
underlying lung disease)
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.


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: MEDI8897 D5290C00003 Statistical Analysis Plan_v4_clean
Document Title:
MEDI8897 D5290C00003 Statistical Analysis Plan_v4_clean
Document ID:
Doc ID-003863084
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
14-Jun-2018 19:15 UTC
Content Approval
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Content Approval
14-Jun-2018 15:08 UTC
Author Approval
14-Jun-2018 03:14 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.


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Statistical Analysis Plan
A Phase 2b 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 Preterm Infants
Protocol Number: D5290C00003


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TABLE OF CONTENTS
1
INTRODUCTION ......................................................................................................5
2
STUDY OVERVIEW .................................................................................................5
2.1
Study Objectives...............................................................................................5
2.1.1Primary Study Objective(s) .......................................................................5
2.1.2Secondary Study Objectives ......................................................................5
2.1.3Exploratory Study Objectives....................................................................6
2.2
Study Design.....................................................................................................6
2.3
Treatment Assignment and Blinding .................................................................6
2.4
Sample Size ......................................................................................................7
3
STATISTICAL METHODS........................................................................................7
3.1
General Considerations .....................................................................................7
3.2
Analysis Populations and Datasets ....................................................................8
Analysis Datasets........................................................................................................8
3.3
Stratification Factors.........................................................................................9
3.4
Study Subjects ..................................................................................................9
3.4.1Subject Disposition and Completion Status ...............................................9
3.4.2Demographics and Baseline Characteristics.............................................10
3.4.3Study Drug Exposure ..............................................................................10
3.5
Efficacy Analyses ...........................................................................................10
3.5.1Primary Efficacy Endpoint and Analyses.................................................11
3.5.1.1
Primary Efficacy Endpoint.....................................................11
3.5.1.2
Primary Efficacy Analysis......................................................11
3.5.1.3
Handling of Dropouts and Missing Data.................................12
3.5.1.4
Additional Analyses of the Primary Efficacy Endpoint...........13
3.5.1.7. Subgroup Analyses for the Primary Efficacy Endpoint .............17
3.5.2Secondary Efficacy Endpoint and Analyses.............................................18
3.5.2.1
Secondary Efficacy Endpoint .................................................18
3.5.2.2
Secondary Efficacy Analyses .................................................18
3.5.2.3
Handling of Dropouts and Missing Data.................................19
3.5.2.4
Additional Analyses of the Secondary Efficacy Endpoint.......19
3.5.2.5
Subgroup Analyses for the Secondary Efficacy Endpoint .......19
3.5.3Other Efficacy Analyses..........................................................................20
3.6
Exploratory Analyses......................................................................................22
3.6.1Healthcare Resource Utilization (HRU)...................................................22
3.6.2Caregiver Burden ....................................................................................24
3.7
Safety Analyses...............................................................................................24
3.7.1Adverse Events and Serious Adverse Events ...........................................24


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3.7.2Adverse Events of Special Interest...........................................................25
3.7.3Skin and Hypersensitivity Reactions........................................................25
3.7.4New Onset Chronic Disease ....................................................................25
3.7.5Subgroup Analyses..................................................................................25
3.7.6Other Safety Evaluations.........................................................................25
3.8
Anti-drug Antibodies ......................................................................................26
3.9
Pharmacokinetics (PK)....................................................................................26
4
REFERENCES .........................................................................................................27
LIST OF IN-TEXT TABLES
Table 3.2-1
Analysis Populations ..........................................................................8
Table 3.5-1
Definition for New Onset of Events..................................................21
LIST OF APPENDICES
Appendix 1
Elements to Evaluate for Case Definition of Medically Attended RSV 
LRTI (Protocol defined) ...................................................................28


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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 
DOB
date of birth
eCRF
electronic case report form
ED
Emergency Department
ER
emergency room
EU
European Union
GA
gestational age
HRU
healthcare resource utilization
ICU
intensive care unit
IDMC
independent data monitoring committee
IM
intramuscular
ITT
intent-to-treat
IWRS
interactive web response system
LRTI
lower respiratory tract infection
MedDRA
Medical Dictionary for Regulatory Activities
OTC
over-the-counter
PK
pharmacokinetic(s)
PT
Preferred Term
RR
relative risk
RSV
respiratory syncytial virus
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SID
subject identification
SOC
System Organ Class
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
US FDA
United States Food and Drug Administration
USA
United States of America


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1
INTRODUCTION
This document describes the statistical analysis plan (SAP) for protocol D5290C00003, a
pivotal Phase 2b study to determine if MEDI8897 is efficacious in reducing medically 
attended respiratory syncytial virus (RSV)-confirmed lower respiratory tract infection (LRTI)
in healthy preterm infants entering their first RSV season. The primary efficacy hypothesis of 
this study is that, compared with placebo, a single 50-mg intramuscular (IM) dose of 
MEDI8897 will be efficacious in reducing medically attended LRTI caused by reverse 
transcriptase-polymerase chain reaction (RT-PCR)-confirmed RSV in healthy preterm infants 
born between 29 weeks 0 days and 34 weeks 6 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 RSV, (2) the 
predicted extended terminal half-life (t1/2) 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 over the 5-month RSV season. These 
hypotheses will be assessed by the incidence of RSV LRTI, RSV hospitalization, ADA, 
pharmacokinetic (PK) parameters, 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.
2
STUDY OVERVIEW
2.1
Study Objectives
2.1.1
Primary Study Objective(s)
To assess the efficacy of MEDI8897 when administered as a single 50 mg IM dose to healthy
preterm infants born between 29 weeks 0 days and 34 weeks 6 days GA and entering their 
first RSV season for the reduction of medically attended LRTI due to RT-PCR-confirmed 
RSV, compared with 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 with placebo
2. To evaluate the safety and tolerability of MEDI8897 when administered as a single fixed 
IM dose, compared with placebo
3. To evaluate single-dose serum concentrations of MEDI8897


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4. To evaluate ADA responses to MEDI8897 in serum
2.1.3
Exploratory Study Objectives
To assess healthcare resource utilization (HRU) and caregiver burden for MEDI8897 
recipients compared with placebo recipients.
2.2
Study Design
The population to be enrolled is healthy preterm infants born between 29 weeks 0 days and 
34 weeks 6 days GA who would not receive RSV prophylaxis based on the American 
Academy of Pediatrics (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 1,500 infants will be randomized in a 2:1 ratio to 
receive a 50 mg IM dose of MEDI8897 (N = 1000) or placebo (N = 500). Randomization 
will be stratified by temperate zones in the northern and southern hemisphere and by subject 
age group at randomization (ie, H 3 months, > 3 to H 6 months, > 6 months). Enrollment of 
infants > 6 months of age will be limited to approximately 500. All infants will be followed 
for approximately 360 days after dosing. 
2.3
Treatment Assignment and Blinding
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 50 mg IM dose of MEDI8897 
(N = 1,000) or placebo (N = 500). Randomization will be stratified by temperate zones in the 
northern and southern hemisphere and by subject age group at randomization (ie, H 3 months, 
> 3 to H 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 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


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•
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 time frame, the unblinded investigational product monitor must be notified 
immediately.
2.4
Sample Size
The sample size of 1,500 subjects is necessary based on advice from the United States Food 
and Drug Administration US FDA requesting that 1,000 preterm infants be exposed to
MEDI8897 in this Phase 2b study. This sample size has approximately > 99% power to 
detect 70% relative-risk reduction, 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 50 mg versus placebo, with 2-sided, N = 0.05.
•
The 70% relative-risk reduction assumption is based on a placebo-controlled study in 
Native American infants in which there was 87% relative reduction in the incidence of 
RSV hospitalization (11.3% placebo; 1.5% motavizumab; p < 0.001) and 71% relative 
reduction in the incidence of outpatient RSV LRTI (10.0% placebo; 2.9% motavizumab; 
p < 0.001) in infants who received motavizumab prophylaxis (O'Brien et al, 2015)
In order to evaluate risk, a sample size of 1,000 subjects exposed to MEDI8897 will provide a
90% probability of observing at least one AE if the true event rate is 0.2%; if no AEs are
observed, this study provides 95% confidence that the true event rate is < 0.3%.
3
STATISTICAL METHODS
3.1
General Considerations
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. 


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There are two planned analyses for this study: the Primary Analysis and the Final Analysis. 
The Primary Analysis will be conducted after all randomized subjects have completed the
Day 151 visit. At the time of this primary analysis, approximately half of all subjects 
enrolled (722 subjects) will have completed the Day 361 visit. The remaining 731 subjects 
will have completed approximately 8 months of the study. MEDI8897’s efficacy will be 
evaluated in the Primary Analysis as intended by the study design. In addition, all available 
PK, ADA, and safety data will be analyzed. The final analysis will be conducted when all 
subjects have completed the last visit of the study.  
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS Institute 
Inc., Cary, NC) in a SAS GRID environment.
3.2
Analysis Populations and Datasets
The analysis populations are defined in Table 3.2-1.
Table 3.2-1
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.
As-treated
population
Subjects who are randomized and receive any study investigational product will be 
included in the as-treated population; in this population, data will be analyzed according 
to the treatment they actually receive.
Per-protocol 
population
The per-protocol population includes 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.  
Analysis Datasets 
!
The Primary Dataset contains all data (efficacy, safety, ADA, PK) from all 
randomized subjects through the Day 151visit and all available safety data as of the
data cutoff date. The Primary Analysis will be performed on the Primary Dataset.
!
The Final Dataset contains all data collected in this study, including data in the 
Primary Dataset and data from the subjects who were ongoing at the time when the 
Primary Dataset was locked. The Final Analysis will be performed on the Final 
Dataset.


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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 H 3 months (ie, age H 91 days), age > 3 to H 6 months (ie, 
age > 91 to H 183 days), age > 6 months (ie, age > 183 days)] 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 
(Belgium, Bulgaria, Canada, Czech Republic, Estonia, Finland, France, Hungary, Italy, 
Latvia, Lithuania, Poland, Spain, Sweden, Turkey, United Kingdom, and United States of 
America [USA]) and Southern Hemisphere (Argentina, Australia, Brazil, Chile, New 
Zealand, 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. In addition, disposition of 
subjects throughout the study and by visit will be provided. This summary will be presented 


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by treatment group and for all subjects combined. The denominators for this summary will 
include all subjects who were randomized into the study.
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. 
Demographic information related to gender, age at randomization (months) calculated from 
the CRF, age at randomization category determined using the CRF age calculation (age H 3 
months, age > 3 to H 6 months, age > 6 months), GA (weeks), GA category (29-32 weeks, 
> 32 weeks), ethnicity, race, weight (kg) on day 1, weight on day 1 category (weight H 2.5 
kg, weight > 2.5 to H 5 kg, weight > 5 kg), birth weight (kg), birth weight category (weight 
H 2.5 kg, weight > 2.5 kg), multiple birth (yes/no), and siblings enrolled in the study (yes/no) 
will be summarized by treatment group and for all subjects combined using the ITT 
population. 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 category
at randomization, country, and by hemisphere.
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.
3.5
Efficacy Analyses
The analyses of the primary efficacy endpoint, the protocol-defined medically attended RSV 
LRTI through 150 days post dose (also described as the medically attended RSV LRTI 
through 150 days post dose in Section 3.5.1., Primary Efficacy Endpoint and Analyses), and 
the secondary efficacy endpoint, the protocol-defined RSV hospitalization through 150 days 
post dose (also described as the RSV LRTI hospitalization in Section 3.5.2., Secondary 
Efficacy Endpoint and Analyses), will be performed on the Primary Dataset. 
The Final Dataset will include the events that occurred 150 days post dose, either medically 
attended RSV LRTI or RSV hospitalization, therefore will be used to summarize these events 


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that occurred after Day 151 or up to Day 361. Efficacy analyses performed on the Primary 
Dataset will be refreshed in the Final Dataset to make sure statistical inferences on 
MEDI8897 efficacy made from the Primary Analysis are consistent with those from the Final 
Dataset.
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 
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 database lock 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 this window 
relative to the initial date seen by the healthcare provider (eg, admission/deterioration date 
associated with the event, urgent care visit, outpatient 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 the ITT 
Population. A Poisson regression model with robust variance (Zou, 2004) will be used as the 
primary efficacy analysis model to estimate the relative risk on the incidence of medically 
attended RSV LRTI between the MEDI8897 and the placebo groups. The model contains the 
term of treatment group and age group at randomization based on the calculation detailed in 
Section 3.3. (ie, age H 3 months, age > 3 to H 6 months, age > 6 months) and dichotomous 
temperate (northern and southern) hemispheres as covariates. The relative risk reduction, 
defined as 1- Relative Risk (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 


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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 
H 0.05.
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 RR reduction is given by [(1 – exp()) * 100%]. The CI for the 
percent of RR reduction is given 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 3.5.1.4) 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. 
3.5.1.3
Handling of Dropouts and Missing Data
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 factors 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 dropped out prior to reaching Day 150 post dose without a medically attended RSV 
LRTI event will be imputed per stratum determined by the two stratification factors 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.


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•
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 factors).
•
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.
•
Step 3: Analyze the complete dataset using a Poisson regression model with robust 
variance to estimate the relative risk on the incidence of medically attended RSV LRTI 
between MEDI8897 and placebo, with the term of treatment group and two stratification 
factors. 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 relative risk and the variance. The random seed is 12345. 
3.5.1.4
Additional Analyses of the Primary Efficacy Endpoint
The following analyses will be conducted on the ITT population. 
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.
•
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 
follow-up will be calculated as (Date of End of Study or Date of Last Assessment, 
whichever is later) – (Date of Dosing) +1.


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•
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). 
A CMH test stratified by hemisphere and age group at randomization (ie, age H 3 months, 
age > 3 to H 6 months, age > 6 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 
relative risk 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 RR 
reduction and the 95% CI will be reported following the relationship of RR reduction (%)
= (1- relative risk)*100%. This analysis will be performed without any imputation of event 
for MEDI9987 subjects who dropped out the study prior to Day 150 post dose and did not 
have a medically attended RSV event.
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 to that 
for follow-up time (see previous). Treatment group differences in time-to-first medically 
attended RSV LRTI will be compared using the stratified log-rank test and Wilcoxon test 
with two stratification factors as the strata.
In addition, all observed medically attended RSV LRTI events 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 emergency department
visits for subjects who did not have a hospitalization due to RSV.
3.5.1.5. Analyses for Medically Attended RSV LRTI beyond the Primary Endpoint
The following analyses will be conducted on the ITT population and based on observed 
events, unless stated otherwise. 
The incidence of medically attended RSV LRTI that occurred > 150 days post dose and 
H 360 days post dose will be summarized by treatment group. ITT subjects who remained in 
the study at the Day 151 visit will be used as the denominator to calculate the incidence rate
for the summary of the incidence > 150 days post dose, and the ITT population will be used 
for the summary of the incidence H 360 days post dose.


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Age at onset of the first medically attended RSV LRTI 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, > 150 Days and through 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, 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 3.5-1 for details). A listing will be 
generated to provide the following information: age at randomization, hemisphere, total 
number of events (at least 14 days apart), total number of events (at 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, after 150 days, and 
through 360 days.
3.5.1.6. Sensitivity Analyses for Subjects who are Not Followed through 150 
Days Post Dose
Sensitivity 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. Subjects who do not have an RSV LRTI and are not followed through 150 days post dose
will be counted as having not met the RSV LRTI endpoint. 
2. Impute the missing values in each treatment group using 2-times the placebo RSV LRTI 
event rate through 150 days post dose (ie, Bernoulli distribution with expected value 
equal to 2-times placebo RSV LRTI event rate).
3. Tipping point analysis by imputing the missing values in the MEDI8897 arm using 
2-times the placebo event rate through 150 days post dose and imputing the missing 


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values in the placebo arm with the placebo rate (ie, Bernoulli distribution with expected 
value equal to 2 or 1-times placebo RSV LRTI event rate).
4. Tipping point analysis by imputing the missing values in the MEDI8897 arm using 
3-times the placebo event rate through 150 days post dose and imputing the missing 
values in the placebo arm with the placebo rate (ie, Bernoulli distribution with expected 
value equal to 3 or 1-times placebo RSV LRTI event rate)
5. Subjects who do not have an RSV LRTI and are not followed through 150 days post dose
will be counted as having met the RSV LRTI endpoint.
6. Multiple imputations
7. Impute the missing values in each treatment group using 1-time, 2-time, and 3-time the 
overall placebo event rate in single imputation approach. 
The sensitivity analyses 2-4 will be conducted following the steps below:
•
Step 1: Determine the observed placebo RSV LRTI rate through 150 days post dose, 
which is calculated as the proportion of all randomized placebo subjects with observed 
RSV.
•
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 arm or the MEDI8897 arm only 
(depending on the sensitivity analysis planed above) using the Bernoulli distribution with 
X-times the observed placebo RSV LRTI rate without involvement of stratification 
factors.
•
Step 3: 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 4: 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 two stratification factors (age group and 
hemispheres) as covariates. 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.
For sensitivity analyses 1 and 5, all subjects who do not have an RSV LRTI and are not 
followed through 150 days post dose will be assumed to either (1) have an RSV LRTI event


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(sensitivity analysis #5) or (2) not have an RSV LRTI event (sensitivity analysis #1). 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 sensitivity analysis 6, 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 sensitivity analysis 7, the number of medically attended RSV LRTI events for those 
MEDI8897-treated subjects who dropped out prior to Day 150 post dose without the event 
will be generated using a binomial distribution with 1-time, 2-time, or 3-time observed 
placebo event rates, respectively. While placebo-treated subjects who dropped out prior to 
Day 150 post dose without the event will be imputed using a 1-time observed placebo rate. 
With the imputed number of events, the RR reduction and the 95% CI will be constructed using 
an exact conditional method based on the number of RSV LRTIs (Breslow and Day, 1987). This 
analysis will be carried out by StatXact PROC Poisson procedure.
3.5.1.7. Subgroup Analyses for the Primary Efficacy 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, 
hemisphere, 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 RR reduction 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 RR reduction 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 relative risk reduction 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.


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The subgroup analysis will be conducted for the following subgroups on the ITT population:
•
Hemisphere
•
Age at randomization stratum (age H 3 months, age > 3 to H 6 months, age > 6 months)
•
Gender
•
Race (Caucasian, non-Caucasian)
•
Weight at birth (weight H 2.5 kg, weight > 2.5 kg)
•
Weight on Day 1 (weight H 2.5 kg, weight > 2.5 to H 5 kg, weight > 5 kg)
•
GA (29-32 weeks, > 32 weeks)
•
Sibling also participating in the study (yes/no)
In addition, incidence of medically attended RSV LRTI will be summarized by Country.
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 reverse transcriptase -polymerase chain reaction 
(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
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


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between MEDI8897 and placebo groups in the ITT population. Relative risk reduction and its 
corresponding 95% CI are estimated from the model implemented by PROC GENMOD as 
detailed in Section 3.5.1.2.
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 H 0.05. In that event, statistically significant 
treatment effect on this secondary efficacy endpoint will be claimed if the 2-sided p-value is 
H 0.05. In this approach, the family-wise Type I error rate of testing the first and the 
secondary efficacy hypotheses is controlled under the significance level of N H 0.05. 
Above stated analysis on RSV LRTI hospitalization will also be conducted on the per-
protocol population. 
3.5.2.3
Handling of Dropouts and Missing Data
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 computation steps are similar to what has been described in the 
Sensitivity analysis 2 for the primary efficacy endpoint (Section 3.5.1.6).
3.5.2.4
Additional Analyses of the Secondary Efficacy Endpoint
The additional analyses, including the CMH test with the only term of treatment for the 
incidence of RSV LRTI hospitalization, and the Kaplan-Meier for time-to-first RSV LRTI 
hospitalization will be conducted. Treatment effect for time-to-first RSV hospitalization will 
be tested by a log-rank test. 
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 hospitalization will also be 
summarized by RSV subtype (A or B). 
3.5.2.5
Subgroup Analyses for the Secondary Efficacy Endpoint
The incidence of RSV LRTI hospitalization will be summarized by the following subgroups. 


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•
Hemisphere
•
Country
•
Age at randomization stratum (age H 3 months, age > 3 to H 6 months, age > 6 months)
•
Gender
•
Race (Caucasian, non-Caucasian)
•
Weight at birth (weight H 2.5 kg, weight > 2.5 kg)
•
Weight on Day 1 (weight H 2.5 kg, weight > 2.5 to H 5 kg, weight > 5 kg)
•
GA (29-32 weeks, > 32 weeks)
•
Sibling also participating in the study (yes/no)
3.5.3
Other Efficacy Analyses
An overall summary of subjects with any medically attended LRTI or hospitalization due to 
any respiratory illness will be presented by treatment group. Summary of medically attended 
LRTI, breaking done by protocol-defined LRTI (RSV or non-RSV) and non-protocol defined 
LRTI (RSV or non-RSV) with each further breaking done by hospitalization status, will be
presented. In this summary, a subject is reported only once even he or she might have 
multiple LRTI 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. For subjects who were hospitalized due to 
any respiratory illness, non-LRTI cases will be further reported and broken done by RSV 
status. A subject is reported only once even he or she might have multiple non-LRTI events
in the time interval of reporting. In that occasion the rule to report is RSV > non-RSV.
For all medically attended LRTI, RSV status (positive, negative or not done) will be 
summarized by 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 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, only first occurrence of RSV LRTI event either by PT-PCR or local testing 
will be reported and the incidence of the event will be calculated based on the number of 
randomized subjects for the respective treatment group.


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In addition, for each treatment group, all 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 emergency department 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 Day 150 post dose (on the ITT population), after 150 days post dose (on the ITT 
population with Day 151 visit), and through 360 days post dose (on ITT population). For 
subjects with multiple events, only the first occurrence will be used in each relevant 
incidence summary.
For various medical events, including the primary endpoint, detailed definitions of new onset 
of events are defined in the following table, Table 3.5-1. For medically attended LRTI 
(regardless RSV Yes or No, or Protocol-defined Yes or No) the total number of event 
occurrences for each subject and the percentage of each outcome will be summarized by 
treatment group on 3 time-intervals: Day 150 post dose (on the ITT population), after 150 
days post dose (on the ITT population with Day 151 visit), and through 360 days post dose
(on ITT population). 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, 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).
Table 3.5-1
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.


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Table 3.5-1
Definition for New Onset of Events
Event
Description
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 150 
days, and through 360 days on the ITT, ITT with Day 151 visit and ITT populations, 
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 Emergency Department [ED], urgent care, outpatient clinic); and 
number of prescription or over the counter [OTC] medications and duration of use) will be 
summarized by treatment group and reported in 3 time period: through 150 days post dose
(on ITT population), after 150 days post dose (on ITT population with Day 151 visit), and 
through 360 days post dose (on ITT population). 
Specifically, following summary tables by treatment group will be used to report the 
magnitudes of HRU (overall for any reason).
!
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 


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mechanical ventilation) and the type of outpatient facility. The percentage will be 
calculated based on ITT population for time interval through 150 days post dose, on 
ITT population with Day 151 visit for time interval after 150 days post dose, and on 
ITT population 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 activity.
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}. 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 (1) medically attended RSV LRTI
(Protocol-Defined), (2) medically attended non-RSV LRTI (Protocol-Defined), (3) medically 
attended RSV LRTI (Non-protocol Defined) and (4) medically attended non-RSV LRTI 
(Non-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 apply for the respective events 
and the HRU must occur during the event being summarized. 
The total number and duration of prescriptions (or OTC medications) related to each of the 4 
previously mentioned events per subject through Day 150 post dose will be summarized 
using descriptive statistics (mean, median, SD, minimum, and maximum) by treatment
group. For each treatment group, the average number of prescriptions and duration per event 


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of interest will also be reported. The average number of prescriptions is calculated by 
dividing the total number of prescriptions across subjects who have had at least one 
prescription for the event over the total number of such events over the time interval of 
interest. The average duration will be calculated similarly. Only subjects with the respective 
event will be included in the above analysis. Similar summaries will be provided for subjects 
by RSV hospitalization or non-RSV LRTI hospitalization status (has had at least one or 
none).
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 an event in the time-
period of reporting. Similar summaries will be provided for medically attended non-RSV LRTI 
(Protocol-defined), medically attended RSV LRTI (Non-protocol Defined) and medically 
attended non-RSV LRTI (Non-protocol Defined), respectively. 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 (i.e., 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. 
3.7
Safety Analyses
All safety analyses will be conducted on As-treated population.
3.7.1
Adverse Events and Serious Adverse Events
Adverse events will be coded by MedDRA version 19 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, if the same AE occurs multiple times within a particular subject, the highest 


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severity and level of relationship observed will be reported. All treatment-emergent AEs
(TEAEs) will be summarized overall, as well as categorized by MedDRA SOC and PT. 
Additional summaries will present TEAEs by SOC, high-level term, SOC, and high-level 
group term. Nontreatment-emergent AEs/serious adverse events (SAEs) will be presented in 
the listings.
3.7.2
Adverse Events of Special Interest
Adverse events of special interest (AESI) will include targeted AEs of hypersensitivity 
(including anaphylaxis), thrombocytopenia, and immune complex disease (eg, vasculitis, 
endocarditis, neuritis, glomerulonephritis), and the type, incidence, and relationship to study 
investigational product will be summarized by treatment group and by SOC and PT based on 
MedDRA. Additional groupings may be added by the Medical Monitor, if warranted.
3.7.3
Skin and Hypersensitivity Reactions
All skin reactions and skin reactions identified as hypersensitivity/allergic reactions and the 
type, incidence, and relationship to study investigational product will be summarized by 
treatment group, and by SOC and PT based on MedDRA. 
3.7.4
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 will be summarized by age group used as randomization stratum (age H 3 months, 
age > 3 to H 6 months, age > 6 months), weight on Day 1 (weight H 2.5 kg, weight > 2.5 to 
H 5 kg, weight > 5 kg), and age at randomization by H 8 months or > 8 months. In addition, 
TEAEs occurring within 1-day and 7-day post dose by age at randomization (H 3 Months, >3 
to H 6 Months, > 6 Months) will also be summarized, respectively. 
3.7.6
Other Safety Evaluations
TEAEs, AESIs, skin reactions, and skin hypersensitivity reactions will also be summarized 
by timing relative to dosing (‘within 1 day/greater than 1 day,’ ‘within 7 days/greater than 
7 days’).


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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. Data listings will be provided and no formal analyses will be conducted on 
these data. 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. 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 neutralizing regions of MEDI8897 will also be summarized.
An additional table will summarize the number and percentage of subjects positive for ADA 
at baseline (ie, ADA prevalence) and positive at any post-baseline time point (ie, ADA 
incidence). For those with a positive post-baseline assessment, the percentage who were 
persistent positive and transient positive will also be presented.
1. Persistent positive is defined as 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 last one post-baseline assessment, and positive 
at only one post-baseline assessment or at _2 post-baseline assessments (with <16 weeks 
between first and last 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 status in three ways: 1) ADA post-baseline status (ie, at least one 
post-baseline ADA positive or not); 2) ADA persistent positive status (Yes or No); 3) ADA 
transient positive status (Yes or No). 
The impact of ADA on PK will be included in the PK report as mentioned in Section 3.9.
3.9
Pharmacokinetics (PK)
Individual and mean MEDI8897 serum concentrations for each nominal sampling time will 
be listed, summarized and plotted versus time. Pharmacokinetic parameters will be listed for 
each subject and summary descriptive statistics will be presented. Individual and mean 
Tmax, Cmax, C150, AUC0-150, and AUC0-last will be graphically illustrated by ADA status 
and MA-LRTI outcome. The details of the analyses and presentation of these data will be 
included in a separate PK report.


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4
REFERENCES
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.


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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 RT-PCR
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
•
Prescription medications 
(only for children with 
underlying lung disease)
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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