A Phase 4, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Safety of 2 New of 6:2 Influenza Virus Reassortants in Adults
Phase: PHASE4
Conditions: Influenza, Healthy
Sponsor: MedImmune LLC

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A Phase 4, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate the Safety of 2 New 6:2 Influenza Virus Reassortants 
in Adults
Sponsor Protocol Number: D2560C00015
Application Number:
Investigational Product:
Influenza Virus Vaccine, Bivalent, Subtype A/H3N2, Type B, 
Live, Cold Adapted
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca 
One MedImmune Way
Gaithersburg, MD 20878, USA
Medical Monitor:
Protocol History, Date:
Original Protocol, 27Mar2018

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PROTOCOL SYNOPSIS
TITLE
A Phase 4, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety of 2 New 6:2 Influenza 
Virus Reassortants in Adults
HYPOTHESIS
The hypothesis for this study is that 2 new live attenuated influenza strains based on Ann Arbor master donor 
viruses (MDVs) (Maassab, 1968; Maassab et al, 1985) will have a safety and tolerability profile consistent with 
previously evaluated strains produced using this technology.
OBJECTIVE
The objective of this study is to assess the safety of a bivalent influenza virus vaccine of 2 new 6:2 influenza 
virus reassortants in healthy adults prior to the release of the quadrivalent vaccine (FluMist® Quadrivalent) 
containing them.
STUDY ENDPOINTS
The primary endpoint of this study is fever (Days 1 through 8), defined as oral temperature ≥101°F.
The secondary endpoints of this study are:
1.
Solicited symptoms that occur within 7 days after vaccination (Days 1-8)
2.
Adverse events (AEs) that occur within 7 days after vaccination (Days 1-8)
3.
Solicited symptoms that occur within 14 days after vaccination (Days 1-15)
4.
AEs that occur within 14 days after vaccination (Days 1-15)
5.
Serious adverse events (SAEs) that occur within 28 days after vaccination (Days 1-29) 
6.
New onset chronic diseases (NOCDs) that occur within 28 days after vaccination (Days 1-29) 
7.
SAEs that occur within 180 days after vaccination (Days 1-181)
8.
NOCDs that occur within 180 days after vaccination (Days 1-181)
STUDY DESIGN  
This prospective, randomized, double-blind, placebo-controlled release study will enroll approximately 
300 healthy adults 18 through 49 years of age (not yet reached their 50th birthday). Eligible subjects will be 
randomly assigned in a 4:1 fashion to receive a single dose of bivalent vaccine or placebo by intranasal spray. 
This study will be conducted at 2 sites in the United States of America (USA). Randomization will be stratified 
by site.
Each subject will receive one dose of investigational product on Day 1. Subjects will be followed through 
180 days after receipt of investigational product.
TARGET SUBJECT POPULATION
The subjects in this study will be healthy adults 18 through 49 years of age (not yet reached their 50th birthday).
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
Eligible subjects will be randomly assigned in a 4:1 ratio to receive a single dose of either bivalent vaccine 
(240 subjects) or placebo (60 subjects) by intranasal spray on Day 1.
STATISTICAL ANALYSIS PLAN
General Considerations
Data will be provided in data listings sorted by treatment group and subject identification number. 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, 

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including mean, standard deviation, median, minimum, and maximum. Confidence intervals (CIs) will be 
two-sided, unless otherwise stated.
The intent-to-treat (ITT) population is defined as all subjects that are randomized and treated with 
investigational product. All analyses will be performed on the ITT population unless otherwise specified.
Sample Size and Power Calculations
Based on the solicited event rates following FluMist® and placebo vaccination in healthy adults 18 to 64 years 
of age in Study AV009, the currently proposed study with 300 evaluable subjects (240 bivalent vaccine and 
60 placebo recipients) will provide at least 98% power to rule out a rate increase of 5 percentage points 
assuming the true difference between the treatment groups is zero and the true fever rate is ≤ 1%. Power is lower 
if the true difference is different from zero. For example, if the true fever rates are 2% and 1% in vaccine and 
placebo recipients, respectively, the power will be 77%. For other solicited symptoms with 300 evaluable 
subjects (240 bivalent vaccine and 60 placebo recipients), the currently proposed study provides at least 87% 
power to rule out a 20 percentage point increase, assuming the true difference between the 2 treatment groups is 
zero. Power is lower if the true difference is greater than zero.
Assessment of Endpoints
The primary endpoint of this study is fever (Days 1 through 8), defined as oral temperature ≥101°F. 
Comparison of the rate of fever between the 2 treatment groups will be based on the upper limit of the two-sided 
95% exact CIs for the rate increase (bivalent vaccine minus placebo) evaluated against the pre-specified 
equivalence criterion of 5 percentage points.
This corresponds to the null hypothesis of:
H0:  Rate difference ≥ 5 percentage points.
The alternative hypothesis is:
HA:  Rate difference < 5 percentage points.
A two-sided 95% CI will be constructed using the exact method based on the score statistic proposed by 
(Chan and Zhang, 1999). This method computes the lower and upper confidence limits by inverting 2 separate 
one-sided tests of half the nominal Type I error rate. Its test statistic is based on the score statistic that is 
computed as the observed difference of the 2 binomial event rates minus the hypothesized value of the rate 
difference (observed rate difference) divided by the standard error of this difference under the alternative 
hypothesis. This test assures that the Type I error does not exceed the pre-specified level. Due to discreteness 
when the sample size is relatively small compared to the expected event rate, the associated Type I error rate 
could be quite conservative, that is, smaller than the pre-specified level.
Secondary endpoints of the study include other reported solicited symptoms and AEs that occur within 7 days 
after vaccination (Days 1 through 8), and all solicited symptoms and AEs that occur within 14 days after 
vaccination (Days 1 through 15). Additional secondary endpoints include SAEs and NOCDs that occur within 
28 days after vaccination (Days 1 through 29) and within 180 days after vaccination (Days 1 through 181).
Fever will be summarized according to the following thresholds:
•
Oral > 100°F
•
Oral ≥ 101°F
•
Oral > 102°F
•
Oral > 103°F
A secondary analysis comparing rates of other solicited symptoms (Days 1 through 8) between the 2 treatment 
groups will be performed. Exact two-sided 95% CIs (Chan and Zhang, 1999) on the rate difference (bivalent 
vaccine minus placebo) will be constructed. There are no pre-specified equivalence criteria for the secondary 
analyses.

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The number of days of solicited symptoms and the proportion of subjects experiencing each event by study day 
will be presented without formal statistical comparison. The distribution of the number of days with each 
individual event will also be summarized without formal statistical comparison. The proportion of subjects using 
antipyretic and analgesic agents within 7 days after vaccination (Days 1 through 8) and 14 days after vaccination 
(Days 1 through 15) will be summarized by treatment group.
Interim Analysis
A safety analysis will be conducted after all subjects have been followed through Day 15 and all data through at 
least Day 8 are locked. The analysis for Days 1 through 15 will include the primary endpoint of this study (fever 
for Days 1 through 8, defined as oral temperature ≥101°F), as well as analysis of safety data (solicited 
symptoms and AEs), and antipyretics and analgesic use reported within 7 days and within 14 days after dosing. 

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TABLE OF CONTENTS
PROTOCOL SYNOPSIS..................................................................................................2
1
INTRODUCTION........................................................................................10
1.1
Disease Background .....................................................................................10
1.2
FluMist Quadrivalent Background ................................................................11
1.3
Summary of Nonclinical Experience.............................................................11
1.4
Summary of Clinical Experience...................................................................13
1.5
Rationale for Conducting the Study ..............................................................14
1.6
Research Hypothesis.....................................................................................14
2
OBJECTIVE.................................................................................................14
2.1
Primary Objective.........................................................................................14
2.2
Study Endpoints............................................................................................15
2.2.1
Primary Endpoint..........................................................................................15
2.2.2
Secondary Endpoints ....................................................................................15
3
STUDY DESIGN .........................................................................................15
3.1
Description of the Study ...............................................................................15
3.1.1
Overview.......... ............................................................................................15
3.1.2
Treatment Regimen.......................................................................................16
3.2
Study Design and Dose Rationale .................................................................16
3.2.1
Dose Rationale..............................................................................................16
3.2.2
Rationale for Study Population .....................................................................16
3.2.3
Rationale for Endpoints ................................................................................17
4
MATERIALS AND METHODS ..................................................................17
4.1
Subjects ........................................................................................................17
4.1.1
Number of Subjects ......................................................................................17
4.1.2
Inclusion Criteria ..........................................................................................17
4.1.3
Exclusion Criteria .........................................................................................18
4.1.4
Subject Enrollment and Randomization ........................................................20
4.1.5
Withdrawal from the Study...........................................................................20
4.1.6
Replacement of Subjects...............................................................................20
4.1.7
Withdrawal of Informed Consent for Data ....................................................21
4.2
Schedule of Study Procedures.......................................................................21
4.2.1
Screening Visit (Visit 1) ...............................................................................23
4.2.2
Treatment Period (Visit 2) ............................................................................23
4.2.3
Follow-up Period (Unscheduled Visit and Telephone Contacts)....................24
4.2.3.1
Unscheduled Visit, Days 2 to 15 for Significant Febrile Illness.....................24
4.2.3.2
Telephone Contact, Days 2 to 15...................................................................24
4.2.3.3
Telephone Contact, Days 31, 61, 91, 121, 151 (+ 7 days)..............................24
4.2.3.4
Telephone Contact, Day 181 (+ 14 days): Last Follow-up Contact and Study 
Termination ..................................................................................................24
4.3
Description of Study Procedures...................................................................24

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4.3.1
Medical History and Physical Examination, Height, Weight, and 
Temperature..................................................................................................24
4.3.2
Clinical Laboratory Tests..............................................................................24
4.4
Investigational Products................................................................................25
4.4.1
Identity of Investigational Products...............................................................25
4.4.1.1
Investigational Product Inspection ................................................................26
4.4.1.2
Treatment Administration.............................................................................26
4.4.1.3
Monitoring of Dose Administration ..............................................................26
4.4.1.4
Reporting Product Complaints ......................................................................26
4.4.2
Additional Study Medications.......................................................................27
4.4.3
Labeling………………. ...............................................................................27
4.4.4
Storage…………………...............................................................................27
4.4.5
Treatment Compliance..................................................................................27
4.4.6
Accountability ..............................................................................................27
4.5
Treatment Assignment and Blinding .............................................................28
4.5.1
Methods for Assigning Treatment Groups.....................................................28
4.5.2
Methods for Ensuring Blinding.....................................................................28
4.5.3
Methods for Unblinding................................................................................28
4.5.3.1
Unblinding in the Event of a Medical Emergency .........................................28
4.5.3.2
Unblinding for Interim Analysis ...................................................................29
4.6
Restrictions During the Study and Concomitant Treatment(s) .......................29
4.6.1
Permitted Concomitant Medications .............................................................29
4.6.2
Prohibited Concomitant Medications ............................................................29
4.7
Statistical Evaluation ....................................................................................30
4.7.1
General Considerations.................................................................................30
4.7.2
Sample Size and Power Calculations.............................................................30
4.7.3
Endpoints.......................................................................................................32
4.7.3.1
Primary Endpoint..........................................................................................32
4.7.3.2
Secondary Endpoints ....................................................................................33
4.7.4
Interim Analysis ...........................................................................................34
5
ASSESSMENT OF SAFETY .......................................................................34
5.1
Definition of Adverse Events........................................................................34
5.2
Definition of Serious Adverse Events ...........................................................35
5.3
Definition of Solicited Symptoms .................................................................35
5.4
Definition of New Onset Chronic Diseases ...................................................36
5.5
Recording of Adverse Events........................................................................36
5.5.1
Time Period for Collection of Adverse Events ..............................................36
5.5.2
Recording of Solicited Symptoms.................................................................36
5.5.3
Follow-up of Unresolved Adverse Events.....................................................37
5.6
Reporting of Serious Adverse Events............................................................37
5.7
Other Events Requiring Immediate Reporting...............................................38
5.7.1
Overdose……………………........................................................................38
5.7.2
Pregnancy………. ........................................................................................38
5.7.2.1
Maternal Exposure........................................................................................38

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6
STUDY AND DATA MANAGEMENT.......................................................39
6.1
Training of Study Site Personnel...................................................................39
6.2
Monitoring of the Study................................................................................39
6.2.1
Source Data ..................................................................................................39
6.2.2
Study Agreements.........................................................................................39
6.2.3
Archiving of Study Documents.....................................................................40
6.3
Study Timetable and End of Study................................................................40
6.4
Data Management.........................................................................................40
6.5
Medical Monitor Coverage ...........................................................................40
7
ETHICAL AND REGULATORY REQUIREMENTS..................................41
7.1
Ethical Conduct of the Study.........................................................................41
7.2
Subject Data Protection.................................................................................41
7.3
Ethics and Regulatory Review ......................................................................41
7.4
Informed Consent .........................................................................................42
7.5
Changes to the Protocol and Informed Consent Form....................................42
7.6
Audits and Inspections..................................................................................43
8
REFERENCES.............................................................................................44
LIST OF IN-TEXT TABLES
Table 1
Highly Effective Methods of Contraception.........................................18
Table 2
Schedule of Study Procedures..............................................................22
Table 3
Identification of Investigational Products.............................................25
Table 4
Summary of Solicited Events (Days 0 Through 7) in Study AV009 .....30
Table 5
Power to Show Similar Fever Rates for N = 300 Subjects....................31
Table 6
Power For Secondary Endpoints ..........................................................32

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LIST OF IN-TEXT FIGURES
Figure 1
Study Flow Diagram............................................................................16
LIST OF APPENDICES
Appendix 1
Signature of Principal Investigator.......................................................45
Appendix 2
Additional Safety Guidance .................................................................47
Appendix 3
FluMist® Quadrivalent Package Insert .................................................49

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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
AE
adverse event
att
attenuated
BD
Becton Dickinson (Accuspray™)
BFS
blow fill seal
ca
cold-adapted
CBER
Center for Biologics Evaluation and Research
CI
confidence interval
eCRF
electronic case report form
EDC
electronic data capture
GMP
Good Manufacturing Practice
hCG
human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web response system
MDV
Master Donor Virus
MVS
Master Virus Seed
NOCD
new onset chronic disease
SAE
serious adverse event
SID
subject identification
ts
temperature-sensitive
USA
United States of America
VRBPAC
Vaccines and Related Biological Products Advisory Committee

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1
INTRODUCTION
1.1
Disease Background
FluMist® Quadrivalent is an intranasally administered influenza vaccine that was developed as 
a successor vaccine to FluMist® seasonal trivalent influenza vaccine. FluMist contained 3 live 
reassortant strains of influenza virus, including 2 type A strains (H1N1 and H3N2) and 
1 type B strain. Developed to address the issues of cocirculation of B strains from 2 lineages 
and mismatch between the single B strain lineage included in seasonal influenza vaccines and 
the predominantly circulating strain, FluMist Quadrivalent contains 4 live reassortant strains 
of influenza virus: A/H1N1, A/H3N2, and 2 type B strains. FluMist Quadrivalent contains 
biologically active components that are identical to those in FluMist except that a fourth strain 
is blended into the final vaccine. The 2 vaccines are produced by the same manufacturing 
process, beginning with the preparation of the Master Virus Seed (MVS) for each strain. The 
MVS for each strain contains 6 gene segments from the cold-adapted (ca) Master Donor Virus 
(MDV) and the hemagglutinin and neuraminidase gene segments from a wild-type virus 
isolate and is called a 6:2 reassortant. In the United States of America (USA), the strains used 
for influenza vaccines each season are recommended annually by the Vaccines and Related 
Biological Products Advisory Committee (VRBPAC) to the Center for Biologics Evaluation 
and Research (CBER). The wild-type strains chosen for a given year are then provided to 
influenza vaccine manufacturers by either CBER or the Centers for Disease Control and 
Prevention for preparation of vaccine. 
Numerous safety tests are conducted for FluMist Quadrivalent during the manufacturing 
process of the vaccine including tests for absence of microorganisms; tests for absence of 
adventitious agents; and confirmation of the vaccine virus phenotype (cold adaptation, 
temperature sensitivity, and attenuation). Additionally, after new reassortants are made to 
match selected strains for the upcoming influenza season, their safety profile is evaluated in a 
clinical study in adults in order to provide further safety data prior to the release of the 
commercial vaccine.
The design of this clinical study will ensure that any new influenza vaccine virus reassortant 
has sufficient attenuation in humans, as demonstrated by the low incidence of fever ≥ 101°F 
(oral or equivalent). In previous clinical studies, the rate of fever in adults following 
administration of FluMist has been low and similar in both vaccinees and placebo recipients. 
For example, in Study AV009 conducted in 4,561 healthy adults 18 through 64 years of age 
(3,041 FluMist recipients and 1,520 placebo recipients), fever ≥ 101°F occurred in 0.57% and 
0.60% of FluMist and placebo recipients, respectively. In Study MI-CP185 conducted in 
1,800 adults 18 through 49 years of age (1,197 FluMist Quadrivalent recipients and 
597 FluMist recipients) fever > 101.3°F occurred in 0.8% and 0.3% of FluMist Quadrivalent 
and FluMist recipients, respectively. Thus, in a placebo-controlled study in healthy adults to 

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evaluate new strains, vaccine recipients would be expected to develop temperature increases at 
rates similar to those of placebo recipients following vaccination.
1.2
FluMist Quadrivalent Background
FluMist Quadrivalent is briefly described below. Refer to the current package insert for details 
(Appendix 3). 
The active agents of FluMist Quadrivalent consist of 2 ca, temperature-sensitive (ts), 
attenuated (att) reassortant influenza strains of type A (ie, A/H1N1 and A/H3N2), 1 ca/ts/att
reassortant influenza strain of type B-Victoria, and 1 ca/ts/att reassortant influenza strain of 
type B-Yamagata. The types A and B MDVs, from which the reassortant strains are derived, 
were adapted to grow in primary chick kidney cells at 25°C by sequential passage at 
progressively lower temperatures. During the process of cold adaptation, each virus acquired 
mutations that conferred unique biological phenotypes of cold adaptation, temperature 
sensitivity, and attenuation, which distinguish these viruses from wild-type influenza viruses.
While the commercial formulation of FluMist Quadrivalent can be stored at 2°C to 8°C, the 
vaccine to be used in this study will require storage in a freezer. 
1.3
Summary of Nonclinical Experience
A number of nonclinical studies of FluMist have been conducted in ferrets, as the ferret has 
been proven to be a good model for studying influenza. 
The nonclinical program for FluMist Quadrivalent was designed to demonstrate that its 
immunogenicity and safety were comparable to those previously established for FluMist since 
1) FluMist Quadrivalent differs from FluMist only in the number of influenza virus strains; 2) 
both FluMist and FluMist Quadrivalent are manufactured in an identical manner; 3) both 
FluMist and FluMist Quadrivalent are based on the same MDV strains; 4) the total viral 
content of FluMist Quadrivalent does not exceed the maximal calculated viral content of 
FluMist; and 5) inactive components of FluMist and FluMist Quadrivalent are identical. 
Because of these similarities, only select nonclinical pharmacologic studies were conducted 
with FluMist Quadrivalent, with FluMist as comparator. Repeat-dose and reproductive and 
developmental toxicology studies were repeated with FluMist Quadrivalent.
Primary pharmacodynamic studies in ferrets have been conducted to evaluate the replication 
and immunogenicity of live, attenuated FluMist strains. Results of replication, 
immunogenicity, and challenge studies in ferrets demonstrated that vaccination with FluMist 
protected animals following challenge with wild-type virus; vaccine-induced immunity in 
these animals substantially decreased replication of the wild-type virus in the lungs as well as 
the upper airways. Studies with FluMist Quadrivalent demonstrated that it was equally 

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immunogenic, had similar replication kinetics, and conferred equally efficient protection 
following challenge with wild-type viruses.
Toxicology studies performed with FluMist and/or FluMist Quadrivalent include 2 repeat-
dose toxicology studies in ferrets, 2 reproductive toxicology studies in rats and ferrets, and 
2 ocular toxicology studies (Draize tests) in a rabbit model to evaluate the potential effects of 
FluMist if inadvertently sprayed into the eye. 
A single- and repeat-dose toxicology study was conducted in ferrets to investigate the 
potential adverse effects of FluMist given once or 3 times to ferrets over a 15-week period. 
The regimen consisted of up to 3 human doses of FluMist administered intranasally at 
Weeks 0, 4, and 14. This dosing regimen is in compliance with International Council for 
Harmonisation (ICH) Guideline M3, which recommends a toxicity study duration of 3 months 
with a product dosing duration of up to 1 month. No clinical indications of toxicity were 
manifest during the course of the study from any of the parameters evaluated. No test 
material-related toxicity was identified in the major organs examined histopathologically, 
except for increased incidence of acute, multifocal, suppurative inflammation of the nasal 
turbinates and lymph node hyperplasia in animals at interim necropsy. These findings were 
most likely due to inoculation 3 days prior to necropsy and the antigenic responses of the 
animals to the inoculum. Overall, in this study and a similar repeat-dose study conducted with 
FluMist Quadrivalent in ferrets, the vaccine was well tolerated. 
Studies with FluMist were conducted to evaluate reproductive and developmental toxicology 
in 2 different animal models (rat and ferret). Results of the study conducted with rats indicated 
that exposure to FluMist once prior to mating and once during pregnancy did not produce any 
maternal toxicity or affect the reproductive capacity of the dam. These exposures did not 
produce embryo-fetal toxicity in near-term fetuses or pups evaluated for 21 days postpartum. 
Results of a similar study in which quadrivalent FluMist was administered 3 times prior to 
mating and again 3 times during gestation showed no safety concerns.
The study in ferrets involved intranasal administration of FluMist to pregnant ferrets at 
4 different time points during gestation. No vaccine treatment-related effects were observed 
with respect to maternal mortality, clinical observations, or body weight during gestation, nor 
were there any treatment-related effects observed in fetal parameters or in maternal 
macroscopic pathology that could be attributed to the intranasal instillation of FluMist. 
The potential for ocular toxicity resulting from the inadvertent instillation of FluMist into the 
eye was evaluated in 2 ocular toxicity studies in rabbits using a standard Draize test. Neither 
study elicited results consistent with ocular toxicity.
The results of the nonclinical studies performed with FluMist and FluMist Quadrivalent 
collectively demonstrate that the vaccine has a favorable safety and tolerability profile.

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1.4
Summary of Clinical Experience
In over 60 clinical studies, more than 120,000 subjects from 6 weeks to > 90 years of age have 
been administered MedImmune’s egg-produced vaccine, FluMist. These studies were 
designed to evaluate the safety, efficacy, and immunogenicity of the vaccine among various 
study populations, including > 90,000 children and adolescents 6 weeks to 17 years of age and 
> 30,000 adults 18 to > 90 years of age. In these studies, FluMist was found to be generally 
safe and well tolerated. In healthy adults 18 through 64 years of age, FluMist recipients 
reported higher rates of runny nose (44%) and sore throat (26%) than placebo recipients (27% 
and 17%, respectively), with a median event duration of 1 day regardless of treatment 
received. Other symptoms, including cough, headache, chills, muscle aches, and 
tiredness/weakness occurred less often and at similar rates between the treatment groups. 
Low-grade fever (temperature > 100ºF) occurred at a similarly low rate for FluMist and 
placebo recipients (1.3% and 1.5%, respectively).
The clinical development of FluMist Quadrivalent included 2 pivotal, double-blind studies 
conducted in the USA, one in children and adolescents 2 to 17 years of age (MI-CP208; 2,312 
subjects) and one in adults 18 through 49 years of age (MI-CP185; 1,800 subjects), both of 
which demonstrated that the immune responses generated by FluMist Quadrivalent were 
noninferior to the immune responses generated by FluMist and the safety and tolerability 
profiles of the 2 vaccines were similar in both populations. Results of an additional study (MI-
CP206; 1,800 subjects), conducted in adults using FluMist Quadrivalent delivered by a novel 
blow fill seal (BFS) delivery system, also demonstrated that the immune responses generated 
by FluMist Quadrivalent were noninferior to the immune responses generated by FluMist 
delivered by Becton Dickinson (BD) Accuspray™, and provided support for the similar safety 
profile of FluMist Quadrivalent. Overall, a total of 3,783 subjects received at least 1 dose of 
FluMist Quadrivalent in the 3 studies, including 1,199 subjects who received FluMist 
Quadrivalent in the BFS device. A total of 1,386 FluMist Quadrivalent recipients were 2 years 
to less than 18 years of age and, of these, 1,041 subjects received 2 doses.
In addition to the clinical study experience, over 200,000 doses of FluMist have been 
administered in 2 post-marketing studies, and more than 
 of FluMist have 
been distributed commercially worldwide from initial licensure in 2003. FluMist was initially 
approved for use in healthy individuals 5 to 49 years of age; however, the age indication was 
expanded to include children 24 to 59 months of age prior to the 2007-2008 influenza season. 
For this study population, there are no risks anticipated other than those described in the 
package insert (Appendix 3).
The 2017-2018 FluMist Quadrivalent Package Insert (Appendix 3) provides the most current 
safety data and product use information.

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1.5
Rationale for Conducting the Study
The World Health Organization (WHO) has made the following recommendation to vaccine 
manufacturers, effective 22Feb2018, regarding the influenza vaccine composition for the 
2018-2019 influenza season:

A/Michigan/45/2015-like virus H1N1pdm09

A/Singapore/INFIMH-16-0019/2016-like virus (H3N2)

B/Phuket/3073/2013-like virus (Yamagata lineage; for quadrivalent formulations)

B/Colorado/06/2017-like virus (Victoria lineage)
Thus, in accordance with this change and these guidelines (Centers for Disease Control and 
Prevention [CDC], 2016), MedImmune has selected the following strains to be FluMist 
Quadrivalent components in the 2018-2019 influenza season:

A/Slovenia/2903/2015 V8 (H1N1)

A/Singapore/INFIMH-16-0019/2016 V2 (H3N2) 

B/Phuket/3073/2013 (Yamagata lineage)

B/Colorado/06/2017 (Victoria lineage)
B/Phuket/3073/2013 (Yamagata lineage) has been 1 of the strains contained in FluMist since 
the 2015-2016 season, and A/Slovenia/2903/2015 (H1N1) was a new strain in the 2017-2018 
season. 
As a result, this study, conducted in healthy adults, will evaluate the safety of a bivalent 
vaccine containing 2 new influenza virus reassortants A/Singapore/INFMH-16-0019/2016 and 
B/Colorado/06/2017 prior to the release of the quadrivalent vaccine (FluMist Quadrivalent) 
containing them.
1.6
Research Hypothesis
The hypothesis for this study is that 2 new live attenuated influenza strains based on Ann
Arbor MDVs (Maassab, 1968; Maassab et al, 1985) will have a safety and tolerability profile 
consistent with previously evaluated strains produced using this technology.
2
OBJECTIVE
2.1
Primary Objective
The objective of this study is to assess the safety of a bivalent influenza virus vaccine of 
2 new 6:2 influenza virus reassortants in healthy adults prior to the release of the quadrivalent 
vaccine (FluMist Quadrivalent) containing them.

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2.2
Study Endpoints
2.2.1
Primary Endpoint
The primary endpoint of this study is fever (Days 1 through 8), defined as oral temperature 
≥101°F. 
2.2.2
Secondary Endpoints
1
Solicited symptoms that occur within 7 days after vaccination (Days 1-8)
2
Adverse events (AEs) that occur within 7 days after vaccination (Days 1-8)
3
Solicited symptoms that occur within 14 days after vaccination (Days 1-15)
4
AEs that occur within 14 days after vaccination (Days 1-15)
5
Serious adverse events (SAEs) that occur within 28 days after vaccination (Days 1-29) 
6
New onset chronic diseases (NOCDs) that occur within 28 days after vaccination (Days 
1-29) 
7
SAEs that occur within 180 days after vaccination (Days 1-181)
8
NOCDs that occur within 180 days after vaccination (Days 1-181)
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview..........
This prospective, randomized, double-blind, placebo-controlled release study will enroll 
approximately 300 healthy adults 18 through 49 years of age (not yet reached their 50th 
birthday). Eligible subjects will be randomly assigned in a 4:1 fashion to receive a single dose 
of bivalent vaccine or placebo by intranasal spray. This study will be conducted at 2 sites in 
the USA. Randomization will be stratified by site.
Each subject will receive one dose of investigational product on Day 1. Subjects will be 
followed through 180 days after receipt of investigational product.
A study schematic is provided in Figure 1.

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Figure 1
Study Flow Diagram
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 4:1 ratio to receive a single dose of either bivalent
vaccine (240 subjects) or placebo (60 subjects) by intranasal spray on Day 1.
3.2
Study Design and Dose Rationale
3.2.1
Dose Rationale
The influenza vaccine virus dose to be used in this study, a single dose of 107.0 ± 0.5 fluorescent 
focus units per strain, is the same as the dose that will be used in the commercial FluMist 
Quadrivalent product.
3.2.2
Rationale for Study Population
Healthy adults 18 through 49 years of age represent the segment of the adult population for 
whom FluMist Quadrivalent is indicated and, in contrast to children, are not a vulnerable 
population. The study’s eligibility criteria are intended to prevent enrollment of individuals 
with medical conditions in whom FluMist Quadrivalent is not indicated, to minimize 
confounding circumstances that would impair the ability to interpret the study results, and to 
maximize the proportion of enrolled subjects completing the study.

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3.2.3
Rationale for Endpoints
Fever has been chosen as a primary endpoint, because it is a common and objective 
consequence of infection with wild-type influenza. Fever occurring at a greater rate in the 
vaccine group than the placebo group would, therefore, suggest that new influenza vaccine 
virus strains might not be sufficiently attenuated. Regulatory authorities have accepted this 
measure of attenuation of new influenza vaccine virus strains over many years and have 
required this testing prior to their authorizing release of the FluMist or FluMist Quadrivalent 
vaccine containing any new influenza strains each year.
Secondary endpoints of the study include other reported solicited symptoms and AEs that 
occur within 7 days after vaccination (Days 1-8), and all solicited symptoms and AEs that 
occur within 14 days after vaccination (Days 1-15). Additional secondary endpoints include 
SAEs and NOCDs that occur within 28 days after vaccination (Days 1-29) and within 180 
days after vaccination (Days 1-181).
The reporting period of 14 days (Days 1 through 15) for solicited symptoms, including fever, 
and AEs is consistent with the incubation period of influenza.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
This study will enroll approximately 300 healthy adults 18 through 49 years of age (not yet 
reached their 50th birthday). Eligible subjects will be randomly assigned in a 4:1 fashion to 
receive a single dose of bivalent vaccine or placebo by intranasal spray.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Age 18 through 49 years at the time of screening (not yet reached their 50th birthday).
2
Written informed consent and any locally required authorization (ie, Health Insurance 
Portability and Accountability Act [HIPAA] in the USA) obtained from the subject/legal 
representative prior to performing any protocol-related procedures, including screening 
evaluations.
3
Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use a highly effective method of contraception for 30 days prior to the 
first dose of investigational product and must agree to continue using such precautions for 
60 days after the final dose of investigational product; cessation of contraception after this 
point should be discussed with a responsible physician. It is strongly recommended for 
the male partner of a female subject to also use male condom plus spermicide throughout 

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this period. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.

Females of childbearing potential are defined as those who are not surgically sterile 
(ie, surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
complete hysterectomy) or postmenopausal (defined as 12 months with no menses 
without an alternative medical cause).

A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. 
Examples of acceptable methods of contraception are described in Table 1. 
4
Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a male condom with spermicide from Day 1 through Day 31, or at least 
30 days after receipt of the final dose of investigational product. It is strongly 
recommended for the female partner of a male subject to also use a highly effective 
method of contraception throughout this period, as shown in Table 1. In addition, male 
subjects must refrain from sperm donation for 30 days after the final dose of 
investigational product as the only dose of investigational product occurs on Day 1.
Table 1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system) 
(eg, Mirena®) a
•
Implants
•
Hormone shot or injection 
•
Combined pill
•
Minipill
•
Patch
a
This is also considered a hormonal method.
5
Healthy by medical history and physical examination
6
Female subjects of childbearing potential must also have a negative urine or blood 
pregnancy test at screening and, if screening and Day 1 do not occur on the same day, on 
the day of vaccination prior to randomization
7
Subject available by telephone
8
Ability to understand and comply with the requirements of the protocol, as judged by the 
investigator
9
Ability to complete follow-up period of 180 days after dosing as required by the protocol
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
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

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2
Concurrent enrollment in another clinical study up to 180 days after receipt of 
investigational product (Day 181) 
3
Employees of the clinical study site or any other individuals involved with the conduct of 
the study, or immediate family members of such individuals
4
History of hypersensitivity to any component of the vaccine, including egg or egg 
proteins or serious, life threatening, or severe reactions to previous influenza vaccinations
5
History of hypersensitivity to gentamicin, gelatin, or arginine
6
Any condition for which the inactivated influenza vaccine is indicated, including chronic 
disorders of the pulmonary or cardiovascular systems (eg, asthma), chronic metabolic 
diseases (eg, diabetes mellitus), renal dysfunction, or hemoglobinopathies that required 
regular medical follow-up or hospitalization during the preceding year
Note: A history of asthma that requires regular medical follow-up or hospitalization during 
the preceding 2 years is exclusionary. Investigator judgment is required to determine whether 
or not a subject has a history of asthma; however, for adult subjects, a remote history of 
wheezing or a remote diagnosis of asthma that the investigator does not consider to be 
relevant to current health does not need to be considered to be a history of asthma.  For 
example, childhood asthma that has not required treatment in adulthood is not necessarily 
exclusionary.
7
Acute febrile (> 100.0°F oral or equivalent) and/or clinically significant respiratory illness 
(eg, cough or sore throat) within 14 days prior to randomization
8
Any known immunosuppressive condition or immune deficiency disease, including 
human immunodeficiency virus infection, or ongoing immunosuppressive therapy
9
History of Guillain-Barre syndrome
10 A household contact who is severely immunocompromised (eg, hematopoietic stem cell 
transplant recipient, during those periods in which the immunocompromised individual 
requires care in a protective environment); additionally, subject should avoid close 
contact with severely immunocompromised individuals for at least 21 days after receipt 
of investigational product
11 Receipt of any investigational agent within 30 days prior to randomization, or expected 
receipt through 30 days after the dose of investigational product (use of licensed agents 
for indications not listed in the Package Insert is permitted) 
12 Receipt of any non-study vaccine within 30 days prior to randomization, or expected 
receipt through 30 days after receipt of investigational product
13 Expected receipt of antipyretic or analgesic medication on a daily or every other day basis 
from randomization through 14 days after receipt of investigational product

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Note: A daily dose of up to 81 mg of aspirin for prophylactic use is not considered a 
contraindication to enrollment.
14 Administration of intranasal medications within 14 days prior to randomization, or 
expected receipt through 14 days after administration of investigational product
15 Receipt of influenza antiviral therapy or influenza antiviral agents within 48 hours prior to 
investigational product administration or expected receipt of influenza antiviral therapy or 
influenza antiviral agents through 14 days after receipt of investigational product
16 Known or suspected mitochondrial encephalomyopathy
17 Nursing mother
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. 
Subjects will be randomized at a 4:1 ratio to receive either a single dose of bivalent vaccine or 
placebo by intranasal spray. Randomization will be stratified by site.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not be 
randomized (if applicable) or receive investigational product.
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). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will be 
seen and assessed by an investigator. Adverse events will be followed up and any worksheets 
will be collected. If a subject withdraws from further participation in the study, then no further 
study visits or data collection should take place.
4.1.6
Replacement of Subjects
Subjects will not be replaced.

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4.1.7
Withdrawal of Informed Consent for Data
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 data collected prior to that time may still be given to and used by 
the sponsor but no new data will be collected unless specifically required to monitor safety of 
the subject.
4.2
Schedule of Study Procedures
A schedule of study procedures is provided in Table 2, followed by a description of each visit. 
A description of study procedures is provided in Section 4.2.1.

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Table 2
Schedule of Study Procedures
Study Period
Screening
Treatment
Follow-up
Visit
Visit 1
Visit 2
Unscheduled 
Visit
Telephone Contact
Procedure/Study Day
Days -14 to 1
Day 1
Days 2 to 15
Days 2 
to 15
Day 31 
(+7)
Day 
61(+7) 
Day 
91(+7) 
Day 
121 
(+7) 
Day 
151 
(+7) 
Day 
181 
(+14) 
Written informed consent/ assignment 
of SID number
X
Verify eligibility criteria
X
X
Medical history & current medication 
use
X
X
Physical examination, height, weight, 
& temperature
X
Xa
X
Pregnancy test
X
Xa
Collect SAEs 
X
X
X
X
X
X
X
X
X
X
Randomization
X
Collect concomitant medications
X
X
X
X
Collect AEs
X
X
X
X
Collect solicited symptoms
X
X
X
Collect NOCDs
X
X
X
X
X
X
X
X
X
Investigational Product 
Administration
X
AE = adverse event; NOCD = new onset chronic disease; SAE = serious adverse event; SID = subject identification number
a
If screening and dosing occur at the same visit, only one evaluation is required (female subjects only, unless exempt from pregnancy testing). 

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4.2.1
Screening Visit (Visit 1)
All screening procedures must be performed within 14 days before or on the same day as 
investigational product administration (Day -14 to Day 1). The screening evaluations may be 
carried out over more than one visit. Written informed consent and any locally required 
privacy act document authorization must be obtained prior to performing any protocol-specific 
procedures, including screening evaluations.
1
Obtain written informed consent and appropriate privacy act document authorization 
2
Assign an SID number
3
Verify eligibility criteria
4
Obtain screening medical history
5
Record current medication use
6
Perform screening physical examination, including temperature, height, and weight
7
Collect urine sample for pregnancy test (female subjects only, unless exempt from 
pregnancy testing); if screening and dosing occur at the same visit, only one test is 
required
8
Assess for AEs, SAEs, and concomitant medication use
4.2.2
Treatment Period (Visit 2)
Day 1: Administration of Investigational Product
1
Verify eligibility criteria
2
Update screening medical history, current medication use (any new findings since 
screening), and physical examination (including height, weight, and temperature)
3
Collect urine sample for pregnancy test (female subjects only, unless exempt from 
pregnancy testing); if screening and dosing occur at the same visit, only one test is 
required; result must be negative for randomization and dosing to occur 
4
Assess for AEs and SAEs
5
Randomize in IWRS to assign investigational product sprayer number
6
Administer investigational product 
7
Observe subject for a minimum of 15 minutes. Provide safety assessment worksheets, 
thermometer, and instructions for completing the worksheets (see Section 5.5.2). Ensure 
that the subject understands how to take his/her temperature. Day 1 temperature is 
recorded by the subject in the evening of Day 1 (day of investigational product 
administration). The safety assessment worksheets will be used for the collection of 
solicited symptoms, AEs, and concomitant medication use, and will be completed by the 
subject to serve as a memory aid for future data collection by study staff during telephone 
contacts.

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8
Record solicited symptoms, AEs, and concomitant medication use
9
Inquire about SAEs and NOCDs
4.2.3
Follow-up Period (Unscheduled Visit and Telephone Contacts)
4.2.3.1
Unscheduled Visit, Days 2 to 15 for Significant Febrile Illness
1
Perform medical evaluation 
2
Record solicited symptoms, AEs, and concomitant medication use 
3
Inquire about SAEs and NOCDs
4.2.3.2
Telephone Contact, Days 2 to 15
Telephone contact every day or every other day to Day 15
1
Record solicited symptoms, AEs, and concomitant medication use
2
Inquire about SAEs and NOCDs
4.2.3.3
Telephone Contact, Days 31, 61, 91, 121, 151 (+ 7 days)
One telephone contact each between Days 31 and 38, 61 and 68, 91 and 98, 121 and 128, 
and 151 and 158
1
Inquire about SAEs and NOCDs
4.2.3.4
Telephone Contact, Day 181 (+ 14 days): Last Follow-up Contact and Study 
Termination
One telephone contact between Days 181 and 195
1
Inquire about SAEs and NOCDs through 180 days post dosing
4.3
Description of Study Procedures
4.3.1
Medical History and Physical Examination, Height, Weight, and 
Temperature
Medical history and current medication use will be collected. A basic physical examination of 
the head, neck, chest, heart, abdomen, and extremities will be performed, to include collection 
of height, weight, and temperature (oral thermometer).
4.3.2
Clinical Laboratory Tests
The only clinical laboratory tests performed in this study will be urine pregnancy tests.

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Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin (hCG; at screening and day of randomization if screening and 
randomization/dosing do not occur on the same day).
4.4
Investigational Products
4.4.1
Identity of Investigational Products
MedImmune will provide the investigators with investigational product (Table 3) using 
designated distribution centers. 
Table 3
Identification of Investigational Products
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
Bivalent influenza vaccine
MedImmune
107.0 ± 0.5 FFU of each of 2 ca, att, ts, 6:2 
reassortant influenza strains per 0.5 mL 
 
 in the BD Accuspray device:
A/Singapore/INFIMH-16-0019/2016 V2
B/Colorado/06/2017
Placebo
MedImmune
0.5 mL of 
 in the BD Accuspray 
device
att = attenuated; BD = Becton Dickinson; ca = cold adapted; ; FFU = fluorescent focus unit; 
 
ts = temperature sensitive
Investigational product will be packaged and stored at -30°C and shipped to the study site 
upon request of the sponsor or designee. The distributor will ship the investigational product 
directly to the clinical study site by express courier. Receiving departments should be notified 
that rapid handling of the shipment is required. Upon receipt at each study site, frozen 
investigational product should be immediately transferred to a -20°C (or -4°F) freezer 
(variations up to ± 5°C are acceptable) in a secure location with limited access. 
Investigational product will be supplied to the site in devices with identical appearances in 
coded kits. Each kit has a unique number that is printed on all labels within the kit (ie, the 
outer carton label and the label of each device within the carton). Labels will be prepared in 
accordance with Good Manufacturing Practice (GMP) and local regulatory guidelines. 
Investigational product should not be removed from storage until the day of dosing (Day 1); 
investigational product may be stored at room temperature during the day of dosing. Any 
broken or damaged sprayer must be identified as damaged and the sprayer number recorded 
on the investigational product accountability record. Damaged sprayers can be stored at room 
temperature until accountability is completed.

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4.4.1.1
Investigational Product Inspection
At room temperature, investigational product is a colorless to pale yellow liquid, and clear to 
slightly cloudy. Some proteinaceous particles may be present but they do not affect the use of 
the product. If there are any defects noted with the investigational product, the investigator 
and site monitor should be notified immediately.  Refer to the Product Complaint section for 
further instructions.
4.4.1.2
Treatment Administration
The first day of dosing is considered Day 1.

Investigational product should be brought to room temperature by holding the sprayer in 
the palm of the hand and supporting the plunger rod with the thumb (see Appendix 3). 
The investigational product should be administered immediately thereafter.

A single administration comprises intranasal delivery of approximately 0.5 mL total 
volume (0.25 mL into each nostril). Each sprayer has a divider that allows delivery of 
approximately half the contents of the sprayer into one nostril. Removal of the divider 
allows delivery of the remaining volume into the other nostril.

The individual administering the investigational product should depress the plunger rod as 
rapidly as possible to generate a fine mist. Half of the contents of each sprayer will be 
sprayed as a fine mist into each nostril while the subject is in an upright position.

After administration, used study sprayers must be placed immediately after use into 
locked containers or sealed bags.
4.4.1.3
Monitoring of Dose Administration
After vaccination, all subjects will be observed for a minimum of 15 minutes by the study 
staff. Emergency management supplies (eg, AMBU bag, adrenaline [epinephrine], 
antihistamine) will be made available for the initial treatment of an allergic reaction if needed. 
Local reactions or systemic events must be recorded.
As with any vaccine, 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.
4.4.1.4
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 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.

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MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
4.4.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.4.3
Labeling……………….  
Labels for the investigational product will be prepared in accordance with GMP and local 
regulatory guidelines. The label will fulfill GMP Annex 13 requirements for labeling. Label 
text will be translated into local languages, as required.
4.4.4
Storage………………….
Investigational product must be stored in the original outer package and must not be thawed. 
The manufacturer’s instructions for shipment and storage will be followed at all times. It is the 
responsibility of the investigator to maintain daily temperature logs for the freezer, at a 
minimum, daily Monday through Friday. The investigator will be provided with temperature 
monitors that record minimum/maximum temperatures, unless temperature monitors are 
already in place.
4.4.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.4.6
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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4.5
Treatment Assignment and Blinding
4.5.1
Methods for Assigning Treatment Groups
An IWRS will be used for randomization to a treatment group and assignment of blinded 
investigational product sprayer 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 sprayer numbers to the 
subject.
Subjects will be randomized at a 4:1 ratio to receive either bivalent influenza vaccine or 
placebo. The randomization will be stratified by site.
Investigational product (bivalent influenza vaccine or placebo) must be administered the same 
day the investigational product is assigned. If there is a delay in the administration of 
investigational product such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately.
4.5.2
Methods for Ensuring Blinding
This is a double-blind study in which bivalent influenza vaccine and placebo are identically
labeled and indistinguishable in appearance. As such, neither the subject/legal representative 
nor any of the investigator or sponsor staff who are involved in the treatment or clinical 
evaluation of the subjects will be aware of the treatment received (ICH E9; see Section 4.5.3.2
for unblinding related to interim planned analysis). In the event that treatment allocation for a 
subject becomes known to the investigator or other study staff involved in the management of 
study subjects, the sponsor must be notified immediately. 
4.5.3
Methods for Unblinding 
4.5.3.1
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. Prior to unblinding the investigational product allocation 
for an individual subject, the investigator must first attempt to contact the medical monitor to 
discuss the medical emergency and the reason for wanting to unblind. 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. 

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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. 
4.5.3.2
Unblinding for Interim Analysis 
An interim analysis is planned for this study as described in Section 4.7.4. To ensure the 
blinding of each subject’s treatment assignment throughout the study, the Day 15 unblinded 
analyses will be performed by defined MedImmune personnel, including the medical monitor, 
the clinical program manager, Patient Safety staff team members, Regulatory (Clinical) staff 
team members, a Medical Writing staff team member, a Biostatistics staff team member, 
Clinical Statistical Analysis System Programming staff team members, and Data Management 
(including data management vendor’s non-MedImmune personnel) staff team members. Study 
site personnel and contract research organization personnel directly associated with the 
conduct of this study and the subjects will remain blinded to the treatment assignment for 
individual subjects until the completion of the study. 
4.6
Restrictions During the Study and Concomitant Treatment(s)
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the electronic case report form (eCRF).
4.6.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.6.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.
4.6.2
Prohibited Concomitant Medications
Other than the medications described above, use of concomitant medications including over-
the-counter medications, herbal supplements, vitamins, etc, from Day 1-15 is discouraged. 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
Use of antipyretic or analgesic medications for all symptoms other than temperatures ≥101°F 
oral (or equivalent) is discouraged from Day 1-15. All medications taken during the 14-day 
post vaccination follow-up period, the indications, the start and stop dates of the medications, 
and the route of administration will be recorded from the time of informed consent through 
Day 15.

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The following medications are exclusionary. The sponsor must be notified if a subject 
receives any of these during the study.
1
Any vaccine or investigational agent from 30 days prior to randomization through 30 days 
post investigational product administration
2
Any intranasal medication from 14 days prior to through 14 days post investigational 
product administration
3
Receipt of influenza antiviral therapy or antiviral agents within 48 hours prior to 
investigational product administration or expected receipt of influenza antiviral therapy or 
antiviral agents through 14 days after receipt of investigational product
4.7
Statistical Evaluation
4.7.1
General Considerations
Data will be provided in data listings sorted by treatment group and subject identification 
number. 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, including mean, standard deviation, median, 
minimum, and maximum. Confidence intervals (CIs) will be two-sided, unless otherwise 
stated.
The intent-to-treat (ITT) population is defined as all subjects that are randomized and treated 
with investigational product. All analyses will be performed on the ITT population unless 
otherwise specified. Missing will be treated as missing and no data will be imputed. 
4.7.2
Sample Size and Power Calculations
It is expected that almost all subjects will provide information on safety and tolerability. 
Table 4 summarizes the solicited event rates following FluMist and placebo vaccination in 
healthy adults 18 through 64 years of age in Study AV009.
Table 4
Summary of Solicited Events (Days 0 Through 7) in Study AV009
Number of Subjects
FluMist a
Placebo a
Difference in 
Proportions
95% CI b
Randomized
3,041
1,520
--
--
Who returned diary cards
2,985
1,490
--
--
Who experienced solicited 
events
n (%)
n (%)
--
--
Fever
Oral temperature > 100.0F
40 (1.34)
20 (1.34)
-0.00
(-0.01, 0.01)
Oral temperature 101.0F
17 (0.57)
9 (0.60)
-0.00
(-0.01, 0.00)

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Table 4
Summary of Solicited Events (Days 0 Through 7) in Study AV009
Number of Subjects
FluMist a
Placebo a
Difference in 
Proportions
95% CI b
Oral temperature > 102.0F
2 (0.07)
2 (0.13)
-0.00
(-0.01, 0.00)
Oral temperature > 103.0F
0
0
0.00
(-0.00, 0.00)
Runny nose
1,323 (44.32)
397 (26.64)
0.18
( 0.15, 0.21)
Sore throat
793 (26.57)
243 (16.31)
0.10
( 0.08, 0.13)
Cough
407 (13.64)
152 (10.20)
0.03
( 0.01, 0.06)
Headache
1,172 (39.26)
555 (37.25)
0.02
(-0.01, 0.05)
Muscle aches
481 (16.11)
216 (14.50)
0.02
(-0.00, 0.04)
Chills
247 (8.28)
91 (6.11)
0.02
( 0.00, 0.04)
Tired/weak
733 (24.56)
306 (20.54)
0.04
( 0.01, 0.07)
Any solicited event
2,117 (70.92)
919 (61.68)
0.09
( 0.06, 0.12)
CI = confidence interval
a
Subjects counted if they experienced an event at least once within 7 days following vaccination.
b
Confidence intervals for the difference in proportions are based on an exact method.
Power to show a similar fever rate with 300 evaluable subjects (240 bivalent vaccine and 
60 placebo recipients) for varying true fever rates ranging from 0.5% to 2.0% in placebo 
recipients is presented in Table 5. Accordingly, the currently proposed study will provide at 
least 98% power to rule out a rate increase of 5 percentage points assuming the true difference 
between the treatment groups is zero and the true fever rate is ≤ 1%. Power is lower if the true 
difference is different from zero. For example, if the true fever rates are 2% and 1% in vaccine 
and placebo recipients, respectively, the power will be 77%.
Table 5
Power to Show Similar Fever Rates for N = 300 Subjects
True Fever Rate
Exact Power a
Exact Type I Error Rate
Vaccine
Placebo
0.5%
0.5%
99.9%
2.2%
1.0%
1.0%
98.0%
2.3%
1.5%
1.5%
92.6%
2.3%
2.0%
2.0%
85.0%
2.3%
2.0%
1.0%
77.0%
2.3%
3.0%
1.0%
43.9%
2.3%
Note: Similar fever rates mean the ability to rule out a 5 percentage point increase in vaccine recipients. Total 
N includes 240 vaccine recipients and 60 placebo recipients.
a
Power was computed using the method proposed by Chan and Zhang, 1999.

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Power to show similar event rates for other solicited symptoms with 300 evaluable subjects 
(240 bivalent vaccine and 60 placebo recipients) for rates ranging from 6% to 37% in placebo 
recipients is presented in Table 6. Accordingly, the currently proposed study provides at least 
87% power to rule out a 20 percentage point increase, assuming the true difference between 
the 2 treatment groups is zero. Power is lower if the true difference is greater than zero.
Table 6
Power For Secondary Endpoints
Solicited Events
True Event Rates
Rate Increase to be 
Ruled Out (PPT)
Power a
Vaccine
Placebo
Runny nose
27%
27%
20
94%
44%
27%
20
8%
44%
27%
36
90%
Sore throat
16%
16%
15
92%
27%
16%
15
13%
27%
16%
27
91%
Cough
10%
10%
15
99%
14%
10%
15
82%
14%
10%
17
93%
Headache
37%
37%
20
87%
Muscle aches
15%
15%
15
93%
Chills
6%
6%
10
95%
Tired/weak
21%
21%
20
98%
25%
21%
20
86%
25%
21%
21
90%
PPT = percentage point
Note: Total number includes 240 bivalent vaccine recipients and 60 placebo recipients.
a
Power was computed using the method proposed by (Chan, 1998) and Proc-Stat (Version 6.2) software.
4.7.3
Endpoints............................
4.7.3.1
Primary Endpoint
The primary endpoint of this study is fever (Days 1 through 8), defined as oral temperature 
≥101°F. Comparison of the rate of fever between the 2 treatment groups will be based on the 
upper limit of the two-sided 95% exact CIs for the rate increase (bivalent vaccine minus 
placebo) evaluated against the pre-specified equivalence criterion of 5 percentage points.
This corresponds to the null hypothesis of:
H0:  Rate difference ≥ 5 percentage points.

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The alternative hypothesis is:
HA:  Rate difference < 5 percentage points.
A two-sided 95% CI will be constructed using the exact method based on the score statistic 
proposed by (Chan and Zhang, 1999). This method computes the lower and upper confidence 
limits by inverting 2 separate one-sided tests of half the nominal Type I error rate. Its test 
statistic is based on the score statistic that is computed as the observed difference of the 
2 binomial event rates minus the hypothesized value of the rate difference (observed rate 
difference) divided by the standard error of this difference under the alternative hypothesis. 
This test assures that the Type I error does not exceed the pre-specified level. Due to 
discreteness when the sample size is relatively small compared to the expected event rate, the 
associated Type I error rate could be quite conservative, that is, smaller than the pre-specified 
level.
4.7.3.2
Secondary Endpoints
Secondary endpoints of the study include other reported solicited symptoms and AEs that 
occur within 7 days after vaccination (Days 1-8), and all solicited symptoms and AEs that 
occur within 14 days after vaccination (Days 1-15). Additional secondary endpoints include 
SAEs and NOCDs that occur within 28 days after vaccination (Days 1-29) and within 
180 days after vaccination (Days 1 through 181).
Fever will be summarized according to the following thresholds:

Oral > 100°F

Oral ≥ 101°F

Oral > 102°F

Oral > 103°F
A secondary analysis comparing rates of other solicited symptoms (Days 1-8) between the 
2 treatment groups will be performed. Exact two-sided 95% CIs (Chan and Zhang, 1999) on 
the rate difference (bivalent vaccine minus placebo) will be constructed. There are no pre-
specified equivalence criteria for the secondary analyses.
The number of days of solicited symptoms and the proportion of subjects experiencing each 
event by study day will be presented without formal statistical comparison. The distribution of 
the number of days with each individual event will also be summarized without formal 
statistical comparison. The proportion of subjects using antipyretic and analgesic agents 
within 7 days after vaccination (Days 1-8) and 14 days after vaccination (Days 1-15) will be 
summarized by treatment group.

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4.7.4
Interim Analysis
A safety analysis will be conducted after all subjects have been followed through Day 15 and 
all data through at least Day 8 are locked. The analysis for Days 1 through 15 will include the 
primary endpoint of this study (fever for Days 1-8, defined as oral temperature ≥101°F), as 
well as analysis of safety data (solicited symptoms and AEs), and antipyretics and analgesic 
use reported within 7 days and within 14 days after dosing. To ensure the blinding of each 
subject’s treatment assignment throughout the study, the Day 15 unblinded analyses will be 
performed by defined MedImmune personnel (see Section 4.5.3.2). Subsequently the 
unblinded results will be reviewed by the project statistician, medical monitor, therapeutic 
area vice president, and the Head of Clinical Biostatistics and Data Management prior to 
approving the release of the unblinded study results to the project team. Since the results of 
the interim analysis for the primary endpoint will be final, the treatment codes will be sent to 
Patient Safety within 1 business day of the release of the study results to update the safety 
databases. Study site personnel and contract research organization personnel directly 
associated with the conduct of this study and the subjects will remain blinded to the treatment 
assignment for individual subjects until the completion of the study. 
The results of the interim analysis will be reported to regulatory authorities in order to receive 
authorization for release of the commercial product including the tested new vaccine virus 
strains.
After the study is complete and the database is locked, all data through 180 days after dosing 
will be summarized by treatment group using the safety population.
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 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 

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failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell 
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
An SAE is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity 

Is a congenital anomaly/birth defect in offspring of the subject

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
5.3
Definition of Solicited Symptoms
Solicited symptoms are events that are considered likely to occur post dosing. For this study, 
solicited symptoms include:

Fever (> 100°F [37.8oC] oral)

Runny nose

Sore throat

Cough

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
Vomiting

Muscle aches

Chills

Decreased activity (tiredness)

Headache
5.4
Definition of New Onset Chronic Diseases
An NOCD is a newly diagnosed medical condition that is of a chronic, ongoing nature 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, autism). Events that would not be considered NOCDs are 
mild eczema, diagnosis of a congenital anomaly present at study entry, or acute illness (eg, 
otitis media, bronchitis). An NOCD should also be reported as an SAE if it meets the 
definition in Section 5.2. If an NOCD occurs within 14 days post dosing, the event should also 
be reported as an AE (Section 5.1).
5.5
Recording of Adverse Events
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the event 
meets criteria of an SAE and therefore requires immediate notification to MedImmune Patient 
Safety. See Section 5.2 for the definition of SAEs and Appendix 2 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported on the SAE Report Form.
5.5.1
Time Period for Collection of Adverse Events
Adverse events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period through 14 days post dosing (Days 1 
through 15).
All SAEs will be recorded from the time of informed consent through 180 days post dosing 
(Days 1 through 181).
5.5.2
Recording of Solicited Symptoms
Solicited symptoms will be reported using the terms as defined in this protocol (Section 5.3). 
Oral thermometers and safety assessment worksheets will be distributed to subjects on the day 
of investigational product administration. Beginning on the evening of the day of 
investigational product administration through 14 days after receipt of investigational product 
(Days 1 through 15), the subject will record on the worksheets his/her temperature and the 

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occurrence of solicited symptoms. Temperatures should be taken at approximately the same 
time each day (preferably in the evening); however, if multiple temperatures are taken during 
a given day, the highest temperature should be recorded on the worksheet regardless of the 
time of day taken.
5.5.3
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated. 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 investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate Sponsor representative(s) within 1 day ie, immediately but no later than 
24 hours  of when he or she becomes aware of it.
The designated Sponsor study representative works with the Investigator to ensure that all the 
necessary information is provided to the Sponsor Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening 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 1 calendar day ie, 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.

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5.7
Other Events Requiring Immediate Reporting
5.7.1
Overdose……………………
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Package Insert (Appendix 3), unless otherwise specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the overdose eCRF 
module. If an overdose on an AstraZeneca/MedImmune study drug occurs in the course 
of the study, then 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 it.
The designated Sponsor study representative works with the Investigator to ensure that all 
relevant information is provided to the Sponsor’s Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply (see Section 5.6). 
For other overdoses, reporting must occur within 30 days.
5.7.2
Pregnancy……….
All pregnancies and outcomes of pregnancies should be reported to the Sponsor.
5.7.2.1
Maternal Exposure
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate Sponsor study representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated sponsor study representative works with the Investigator to ensure that all 
relevant information is provided to the Sponsor’s Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 5.2) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.

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The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
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 MedImmune representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, 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)
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
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/the 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 

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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), 
regardless of the number of doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5).
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. This date will 
be 180 days after the final subject is entered into the study (Day 181).
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.
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 

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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, and applicable 
regulatory requirements.
7.2
Subject Data Protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune Medical Monitor or an investigator might know a 
subject’s identity and also have access to his or her genetic data. Also Regulatory Authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
7.3
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the 
Informed Consent Form and any other written information and/or materials to be provided to 
the subjects. The 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. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.

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Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
MedImmune will handle the distribution of any of these documents to the national regulatory 
authorities.
MedImmune will provide Regulatory Authorities, IRB/IEC and Principal Investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions, 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 is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the Investigator’s 
Study File

Ensure a copy of the signed Informed Consent Form is given to the subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the Informed Consent Form that is approved by an IRB/IEC
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Coordinating 
Investigator, the Principal Investigator, 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.

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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 Informed Consent Form, MedImmune 
and the site’s IRB/IEC are to approve the revised Informed Consent Form 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 center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to assess whether these activities were conducted and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice, 
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
Centers for Disease Control and Prevention (CDC), 2016. Selecting viruses for the seasonal 
influenza vaccine. Available from: https://www.cdc.gov/flu/about/season/vaccine-
selection.htm.
Chan IS. Exact tests of equivalence and efficacy with a non-zero lower bound for comparative 
studies. Stat Med. 1998;17:1403-13.
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics. 1999;55:1202-9.
Maassab HF. Plaque formation of influenza virus at 25 degrees C. Nature. 1968;219:645-6.
Maassab H, DeBorde D, Donabedian A, Smitka C. Development of cold-adapted master 
strains for type-B influenza virus vaccines. In: Lerner R, Chanock R, Brown, F, editors. 
Vaccines Vol 85. Cold Spring Harbor Laboratory. 1985;p. 327-32.

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Appendix 1
Signature of Principal Investigator

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Signature of Principal Investigator
A Phase 4, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety of 2
New 6:2 Influenza Virus Reassortants in Adults 
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
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below.
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 regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
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:

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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 SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).

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Appendix 3
FluMist® Quadrivalent Package Insert 

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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: d2560c00015-csp-v1
Document Title:
d2560c00015 clinical study protocol version 1
Document ID:
Doc ID-003765938
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
06-Apr-2018 13:21 UTC
Author Approval
05-Apr-2018 18:45 UTC
Author Approval
05-Apr-2018 19:38 UTC
Author Approval
05-Apr-2018 18:40 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.