A Phase 2/3 Randomized, Double-blind, Palivizumab-controlled Study to Evaluate the Safety of MEDI8897, a Monoclonal Antibody With an Extended Half-life Against Respiratory Syncytial Virus, in High-risk Children (MEDLEY)
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Infections
Sponsor: AstraZeneca

MedImmune
MEDI8897
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
A Phase 2/3 Randomized, Double-blind, Palivizumab-controlled
Study to Evaluate the Safety of MEDI8897, a Monoclonal
Antibody With an Extended Half-life Against Respiratory
Syncytial Virus, in High-risk Children (MEDLEY)
Sponsor Protocol Number:
Application Number:
Investigational Product:
Sponsor:
D5290C00005
IND number 118524
MEDI8897
MedImmune, LLC, a wholly owned subsidiary of
AstraZeneca PLC,
, Gaithersburg,
Maryland, 20878, USA
Medical Monitor:
, AstraZeneca
Contract Research Organization:
Protocol History, Date:
Original Protocol, 05Apr2019
Protocol Amendment 1, 31Mar2021
This document contains trade secrets and commercial information that is privileged or
confidential and may not be disclosed without prior authorization from MedImmune.
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MEDI8897
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Amendment 1 (31Mar2021)
Overall Rationale for the Amendment
The principal reason for this amendment was to update the sample size for target enrollment,
introduce a primary analysis and Season 2 analysis to allow earlier assessment of Season 1
and Season 2 data, respectively, and add a description about the process to safeguard the
blind.
Section
Title Page
Synopsis,
1.7 Research Hypotheses,
4.8.2 Sample Size
Synopsis,
3.1.1 Overview,
4.1.1 Number of Subjects,
4.8.2 Sample Size,
4.8.4 Efficacy
Synopsis,
4.8 Statistical Evaluation
Synopsis,
4.8.4 Efficacy
Synopsis,
4.8.6.3 Healthcare
Resource Utilization and
Caregiver Burden
4.5.1.4 Reporting Product
Complaints
Description of Change
Updated the medical monitor
information
Removed hypotheses section with
clarification
Updated the sample size
Added primary analysis and Season 2
analysis
Removed side-by-side efficacy
summaries for 2 consecutive seasons
Summarized HRU overall and for
subjects with at least 1 one medically
attended RSV LRTI (protocol defined);
other subgroups were removed
Removed the fax number and the
+1-877-MEDI-411 (+1-877-633-4411)
phone number
Brief Rationale
Change in medical monitor for this
study
The study is descriptive by design
and there is no formal hypothesis
testing, therefore the hypotheses
section was removed to avoid
potential confusion. Also added a
clarification/rationale to describe
why formal hypothesis testing for
efficacy is not feasible.
Given the challenge of study
enrollment due to the COVID-19
pandemic, the sample size was
reduced from originally planned in
the protocol.
To allow earlier assessment of
Season 1 and Season 2 data
As the incidence of medically
attended RSV LRTI and RSV
hospitalization (and the relevant
HRU) are expected to be lower in
Season 2 (infant’s second RSV
season) than that in Season 1,
combining the events from Season 1
and Season 2 may not confer value in
addition to the individual summary
for each season
To focus HRU and caregiver burden
summaries on the most important
efficacy events, which are medically
attended RSV LRTIs (protocol
defined), especially given that
COVID-19 pandemic has a high
impact on the number of RSV and
non-RSV LRTIs
The numbers removed are no longer
in use
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Section
4.8.1 General
Considerations
5.3.1 Hypersensitivity,
Including Anaphylaxis,
5.7.3.1 Hypersensitivity,
Including Anaphylaxis
Throughout
Description of Change
Added description about strategy to
maintain the blind
Clarified hypersensitivity by adding
immediate (type I)
Minor editorial revisions
Brief Rationale
To ensure trial integrity and the
blinding of the Season 2 treatment
assignment for CLD/CHD subjects
who were randomized to the
palivizumab arm in Season 1
For clarity
Minor, therefore, were not
summarized
CHD = congenital heart disease; CLD = chronic lung disease; COVID-19 = coronavirus disease 2019;
HRU = healthcare resource utilization; LRTI = lower respiratory tract infection; RSV = respiratory syncytial
virus.
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31Mar2021; Final
PROTOCOL SYNOPSIS
TITLE
A Phase 2/3 Randomized, Double-blind, Palivizumab-controlled Study to Evaluate the Safety of MEDI8897, a
Monoclonal Antibody With an Extended Half-life Against Respiratory Syncytial Virus, in High-risk Children
(MEDLEY)
OBJECTIVES and ASSOCIATED ENDPOINTS
Type
Primary
Safety
Secondary
Objective
To evaluate the safety and tolerability of
MEDI8897 compared to palivizumab
when administered to preterm infants
entering their first RSV season and
children with CLD or CHD entering their
first and second RSV season
Endpoint
Safety and tolerability of MEDI8897 as
assessed by the occurrence of all TEAEs,
TESAEs, AESIs, and NOCDs
PK
To evaluate serum concentrations of
MEDI8897 and palivizumab
• MEDI8897 and palivizumab serum
concentrations
• MEDI8897 and palivizumab PK
parameters: Summary of serum
concentrations and estimated PK
parameters (Cmax, AUC, apparent
clearance, and t1/2, if data permit)
ADA
Efficacy
To evaluate ADA responses to MEDI8897
and to palivizumab in serum
To assess the descriptive efficacy of
MEDI8897 when administered as a single
IM dose of 50 mg to infants < 5 kg or
100 mg to infants ≥ 5 kg in the first RSV
season or a single 200-mg IM dose
administered in the second RSV season, in
reducing medically attended LRTI
(inpatient and outpatient) and
hospitalization due to RT-PCR-confirmed
RSV, compared to palivizumab
Incidence of ADA to MEDI8897 and
palivizumab in serum
• Incidence of medically attended LRTI
(inpatient and outpatient) due to RT-PCR-
confirmed RSV through 150 days after
Dose 1 for Season 1 and Season 2
• Incidence of hospitalizations due to
RT-PCR-confirmed RSV through 150 days
after Dose 1 for Season 1 and Season 2
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Type
Objective
Endpoint
Exploratory
RSV
neutralizing
antibody
To determine anti-RSV neutralizing
antibody levels in serum afforded by a
single dose of MEDI8897 compared to
5 monthly doses of palivizumab
• Anti-RSV neutralizing antibody levels
(IU/mL) in serum for MEDI8897 recipients
compared to palivizumab recipients
• Summary of serum RSV neutralizing
antibody levels (may include GMT, GMFR,
Cmax, apparent clearance, and t1/2)
RSV
serology
To evaluate exposure to RSV by
measuring seroresponses to different RSV
proteins in MEDI8897 and palivizumab
recipients
To evaluate the levels of maternal RSV-
specific antibody in MEDI8897 and
palivizumab recipients
• Antibody levels to RSV F, Ga, Gb, or N at
different time points
• Changes in RSV antibody levels
(seroresponse) indicating exposure to RSV
• RSV antigen antibody levels (AbU/mL)
to multiple RSV antigens
• Summary of serum RSV antibody levels
(may include GMT, GMFR,
seroconversion rates, apparent clearance,
and t1/2)
HRU and
caregiver
burden
To assess HRU and caregiver burden for
MEDI8897 recipients compared to
palivizumab recipients
• Magnitude of HRU (eg, number of
admissions to hospitals and ICUs and
duration of stay; number of subjects who
require respiratory support and
supplemental oxygen and the duration of
use; number and type of outpatient visits
[eg, ER, urgent care, outpatient clinic]; and
number of prescription and OTC
medications and duration of use) for
MEDI8897 recipients compared to
palivizumab recipients
• Caregiver burden (eg, caregiver missed
work days, subject absence from day care)
for subjects with medically attended LRTI
caused by RT-PCR-confirmed RSV
RSV
resistance
monitoring
RSV LRTI
after Day 151
To characterize resistance to MEDI8897
and palivizumab through genotypic and
phenotypic analyses
To assess the incidence of medically
attended LRTI due to RT-PCR-confirmed
RSV, compared to palivizumab after
Day 151
Genotypic analysis and susceptibility of RSV
variants to neutralization by MEDI8897 and
palivizumab
Incidence of medically attended LRTI
(inpatient and outpatient) due to RT-PCR-
confirmed RSV from Day 152 to Day 361 for
Season 1 and Season 2
AbU/mL = antibody unit per mL; ADA = anti-drug antibody; AESI = adverse event of special interest; AUC
= area under the concentration-time curve ; CHD = congenital heart disease; CLD = chronic lung disease;
Cmax = maximum observed concentration; ER = emergency room; GMFR = geometric mean fold-rise; GMT
= geometric mean titer; HRU = healthcare resource utilization; ICU = intensive care unit; IM =
intramuscular; LRTI = lower respiratory tract infection; NOCD = new onset chronic disease; OTC = over-
the-counter; PK = pharmacokinetic; RSV = respiratory syncytial virus; RT-PCR = reverse transcriptase-
polymerase chain reaction; t1/2 = terminal half-life; TEAE = treatment-emergent adverse event; TESAE =
treatment-emergent serious adverse event.
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STUDY DESIGN
Study D5290C00005 (MEDLEY) is a pivotal Phase 2/3 randomized, double-blind, palivizumab-controlled
study to evaluate the safety, PK, ADA response, and descriptive efficacy for MEDI8897 in high-risk infants
eligible to receive palivizumab when entering their first or second RSV season (Season 1 or Season 2,
respectively). Approximately 900 palivizumab-eligible infants entering their first RSV season will be enrolled
into one of 2 cohorts: (1) preterm cohort, including approximately 600 preterm infants (≤ 35 weeks gestational
age [GA]) without CLD/CHD, or (2) CLD/CHD cohort, including approximately 300 infants with CLD of
prematurity or hemodynamically significant CHD. A minimum of 100 infants with hemodynamically
significant CHD will be enrolled. Within each cohort, randomization will be stratified by hemisphere
(northern, southern) and subject age at the time of Season 1 randomization (≤ 3 months, > 3 to ≤ 6 months,
> 6 months).
Season 1, Preterm and CLD/CHD Cohorts
All subjects will be randomized 2:1 to either the MEDI8897 group (approximately 600 subjects, including
approximately 400 subjects in the preterm cohort and approximately 200 subjects in the CLD/CHD cohort) or
palivizumab group (approximately 300 subjects, including approximately 200 subjects in the preterm cohort
and approximately 100 subjects in the CLD/CHD cohort). Subjects in the MEDI8897 group will receive a
single fixed IM dose of MEDI8897 followed by 4 once-monthly IM doses of placebo. The MEDI8897 dose
level will be stratified by weight band, ie, 50 mg for infants weighing < 5 kg or 100 mg for infants weighing ≥
5 kg. Subjects in the palivizumab group will receive 5 once-monthly IM doses of 15 mg/kg palivizumab.
Season 2, CLD/CHD Cohort Only
•
 Subjects with CLD/CHD ≤ 24 months of age who were randomized to the MEDI8897 group for
Season 1 will receive a single fixed IM dose of 200 mg MEDI8897 followed by 4 once-monthly
IM doses of placebo (approximately 200 subjects).
•
Subjects with CLD/CHD ≤ 24 months of age who were randomized to the palivizumab group for
Season 1 will be re-randomized 1:1 to either the MEDI8897 group or the palivizumab group. Subjects in
the MEDI8897 group will receive a single fixed IM dose of 200 mg MEDI8897 followed by
4 once-monthly IM doses of placebo (approximately 50 subjects). Subjects in the palivizumab group will
receive 5 once-monthly IM doses of 15 mg/kg palivizumab (approximately 50 subjects).
In Season 1 or Season 2, subjects in the CLD/CHD cohort who undergo cardiac surgery with cardiopulmonary
bypass after receipt of Dose 1 but prior to receipt of Dose 5 will receive a replacement dose of the study drug
they received for Dose 1 immediately following the surgery when determined by the physician to be medically
stable for an IM injection. Any subsequent doses of study drug will continue to be given according to the
protocol-specified dosing schedule.
Subjects in the preterm cohort will be followed through 1 year after Season 1/Dose 1, and subjects in the
CLD/CHD cohort will be followed through 1 year after Season 2/Dose 1. Subjects in the CLD/CHD cohort
who receive a replacement dose in Season 2 will be followed through 1 year after the last replacement dose.
Subjects will be monitored throughout the study for LRTI. All subjects seeking medical attention for a
respiratory illness (in either the inpatient or outpatient setting) will be evaluated for LRTI, including protocol-
defined medically attended RSV LRTI. All subjects evaluated for LRTI will have respiratory samples
obtained and tested centrally for RSV using the United States Food and Drug Administration-cleared and
Conformité Européenne or European Conformity-marked in vitro diagnostic real-time RT-PCR assay.
Blood samples will be collected for PK, ADA, and RSV neutralizing antibody and RSV serology.
TARGET SUBJECT POPULATION
Preterm infants entering their first RSV season who are eligible to receive palivizumab, and children with
CLD or CHD who are entering their first RSV season and the same children ≤ 24 months of age entering their
second RSV season
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3, 4, 5
Dose 1
MedImmune
MEDI8897
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
TREATMENT GROUPS AND REGIMENS
Subjects will be randomly assigned to receive study drug as described in the Study Design section and
presented below:
Cohort
Preterm
(N = 600)
MEDI8897
(N = 400)
Season 1
50 mg (if < 5 kg) or
100 mg (if ≥ 5 kg) IM
Doses 2,
Placebo IM
Season 2
Not applicable
CLD/CHD
(N = 300
Palivizumab
(N = 200)
MEDI8897
(N = 200)
Palivizumab
(N = 100)
Doses 1,
2, 3, 4, 5
Dose 1
Doses 2,
3, 4, 5
Doses 1,
2, 3, 4, 5
15 mg/kg IM
50 mg (if < 5 kg) or
100 mg (if ≥ 5 kg) IM
Placebo IM
15 mg/kg IM
MEDI8897
(N = 200)
MEDI8897
(N = 50)
Palivizumab
(N = 50)
Dose 1
Doses 2,
3, 4, 5
Dose 1
Doses 2,
3, 4, 5
Doses 1,
2, 3, 4, 5
200 mg IM
Placebo IM
200 mg IM
Placebo IM
15 mg/kg IM
STATISTICAL METHODS
Sample Size: With respect to safety, 600 subjects exposed to MEDI8897 in Season 1 will provide a
95% probability of observing at least 1 adverse event (AE) if the true event rate is 0.5%; if no AEs are
observed, this study provides 95% confidence that the true event rate is < 0.5%. The sample size is for safety
consideration.
With respect to efficacy, approximately 600 subjects will be exposed to MEDI8897 and 300 subjects will be
exposed to palivizumab in Season 1 to observe numerically similar efficacy for both monoclonal antibodies.
Because of the reduced incidence of RSV disease in this population following the introduction of palivizumab,
a superiority or non-inferiority design is not practical. A valid non-inferiority margin cannot be established
due to the lack of historical efficacy data for the medically attended RSV LRTI endpoint for palivizumab.
Therefore, there is no hypothesis testing for efficacy. Using an assumption of a 6% RSV LRTI rate in
palivizumab recipients, approximately 18 events will be observed in that group. The 6% RSV LRTI rate
(1.9% RSV hospitalizations and 3.9% outpatient RSV illness) was based on a prior study in preterm infants
with and without CLD who received palivizumab. Assuming a 6% rate of RSV LRTI in MEDI8897
recipients, 600 MEDI8897 subjects in Season 1 will provide approximately 36 events in that group. However,
because of the largely reduced RSV circulation due to COVID-19 pandemic-related measures, the observed
event rates could be much lower. Only summaries will be provided for efficacy unless specified otherwise.
Statistical Analyses
There are 3 planned analyses for this study: the primary analysis, Season 2 analysis, and the final analysis.
The primary analysis will be conducted after all randomized subjects have completed follow-up through the
first 5-month RSV season (ie, Season 1 Day 151 visit) and include all available Season 1 safety, efficacy, PK,
and ADA data at the time of the data cutoff. The Season 2 analysis will be conducted after all CLD/CHD
subjects have completed follow-up through the second 5-month RSV season (ie, Season 2 Day 151 visit) and
include all available Season 1 data and Season 2 safety, efficacy, PK, and ADA data at the time of the data
cutoff. The final analysis will be conducted when all subjects have completed the last visit of the study and
include all data collected in the study.
Safety: Safety of MEDI8897 will be summarized by treatment group based on the As-treated Population
(defined as all subjects who receive any investigational product analyzed according to treatment received) for
each season, as well as for the 2 consecutive RSV seasons (ie, Season 1 and Season 2). For the Season 1
summary, the analysis dataset will include subjects from the preterm cohort and CLD/CHD cohort, presented
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by the treatment received in Season 1; for the Season 2 summary and the 2 consecutive-season summary, the
analysis dataset will include subjects from the CLD/CHD cohort, presented by the treatment received through
the 2 seasons.
AEs will be graded according to the current version of the National Cancer Institute Common Terminology
Criteria for Adverse Events where applicable for pediatric assessments. AEs will be coded by Medical
Dictionary for Regulatory Activities and the type, incidence, severity, and relationship to study drug will be
summarized by treatment group. Other safety assessments will include the occurrence of AESIs, defined as
AEs of hypersensitivity to study drug (including anaphylaxis), thrombocytopenia, and immune complex
disease (eg, vasculitis, endocarditis, neuritis, glomerulonephritis), and NOCDs following study drug
administration.
Efficacy: All efficacy summaries will be based on the Intent-to-treat (ITT) Population (defined as all
randomized subjects analyzed according to randomized treatment assignment). The incidence of medically
attended RSV LRTI (inpatient and outpatient) through 150 days post Dose 1 (ie, during a typical 5-month
RSV season) in Season 1, based on RSV test results (performed centrally using real-time RT-PCR) and
objective protocol-defined LRTI criteria, is the primary efficacy endpoint and will be summarized by Season 1
treatment group for all 900 subjects. The 95% confidence interval (CI) of the percentage of subjects meeting
the primary efficacy endpoint will be presented by treatment group. In addition, the incidence of RSV LRTI
through 150 days post Dose 1 in Season 2 will be summarized for the 300 subjects in the CLD/CHD cohort
based on the treatment assignments through Season 1 and Season 2: ie, (a) MEDI8897 (Season 1)/MEDI8897
(Season 2), (b) palivizumab (Season 1)/MEDI8897 (Season 2), and (c) palivizumab (Season 1)/palivizumab
(Season 2).
The incidence of RSV hospitalization through 150 days after dosing (ie, during the 5-month RSV season) will
be summarized by treatment group using a similar strategy as described for RSV LRTI.
PK: Individual MEDI8897 and palivizumab serum concentration data will be tabulated by treatment group
along with descriptive statistics. PK parameters will be estimated using non-compartmental analysis, if data
permit.
ADA: The incidence of ADA to MEDI8897 and to palivizumab will be assessed and summarized by number
and percentage of subjects who are ADA positive by treatment group. The impact of ADA on PK, and
association with TEAEs and TESAEs, will be assessed.
RSV neutralizing antibody: Individual MEDI8897 and palivizumab serum anti-RSV neutralizing antibody
levels will be tabulated by treatment group along with descriptive statistics. Anti-RSV neutralizing antibody
levels in serum will be summarized by geometric mean titer and geometric mean-fold rise and corresponding
95% CI for each treatment group at each visit. Anti-RSV neutralizing antibody level t1/2 will be estimated
using non-compartmental analysis, if data permit.
RSV serology: Analysis of anti-RSV antigens antibody levels in serum in MEDI8897 and palivizumab
recipients will be summarized by geometric mean titer and geometric mean-fold rise and corresponding
95% CI for each treatment group at each visit. Seroresponses in MEDI8897 and palivizumab recipients will be
determined by examining the fold-rise in antibodies to Ga, Gb, and N antigens.
HRU and caregiver burden: The HRU and caregiver burden summaries will be performed on the ITT
Population. The magnitude of HRU (eg, number of admissions to hospitals and ICUs and duration of stay;
number of subjects who require respiratory support and supplemental oxygen and the duration of use; number
and types of outpatient visits, eg, ER, urgent care, outpatient clinic; and number of prescription and OTC
medications and duration of use) will be summarized overall by treatment group and for subjects with at least
one medically attended LRTI (protocol defined) caused by RT-PCR-confirmed RSV.
Caregiver burden (eg, caregiver missed work days, subject absence from day care) for subjects with medically
attended LRTI (protocol defined) caused by RT-PCR-confirmed RSV will be summarized by treatment group.
Monitoring RSV resistance to MEDI8897 and palivizumab: Genotypic analysis of the full-length mature
F protein will be conducted on all RSV-positive isolates confirmed centrally using the Lyra RSV + human
metapneumovirus real-time RT-PCR assay manufactured by Quidel Corporation. RSV genotypic analysis will
report the sequence changes in the mature F protein from all RSV positive isolates compared to contemporary
RSV A and RSV B reference strains. Susceptibility of novel RSV variants to MEDI8897 and palivizumab will
be tested and compared to control viruses.
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RSV LRTI occurring from Day 152 to Day 361: The incidence of medically attended RSV LRTI (inpatient
and outpatient) from Day 152 to Day 361 for Season 1 and Season 2 will be based on RSV test results
(performed centrally via RT-PCR) and objective clinical LRTI criteria and will be summarized by treatment
group.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE....................................2
PROTOCOL SYNOPSIS......................................................................................................4
LIST OF ABBREVIATIONS ............................................................................................. 14
1
1.1
1.2
1.3
1.4
1.4.1
1.5
1.6
1.6.1
1.6.2
1.6.3
2
2.1
2.1.1
2.1.2
3
3.1
3.1.1
3.1.2
3.1.2.1
3.1.2.2
3.1.2.3
3.2
3.2.1
3.2.2
3.2.3
4
4.1
4.1.1
4.1.2
4.1.3
4.1.4
4.1.5
4.1.6
4.1.7
4.1.8
INTRODUCTION............................................................................................ 16
Disease Background ......................................................................................... 16
MEDI8897 Background.................................................................................... 17
Summary of Nonclinical Experience................................................................. 18
Summary of Clinical Experience....................................................................... 18
Study D5290C00003......................................................................................... 18
Rationale for Conducting the Study .................................................................. 20
Benefit-Risk and Ethical Assessment................................................................ 21
Potential Benefit ............................................................................................... 21
Potential Risk ................................................................................................... 21
Overall Benefit-Risk......................................................................................... 22
OBJECTIVES AND ENDPOINTS................................................................... 22
Primary Objective and Associated Endpoint ..................................................... 22
Secondary Objectives and Associated Endpoints............................................... 22
Exploratory Objectives and Associated Endpoints ............................................ 23
STUDY DESIGN ............................................................................................. 24
Description of the Study ................................................................................... 24
Overview.......................................................................................................... 24
Dosing Regimen ............................................................................................... 27
Season 1, Preterm Cohort and CLD/CHD Cohort.............................................. 27
Season 2, CLD/CHD Cohort............................................................................. 27
Season 1 or Season 2, CLD/CHD Cohort - Replacement Dose.......................... 28
Rationale for Dose, Population, and Endpoints ................................................. 29
Dose Rationale.................................................................................................. 29
Rationale for Study Population ......................................................................... 30
Rationale for Endpoints .................................................................................... 30
MATERIALS AND METHODS ...................................................................... 31
Subjects ............................................................................................................ 31
Number of Subjects .......................................................................................... 31
Inclusion Criteria .............................................................................................. 32
Exclusion Criteria ............................................................................................. 32
Subject Enrollment and Randomization ............................................................ 33
Withdrawal from the Study............................................................................... 34
Discontinuation of Investigational Product........................................................ 34
Replacement of Subjects................................................................................... 34
Withdrawal of Informed Consent for Data and Biological Samples................... 34
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4.2
4.2.1
4.2.2
4.3
4.3.1
4.3.1.1
4.3.1.2
4.3.1.3
4.3.2
4.3.3
4.3.4
4.3.5
4.3.5.1
4.3.5.2
4.3.6
4.3.7
4.3.8
4.4
4.5
4.5.1
4.5.1.1
4.5.1.2
4.5.1.3
4.5.1.4
4.5.2
4.5.3
4.5.4
4.5.5
4.5.6
4.6
4.6.1
4.6.2
4.6.3
4.6.3.1
4.7
4.7.1
4.7.2
4.8
4.8.1
4.8.2
4.8.3
4.8.3.1
4.8.4
4.8.5
4.8.5.1
Schedule of Study Procedures........................................................................... 35
Enrollment/Screening Period ............................................................................ 35
Treatment and Follow-up Periods ..................................................................... 36
Description of Study Procedures....................................................................... 43
Efficacy. ........................................................................................................... 43
Lower Respiratory Tract Infection .................................................................... 43
Respiratory Secretions for RSV Detection ........................................................ 46
Monitoring for RSV Resistance ........................................................................ 46
Medical History and Physical Examination, Weight, and Vital Signs................ 47
Pharmacokinetic Evaluation and Methods......................................................... 47
Anti-drug Antibody Evaluation and Methods.................................................... 48
RSV-neutralizing Antibody and RSV Serology Evaluations and Methods......... 48
RSV Neutralizing Antibody.............................................................................. 48
RSV Serology................................................................................................... 48
Healthcare Resource Utilization and Caregiver Burden..................................... 48
Skin Reactions.................................................................................................. 48
Estimate of Volume of Blood to be Collected ................................................... 49
Study or Study Component Suspension or Termination..................................... 49
Investigational Products.................................................................................... 50
Identity of Investigational Products................................................................... 50
Investigational Product Inspection .................................................................... 51
Dose Preparation Steps and Treatment Administration...................................... 51
Monitoring of Dose Administration .................................................................. 54
Reporting Product Complaints .......................................................................... 55
Additional Study Medications........................................................................... 55
Labeling ........................................................................................................... 55
Storage ............................................................................................................. 55
Treatment Compliance...................................................................................... 55
Accountability .................................................................................................. 55
Treatment Assignment and Blinding................................................................. 56
Methods for Assigning Treatment Groups......................................................... 56
Methods to Ensure Blinding.............................................................................. 56
Methods for Unblinding.................................................................................... 56
Unblinding in the Event of a Medical Emergency ............................................. 56
Restrictions During the Study and Concomitant Treatment(s) ........................... 57
Permitted Concomitant Medications ................................................................. 57
Prohibited Concomitant Medications ................................................................ 57
Statistical Evaluation ........................................................................................ 57
General Considerations..................................................................................... 57
Sample Size...................................................................................................... 58
Safety ............................................................................................................... 59
Analysis of Adverse Events .............................................................................. 59
Efficacy………................................................................................................. 59
Analysis of Pharmacokinetics and Anti-drug Antibody..................................... 60
Pharmacokinetic Analysis................................................................................. 60
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4.8.5.2
4.8.6
4.8.6.1
4.8.6.2
4.8.6.3
4.8.6.4
4.8.6.5
4.8.7
5
5.1
5.2
5.3
5.3.1
5.3.2
5.3.3
5.4
5.5
5.5.1
5.5.2
5.5.3
5.5.4
5.5.5
5.6
5.7
5.7.1
5.7.2
5.7.3
5.7.3.1
5.7.3.2
5.7.3.3
5.7.4
6
6.1
6.2
6.2.1
6.2.2
6.2.3
6.3
6.4
6.5
7
7.1
Anti-drug Antibody Analysis ............................................................................ 60
Exploratory Analyses........................................................................................ 60
RSV Neutralizing Antibody.............................................................................. 60
RSV Serology................................................................................................... 61
Healthcare Resource Utilization and Caregiver Burden..................................... 61
RSV Resistance Monitoring.............................................................................. 61
RSV LRTI Occurring From Day 152 to Day 361 .............................................. 61
Independent Data Monitoring Committee ......................................................... 61
ASSESSMENT OF SAFETY ........................................................................... 61
Definition of Adverse Events............................................................................ 61
Definition of Serious Adverse Events ............................................................... 62
Definition of Adverse Events of Special Interest............................................... 62
Hypersensitivity, Including Anaphylaxis........................................................... 63
Immune Complex Disease ................................................................................ 63
Thrombocytopenia............................................................................................ 63
Definition of New Onset Chronic Disease......................................................... 64
Recording of Adverse Events............................................................................ 64
Time Period for Collection of Adverse Events .................................................. 64
Follow-up of Unresolved Adverse Events......................................................... 65
Deaths .............................................................................................................. 65
Adverse Events Based on Signs and Symptoms ................................................ 65
Adverse Events Based on Examination and Tests.............................................. 65
Reporting of Serious Adverse Events................................................................ 66
Other Events Requiring Immediate Reporting................................................... 66
Overdose .......................................................................................................... 66
Medication Error............................................................................................... 67
Adverse Events of Special Interest.................................................................... 68
Hypersensitivity, Including Anaphylaxis........................................................... 68
Immune Complex Disease ................................................................................ 68
Thrombocytopenia............................................................................................ 68
New Onset Chronic Disease.............................................................................. 69
STUDY AND DATA MANAGEMENT........................................................... 69
Training of Study Site Personnel....................................................................... 69
Monitoring of the Study.................................................................................... 69
Source Data ...................................................................................................... 70
Study Agreements............................................................................................. 70
Archiving of Study Documents......................................................................... 70
Study Timetable and End of Study.................................................................... 70
Data Management............................................................................................. 70
Medical Monitor Coverage ............................................................................... 71
ETHICAL AND REGULATORY REQUIREMENTS...................................... 71
Subject Data Protection..................................................................................... 71
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7.2
Ethics and Regulatory Review .......................................................................... 71
7.3
Informed Consent ............................................................................................. 72
7.4
Changes to the Protocol and Informed Consent Form........................................ 72
7.5
Audits and Inspections...................................................................................... 73
8
REFERENCES................................................................................................. 74
LIST OF TABLES
Table 1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
Table 8
Table 9
Table 10
Table 11
Primary Objective and Associated Endpoint ............................................ 22
Secondary Objectives and Associated Endpoints...................................... 22
Exploratory Objectives and Endpoints ..................................................... 23
Schedule of Screening Procedures ........................................................... 35
Schedule of Treatment Period and Follow-up Period Study Procedures:
Season 1, Preterm and CLD/CHD Cohorts............................................... 37
Schedule of Treatment Period and Follow-up Period Study Procedures:
Season 2, CLD/CHD Cohort Only ........................................................... 40
Criteria for Meeting the Protocol-defined Endpoint of Medically
Attended RSV LRTI - Subjects Without Underlying Lung Disease.......... 44
Criteria for Meeting the Protocol-defined Endpoint of Medically
Attended RSV LRTI – Subjects With Underlying Lung Disease (CLD or
CHD)....................................................................................................... 45
Volume of Blood to be Collected, Season 1 ............................................. 49
Volume of Blood to be Collected, Season 2 ............................................. 49
Identification of Investigational Products................................................. 50
LIST OF FIGURES
Figure 1
Figure 2
Figure 3
Figure 4
Study Flow Diagram................................................................................ 26
Dosing Regimen: Season 1 – Preterm Cohort and CLD/CHD Cohort....... 27
Dosing Regimen: Season 2 – CLD/CHD Cohort, MEDI8897 Group in
Season 1 .................................................................................................. 28
Dosing Regimen: Season 2 – CLD/CHD Cohort, Palivizumab Group in
Season 1 .................................................................................................. 28
LIST OF APPENDICES
Appendix A
Appendix B
Additional Safety Guidance ..................................................................... 77
National Institute of Allergy and Infectious Diseases and Food Allergy
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.............. 80
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LIST OF ABBREVIATIONS
Abbreviation or
Specialized Term
aa
amino acid
Definition
AAP
American Academy of Pediatrics
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ATP
As-treated Population
AUC
area under the concentration-time curve
CE
Conformité Européenne
CHD
congenital heart disease
CI
confidence interval
CLD
chronic lung disease
Cmax
maximum observed concentration
eCRF
electronic case report form
EDC
electronic data capture
ER
emergency room
EU
European Union
F
fusion
GA
gestational age
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
hMPV
human metapneumovirus
HRU
healthcare resource utilization
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgG1κ
immunoglobulin G1 kappa
IM
intramuscular
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
intravenous
IWRS
interactive web response system
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Abbreviation or
Specialized Term
JCVI
LRTI
mAb
MEDLEY
NCI CTCAE
NOCD
OTC
PK
RRR
RSV
RT-PCR
SAE
SID
t1/2
TEAE
TESAE
UK
US FDA
USA
YTE
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Definition
Joint Committee on Vaccination and Immunisation
lower respiratory tract infection
monoclonal antibody
Study D5290C00005
National Cancer Institute Common Terminology Criteria for Adverse Events
new onset chronic disease
over-the-counter
pharmacokinetic(s)
relative risk reduction
respiratory syncytial virus
reverse transcriptase-polymerase chain reaction
serious adverse event
subject identification
terminal half-life
treatment-emergent adverse event
treatment-emergent serious adverse event
United Kingdom
United States Food and Drug Administration
United States of America
M257Y/S259T/T261E [M252Y/S254T/T256E triple amino acid substitution
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1
INTRODUCTION
Prevention of respiratory syncytial virus (RSV) illnesses in all infants is a major public health
priority. However, despite more than 50 years of attempted vaccine development, there are no
licensed vaccines and no approved RSV prophylaxis for the broader population of healthy
infants. There are no specific RSV therapeutic options so the current medical management is
limited to supportive care.
The only currently approved prophylaxis for RSV, palivizumab (Synagis®) was developed by
MedImmune and is only indicated for use in high-risk children: preterm infants ≤ 35 weeks
gestational age (GA), children with chronic lung disease (CLD) of prematurity, and children
with hemodynamically significant congenital heart disease (CHD). In addition, further
restrictions have been implemented by local or national recommending bodies on the use of
palivizumab. For example, in the United States of America (USA) per the American Academy
of Pediatrics (AAP) guidelines, palivizumab is not recommended for healthy preterm infants
≥ 29 weeks GA (American Academy of Pediatrics, 2014). In the United Kingdom (UK),
palivizumab is recommended by the Joint Committee on Vaccination and Immunisation
(JCVI) for preterm infants with CLD or hemodynamically significant, acyanotic CHD
based on the GA at birth and chronological age at the start of the RSV season (JCVI, 2010a,
2010b).
1.1
Disease Background
RSV is the most common cause of lower respiratory tract infection (LRTI) among infants
and young children, resulting in annual epidemics worldwide (Hall et al, 2009; Hall, 2012;
Madhi et al, 2006; Shay et al, 1999; Shi et al, 2017; Stockman et al, 2012). All children,
including healthy term infants, are at risk for severe LRTI with primary RSV infection during
infancy. Ninety percent of children are infected with RSV in the first 2 years of life, and up to
40% of them will have LRTI with the initial episode (American Academy of Pediatrics, 2014;
Greenough et al, 2001; Meissner, 2003; Parrott et al, 1973). RSV LRTI, characterized
predominantly as bronchiolitis or pneumonia, represents a serious illness with
acute and perhaps long-term consequences to the developing lungs in these young children
(Blanken et al, 2013). It is estimated that RSV causes up to 90% of childhood bronchiolitis
and up to 40% of pediatric pneumonias (Hall, 2001). RSV bronchiolitis was the leading cause
of hospital admissions for infants < 1 year of age for any reason between 1997 and 1999
(Leader and Kohlhase, 2002). In 2015, an estimated 33.1 million (uncertainty range, 21.6 to
50.3 million) new episodes of RSV-associated LRTI occurred worldwide in children younger
than 5 years (28% of LRTI episodes), with approximately 3.2 million (range, 2.7 to
3.8 million) episodes necessitating hospitalization, leading to 59,600 (range, 48,000 to 74,500)
in-hospital deaths. Children younger than 1 year of age had an estimated 2.3 million hospital
admissions. The overall mortality due to RSV LRTI was estimated to be as high as 118,200
(uncertainty range, 94,600 to 149,400)(Shi et al, 2017).
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Although hospitalization is well recognized as an important consequence of RSV illness,
a large percentage of the healthcare burden from RSV occurs outside of the hospital (Carroll
et al, 2008; Hall et al, 2009; Paramore et al, 2010) such that office visits and emergency
department visits are more frequent than subsequent hospitalization, especially in healthy
infants. The general severity of RSV infection observed among infants in outpatient settings is
almost as severe as those observed in hospitalized infants, including labored breathing
requiring supplemental oxygen, wheezing, and fever (Hall, 2012). While 95% of children
hospitalized with RSV had labored respirations, similar percentages of outpatients were also
observed to have labored respirations (85% of children cared for in emergency departments
and 73% of children treated in private practice settings (Hall et al, 2009). The outpatient
burden and severity of disease accounts for a significant portion of the morbidity associated
with RSV in all infants.
Palivizumab is the only approved agent for RSV prophylaxis, and its use is limited to
high-risk children. Because of its terminal half-life (t½) of approximately 1 month, infants and
young children need to receive monthly intramuscular (IM) doses of palivizumab throughout
the typical 5-month RSV season to maintain protection. This constitutes a significant burden
on healthcare providers as well as the infants/children and their families. Additionally, many
infants who receive palivizumab are unable to comply with the monthly dosing
schedule and non-compliance has been shown to result in increased risk of hospitalization
(Frogel et al, 2010; Stewart et al, 2013). Furthermore, the cost of palivizumab prophylaxis has
led to additional restrictions being implemented by many countries, including the USA
(American Academy of Pediatrics, 2014) and the UK (JCVI, 2010a, 2010b).
1.2
MEDI8897 Background
MEDI8897 is briefly described below. Refer to the current Investigator’s Brochure for details.
MEDI8897 is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody
(mAb) directed against the prefusion conformation of the RSV fusion (F) protein. The
antibody has been engineered with a triple amino acid substitution (YTE;
M257Y/S259T/T261E [M252Y/S254T/T256E, according to the European Union (EU)
numbering system]) in the fragment crystallizable (Fc) region to prolong the t1/2, which is
expected to provide protection from serious RSV disease for the duration of the RSV season.
MEDI8897 neutralizes RSV by binding the prefusion conformation of the RSV F protein at a
site distinct from that bound by palivizumab. In preclinical studies, MEDI8897 was
> 150-fold more potent than palivizumab in vitro and approximately 9-fold more potent than
palivizumab in vivo in the cotton rat model (Zhu et al, 2017). MEDI8897 is currently under
development by MedImmune for the passive immunization of all infants entering their first
RSV season and children with CLD or CHD entering their first and second RSV season for
the prevention of LRTI caused by RSV. MEDI8897 may provide a cost-effective opportunity
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to protect all infants from RSV disease based on an improvement in potency and the extended
t1/2 that is expected to support once-per-RSV-season dosing.
1.3
Summary of Nonclinical Experience
Toxicity, toxicokinetics, and immunogenicity of MEDI8897 were evaluated in a Good
Laboratory Practice-compliant repeat-dose intravenous (IV) and IM toxicology study
conducted in cynomolgus monkeys. Toxicology studies in cynomolgus monkeys indicate that
there is no evidence of MEDI8897 toxicity in these animal models.
Overall, data from
nonclinical studies do not reveal any MEDI8897-related safety concerns.
Details of these studies are included in the current Investigator’s Brochure.
1.4
Summary of Clinical Experience
MEDI8897 has been investigated in 3 completed clinical studies, including a first-time-in-
human Phase 1a study in healthy adults (Study D5290C00001), a first-time-in-pediatric
Phase 1b/2a study in healthy preterm infants (Study D5290C00002), and a Phase 2b safety
and efficacy study in healthy preterm infants (Study D5290C00003). MEDI8897 had a
favorable safety profile, with generally similar proportions of treatment-emergent adverse
events (TEAEs) reported in the MEDI8897 and placebo-control groups across the 3 studies.
A summary of Study D5290C00003 is presented below. Refer to the current Investigator’s
Brochure for details on all MEDI8897 clinical studies.
1.4.1
Study D5290C00003
The Phase 2b Study D5290C00003 was a randomized, double-blind, placebo-controlled
single-dose study that evaluated the safety, efficacy, PK, and ADA response of MEDI8897 in
healthy preterm infants. Subjects were 29 to < 35 weeks GA entering their first RSV season
who would not receive RSV prophylaxis based on the JCVI, AAP, or other local or national
guidelines. Overall, 1,453 subjects were randomized 2:1 to receive a single dose of 50 mg IM
MEDI8897 (n = 969) or placebo (n = 484). A total of 1,447 subjects were dosed, including
966 subjects in the MEDI8897 group and 481 subjects in the placebo group. Subjects were
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followed for approximately 360 days after dosing. The study was completed on 06Dec2018
(last subject last visit).
Results from the planned primary analysis conducted after all randomized subjects who
remained in the study completed the Day 151 visit demonstrated a statistically significant
relative risk reduction (RRR) in the incidence of the primary endpoint of RSV-confirmed
LRTI (inpatient and outpatient) and the secondary endpoint of RSV hospitalization.
Based on the primary analysis, the safety profile for the MEDI8897 group was comparable to
the placebo group, with no identified risks. Overall,
of subjects in the MEDI8897
group and
of subjects in the placebo group had at least 1 TEAE. The majority of the
TEAEs were mild or moderate in severity. TEAEs ≤ 1 day post dose occurred in 2.5% of
subjects in both groups. In comparison to the placebo group, the MEDI8897 group had a
lower incidence of TEAEs occurring ≤ 7 days post dose (15.2% vs 12.5%, respectively),
TEAEs ≥ Grade 3 in severity (12.3% vs 7.4%, respectively), and treatment-emergent serious
adverse events (TESAEs; 16.7% vs 10.4%, respectively). The most common TESAEs, based
on the MEDI8897 group, were bronchiolitis (2.1% MEDI8897, 4.2% placebo), LRTI
(1.4% MEDI8897, 2.7% placebo), pneumonia (1.4% MEDI8897, 2.1% placebo), and
bronchitis (1.2% MEDI8897, 2.3% placebo). None of the TESAEs were considered related to
study treatment by the investigator. Five deaths were reported during the study through
Day 361, including 2 subjects (0.2%) in the MEDI8897 group and 3 subjects (0.6%) in the
placebo group. None of the deaths were related to study drug according to the investigator.
Overall, the incidence of investigational product-related TEAEs (MEDI8897 2.3%, placebo
2.1%); adverse events of special interest (AESIs), including hypersensitivity, immune
complex disease, and thrombocytopenia (MEDI8897 0.5%, placebo 0.6%); and new onset
chronic diseases
was low and generally
comparable between the placebo and MEDI8897 groups. AESIs were reported in 5 subjects
(4 subjects with rash or rash macular and 1 subject with petechiae) in the MEDI8897 group
and 3 subjects (rash or rash papular) in the placebo group. All events were Grade 1 in severity.
The TEAE of petechiae that was reported as an AESI was 1-day duration and was reported by
the site investigator based on description by the parent. There were no laboratory assessments
for the petechiae.
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TEAEs that involved the skin and subcutaneous tissues (including diaper rash) were collected
as skin reactions, with a few exceptions for skin reactions that could be definitively diagnosed
such as impetigo, varicella, and scabies.
Following a single fixed 50-mg IM dose of MEDI8897, over 95% of measurable Day 151
concentrations were greater than the nonclinical EC90 target of 6.8 μg/mL. The median area
under the concentration-time curve from time 0 to infinity (AUC0-∞) and estimated apparent
t½ were 5.3 day.mg/mL (range, 3.2 to 10.2 day.mg/mL) and 56.5 days (range, 46.8 to
81.1 days), respectively.
Overall, the rate and titers of ADA were low, and in ADA-positive subjects there was no
effect on PK or safety. Of the subjects who had serum samples available for testing, ADA was
detected post baseline in 4.3% (40/921) of subjects in the MEDI8897 group and
2.8% (13/466) of subjects in the placebo group; with less than 5% of subjects in either group
being ADA positive at any visit. ADA titers ranged from 1:50 to 1:3,200 in the MEDI8897
group and 1:50 to 1:200 in the placebo group. Of the MEDI8897 subjects who were
post-baseline ADA positive, ADA targeting the YTE domain was observed in 4/17 subjects
on Day 151 and 10/15 on Day 361. Two MEDI8897 subjects had ADA on Day 361.
1.5
Rationale for Conducting the Study
Prevention of RSV illnesses in all infants is a major public health priority; however, despite
more than 50 years of attempted vaccine development, there are no licensed vaccines. While
RSV prevention exists in the form of a specific RSV IgG (Synagis®, palivizumab) requiring
5 once-monthly injections, it is licensed only for infants who experience the greatest
morbidity and mortality from RSV: preterm infants born ≤ 35 weeks GA, children with CLD
of prematurity, and children with hemodynamically significant CHD. In addition, due to the
cost of prophylaxis, further restrictions have been implemented by local or national
recommending bodies. For example, the USA national guidelines provided by the American
Academy of Pediatrics (American Academy of Pediatrics, 2014) limit the recommendation for
palivizumab to (a) preterm infants born before 29 weeks GA who are younger than 12 months
of age at the start of the RSV season, (b) preterm infants with a GA of < 32 weeks and CLD
for the first year of life with consideration of prophylaxis during the second year if continued
medical support is required, and (c) infants with hemodynamically significant CHD who are
12 months of age or younger. In the UK, palivizumab is recommended by the Joint Committee
on Vaccination and Immunisation (JCVI) for preterm infants with CLD or hemodynamically
significant, acyanotic CHD based on the GA at birth and chronological age at the start of the
RSV season (JCVI, 2010a, 2010b). MEDI8897 is being developed as a cost-effective
opportunity to protect all infants, including those who currently receive palivizumab, from
RSV disease based on improved potency and an extended t1/2, which is expected to support
once-per-RSV-season dosing.
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The MEDI8897 clinical development program includes two pivotal studies for infants entering
their first RSV season: the completed Phase 2b study (D5290C00003) and a planned Phase 3
study (D5290C00004 [MELODY]). Because of the significant advantage of one dose per RSV
season that MEDI8897 would provide, MedImmune recognizes the potentially important
benefits for the current pediatric population receiving palivizumab who must receive monthly
injections during the typical 5-month RSV season for protection. Therefore, this Phase 2/3
study is planned to support an indication in the high-risk palivizumab-eligible population
entering their first and second RSV seasons to compare the safety, PK, ADA, and efficacy
trend of MEDI8897 once-per-RSV-season dosing with palivizumab once-per-month dosing
during the RSV season.
1.6
Benefit-Risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the
Declaration of Helsinki and are consistent with International Council for Harmonisation
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
See Section 1.4 for a summary of MEDI8897 clinical safety and efficacy. More detailed
information about the known and expected benefits and risks of MEDI8897 can be found in
the Investigator’s Brochure.
1.6.1
Potential Benefit
Palivizumab, the only currently approved RSV prophylaxis, requires 5 once-monthly
injections for protection and due to cost is restricted for use only in infants at the greatest risk
for morbidity and mortality from RSV. As there is no approved treatment for active RSV
infection, the current standard of care for patients with serious RSV illness is supportive care.
Thus, there is a significant unmet medical need for RSV prophylaxis in high-risk infants and
children. Favorable efficacy and safety data from the Phase 2b Study D5290C00003 in
preterm infants who received a single dose of MEDI8897, suggest that MEDI8897 may
provide an important alternative and cost-effective option.
1.6.2
Potential Risk
MEDI8897 has no endogenous targets, and no safety concerns were identified in nonclinical
studies. The potential risks are based primarily on common safety risks observed with any
immunoglobulin, including mAbs such as palivizumab. These potential risks include, but are
not limited to, hypersensitivity (including anaphylaxis), immune complex disease,
thrombocytopenia, and injection site reactions. To date, there have been no observed events of
anaphylaxis, significant hypersensitivity reactions, immune complex disease, or
thrombocytopenia attributable to MEDI8897 in the clinical studies. Nonetheless, subjects in
MEDI8897 clinical studies will be monitored for important potential risks, and routine
pharmacovigilance and risk minimization activities will be performed accordingly.
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1.6.3
Overall Benefit-Risk
The current study will compare the safety, PK, ADA, and descriptive statistics of MEDI8897
with palivizumab in high-risk preterm infants and children. The single-dose regimen for
MEDI8897 vs the 5 once-monthly dosing regimen for palivizumab presents a potentially
important and cost-effective treatment option for RSV prophylaxis in this high-risk pediatric
population of preterm infants and children up to 2 years of age with CLD or CHD.
The design of the current study aims to minimize the risks to subjects and includes the
protocol inclusion and exclusion criteria, restrictions on concomitant medication during the
study, safety monitoring (including review of all safety data by the independent data
monitoring committee), and study stopping criteria.
Overall, the benefit-risk assessment for this Phase 2/3 study is acceptable.
2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 1                Primary Objective and Associated Endpoint
Type
Objective
Endpoint
To evaluate the safety and tolerability of
administered to preterm infants entering their
Safety and tolerability of MEDI8897 as
first RSV season and children with CLD or
CHD entering their first and second RSV
season
AESI = adverse event of special interest; CHD = congenital heart disease; CLD = chronic lung disease;
NOCD = new onset chronic disease; RSV = respiratory syncytial virus; TEAE = treatment-emergent adverse
event; TESAE = treatment-emergent serious adverse event.
2.1.1
Secondary Objectives and Associated Endpoints
Table 2                Secondary Objectives and Associated Endpoints
Type
PK
Objective
To evaluate serum concentrations of
MEDI8897 and palivizumab
Endpoint
• MEDI8897 and palivizumab serum
concentrations
• MEDI8897 and palivizumab PK
parameters: Summary of serum
concentrations and estimated PK
parameters (Cmax, AUC, apparent
clearance, and t1/2, if data permit)
ADA
To evaluate ADA responses to MEDI8897
and to palivizumab in serum
Incidence of ADA to MEDI8897 and
palivizumab in serum
To assess the descriptive efficacy of
MEDI8897 when administered as a single
Efficacy
IM dose of 50 mg to infants < 5 kg or
100 mg to infants ≥ 5 kg in the first RSV
season or a single 200-mg IM dose
• Incidence of medically attended LRTI
(inpatient and outpatient) due to
RT-PCR-confirmed RSV through
150 days after Dose 1 for Season 1 and
Season 2
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Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
administered in the second RSV season, in
• Incidence of hospitalizations due to
reducing medically attended LRTI (inpatient           RT-PCR-confirmed RSV through
and outpatient) and hospitalization due to
150 days after Dose 1 for Season 1 and
RT-PCR-confirmed RSV, compared to
Season 2
palivizumab
ADA = anti-drug antibody; AUC = area under the concentration-time curve; Cmax = maximum observed
concentration; IM = intramuscular; LRTI = lower respiratory tract infection; PK = pharmacokinetic; RSV =
respiratory syncytial virus; RT-PCR = reverse transcriptase-polymerase chain reaction; t1/2 = terminal half-life.
2.1.2
Exploratory Objectives and Associated Endpoints
Table 3                Exploratory Objectives and Endpoints
Type
RSV neutralizing
antibody
RSV serology
HRU and
caregiver burden
Objective
To determine anti-RSV neutralizing
antibody levels in serum afforded by a
single dose of MEDI8897 compared to
5 monthly doses of palivizumab
To evaluate exposure to RSV by
measuring seroresponses to different RSV
proteins in MEDI8897 and palivizumab
recipients
To evaluate the levels of maternal RSV-
specific antibody in MEDI8897 and
palivizumab recipients
To assess HRU and caregiver burden for
MEDI8897 recipients compared to
palivizumab recipients
Endpoint
• Anti-RSV neutralizing antibody levels
(IU/mL) in serum for MEDI8897
recipients compared to palivizumab
recipients
• Summary of serum RSV neutralizing
antibody levels (may include GMT,
GMFR, Cmax, apparent clearance, and t1/2)
• Antibody levels to RSV F, Ga, Gb, or N
at different time points
• Changes in RSV antibody levels
(seroresponse) indicating exposure to
RSV
• RSV antigen antibody levels (AbU/mL)
to multiple RSV antigens
• Summary of serum RSV antibody levels
(may include GMT, GMFR,
seroconversion rates, apparent clearance,
and t1/2)
• Magnitude of HRU (eg, number of
admissions to hospitals and ICUs and
duration of stay; number of subjects who
require respiratory support and
supplemental oxygen and the duration of
use; number and type of outpatient visits
[eg, ER, urgent care, outpatient clinic];
and number of prescription and OTC
medications and duration of use) for
MEDI8897 recipients compared to
palivizumab recipients
• Caregiver burden (eg, caregiver missed
work days, subject absence from day
care) for subjects with medically attended
LRTI caused by RT-PCR-confirmed RSV
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Table 3
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Exploratory Objectives and Endpoints
Type
Objective
Endpoint
To characterize resistance to MEDI8897
Genotypic analysis and susceptibility of
and palivizumab through genotypic and
RSV variants to neutralization by
phenotypic analyses
MEDI8897 and palivizumab
To assess the incidence of medically
Incidence of medically attended LRTI
RSV LRTI after
attended LRTI due to RT-PCR-confirmed
(inpatient and outpatient) due to RT-PCR-
Day 151
RSV, compared to palivizumab after
confirmed RSV from Day 152 to Day 361
Day 151
for Season 1 and Season 2
AbU/mL = antibody unit per mL; Cmax = maximum observed concentration; ER = emergency room; GMFR =
geometric mean fold-rise; GMT = geometric mean titer; HRU = healthcare resource utilization; ICU = intensive
care unit; LRTI = lower respiratory tract infection; OTC = over-the-counter; RSV = respiratory syncytial virus;
RT-PCR = reverse transcriptase-polymerase chain reaction; t1/2 = terminal half-life.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
Study D5290C00005 (MEDLEY) is a pivotal Phase 2/3 randomized, double-blind,
palivizumab-controlled study to evaluate the safety, PK, ADA response, and descriptive
efficacy for MEDI8897 in high-risk infants eligible to receive palivizumab when entering
their first or second RSV season (Season 1 or Season 2, respectively). Approximately
900 palivizumab-eligible infants entering their first RSV season will be enrolled into one of
2 cohorts (Figure 1): (1) preterm cohort, including approximately 600 preterm infants
(≤ 35 weeks GA) without CLD/CHD, or (2) CLD/CHD cohort, including approximately
300 infants with CLD of prematurity or hemodynamically significant CHD. As minimum of
100 infants with hemodynamically significant CHD will be enrolled. Within each cohort,
randomization will be stratified by hemisphere (northern, southern) and subject age at the time
of Season 1 randomization (≤ 3 months, > 3 to ≤ 6 months, > 6 months).
Season 1, Preterm and CLD/CHD Cohorts
All subjects will be randomized 2:1 to either the MEDI8897 group (approximately
600 subjects, including approximately 400 subjects in the preterm cohort and approximately
200 subjects in the CLD/CHD cohort) or palivizumab group (approximately 300 subjects,
including approximately 200 subjects in the preterm cohort and approximately 100 subjects in
the CLD/CHD cohort). Subjects in the MEDI8897 group will receive a single fixed IM dose
of MEDI8897 followed by 4 once-monthly IM doses of placebo. The MEDI8897 dose level
will be stratified by weight band, ie, 50 mg for infants weighing < 5 kg or 100 mg for infants
weighing ≥ 5 kg. Subjects in the palivizumab group will receive 5 once-monthly IM doses of
15 mg/kg palivizumab.
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Season 2, CLD/CHD Cohort Only

 Subjects with CLD/CHD ≤ 24 months of age who were randomized to the MEDI8897
group for Season 1 will receive a single fixed IM dose of 200 mg MEDI8897 followed by
4 once-monthly IM doses of placebo (approximately 200 subjects).

 Subjects with CLD/CHD ≤ 24 months of age who were randomized to the palivizumab
group for Season 1 will be re-randomized 1:1 to either the MEDI8897 group or the
palivizumab group. Subjects in the MEDI8897 group will receive a single fixed IM dose
of 200 mg MEDI8897 followed by 4 once-monthly IM doses of placebo (approximately
50 subjects). Subjects in the palivizumab group will receive 5 once-monthly IM doses of
15 mg/kg palivizumab (approximately 50 subjects).
In Season 1 or Season 2, subjects in the CLD/CHD cohort who undergo cardiac surgery with
cardiopulmonary bypass after receipt of Dose 1 but prior to receipt of Dose 5 will receive a
replacement dose of the study drug they received for Dose 1 immediately following the
surgery when determined by the physician to be medically stable for an IM injection. Any
subsequent doses of study drug will continue to be given according to the protocol-specified
dosing schedule. See Section 3.1.2.3 for details on replacement dosing.
Subjects in the preterm cohort will be followed through 1 year after Season 1/Dose 1, and
subjects in the CLD/CHD cohort will be followed through 1 year after Season 2/Dose 1.
Subjects in the CLD/CHD cohort who receive a replacement dose in Season 2 will be
followed through 1 year after the last replacement dose.
Subjects in the CLD/CHD cohort with a weight < 7 kg at the time of dosing for Season 2 will
have increased monitoring of adverse events (AEs). Any SAEs or Grade 3 or Grade 4 AEs
that occur in the first month after dosing will be sent to the independent data monitoring
committee for immediate review.
Subjects will be monitored throughout the study for LRTI (see Section 4.3.1). All subjects
seeking medical attention for a respiratory illness (in either the inpatient or outpatient setting)
will be evaluated for LRTI, including protocol-defined medically attended RSV LRTI
(Table 7 and Table 8). All subjects evaluated for LRTI will have respiratory samples obtained
and tested centrally for RSV using the United States Food and Drug Administration
(US FDA)-cleared and Conformité Européenne (CE) or European Conformity-marked in vitro
diagnostic real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay (see
Section 4.3.1.2).
Blood samples will be collected for PK, ADA, and RSV neutralizing antibody and RSV
serology as defined in Sections 4.3.3, 4.3.4, and 4.3.5, respectively.
The endpoints to be measured in this study are described in Section 2.
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Figure 1
Study Flow Diagram
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
ADA = anti-drug antibody; CHD = congenital heart disease; CLD = chronic lung disease; IM = intramuscular; PK = pharmacokinetic.
SEASON 1: Randomization for Season 1 Day 1, 2:1 MEDI8897 or palivizumab group
SEASON 2 (CLD/CHD cohort only): Randomization for Season 2 Day 1: Subjects who were randomized in Season 1 to receive MEDI8897 will receive MEDI8897 in Season 2.
Subjects who were randomized to receive palivizumab in Season 1 will receive MEDI8897 or palivizumab in Season 2
Blood samples for PK and ADA: Season 1 for both cohorts – Screening or Day 1 predose and on Days 31 (predose), 151, and 361 (for CLD/CHD cohort, prior to Season 2
dosing); Season 2 for CLD/CHD cohort only - Days 31 (predose), 151, and 361. Additionally, samples will be collected during both seasons from all subjects hospitalized for a
respiratory infection, and before and after cardiac surgery with cardiopulmonary bypass for subjects with CHD requiring a replacement dose of study drug.
Safety assessments will be performed through Day 361 for each respective season.
a
In the MEDI8897 group Season 1, dose level will be stratified by body weight at time of dosing; subjects will receive 50 mg MEDI8897 if < 5 kg or 100 mg MEDI8897 if
≥ 5 kg.
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3.1.2
Dosing Regimen
Subjects will be randomly assigned to receive study drug as outlined in Figure 1.
3.1.2.1
Season 1, Preterm Cohort and CLD/CHD Cohort
In Season 1, subjects in the preterm cohort and CLD/CHD cohort will receive either
MEDI8897 or palivizumab as presented in Figure 2. Section 3.1.2.3 provides details on
replacement dosing for subjects in the CLD/CHD cohort who undergo cardiac surgery with
cardiopulmonary bypass surgery.
Figure 2
Dosing Regimen: Season 1 – Preterm Cohort and CLD/CHD Cohort
CHD = congenital heart disease; CLD = chronic lung disease; IM = intramuscular.
a
Visit 1/Screening and Visit 2/Day 1 and can occur on the same day.
b
Based on body weight at time of dosing.
3.1.2.2
Season 2, CLD/CHD Cohort
In Season 2, subjects in the CLD/CHD cohort only will receive either MEDI8897 or
palivizumab based on their randomized dosing group in Season 1. Figure 3 presents the dosing
regimen for subjects who were randomized to receive MEDI8897 in Season 1. Figure 4
presents the dosing regimen for subjects who were randomized to receive palivizumab in
Season 1. Section 3.1.2.3 provides details on replacement dosing for subjects in the
CLD/CHD cohort who undergo cardiac surgery with cardiopulmonary bypass surgery.
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Figure 3
Protocol D5290C00005 (MEDLEY) Amendment 1
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Dosing Regimen: Season 2 – CLD/CHD Cohort, MEDI8897 Group in
Season 1
CHD = congenital heart disease; CLD = chronic lung disease; IM = intramuscular.
Figure 4
Dosing Regimen: Season 2 – CLD/CHD Cohort, Palivizumab Group in
Season 1
CHD = congenital heart disease; CLD = chronic lung disease; IM = intramuscular.
a
Based on body weight at time of dosing.
3.1.2.3
Season 1 or Season 2, CLD/CHD Cohort - Replacement Dose
Subjects in the CLD/CHD cohort who undergo cardiac surgery with cardiopulmonary bypass
after receipt of Dose 1 but prior to receipt of Dose 5 will receive a replacement dose of the
study drug that they received for Dose 1 immediately following the surgery when determined
by the physician to be medically stable for an IM injection. Any subsequent doses of study
drug will continue to be given according to the protocol-specified dosing schedule. In subjects
requiring multiple surgeries during the same season, the dosing and timing scheme described
below should be followed relative to the most recent replacement dose.
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Details for the replacement dose by randomized group are presented below.
MEDI8897 Group

Season 1

 Subjects undergoing surgery < 90 days post first dose who originally received 50 mg
MEDI8897 will receive a single 50-mg MEDI8897 IM replacement dose if < 5 kg
body weight at time of replacement dosing or a single 100-mg MEDI8897 IM
replacement dose if ≥ 5 kg body weight at time of replacement dosing.

Subjects undergoing surgery < 90 days post first dose who originally received
100 mg MEDI8897 will receive a single 100-mg MEDI8897 IM replacement dose.

 Subjects undergoing surgery ≥ 90 days post first dose who originally received either
50 mg or 100 mg MEDI8897 will receive a single 50-mg MEDI8897 IM replacement
dose.

Season 2

Subjects undergoing surgery < 90 days post first dose will receive a single 200-mg
MEDI8897 IM replacement dose.

Subjects undergoing surgery ≥ 90 days post first dose will receive a single 100-mg
MEDI8897 IM replacement dose.
Palivizumab Group
Subjects will receive a 15 mg/kg palivizumab IM replacement dose. Thereafter, doses should
be given according to the protocol-specified dosing schedule.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
A single fixed 50-mg IM dose was shown to be efficacious in the Phase 2b Study
D5290C00003 in preterm infants (29 to < 35 weeks GA) in their first RSV season.
Model-based analyses of the Phase 2b clinical PK and efficacy data identified a projected
serum AUC0-∞ of
as the protective exposure threshold. The risk of medically
attended RSV-confirmed LRTI over the course of the RSV season was significantly lower in
infants with higher projected AUC0-∞. Infants with AUC0-∞ above
had a
statistically significantly higher probability of protection based on exposure-response analysis
using Cox proportional hazard regression.
Henceforth, based on
these analyses, a stratified fixed dosing strategy by weight bands will be implemented to
ensure an adequate dose to maintain MEDI8897 serum concentrations above the target AUC
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throughout the RSV season. Based on dose optimization analysis designed to maximize the
proportion of infants with clinically efficacious MEDI8897 serum exposure, a single fixed
50-mg IM dose will be administered for infants < 5 kg in their first RSV season while a single
fixed 100-mg dose will be administered for those weighing ≥ 5 kg entering their first RSV
season. Additionally, the body weight range for the Phase 2/3 population in the second year of
life at time of dosing is expected to be approximately 8.5 to 15 kg. Therefore, with the same
rationale, a single fixed 200-mg dose of MEDI8897 is proposed for infants in the second year
of life to achieve and maintain efficacious exposure during the entire second RSV season.
The approved palivizumab dosing regimen of 15 mg/kg administered IM once monthly during
the RSV season (ie, once monthly for 5 months) will be used for this study.
3.2.2
Rationale for Study Population
MEDI8897 has the potential to address a serious unmet medical need by protecting all infants
from RSV disease based on its demonstrated increased potency and expected extended
half-life that may support once per season dosing. Because of these significant advantages
over palivizumab, including the potential for a single dose versus up to 5 monthly doses of
palivizumab, MEDI8897 may also provide a significant improvement for prevention of RSV
disease in the pediatric population indicated for palivizumab, ie, high-risk preterm infants and
children up to 2 years of age with CLD or CHD. Therefore, this Phase 2/3 study is planned to
evaluate MEDI8897 in high-risk palivizumab-eligible infants and young children entering
their first and second RSV seasons.
3.2.3
Rationale for Endpoints
MEDI8897 is being developed to provide RSV immunoprophylaxis for all infants entering
their first RSV season and children with CLD of prematurity or hemodynamically significant
CHD entering their first and second seasons. The primary endpoint for this study is safety and
tolerability, with the aim of comparing the profiles for MEDI8897 and palivizumab in this
population. The standard measures of TEAEs/TESAEs, AESIs, and NOCDs will be used for
this assessment. All subjects will be followed for approximately 1 year after the last dose of
MEDI8897. Subjects with CLD/CHD who receive MEDI8897 for Season 1 and Season 2 and
subjects who receive a replacement dose of MEDI8897 after cardiopulmonary bypass will
provide data for the safety assessment of infants who receive more than a single dose of
MEDI8897.
Serum concentration of MEDI8897 at selected time points will be evaluated as a secondary
endpoint to confirm that serum concentrations are maintained at an efficacious level for at
least 5 months after dosing. Palivizumab serum concentrations will also be evaluated.
MEDI8897 and palivizumab PK data will be summarized by non-compartmental analysis.
Additionally, serum concentration data will be used to characterize the PK of MEDI8897 in
infants using a population PK approach separately. For infants who require hospitalization for
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LRTI or any respiratory infection, an additional serum sample for measurement of
MEDI8897/palivizumab concentration and ADA will be obtained contemporaneous with time
of hospitalization. Exposure-response analysis will be performed to relate MEDI8897 serum
concentrations and efficacy endpoints (LRTI including RSV-associated hospitalization).
To determine MEDI8897 and palivizumab serum levels post dosing and to correlate with the
potential development of ADA, serum concentrations will be measured up to 360 days post
Dose 1 (when MEDI8897 would be given) for both Season 1 and, as applicable, Season 2.
ADA to MEDI8897 and to palivizumab will be measured at selected time points throughout
the study and up to 360 days post Dose 1 for each season as well.
This study will also summarize efficacy of MEDI8897 and palivizumab in terms of incidence
of RSV LRTI. Respiratory syncytial virus results in a significant burden of disease consisting
of hospitalization, visits to the emergency room (ER), and visits to outpatient clinics. This
endpoint is designed to allow the capture of this total burden of disease. A separate endpoint
of RSV hospitalization will also be evaluated. Because of the reduced incidence of RSV
disease in this population following the introduction of palivizumab, a superiority or
non-inferiority design (with RRR of MEDI8897 over palivizumab as the endpoint) is not
practical. This Phase 2/3 study is designed to confirm the safety and PK while incidence of
RSV LRTI (and RSV hospitalization) will be summarized and no formal statistical test will be
conducted. It is anticipated that efficacy from the Phase 2b and Phase 3 studies in preterm and
term infants will be predictive of efficacy in the palivizumab population.
Exploratory endpoints will examine magnitude of healthcare resource utilization (HRU) and
caregiver burden due to RSV illness in the current population. This will allow the
determination of social and economic resources that are required for infants who have LRTI.
Serum anti-RSV neutralizing antibody levels will be evaluated for correlation with serum
MEDI8897 and palivizumab concentrations. RSV serology will be evaluated to identify
potential exposure to RSV. To monitor for RSV resistance, the F protein from collected RSV
isolates will be genetically characterized and novel variants will be phenotypically
characterized for MEDI8897 and palivizumab susceptibility. The incidence of medically
attended LRTI (inpatient and outpatient) due to RT-PCR-confirmed RSV from Day 152 to
Day 361 in Season 1 and Season 2 will be assessed to determine if there is a possible effect of
MEDI8897 past Day 151.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of approximately 900 subjects will be enrolled and randomized to either the
MEDI8897 group (approximately 600 subjects, including approximately 400 subjects in the
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preterm cohort and approximately 200 subjects in the CLD/CHD cohort) or palivizumab
group (approximately 300 subjects, including approximately 200 subjects in the preterm
cohort and approximately 100 subjects in the CLD/CHD cohort).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
For the preterm cohort (excluding subjects with CLD or hemodynamically significant
CHD): preterm infants in their first year of life and born ≤ 35 weeks 0 days GA eligible to
receive palivizumab in accordance with national or local guidelines, including those with:
(a) Uncomplicated small atrial or ventricular septal defects or patent ductus arteriosus, or
(b) Aortic stenosis, pulmonic stenosis, or coarctation of the aorta alone
2
For the CLD/CHD cohort:
(a) Subjects with CLD - infants in their first year of life and a diagnosis of CLD of
prematurity requiring medical intervention/management (ie, supplemental oxygen,
bronchodilators, or diuretics) within the 6 months prior to randomization
(b) Subjects with CHD - infants in their first year of life and documented,
hemodynamically significant CHD (must be unoperated or partially corrected CHD)
Note: Infants with hemodynamically significant acyanotic cardiac lesions must have
pulmonary hypertension (≥ 40 mmHg measured pressure in the pulmonary artery) or
the need for daily medication to manage CHD
3
Infants who are entering their first RSV season at the time of screening
4
Written informed consent and any locally required authorization (eg, Health Insurance
Portability and Accountability Act in the USA, EU Data Privacy Directive in the EU)
obtained from the subject's parent(s)/legal representative(s) prior to performing any
protocol-related procedures, including screening evaluations
5
Subject's parent(s)/legal representative(s) able to understand and comply with the
requirements of the protocol including follow-up and illness visits as judged by the
investigator
6
 Subject is available to complete the follow-up period, which will be 1 year after Season 1/
Dose 1 for subjects without CLD/CHD, or 1 year after Season 2/Dose 1 (or last
replacement dose as applicable for CHD) for subjects with CLD/CHD
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
Any fever (≥ 100.4°F [≥ 38.0°C], regardless of route) or acute illness within 7 days prior
to randomization
2
Any history of LRTI or active LRTI prior to, or at the time of, randomization
3
Known history of RSV infection or active RSV infection prior to, or at the time of,
randomization
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4
Hospitalization at the time of randomization, unless discharge is expected within the
7 days after randomization
5
Requirement for mechanical ventilation, extracorporeal membrane oxygenation, CPAP,
or other mechanical respiratory or cardiac support at the time of randomization
6
Anticipated cardiac surgery within 2 weeks after randomization
7
Anticipated survival of < 6 months after randomization
8
Receipt of any investigational drug
9
Known renal impairment
10 Known hepatic dysfunction including known or suspected active or chronic hepatitis
infection
11 Clinically significant congenital anomaly of the respiratory tract
12 Chronic seizure, or evolving or unstable neurologic disorder
13 Prior history of a suspected or actual acute life-threatening event
14 Known immunodeficiency, including human immunodeficiency virus (HIV)
15 Mother with HIV infection (unless the child has been proven to be not infected)
16 Any known allergy, including to immunoglobulin products, or history of allergic reaction
17 Receipt of palivizumab or other RSV mAb or any RSV vaccine, including maternal RSV
vaccination
18 Receipt of any monoclonal or polyclonal antibody (for example, hepatitis B immune
globulin, intravenous immunoglobulin) or anticipated use during the study
19 Any condition that, in the opinion of the investigator, would interfere with evaluation of
the study drug or interpretation of subject safety or study results
20 Concurrent enrollment in another interventional study
21 Children of employees of the sponsor, clinical study site, or any other individuals
involved with the conduct of the study, or immediate family members of such individuals
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is
obtained. Once informed consent is obtained, a subject identification (SID) number will be
assigned by a central system (eg, an interactive web response system [IWRS]), and the
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The
SID number will be used to identify the subject during the screening process and throughout
study participation, if applicable.
A master log of all consented subjects will be maintained at the site and will document all
screening failures (ie, subjects who are consented but do not meet study eligibility criteria
and/or are not randomized), including the reason(s) for screening failure.
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Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not be
randomized or administered study drug. The investigator must consult with the sponsor before
a subject who has failed screening may be considered for rescreening.
4.1.5
Withdrawal from the Study
Subjects may at any time be withdrawn from the study without prejudice to further treatment
(withdrawal of consent). The caregivers of such subjects will always be asked about the
reason(s) for withdrawal and the presence of any AEs. If possible, the subject will be seen and
assessed by the investigator. AEs will be followed up. If a subject withdraws from further
participation in the study, then no further study visits or data collection should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive additional doses of study drug, including continued
dosing in Season 2 for subjects with CLD/CHD, if any of the following occur in the subject in
question:
1
Withdrawal of consent
2
Hypersensitivity reaction assessed as related to study drug
Subjects who have received any study drug will be followed for protocol-specified
assessments including follow-up of any AEs unless consent is withdrawn specifically from
further study participation (Section 4.1.5) or the subject is lost to follow-up. Subjects who
have not received study drug, regardless of reason, will not be followed.
4.1.7
Replacement of Subjects
Subjects will not be replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
MedImmune ensures that biological samples are destroyed at the end of a specified period as
described in the informed consent.
If a subject withdraws consent to the use of donated biological samples, the samples will be
disposed of/destroyed, and the action documented. If samples are already analyzed,
MedImmune is not obliged to destroy the results of this research.
The Principal Investigator:

 Ensures subjects’ withdrawal of informed consent to the use of donated samples is
notified immediately to MedImmune.

 Ensures that biological samples from that subject, if stored at the study site, are
immediately identified, disposed of/destroyed, and the action documented.
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
Ensures the organization(s) holding the samples is/are informed about the withdrawn
consent immediately and that samples are disposed of/destroyed, the action documented,
and the signed document returned to the study site.

Ensures that the subject and MedImmune are informed about the sample disposal.
MedImmune ensures the organizations holding the samples is/are informed about the
withdrawn consent immediately and that samples are disposed of/destroyed and the action
documented and returned to the study site.
4.2
Schedule of Study Procedures
Whenever vital signs and blood draws are scheduled for the same nominal time, vital signs
should occur prior to blood draws.
4.2.1
Enrollment/Screening Period
Table 4 shows all procedures to be conducted at the screening visit.
Table 4
Schedule of Screening Procedures
Study Period
Visit Number
Procedure / Study Day
Written informed consent/ assignment of SID number
Medical history
Physical examination
Weight
Vital signs
Blood sample for PK, ADA, RSV neut Ab, and RSV serology a
Assessment of AEs/SAEs
Concomitant medications
Verify eligibility criteria
Screening
V1
Day -30 to Day 1
X
X
X
X
X
X
X
X
X
ADA = anti-drug antibody; AEs = adverse events; neut Ab = neutralizing antibody; PK = pharmacokinetic;
RSV = respiratory syncytial virus; SAEs = serious adverse events; SID = subject identification; V = visit.
Visit 1/Screening and Visit 2/Day 1 visits may occur on the same day.
a
If Visit 1/Screening and Visit 2/Day 1 do not occur on the same day, blood sample for PK, ADA, RSV
neut Ab, and RSV serology can be collected at either Visit 1/Screening or Visit 2/Day 1 predose.
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4.2.2
Treatment and Follow-up Periods
All procedures to be conducted during the treatment and follow-up periods are presented in
Table 5 for Season 1, preterm and CLD/CHD cohorts and Table 6 for Season 2, CLD/CHD
cohort only.
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Table 5
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Schedule of Treatment Period and Follow-up Period Study Procedures: Season 1, Preterm and CLD/CHD
Cohorts
Study Period
Treatment Period
Follow-up Period
Visit Number
V2 a
TC
V3
V4
V5
V6
V7
V8
V9 b
TC
LRTI
Skin
Reaction
Procedure /
Study Day
Medical history
update
Physical
examination
Weight
Vital signs
Blood sample for
PK, ADA, RSV
neut Ab, and RSV
serology d
Assessment of
AEs/SAEs, AESIs,
NOCDs
Concomitant
medications
Verify eligibility
criteria
Randomization g
Study drug
administration h
Assessment of LRTI
or any respiratory
infection that
requires
hospitalization
Nasal swab
collection
Assessment of skin
reaction
D8
D15
D31
D1
(± 2
(± 2
(± 2
days)
days)
days)
X
X
X
X
X
X
X
X
X
X c
X              X c
X
X e
(pre-
dose)
X
X
X
X
X
X
X
X
X
X
X
X
D61           D91          D121          D151
(± 2           (± 2           (± 2            (± 7
days)         days)         days)         days)
X
X
X
X
X
X
X
X
X               X               X                X
X c                X c                X c                  X
X
X
X
X
X
X
X
X
X
X
X
X
D361
D1-151
(± 7              Q2W
days)
(± 5 days)
X
X
X
X
X
X
X
X
X
D152-361
monthly
(± 5 days)
X
X
D1-361
as needed
X f
X
X
X f
X f
D1-361
as needed
X
X
X i
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X
MedImmune
MEDI8897
Table 5
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Schedule of Treatment Period and Follow-up Period Study Procedures: Season 1, Preterm and CLD/CHD
Cohorts
Study Period
Treatment Period
Follow-up Period
Visit Number
V2 a
TC
V3
V4
V5
V6
V7
V8
V9 b
TC
LRTI
Skin
Reaction
Procedure /
Study Day
Telephone
contact j
D8
D15
D31
D1
(± 2
(± 2
(± 2
days)
days)
days)
X
D61           D91          D121          D151
(± 2           (± 2           (± 2            (± 7
days)         days)         days)         days)
D361
D1-151
(± 7              Q2W
days)
(± 5 days)
X
D152-361
monthly
(± 5 days)
X
D1-361
as needed
D1-361
as needed
HRU and caregiver
burden k
ADA = anti-drug antibody; AEs = adverse events; AESIs = adverse events of special interest; CHD = congenital heart disease; CLD = chronic lung disease; D = study day; ER
= emergency room; HRU = healthcare resource utilization; ICU = intensive care unit; IM=intramuscular; LRTI = lower respiratory tract infection; neut Ab = neutralizing
antibody; NOCDs = new onset chronic diseases; OTC = over-the-counter; PK = pharmacokinetic; Q2W = once every 2 weeks; RSV = respiratory syncytial virus; SAEs =
serious adverse events; SID = subject identification; TC = telephone call; V = visit.
a
Visit 2/Day 1 and Visit 1/Screening can occur on the same day.
b
For subjects in the CLD/CHD cohort, the Season 1 Visit 9/Day 361 may be the same as the Season 2 Visit 10/Day 1 (Dose 1).
c
 All vital signs (temperature, blood pressure, heart rate, and respiratory rate) should be obtained within 60 minutes prior to dosing, and at 30 minutes (± 5 minutes) and
60 minutes (± 5 minutes) post dose.
d
Subjects requiring a replacement dose of study drug due to cardiac surgery with cardiopulmonary bypass will have a blood sample collected before and after surgery
(prior to administering replacement dose) for PK evaluation.
e
If Visit 1/Screening and Visit 2/Day 1 do not occur on the same day, blood sample for PK, ADA, RSV neut Ab, and RSV serology can be collected at either
Visit 1/Screening or Visit 2/Day 1 predose.
f
Nasal samples will be collected from all subjects with LRTIs (inpatient or outpatient) and from all hospitalized subjects with any new respiratory infection (upper or
lower) within approximately 2 days after the initial healthcare provider assessment and diagnosis.
Blood samples will be collected from all subjects hospitalized with LRTI or any respiratory infection within approximately 2 days following hospital admission.
g
Subjects in each cohort (preterm and CLD/CHD cohorts) will be randomized 2:1 to receive either MEDI8897 administered as a stratified dose by weight band, which
includes a single fixed 50-mg IM dose for infants weighing < 5 kg or 100-mg IM dose for infants weighing ≥ 5 kg, followed by 4 once-monthly IM doses of placebo; or
5 once-monthly IM doses of 15 mg/kg palivizumab.
h
Subjects who undergo cardiac surgery with cardiopulmonary bypass after receipt of Dose 1 but prior to receipt of Dose 5 will receive a replacement dose of the study drug
that they received for Dose 1 immediately following the surgery when determined by the physician to be medically stable for an IM injection. Any subsequent doses of
study drug will continue to be given according to the protocol-specified dosing schedule. See Section 3.1.2.3 for details.
i
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction regardless of severity, duration, time of onset post dosing, or relationship to study
drug.
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MEDI8897
Table 5
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Schedule of Treatment Period and Follow-up Period Study Procedures: Season 1, Preterm and CLD/CHD
Cohorts
Study Period
Treatment Period
Follow-up Period
Visit Number
V2 a
TC
V3
V4
V5
V6
V7
V8
V9 b
TC
LRTI
Skin
Reaction
Procedure /
Study Day
D8
D15
D31
D1
(± 2
(± 2
(± 2
days)
days)
days)
D61           D91          D121          D151
(± 2           (± 2           (± 2            (± 7
days)         days)         days)         days)
D361
D1-151
(± 7              Q2W
days)
(± 5 days)
D152-361
monthly
(± 5 days)
D1-361
as needed
D1-361
as needed
j
Telephone contact must be verbal communication. Written communication via text, email, or other written form is not acceptable.
k
 HRU includes admission and duration of hospital and ICU stay, number of subjects who require respiratory support and supplemental oxygen use, duration of respiratory
support and supplemental oxygen use, number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and number and days of prescription and OTC
medication. Caregiver burden includes days of worked missed by the parent(s)/legal representative or other household member as a result of the subject’s illness, and days
of daycare/babysitting missed by the subject as a result of illness.
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MEDI8897
Table 6
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Schedule of Treatment Period and Follow-up Period Study Procedures: Season 2, CLD/CHD Cohort Only
Study Period
Treatment Period
Follow-up Period
Visit Number
V10 a
TC
V11
V12
V13
V14
V15
V16
V17
TC
LRTI
Skin
Reaction
Replacement
Dose
Follow-up b
Procedure /
Study Day
Medical history
update
Physical
examination
Weight
Vital signs
Blood sample for
PK, ADA, RSV
neut Ab, and RSV
serology d
Assessment of
AEs/SAEs, AESIs,
NOCDs
Concomitant
medications
Randomization f
Study drug
administration g
D8
D15
D31
D1
(± 2
(± 2
(± 2
days)
days)
days)
X
X
X
X
X
X
X
X
X
X c
X             X c
X
(pre-
dose)
X
X
X
X
X
X
X
X
X
X
X
D61          D91
(± 2           (± 2
days)        days)
X
X
X
X
X
X
X c                X c
X
X
X
X
X
X
D121       D151
(± 2          (± 7
days)       days)
X
X
X
X
X             X
X c                X
X
X
X
X
X
X
D361
D1-151
(± 7           Q2W
days)
(± 5 days)
X
X
X
X
X
X
X
X
X
D152–361     D1-361
D1-361
monthly
as                as
(± 5 days)
needed
needed
X e
X
X
X
X
X
X
360 days
post last
replacement
dose
(± 7 days)
X
X
X
X
X
X
X
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MEDI8897
Table 6
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Schedule of Treatment Period and Follow-up Period Study Procedures: Season 2, CLD/CHD Cohort Only
Study Period
Treatment Period
Follow-up Period
Visit Number
V10 a
TC
V11
V12
V13
V14
V15
V16
V17
TC
LRTI
Skin
Reaction
Replacement
Dose
Follow-up b
Procedure /
Study Day
Assessment of LRTI
or any respiratory
infection that
requires
hospitalization
Nasal swab
collection
Assessment of skin
reaction
Telephone
contact i
HRU and caregiver
burden j
D8
D15
D31
D1
(± 2
(± 2
(± 2
days)
days)
days)
X
D61          D91
(± 2           (± 2
days)        days)
D121       D151
(± 2          (± 7
days)       days)
D361
D1-151
(± 7           Q2W
days)
(± 5 days)
X
D152–361     D1-361
D1-361
monthly
as                as
(± 5 days)
needed
needed
X e
X e
X h
X
X
360 days
post last
replacement
dose
(± 7 days)
ADA = anti-drug antibody; AEs = adverse events; AESIs = adverse events of special interest; CHD = congenital heart disease; CLD = chronic lung disease; D = study day;
ER = emergency room; HRU = healthcare resource utilization; ICU = intensive care unit; IM=intramuscular; LRTI = lower respiratory tract infection; neut Ab = neutralizing
antibody; NOCDs = new onset chronic diseases; OTC = over-the-counter; PK = pharmacokinetic; Q2W = once every 2 weeks; RSV = respiratory syncytial virus; SAEs =
serious adverse events; SID = subject identification; TC = telephone call; V = visit.
a
The Season 2 Visit 10/Day 1 (Dose 1) may be the same as the Season 1 Visit 9/Day 361.
b
Subjects who receive a replacement dose of study drug due to cardiac surgery with cardiopulmonary bypass will be followed for 360 days after the last replacement dose
with the same schedule for telephone calls and a final visit 360 days post the last replacement dose.
c
 All vital signs (temperature, blood pressure, heart rate, and respiratory rate) should be obtained within 60 minutes prior to dosing, and at 30 minutes (± 5 minutes) and
60 minutes (± 5 minutes) post dose.
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MEDI8897
Table 6
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Schedule of Treatment Period and Follow-up Period Study Procedures: Season 2, CLD/CHD Cohort Only
Study Period
Treatment Period
Follow-up Period
Visit Number
V10 a
TC
V11
V12
V13
V14
V15
V16
V17
TC
LRTI
Skin
Reaction
Replacement
Dose
Follow-up b
Procedure /
Study Day
D8
D15
D31
D1
(± 2
(± 2
(± 2
days)
days)
days)
D61          D91
(± 2           (± 2
days)        days)
D121       D151
(± 2          (± 7
days)       days)
D361
D1-151
(± 7           Q2W
days)
(± 5 days)
D152–361     D1-361
D1-361
monthly
as                as
(± 5 days)
needed
needed
360 days
post last
replacement
dose
(± 7 days)
d
 Subjects requiring a replacement dose of study drug due to cardiac surgery with cardiopulmonary bypass will have a blood sample collected before and after surgery (prior
to administering replacement dose) for PK evaluation.
e
 Nasal samples will be collected from all subjects with LRTIs (inpatient or outpatient) and from all hospitalized subjects with any new respiratory infection (upper or lower)
within approximately 2 days after the initial healthcare provider assessment and diagnosis.
Blood samples will be collected from all subjects hospitalized with LRTI or any respiratory infection within approximately 2 days following hospital admission.
f
Subjects who were randomized to receive MEDI8897 for Season 1 will receive a single 200-mg IM dose of MEDI8897 followed by 4 once-monthly IM doses of placebo
for Season 2. Subjects who were randomized to receive palivizumab for Season 1 will be re-randomized 1:1 to receive a single 200-mg IM dose of MEDI8897 followed by
4 once-monthly IM doses of placebo, or 5 once-monthly IM doses of 15 mg/kg palivizumab for Season 2.
g
 Subjects who undergo cardiac surgery with cardiopulmonary bypass after receipt of Dose 1 but prior to receipt of Dose 5 will receive a replacement dose of the study drug
that they received for Dose 1 immediately following the surgery when determined by the physician to be medically stable for an IM injection. Any subsequent doses of
study drug will continue to be given according to the protocol-specified dosing schedule. See Section 3.1.2.3 for details.
h
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction regardless of severity, duration, time of onset post dosing, or relationship to study
drug.
i
Telephone contact must be verbal communication. Written communication via text, email, or other written form is not acceptable.
j
 HRU includes admission and duration of hospital and ICU stay, number of subjects who require respiratory support and supplemental oxygen use, duration of respiratory
support and supplemental oxygen use, number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and number and days of prescription and OTC
medication. Caregiver burden includes days of worked missed by the parent(s)/legal representative or other household member as a result of the subject’s illness, and days
of daycare/babysitting missed by the subject as a result of illness.
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MEDI8897
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
4.3
4.3.1
4.3.1.1
Description of Study Procedures
Efficacy
Lower Respiratory Tract Infection
Subjects will be monitored throughout the study for LRTI (see Table 5 and Table 6). All
subjects seeking medical attention for a respiratory illness (in either the inpatient or outpatient
setting) will be evaluated for LRTI. All subjects found to have an LRTI and all subjects who
require hospitalization for a respiratory infection, even if there is not a diagnosis of LRTI,
should have respiratory samples obtained and respiratory assessment forms completed.
Samples should be collected for all of these respiratory events even those not meeting the
protocol definition of LRTI. Subjects who have a primary hospitalization for a respiratory
infection (ie, upper or lower tract) or a respiratory deterioration during a hospitalization, or
who seek outpatient medical attention (including ER visits) for a lower respiratory illness, will
be assessed clinically for the presence of LRTI and for RSV by central laboratory diagnostic
testing of respiratory secretions. Testing for RSV will be performed using the US FDA-cleared
and CE-marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV + human
metapneumovirus [hMPV] assay; Quidel Corporation, San Diego, CA, www.quidel.com; see
Section 4.3.1.2). A diagnosis of RSV LRTI requires having a respiratory sample positive for
RSV by the central laboratory RT-PCR assay.
In addition to the clinical assessment of LRTI, there is a protocol definition using objective
criteria for the determination of a medically attended protocol-defined LRTI.
For subjects with no underlying lung disease:
To meet the protocol-defined endpoint of medically attended RSV LRTI, subjects with signs
of LRTI must have documented at least one physical examination finding of rhonchi, rales,
crackles, or wheeze AND at least one of the following clinical signs (see Table 7):

Increased respiratory rate at rest (age: < 2 months, ≥ 60 breaths/min; 2 to 6 months,
≥ 50 breaths/min; > 6 months, ≥ 40 breaths/min), OR

Hypoxemia (in room air: oxygen saturation < 95% at altitudes ≤ 1,800 meters or < 92% at
altitudes > 1,800 meters), OR

 Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new
onset apnea, nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting)
or dehydration secondary to inadequate oral intake due to respiratory distress (need for
intravenous fluid).
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MEDI8897
Table 7
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Criteria for Meeting the Protocol-defined Endpoint of Medically
Attended RSV LRTI - Subjects Without Underlying Lung Disease
RSV
RSV Confirmed:
Lower Respiratory Tract
Documented physical
Medical Significance
Objective measures of clinical severity:
•
Positive by central
laboratory real-time
RT-PCR assay
examination findings localizing
to lower respiratory tract:
•
Rhonchi
•
Rales
•
Crackles
•
Wheeze
•
Increased respiratory rate
•
Hypoxemia
•
Acute hypoxic or ventilatory failure
•
New onset apnea
•
Nasal flaring
•
Retractions
•
Grunting
•
 Dehydration due to respiratory
distress
LRTI = lower respiratory tract infection; RSV = respiratory syncytial virus; RT-PCR = reverse transcriptase-
polymerase chain reaction.
Note: One item from each column is required to meet the protocol-defined endpoint of medically attended
RSV LRTI.
For subjects with underlying lung disease (CLD or CHD):
To meet the protocol-defined endpoint of medically attended RSV LRTI, subjects with signs
of LRTI must have documented at least one new or worsened physical examination finding of
rhonchi, rales, crackles, or wheeze AND at least one of the following clinical signs (see
Table 8):

 Increase in baseline respiratory rate by ≥ 20% at rest and that rate is greater than the
age-based criteria established for children with no underlying lung disease
(age: < 2 months, ≥ 60 breaths/min; 2 to 6 months, ≥ 50 breaths/min; > 6 months,
≥ 40 breaths/min), OR

Hypoxemia (O2 saturation < 95% in room air or O2 saturation drop of 5 percentage points
from baseline in children with baseline O2 saturation < 95% in room air, or acute
documented need for supplemental O2 or increased O2 requirement compared with
baseline), OR

Clinical signs of severe respiratory disease (eg, acute hypoxic or ventilatory failure, new
onset apnea, nasal flaring, intercostal, subcostal or supraclavicular retractions, grunting)
or dehydration secondary to inadequate oral intake due to respiratory distress (need for
intravenous fluid), OR

 Prescription of new or increased (from baseline) dose of medications including
bronchodilators, steroids, diuretics, cardiac medications
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MEDI8897
Table 8
Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Criteria for Meeting the Protocol-defined Endpoint of Medically
Attended RSV LRTI – Subjects With Underlying Lung Disease (CLD
or CHD)
RSV
RSV Confirmed:
Lower Respiratory Tract
Documented new or worsened
Medical Significance
Objective measures of clinical severity:
•
Positive by central
laboratory real-time
RT-PCR assay
physical examination findings
localizing to lower respiratory
tract:
•
Increased respiratory rate (from
baseline)
•
Hypoxemia
•
Rhonchi
•
Rales
•
Crackles
•
Wheeze
•
Acute hypoxic or ventilatory failure
•
New onset apnea
•
Nasal flaring
•
Retractions
•
Grunting
•
 Dehydration due to respiratory
distress
•
Prescription of new or increased
(from baseline) dose of medications
including bronchodilators, steroids,
diuretics, cardiac medication
CHD = congenital heart disease; CLD = chronic lung disease; LRTI = lower respiratory tract infection; PE =
physical examination; RSV = respiratory syncytial virus; RT-PCR = reverse transcriptase-polymerase chain
reaction.
Note: One item from each column is required to meet the protocol-defined endpoint of medically attended
RSV LRTI.
RSV Hospitalization
An RSV hospitalization is defined as either (1) a respiratory hospitalization with a positive
RSV test within approximately 2 days of hospital admission (primary) or (2) a new onset of
respiratory symptoms in an already hospitalized subject, with an objective measure of
worsening respiratory status and positive RSV test (nosocomial). Primary and nosocomial
RSV hospitalization are further defined below.
Primary RSV Hospitalization
RSV diagnostic testing will be performed on respiratory secretions obtained within
approximately 2 days before or after admission for subjects hospitalized for any respiratory
infection (upper or lower respiratory tract). If the RSV diagnostic test (performed centrally via
RT-PCR) is positive, the hospitalization will be classified as a primary RSV hospitalization.
Deaths that can be demonstrated as caused by RSV (by autopsy or clinical history and
virologic evidence) will also be considered as primary RSV hospitalization endpoints.
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Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
Nosocomial RSV Hospitalization
Subjects hospitalized for a respiratory illness or non-respiratory illness whose RSV diagnostic
test is negative may develop nosocomial RSV illness during the study.
If signs (such as retractions, rhonchi, wheezing, crackles or rales) of a new lower respiratory
illness occur during a hospitalization, whatever the reason for hospitalization, and there is an
objective measure of worsening respiratory status (that is, new requirement for supplemental
oxygen, increase in supplemental oxygen requirement from prior to the onset of symptoms, or
need for new or additional mechanical ventilation), a specimen will be collected within
approximately 2 days from worsening of respiratory status for RSV diagnostic testing by the
central laboratory. For any subject who is hospitalized for a respiratory infection (upper or
lower respiratory tract), the subject must return to his/her baseline respiratory status or be
clearly resolving the preceding respiratory illness before a subsequent respiratory deterioration
for a nosocomial RSV hospitalization event can be determined.
If the RSV diagnostic test (performed centrally via RT-PCR) is positive, the subsequent
hospital days will count as a nosocomial RSV hospitalization. The days of RSV
hospitalization will be counted beginning with the start of the respiratory deterioration that
resulted in the RSV diagnostic test.
RSV LRTI Outpatient Events
Subjects who seek outpatient medical attention, including ER and urgent care visits, for an
LRTI should have respiratory secretions obtained within approximately 2 days after the initial
healthcare provider assessment.
4.3.1.2
Respiratory Secretions for RSV Detection
Respiratory secretions for RSV testing must be collected from all subjects with LRTIs
(inpatient or outpatient) and from all hospitalized subjects with any new respiratory infection
(upper or lower) within approximately 2 days after the initial healthcare provider assessment
and diagnosis. Nasal secretions will be obtained unless the subject is intubated, and then
tracheal secretions may be obtained.
Respiratory secretions will be tested in a central laboratory for RSV using the US FDA-
cleared and CE-marked in vitro diagnostic real-time RT-PCR assay (Lyra RSV + hMPV
assay; Quidel Corporation, San Diego, CA, www.quidel.com). Testing may include other
respiratory pathogens.
4.3.1.3
Monitoring for RSV Resistance
As an exploratory endpoint, novel RSV F variants identified in RSV-positive nasal specimens
(based on the RSV diagnostic test results; Section 4.3.1.2) from all subjects will be evaluated
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MEDI8897
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31Mar2021; Final
by genotypic and phenotypic methods to monitor potential susceptibility changes to
MEDI8897 and palivizumab neutralization. The subtype and genotypic determination of RSV
will be performed directly on the nasal specimens that are collected from all subjects who are
confirmed RSV-positive using the Lyra RSV + hMPV real-time RT-PCR assay manufactured
by Quidel Corporation (Lyra RSV + hMPV assay; Quidel Corporation, San Diego CA,
www.quidel.com). The full-length F gene will be amplified using a standard, single-tube
population-based RT-PCR method and sequenced by Sanger sequencing methodology. Amino
acid substitution(s) within the MEDI8897 binding site (amino acid [aa] 62-69 and aa 196-212)
and outside the binding site in the extracellular regions of mature F protein (aa 24-109 and
aa 137-524) will be reported and compared to F protein sequences of contemporary reference
RSV strains. In vitro phenotypic analysis (susceptibility to MEDI8897 and palivizumab
neutralization) will be attempted using an RSV neutralization assay with either RSV viruses
constructed through site-directed mutagenesis of the F gene and reverse genetics or by cloning
the F gene from the isolate into a laboratory-adapted RSV strain such as A2 or B9320.
4.3.2
Medical History and Physical Examination, Weight, and Vital Signs
A complete medical history will be obtained at screening and a medical history update will be
obtained during the treatment and follow-up period as defined in Section 4.2. Assessment will
include history and current medical conditions, past or present cardiovascular disorders,
respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, hematologic,
immunologic, dermatological, genitourinary, drug and surgical history, or any other diseases
or disorders.
A physical examination, including weight, will be performed at screening and during the
treatment and follow-up period as defined in Section 4.2.
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) will be collected at
screening and during the treatment and follow-up period as defined in Section 4.2. On days
when study drug is administered, vital signs will be obtained within 60 minutes prior to
dosing, and at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post dose.
Baseline information will be collected on breastfeeding, smoking in the household, and if the
infant attends day care.
4.3.3
Pharmacokinetic Evaluation and Methods
A Laboratory Manual will be provided to the sites that specifies the procedures for collection,
processing, storage, and shipment of samples, as well as laboratory contact information,
specific to this clinical research study.
Blood samples will be collected to evaluate PK of MEDI8897 and palivizumab in serum (see
Section 4.2.2 for collection time points). Subjects in the CLD/CHD cohort requiring a
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Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
replacement dose of study drug due to cardiac surgery with cardiopulmonary bypass will have
a blood sample collected before and after surgery (prior to administering replacement dose) to
evaluate serum concentration of MEDI8897 or palivizumab. The PK of MEDI8897 and
palivizumab will be measured utilizing validated assays.
4.3.4
Anti-drug Antibody Evaluation and Methods
Blood samples will be collected to evaluate ADA responses to MEDI8897 and palivizumab in
serum (see Section 4.2.2 for collection time points). Evaluation will be performed using
validated immunoassays. Tiered analyses will be performed to include screening,
confirmatory, and titer assay components, and the positive-negative cut points will be
statistically determined from drug-naive validation samples. Samples will be utilized for
further characterization of the ADA response, including ADA to the YTE domain on
MEDI8897 and the assessment of neutralizing antibody to MEDI8897 or palivizumab.
4.3.5
4.3.5.1
RSV-neutralizing Antibody and RSV Serology Evaluations and
Methods
RSV Neutralizing Antibody
Blood samples will be collected to evaluate anti-RSV neutralizing antibody levels in
serum (see Section 4.2.2 for collection time points). Analyses will be performed
using an RSV neutralizing antibody assay previously described by Shambaugh et al
(Shambaugh et al, 2017).
4.3.5.2
RSV Serology
Blood samples will be collected to measure RSV antigen-specific antibody levels in serum
(see Section 4.2.2 for collection time points). Evaluations will be performed using a validated
immunoassay similar to the assay described by Maifeld et al (Maifeld et al, 2016).
4.3.6
Healthcare Resource Utilization and Caregiver Burden
Information on HRU and caregiver burden will be collected for all events of medically
attended LRTI (see Table 5 and Table 6). This will include admission to and duration of
hospital and intensive care unit (ICU) stay, number of subjects who require respiratory
support and supplemental oxygen use, duration of respiratory support and supplemental
oxygen use, number and type of outpatient visits (eg, ER, urgent care, outpatient clinic), and
the number of prescription and over-the-counter (OTC) medications and their duration of use.
Caregiver burden will be assessed through, for example, caregiver missed work days and the
subject’s absence from day care.
4.3.7
Skin Reactions
Skin reaction assessment will be done for any post-dosing skin or skin-related reaction to
assist in determination of the etiology of the reaction (see Table 5 and Table 6). Information
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Protocol D5290C00005 (MEDLEY) Amendment 1
31Mar2021; Final
will be collected regardless of event severity, duration, time of onset post dosing, or
relationship to investigational product. Parents/legal representatives of study subjects will be
given a hypersensitivity card and instructed to call the study site immediately for signs of
hypersensitivity or allergic reaction. Sites must notify MedImmune within 24 hours of
knowledge of such events. For any skin or skin-related reactions, including all rashes that
occur within 7 days after dosing, the child will be brought to the study site as soon as possible
for evaluation.
4.3.8
Estimate of Volume of Blood to be Collected
Blood volume estimates are provided by visit/study day for Season 1 (Table 9) and Season 2
(Table 10).
Table 9
Volume of Blood to be Collected, Season 1
Visit/Study Day
Visit 1/Screening or Visit 2/Day 1
Visit 4 /Day 31
Visit 8/Day 151
Visit 9/Day 361
Total
Estimated Blood Volume (mL)
1.5 mL
1.5 mL
1.5 mL
1.5 mL
6.0 mL
Table 10
Volume of Blood to be Collected, Season 2
Visit/Study Day
Visit 12/Day 31
Visit 16/Day 151
Visit 17/Day 361
Total
Estimated Blood Volume (mL)
1.5 mL
1.5 mL
1.5 mL
4.5 mL
4.4
Study or Study Component Suspension or Termination
MedImmune reserves the right to temporarily suspend or permanently terminate this study or
component of the study at any time. The reasons for temporarily suspending or permanently
terminating the study may include but are not limited to the following:
1
Death in any subject in which the cause of death is assessed as related to investigational
product (in this case the study will be paused for the sponsor safety review committee to
evaluate the events)
2
Anaphylactic reaction that is related to investigational product (see Appendix B for a
definition of anaphylaxis; in this case the study will be paused for the sponsor safety
review committee to evaluate the events)
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Identification of Investigational Products
Investigational Product
Palivizumab
Manufacturer
AstraZeneca
Concentration and Formulation as Supplied
Supplied as 50 mg (nominal) per vial solution. The
solution contains 100 mg/mL palivizumab, 25 mM
Histidine, 1.6 mM glycine, 12.5 mM chloride, pH 6.0.
The nominal fill volume is 0.5 mL.
HCl = hydrochloride; w/v = weight/volume.
MEDI8897 and palivizumab will be supplied to the site in open-labeled kits. Each kit has a
unique number printed on all labels within the kit (ie, the outer carton label and the label of
each vial).
4.5.1.1
Investigational Product Inspection
Each vial selected for dose administration should be inspected. Refer to Table 11 for
identification of investigational product.
If there are any defects noted with the investigational product, the investigator and site
monitor should be notified immediately. Refer to the Product Complaint section
(Section 4.5.1.4) for further instructions.
4.5.1.2
Dose Preparation Steps and Treatment Administration
The first day of dosing is considered Day 1.
Study drug (MEDI8897, placebo, and palivizumab) will be supplied by an unblinded
investigational product manager. Blinding will be performed at the site level to ensure that
MEDI8897, placebo, and palivizumab are indistinguishable in appearance and are not labeled
to reveal treatment identity.
No incompatibilities between MEDI8897 or palivizumab and polycarbonate or polypropylene
syringes have been observed.
MEDI8897 and palivizumab do not contain preservatives and any unused portion must be
discarded. Total in-use storage time from needle puncture of the study drug vial to
administration should not exceed 4 hours at room temperature. If storage time exceeds these
limits, a new vial should be used.
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MEDI8897 group: Season 1 and Season 2, including replacement dose(s) after
cardiopulmonary bypass
Subjects will receive MEDI8897 for Dose 1 and placebo for Doses 2 through 5:
1
Season 1
(a) Infants < 5 kg body weight at time of dosing:
o Dose 1: A dose of 50 mg (ie, 0.5 mL) MEDI8897 will be obtained by
withdrawing the entire contents of 1 investigational vial with an appropriately
sized syringe, and administered as one single (ie, 0.5 mL) injection
o Doses 2 through 5: A corresponding volume (0.5 mL) of saline will be obtained,
and administered as one single (ie, 0.5 mL) injection
(b) Infants ≥ 5 kg body weight at time of dosing:
o Dose 1: A dose of 100 mg (ie, 1.0 mL) MEDI8897 will be obtained by
withdrawing the entire contents of 2 investigational vials
o Doses 2 through 5: A corresponding volume (1.0 mL) of saline will be
administered
o To maintain the blind:
 If the weight is ≥ 5 kg to < 6.7 kg then the dose should be administered as
one single (ie, 1.0 mL) injection
 If the weight is ≥ 6.7 kg, then the volume of MEDI8897 or saline should be
divided equally into 2 syringes
2
Season 2
o Dose 1: A dose of 200 mg (ie, 2.0 mL) MEDI8897 will be obtained by withdrawing
the entire contents of 4 investigational vials
o Doses 2 through 5: A corresponding volume (2.0 mL) of saline will be administered
o To maintain the blind:
 If the weight is < 13.4 kg, then the dose should be administered as two 1.0 mL
injections (ie, 1.0 mL per injection)
 If the weight is ≥ 13.4 kg, then the volume of MEDI8897 or saline should be
divided equally into 3 syringes
3
Replacement dose(s) after cardiopulmonary bypass
Season 1
(a) Cardiopulmonary bypass < 90 days post first dose of MEDI8897 (or most recent
replacement dose if previous cardiopulmonary bypass) for infants < 5 kg:
o Replacement dose: A dose of 50 mg (ie, 0.5 mL) MEDI8897 will be obtained by
withdrawing the entire contents of 1 investigational vial with an appropriately
sized syringe, and administered as one single (ie, 0.5 mL) injection
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(b) Cardiopulmonary bypass < 90 days post first dose of MEDI8897 (or most recent
replacement dose if previous cardiopulmonary bypass) for infants ≥ 5 kg:
o Replacement dose: A dose of 100 mg (ie, 1.0 mL) MEDI8897 will be obtained
by withdrawing the entire contents of 2 investigational vials
o To maintain the blind:
 If the weight is ≥ 5 kg to < 6.7 kg then the dose should be administered as one
single (ie, 1.0 mL) injection
 If the weight is ≥ 6.7 kg, then the volume of MEDI8897 should be divided
equally into 2 syringes
(c) Cardiopulmonary bypass ≥ 90 days post first dose (or most recent replacement dose
if previous cardiopulmonary bypass) for all weights:
o Replacement dose: A dose of 50 mg (ie, 0.5 mL) MEDI8897 will be obtained by
withdrawing the entire contents of 1 investigational vial with an appropriately
sized syringe, and administered as one single (ie, 0.5 mL) injection
Season 2
(a) Cardiopulmonary bypass < 90 days post first dose:
o Replacement dose: A dose of 200 mg (ie, 2.0 mL) MEDI8897 will be obtained
by withdrawing the entire contents of 4 investigational vials
o To maintain the blind:
 If the weight is < 13.4 kg, then the dose should be administered as two 1.0 mL
injections (ie, 1.0 mL per injection)
 If the weight is ≥ 13.4 kg, then the volume of MEDI8897 should be divided
equally into 3 syringes
(b) Cardiopulmonary bypass ≥ 90 days post first dose (or most recent replacement dose
if previous cardiopulmonary bypass):
o Replacement dose: A dose of 100 mg (ie, 1.0 mL) MEDI8897 will be obtained
by withdrawing the entire contents of 2 investigational vials
o To maintain the blind:
 If the weight is ≥ 5 kg to < 6.7 kg then the dose should be administered as one
single (ie, 1.0 mL) injection
 If the weight is ≥ 6.7 kg, then the volume of MEDI8897 should be divided
equally into 2 syringes
4
Switch the needle prior to administration
5
 MEDI8897 or placebo (saline) should be administered in the anterolateral aspect of the
thigh according to standard practice procedures for IM injections. The injection should be
given using standard aseptic technique. When possible, injection sites for subsequent
injections should use alternating sites (eg, right then left thigh). The maximum volume to
be administered with each injection is 1.0 mL
6
MEDI8897 or placebo (saline) should be administered using the appropriate size needle
ranging from 22 to 25 gauge and 5/8 to 1.0 inches based on muscle size and weight of the
subject
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Palivizumab group: Season 1 and Season 2, including replacement dose(s) after
cardiopulmonary bypass
1
 A dose of 15 mg/kg palivizumab will be obtained by withdrawing the calculated volume
of drug to the nearest 0.01 mL as described below:
The dose of palivizumab will be calculated based on the subject’s weight (to the nearest
0.01 kg) using the following formula:
Dose (mL) = [subject weight (kg) × dose level (15 mg/kg)] ÷
palivizumab concentration (100 mg/mL)
The corresponding volume of palivizumab should be rounded to the nearest 0.01 mL.
Examples:
A patient who weighs 4.90 kg at the time of injection receives 0.74 mL of study drug
(4.90 kg x 15 mg/kg) ÷ 100 mg/mL = 0.735 mL (rounded to 0.74 mL)
A patient who weighs 3.70 kg at the time of injection receives 0.56 mL of study drug
(3.70 kg x 15 mg/kg) ÷ 100 mg/mL = 0.555 mL (rounded to 0.56 mL)
2
Switch the needle prior to administration
3
Palivizumab should be administered in the anterolateral aspect of the thigh according to
standard practice procedures for IM injections. The injection should be given using
standard aseptic technique. When possible, injection sites for subsequent injections
should use alternating sites (eg, right then left thigh). The maximum volume to be
administered with each injection is 1 mL
4
Palivizumab should be administered using the appropriate size needle ranging from 22 to
25 gauge and 5/8 to 1.0 inches based on muscle size and weight of the subject
4.5.1.3
Monitoring of Dose Administration
Subjects will be monitored before and after investigational product administration through
assessment of vital signs (temperature, blood pressure, heart rate, and respiratory rate). All
vital signs should be obtained within 60 minutes prior to dosing, and at 30 minutes
(± 5 minutes) and 60 minutes (± 5 minutes) post dose.
As with any biologic product, allergic reactions to dose administration are possible. Therefore,
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be
immediately available, and study personnel must be trained to recognize and treat
anaphylaxis.
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4.5.1.4
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the MedImmune
Product Complaint Department by the site with further notification to the site monitor. All
defects will be communicated to MedImmune and investigated further with the Product
Complaint Department. During the investigation of the product complaint, all investigational
product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email:
Phone:
Mail:
MedImmune
Attn: Product Complaint Department
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good
Manufacturing Practice and local regulatory guidelines. Label text will be translated into local
languages, as required.
4.5.4
Storage
Store MEDI8897 and palivizumab at 2°C to 8°C. Placebo (saline) should be stored according
to the manufacturer instructions.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain
accurate investigational product accountability records. Upon completion of the study, copies
of investigational product accountability records will be returned to MedImmune. All unused
MEDI8897 and palivizumab will be returned to a MedImmune-authorized depot or disposed
of upon authorization by MedImmune.
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4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IWRS will be used for randomization to a treatment group and assignment of blinded
investigational product kit numbers. A subject is considered randomized into the study when
the investigator notifies the IWRS that the subject meets eligibility criteria and the IWRS
provides the assignment of blinded investigational product kit numbers to the subject.
In Season 1, subjects in the preterm and CLD/CHD cohorts will be randomized using a
2:1 ratio to either the MEDI8897 group or palivizumab group. Within each cohort, the
randomization will be stratified by hemisphere (northern, southern) and subject age at the time
of Season 1 randomization (≤ 3 months, > 3 to ≤ 6 months, > 6 months).
In Season 2, subjects in the CLD/CHD cohort only will be randomized. Subjects who were
randomized to the MEDI8897 group in Season 1 will remain in the MEDI8897 group.
Subjects who were randomized to the CLD/CHD group in Season 1 will be re-randomized
using a 1:1 ratio to either the MEDI8897 or palivizumab group.
Study drug (MEDI8897, placebo, or palivizumab) must be administered the same day the
study drug is assigned. If there is a delay in the administration of study drug such that it will
not be administered within the specified timeframe, the unblinded investigational product
monitor must be notified immediately.
4.6.2
Methods to Ensure Blinding
This is a double-blind study in which MedImmune will provide sites with MEDI8897 and
palivizumab. Sites will use commercially available saline as the placebo. Syringe barrels will
be covered by the unblinded investigational product manager. Neither the subject/legal
representative nor the investigator or any of the site staff who are involved in the treatment or
clinical evaluation of the subjects will be aware of the treatment received (ICH E9). In the
event that treatment allocation for a subject becomes known to the investigator or other
blinded study staff involved in the management of study subjects, the sponsor must be notified
immediately. If the treatment allocation for a subject needs to be known to treat an individual
subject for an AE, the investigator must notify the sponsor immediately. The site will maintain
a written plan detailing which staff members are blinded/unblinded and the process of
investigational product administration used to maintain the blind.
4.6.3
4.6.3.1
Methods for Unblinding
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s
investigational product allocation. Instructions for unblinding an individual subject’s study
drug allocation are contained in the IWRS manual. In general, unblinding should only occur if
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management of the medical emergency would be different based on the subject having
received study drug. In the majority of cases, the management of a medical emergency would
be the same whether or not study drug was received by the subject. If this was the case, the
study drug allocation should not be unblinded. In the event there is unblinding, the
investigator should promptly document and explain to MedImmune the reason for any
premature unblinding.
MedImmune retains the right to unblind the treatment allocation for SAEs that are unexpected
and are suspected to be causally related to a study drug and that potentially require expedited
reporting to regulatory authorities.
If a subject’s study drug allocation is unblinded to the blinded staff or blinded
MedImmune/contract research organization study team, the subject should be discontinued
from study drug.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the
time of screening until the final study visit. Any concomitant medication(s), including herbal
preparations, taken during the study will be recorded in the electronic case report form
(eCRF).
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to
provide adequate supportive care including routine vitamins and iron. 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.
4.7.2
Prohibited Concomitant Medications
Use of concomitant medications including over-the-counter medications (except for routine
vitamins and iron), herbal supplements, etc from Day 1 through Day 15 post dose is
discouraged. Subject’s legal representative must be instructed not to administer any
medications, including over-the-counter products, without first consulting with the
investigator.
4.8
Statistical Evaluation
4.8.1
General Considerations
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
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summarized by descriptive statistics. Additional details of statistical analyses will be
described in the statistical analysis plan.
The Intent-to-treat (ITT) Population is defined as all randomized subjects, analyzed according
to randomized treatment assignment. All efficacy analyses will be performed on the ITT
Population.
The As-treated Population (ATP) is defined as all subjects who receive any investigational
product, analyzed according to treatment received. All analyses, with the exception of
efficacy, will be performed on the ATP unless otherwise specified.
A primary analysis, Season 2 analysis, and final analysis are planned for the study. The
primary analysis will be conducted after all randomized subjects have completed follow-up
through the first 5-month RSV season (ie, Season 1 Day 151 visit) and include all available
Season 1 safety, efficacy, PK, and ADA data at the time of the data cutoff. Season 2 analysis
will be conducted after all the CLD/CHD subjects have completed follow-up through the
second 5-month RSV season (ie, Season 2 Day 151 visit) and include all available Season 1
data and Season 2 safety, efficacy, PK, and ADA data at the time of the data cutoff. The final
analysis will be conducted when all subjects have completed the last visit of the study and
include all data collected in the study.
At the time of the primary analysis, the Season 1 data will be unblinded to the
Sponsor/designated clinical research organization associated with the analysis, write-up, and
regulatory submission.
To ensure the blinding of Season 2 treatment assignment for CLD/CHD subjects who were
randomized to the palivizumab arm in Season 1, any data with potential unblinding risk will
be split by Season 1 and Season 2 by the corresponding third party data vendors and when the
primary database lock occurs, only unblinding data from Season 1 will be transferred to the
Sponsor for analysis.
The site personnel, participants, and the study team members who participate in the advice or
decisions involving study subjects and/or day-to-day interactions with the site, will remain
blinded until the end of the study to ensure the trial integrity is maintained. Further details will
be specified in the unblinding plan prior to database lock for the primary analysis.
4.8.2
Sample Size
With respect to safety, 600 subjects exposed to MEDI8897 in Season 1 will provide a
95% probability of observing at least one AE if the true event rate is 0.5%; if no AEs are
observed, this study provides 95% confidence that the true event rate is < 0.5%. The sample
size is for safety consideration.
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With respect to efficacy, approximately 600 subjects will be exposed to MEDI8897 and 300
subjects will be exposed to palivizumab in Season 1 to observe numerically similar efficacy
for both mAbs. Because of the reduced incidence of RSV disease in this population following
the introduction of palivizumab, a superiority or non-inferiority design is not practical. A valid
non-inferiority margin cannot be established due to the lack of historical efficacy data for the
medically attended RSV LRTI endpoint for palivizumab. Therefore, there is no hypothesis
testing for efficacy. Using an assumption of a 6% RSV LRTI rate in palivizumab recipients,
approximately 18 events will be observed in that group. The 6% RSV LRTI rate (1.9% RSV
hospitalizations and 3.9% outpatient RSV illness) was based on a prior study in preterm
infants with and without CLD who received palivizumab (Carbonell-Estrany et al, 2010).
Assuming a 6% rate of RSV LRTI in MEDI8897 recipients, 600 MEDI8897 subjects in
Season 1 will provide approximately 36 events in that group. However, because of the largely
reduced RSV circulation due to COVID-19 pandemic-related measures, the observed event
rates could be much lower. Only summaries will be provided for efficacy unless specified
otherwise.
4.8.3
4.8.3.1
Safety
Analysis of Adverse Events
AEs will be graded according to the current version of the NCI CTCAE where applicable for
pediatric assessments. AEs will be coded by the Medical Dictionary for Regulatory Activities
and the type, incidence, severity, and relationship to study drug will be summarized by
treatment group. Other safety assessments will include the occurrence of AESIs defined as
AEs of hypersensitivity to study drug (including anaphylaxis), thrombocytopenia, and
immune complex disease (eg, vasculitis, endocarditis, neuritis, glomerulonephritis) following
study drug administration, and the occurrence of NOCDs following study drug administration.
Safety of MEDI8897 will be summarized by treatment group based on the ATP. The safety
summary will be provided for each season, as well as for the 2 consecutive RSV seasons
(ie, Season 1 and Season 2). For the Season 1 summary, the analysis dataset will include
subjects from the preterm cohort and CLD/CHD cohort, presented by the treatment received
in Season 1; for the Season 2 summary and the 2 consecutive-season summary, the analysis
dataset will include subjects from the CLD/CHD cohort, presented by the treatment received
through the 2 seasons.
4.8.4
Efficacy
The primary efficacy endpoint is the incidence of medically attended RSV LRTI (inpatient
and outpatient) through 150 days post Dose 1 (ie, during a typical 5-month RSV season) in
Season 1. The determination of the primary efficacy endpoint will be based on RSV test
results (performed centrally using real-time RT-PCR; see Section 4.3.1.2) and objective
protocol-defined LRTI criteria (see Table 7 and Table 8), and will be summarized by Season 1
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treatment group for all 900 subjects. The 95% CI of the percentage of subjects meeting the
primary efficacy endpoint will be presented by treatment group. For subjects with multiple
medically attended RSV LRTI events, only the first occurrence will be used in the primary
efficacy summary.
In addition, the summary of incidence of RSV LRTI through 150 days post Dose 1 in
Season 2 will be provided for the 300 subjects in the CLD/CHD cohort based on the treatment
assignments through Season 1 and Season 2: ie, (a) 50 mg MEDI8897 for infants with body
weight < 5 kg and 100 mg MEDI8897 for infants with body weight ≥ 5 kg (Season 1)/200 mg
MEDI8897 (Season 2), (b) palivizumab (Season 1)/200 mg MEDI8897 (Season 2), and
(c) palivizumab (Season 1)/palivizumab (Season 2).
The incidence of RSV hospitalization through 150 days after dosing (ie, during the 5-month
RSV season) will be summarized by treatment group using a similar strategy as described
above for RSV LRTI.
Additional analyses will include summarizing RSV-positive LRTI endpoints using results
from either the central laboratory or local laboratory.
All efficacy summaries will be based on the ITT Population.
4.8.5
4.8.5.1
Analysis of Pharmacokinetics and Anti-drug Antibody
Pharmacokinetic Analysis
Individual MEDI8897 and palivizumab serum concentration data will be tabulated by
treatment group along with descriptive statistics. PK parameters, eg, maximum observed
concentration (Cmax), AUC, apparent clearance, and t1/2 will be estimated using
non-compartmental analysis, if data permit.
4.8.5.2
Anti-drug Antibody Analysis
The incidence of ADA to MEDI8897 and to palivizumab will be assessed and summarized by
number and percentage of subjects who are ADA positive by treatment group. The impact of
ADA on PK, and association with TEAEs and TESAEs, will be assessed.
4.8.6
4.8.6.1
Exploratory Analyses
RSV Neutralizing Antibody
Individual MEDI8897 and palivizumab serum anti-RSV neutralizing antibody levels will be
tabulated by treatment group along with descriptive statistics. Anti-RSV neutralizing antibody
levels in serum will be summarized by geometric mean titer and geometric mean-fold rise and
corresponding 95% CI for each treatment group at each visit. Anti-RSV neutralizing antibody
level t1/2 will be estimated using non-compartmental analysis, if data permit.
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4.8.6.2
RSV Serology
Analysis of anti-RSV antigens antibody levels in serum in MEDI8897 and palivizumab
recipients will be summarized by geometric mean titer and geometric mean-fold rise and
corresponding 95% CI for each treatment group at each visit. Seroresponses in MEDI8897
and palivizumab recipients will be determined by examining the fold-rise in antibodies to Ga,
Gb, and N antigens.
4.8.6.3
Healthcare Resource Utilization and Caregiver Burden
The magnitude of HRU (eg, number of admissions to hospitals and ICUs and duration of stay;
number of subjects who require respiratory support and supplemental oxygen and the duration
of use; number and types of outpatient visits, eg, ER, urgent care, outpatient clinic; and
number of prescription and OTC medications and duration of use) will be summarized overall
by treatment group and for subjects with at least one medically attended LRTI (protocol
defined) caused by RT-PCR-confirmed RSV.
Caregiver burden (eg, caregiver missed work days, subject absence from day care) for subjects
with medically attended LRTI (protocol defined) caused by RT-PCR-confirmed RSV will be
summarized by treatment group.
The HRU and caregiver burden summaries will be performed on the ITT Population.
4.8.6.4
RSV Resistance Monitoring
RSV genotypic analysis will report the sequence changes in the mature F protein from all
RSV positive isolates compared to contemporary RSV A and RSV B reference strains.
Susceptibility of novel RSV variants to MEDI8897 and palivizumab will be tested and
compared to control viruses.
4.8.6.5
RSV LRTI Occurring From Day 152 to Day 361
The incidence of medically attended RSV LRTI (inpatient and outpatient) from Day 152 to
Day 361 for Season 1 and Season 2 will be based on RSV test results (performed centrally via
RT-PCR) and objective clinical LRTI criteria and will be summarized by treatment group.
4.8.7
Independent Data Monitoring Committee
An independent data monitoring committee will review safety data regularly and make
recommendations regarding further study conduct.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a subject or
clinical study subject administered a medicinal product and which does not necessarily have a
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causal relationship with this treatment. An AE can therefore be any unfavorable and
unintended sign (eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or
disease temporally associated with the use of a medicinal product, whether or not considered
related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a
deterioration of a pre-existing medical occurrence. An AE may occur at any time even if no
study treatment has been administered.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to
the subject being enrolled into the study) for a documented pre-existing condition that did not
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical
event occurring during the prescheduled elective procedure or routinely scheduled treatment
should be recorded as an AE or SAE.
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 ER or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not
result in hospitalizations.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the
investigational product and may require close monitoring and rapid communication by the
investigator to MedImmune. An AESI may be serious or nonserious. The rapid reporting of
AESIs allows ongoing surveillance of these events in order to characterize and understand
them in association with the use of this investigational product.
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5.3.1
Hypersensitivity, Including Anaphylaxis
Administration of polyclonal immunoglobulin preparations and mAbs has been associated
with immediate (type I) hypersensitivity (including anaphylaxis) that occurs during or after
dosing. An immediate hypersensitivity reaction is defined as an acute onset of an illness with
involvement of the skin, mucosal tissue, or both during administration of investigational
product (but does not meet the definition of anaphylaxis). Anaphylaxis is a rare event, usually
occurring after subsequent exposure to antigen, and it is most commonly accompanied by
severe systemic skin and or mucosal reactions. It is potentially a fatal, systemic allergic
reaction that is distinct from simple allergic reactions (eg, rash, pruritus) because of the
simultaneous involvement of several organ systems (Sampson et al, 2006). A full definition of
anaphylaxis is provided in Appendix B. See Section 5.5 for recording AEs.
5.3.2
Immune Complex Disease
Immune complex disease can manifest in the form of a number of conditions such as
vasculitis, endocarditis, neuritis, glomerulonephritis, serum sickness, and arthralgias.
Drug-induced immune complex (type III) hypersensitivity reactions can occur when host
immune system generates antibodies to drug resulting in soluble circulating antigen-antibody
complexes formation and their deposition in blood vessels. Subsequently this initiates tissue
damaging inflammatory reactions mediated by complement and/or leukocytes and mast cells.
The pathology and clinical manifestations are dependent on the tissues/organs involved, with
vascular, skin and renal tissues being common sites of injury. Common examples of immune
complex hypersensitivity reactions are serum sickness (systemic) and Arthus reactions (local).
The clinical manifestations of serum sickness include skin rash, fever, malaise, and
polyarthralgias or polyarthritis. Symptoms typically develop 1 to 2 weeks after first exposure
to antigen and usually resolve in several weeks after withdrawal of the causative agent. Serum
sickness needs to be differentiated from other ‘serum-sickness-like’ reactions that have a
similar clinical presentation (eg, viral infections, anti-seizure drugs), but are believed to have
different pathogenic mechanisms. Both serum sickness and serum sickness-like reactions have
been reported with mAbs (eg, rituximab, infliximab). Clinical presentation and time to onset
should be taken into account for the diagnosis and differentiation of these reactions. Diagnosis
of these suspected reactions is best confirmed via biopsy of the affected tissues. See
Section 5.5 for recording AEs.
5.3.3
Thrombocytopenia
Thrombocytopenia is a disorder in which there is an abnormally low platelet count; a normal
platelet count ranges from 150,000 to 450,000 platelets per μL. The 3 major causes of low
platelet counts include: (1) insufficient platelet synthesis in the bone marrow; (2) increased
breakdown of platelets in the bloodstream; and (3) increased breakdown of platelets in the
spleen or liver. General symptoms of thrombocytopenia include bleeding in the mouth and
gums, bruising, nosebleeds, and petechiae (pinpoint red spots/rash). Severe bleeding is the
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major complication, which may occur in the brain or gastrointestinal tract. Drug-induced
thrombocytopenia is a reversible form of thrombocytopenia that should be suspected in a
subject who presents with new onset thrombocytopenia or recurrent episodes of acute
thrombocytopenia, without an obvious alternative etiology. It is commonly induced by drug
dependent antibodies that cause platelet destruction or clearance by the reticuloendothelial
system (drug-induced immune thrombocytopenia), and less commonly by drug-induced bone
marrow suppression or autoimmune thrombocytopenia that is initiated by exposure to the
offending drug but persists in its absence. The initial approach to the subject with suspected
drug-induced thrombocytopenia involves confirming thrombocytopenia, establishing a
temporal relationship to a drug, and eliminating other causes of thrombocytopenia. The
diagnosis is made clinically by documenting prompt resolution of thrombocytopenia after
discontinuation of the suspected drug (typically within 1 week). Most subjects with
drug-induced thrombocytopenia require no specific treatment, as their platelet counts will
recover promptly following withdrawal of the causative agent. See Section 5.5 for recording
AEs.
5.4
Definition of New Onset Chronic Disease
An NOCD is a newly diagnosed medical condition that is of a chronic, ongoing nature. It is
observed after receiving the investigational product and is assessed by the investigator as
medically significant. Examples of NOCDs include, but are not limited to diabetes,
autoimmune disease (eg, lupus, rheumatoid arthritis), and neurological disease (eg, epilepsy).
Events that would not be considered as NOCDs are mild eczema, diagnosis of a congenital
anomaly present at study entry, or acute illness (eg, upper respiratory infection, otitis media,
bronchitis). See Section 5.5 for recording AEs.
5.5
Recording of Adverse Events
AEs, including SAEs, AESIs, and NOCDs, will be recorded on the eCRF using a recognized
medical term or diagnosis that accurately reflects the event. These events will be assessed by
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 (see Section 5.6). See Section 5.2 for the definition of SAEs and Appendix A
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
AEs and SAEs will be recorded from the time of signature of informed consent through the
follow-up period (Day 361).
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All AESIs and NOCDs will be recorded from the time of dosing with study drug through the
follow-up period (Day 361).
5.5.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the
investigator for as long as medically indicated, but without further recording in the eCRF.
MedImmune retains the right to request additional information for any subject with ongoing
AE(s)/SAE(s) at the end of the study, if judged necessary.
5.5.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must
be reported. Deaths with an unknown cause should always be reported as an SAE. A
post-mortem (autopsy) may be helpful in the assessment of the cause of death, and if
performed a copy of the post-mortem results should be forwarded to MedImmune
representative(s) within the usual timeframes (refer to Section 5.6 for additional information).
5.5.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the care provider or reported in response to the open
question from the study site staff: ‘Has the child had any health problems since the previous
visit?’, or revealed by observation will be collected and recorded in the eCRF. When
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be
recorded separately.
5.5.5
Adverse Events Based on Examination and Tests
An abnormal laboratory finding that requires medical intervention by the investigator, or a
finding judged by the investigator as medically significant should be reported as an AE. If
clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical
condition should be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg,
elevated creatinine, urine red blood cell increased)
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms,
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign
will be considered as additional information. Wherever possible the reporting investigator
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination
as compared with the baseline assessment will be reported as an AE.
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5.6
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel must
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later
than 24 hours after becoming aware of the event.
The designated study representative works with the investigator to ensure that all the
necessary information is provided to the sponsor’s patient safety data entry site within
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor
representatives of any follow-up information on a previously reported SAE within 1 calendar
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators or other site personnel indicate an AE is serious in the electronic data
capture (EDC) system, an automated email alert is sent to inform the designated sponsor
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports
an SAE to the appropriate sponsor representative by telephone. The sponsor representative
will advise the investigator/study site personnel how to proceed.
5.7
Other Events Requiring Immediate Reporting
5.7.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of
that specified in the IB, unless otherwise specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the
relevant AE modules in the eCRF and on the Overdose eCRF module.

 An overdose without associated symptoms is only reported on the Overdose eCRF
module.
If an overdose on a MedImmune investigational product occurs during the course of the study,
then the investigator or other site personnel should inform appropriate sponsor representatives
immediately, but no later than 24 hours after becoming aware of the event.
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The designated sponsor representative works with the investigator to ensure that all relevant
information is provided to the sponsor’s Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.6.
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within
30 days.
5.7.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake
in the treatment process for a MedImmune study drug that either causes harm to the subject or
has the potential to cause harm to the subject.
A medication error is not lack of efficacy of the drug, but rather a human- or process-related
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to
the subject

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not stored as instructed, eg, kept at room temperature when it should be in the
refrigerator

Wrong subject received the medication (excluding IWRS errors)

Wrong drug administered to subject (excluding IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IWRS - including those which lead to one of the above
listed events that would otherwise have been a medication error

Accidental overdose (will be captured as an overdose)
Medication errors are not regarded as AEs but AEs may occur as a consequence of the
medication error.
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If a medication error occurs in the course of the study, then the investigator or other site
personnel informs the appropriate MedImmune representatives within 1 day, ie, immediately
but no later than 24 hours of when he or she becomes aware of it.
The designated MedImmune representative works with the investigator to ensure that all
relevant information is completed within 1 or 5 calendar days if there is an SAE associated
with the medication error (see Section 5.6) and within 30 days for all other medication errors.
Medication errors should be reported using a Medication Error Report Form.
5.7.3
5.7.3.1
Adverse Events of Special Interest
Hypersensitivity, Including Anaphylaxis
Events of immediate (type I) hypersensitivity, including anaphylaxis (as defined in
Appendix B), require that the investigator or other site personnel inform appropriate sponsor
study representatives immediately, or no later than 24 hours of when he or she becomes
aware of the event. The designated sponsor study representative works with the investigator to
ensure that all relevant information is provided and entered in EDC. If the event is considered
serious it must be reported as an SAE (see Section 5.6).
Signs of immediate hypersensitivity include urticaria, pruritus, angioedema, skin rash,
difficulty breathing, and wheezing. Parent(s)/legal representatives will be provided a card with
this information to aid in prompt identification and reporting of these signs. Parent(s)/legal
representatives will be instructed to immediately report the occurrence of any of these findings
to the site investigator who should then report the events to appropriate sponsor study
representatives immediately, or no later than 24 hours of when he or she becomes aware of
the event.
5.7.3.2
Immune Complex Disease
Events of immune complex disease (as defined in Section 5.3.2) require that the investigator
or other site personnel inform appropriate sponsor study representatives immediately, or no
later than 24 hours of when he or she becomes aware of the event. The designated sponsor
study representative works with the investigator to ensure that all relevant information is
provided and entered into EDC. If the event is considered serious it must be reported as an
SAE (see Section 5.6).
5.7.3.3
Thrombocytopenia
Events of thrombocytopenia (platelet count < 120,000 per µL) require that the investigator or
other site personnel inform appropriate sponsor study representatives immediately, or no later
than 24 hours of when he or she becomes aware of the event. The designated sponsor study
representative works with the investigator to ensure that all relevant information is provided
and entered into EDC. If the event is considered serious it must be reported as an SAE (see
Section 5.6).
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5.7.4
New Onset Chronic Disease
If a case of NOCD occurs in the course of this study, the investigator or other site personnel
must inform appropriate sponsor representatives immediately, or no later than 24 hours of
when he or she becomes aware of it. The designated sponsor study representative works with
the investigator to ensure that all relevant information is provided and entered into EDC. If the
event is considered serious it must be reported as an SAE (see Section 5.6).
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review and
discuss the requirements of the protocol and related documents with the investigational staff
and also train them in any study-specific procedures and system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to
all of these staff, and that any new information relevant to the performance of this study is
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site,
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

 Confirm that the investigational team is adhering to the protocol, that data are being
accurately and timely recorded in the eCRFs, that biological samples are handled in
accordance with the Laboratory Manual and that study drug accountability checks are
being performed

Perform source data verification (a comparison of the data in the eCRFs with the subject’s
medical records at the hospital or practice, and other records relevant to the study)
including verification of informed consent of participating subjects. This will require
direct access to all original records for each subject (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is
reported and biological samples are identified and disposed of/destroyed accordingly, and
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other
staff at the center needs information and advice about the study conduct.
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6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each study site should comply with all the terms, conditions, and
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol
shall prevail with respect to the conduct of the study and the treatment of subjects and in all
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical
Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was
followed through their last protocol-specified visit/assessment (including telephone contact).
Subjects will be considered not to have completed the study if consent was withdrawn or the
subject was lost to follow-up (see Sections 4.1.5 and 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified
visit/assessment (including telephone contact) for the last subject in the study.
6.4
Data Management
Data management will be performed by MedImmune Data Management staff or other party
according to the Data Management Plan.
An electronic data capture system will be used for data collection and query handling. The
investigator will ensure that data are recorded in the eCRFs as specified in the study protocol
and in accordance with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and
of the provision of answers to data queries according to the Clinical Study Agreement. The
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived
at the study site.
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6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In
addition, each subject will receive a toll-free number intended to provide the subject’s
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a
subject presents to a medical facility where the treating physician or health care provider
requires access to a physician who has knowledge of the investigational product and the
clinical study protocol and the Principal Investigator is not available, the treating physician or
health care provider can contact a medical monitor through this system, which is managed by
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept
separate from the study data. Subject data that are relevant to the trial, eg, demographic
information, physical or mental health condition, diagnosis, comorbidities, laboratory test
results, etc. will only be collected with the subject’s informed consent. The informed consent
form will incorporate (or, in some cases, be accompanied by a separate document
incorporating) wording that describes how subject data will be collected, used, and distributed
in compliance with relevant data protection and privacy legislation.
7.2
Ethics and Regulatory Review
The IRB/IEC responsible for each site must review and approve the final study protocol,
including the final version of the Informed Consent Form and any other written information
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising
used to recruit subjects for the study. The investigator is responsible for submitting these
documents to the applicable IRB/IEC, and distributing them to the study site staff.
The opinion of the IRB/IEC must be given in writing. The investigator must provide a copy of
the written approval to MedImmune before enrolment of any subject into the study.
MedImmune should approve any substantive modifications to the Informed Consent Form that
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually.
Before the study is initiated, MedImmune will ensure that the national regulatory authority in
each country has been notified and their approval has been obtained, as required. MedImmune
will provide safety updates/reports according to local requirements, including suspected
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unexpected serious adverse reactions where relevant, to regulatory authorities, IRB/IEC, and
principal investigators.
Each Principal Investigator is responsible for providing reports of any serious and unexpected
adverse drug reactions from any other study conducted with the investigational product to the
IRB/IEC. MedImmune will provide this information to the Principal Investigator so that
he/she can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation
process that addresses all elements required by ICH/GCP. MedImmune will develop a core
informed consent form for use by all investigators in the clinical study. MedImmune must
approve any modifications to the informed consent form that are needed to meet local
requirements.
The Principal Investigator(s) at each center will:

Ensure each subject’s legal guardian is notified that they are free to discontinue from the
study at any time

 Ensure that each subject’s legal guardian is given the opportunity to ask questions and
allowed time to consider the information provided

Ensure each subject’s legal guardian provides signed and dated informed consent before
conducting any procedure specifically for the study

Ensure the original, signed informed consent form(s) is/are stored in the Investigator’s
Study File

Ensure a copy of the signed informed consent form is given to the subject’s legal guardian

 Ensure that any incentives for subjects and/or their legal guardians who participate in the
study as well as any provisions for subjects harmed as a consequence of study
participation are described in the informed consent form that is approved by an IRB/IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the investigators and
MedImmune. Any changes must be documented in a study protocol amendment.
For a substantial change to the protocol, MedImmune will distribute amended versions of the
protocol to the Principal Investigator(s). Before implementation, amended protocols must be
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority
requirements. The IRB/IEC must also approve revisions to the informed consent form,
advertising, and any other written information and/or materials resulting from the change to
the protocol.
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Any non-substantial changes will be communicated to or approved by each IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may
perform audits or inspections at the center, including source data verification. The purpose of
an audit or inspection is to systematically and independently examine all study-related
activities and documents, to determine whether these activities were conducted, and data were
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the
ICH, and any applicable regulatory requirements. The investigator will contact MedImmune
immediately if contacted by a regulatory agency about an inspection at the site.
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8
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Carbonell-Estrany X, Simoes EA, Dagan R, Hall CB, Harris B, Hultquist M et al.
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Carroll KN, Gebretsadik T, Griffin MR, Wu P, Dupont WD, Mitchel EF et al. Increasing
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Frogel MP, Stewart DL, Hoopes M, Fernandes AW, Mahadevia PJ. A systematic review of
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Greenough A, Cox S, Alexander J, Lenney W, Turnbull F, Burgess S et al. Health care
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Madhi SA, Kuwanda L, Cutland C, Klugman KP. Five-year cohort study of hospitalization for
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respiratory syncytial virus infection in Washington, D.C. II. Infection and disease with respect
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Shambaugh C, Azshirvani S, Yu L, Pache J, Lambert SL, Zuo F et al. Development of a high-
throughput respiratory syncytial virus fluorescent focus-based microneutralization assay. Clin
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Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-
associated hospitalizations among US children, 1980-1996. JAMA. 1999;282(15):1440-6.
Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD et al. Global,
regional, and national disease burden estimates of acute lower respiratory infections due to
respiratory syncytial virus in young children in 2015: a systematic review and modelling
study. Lancet. 2017;390(10098):946-58.
Stewart DL, Ryan KJ, Seare JG, Pinsky B, Becker L, Frogel M. Association of RSV-related
hospitalization and non-compliance with palivizumab among commercially insured infants: a
retrospective claims analysis. BMC Infect Dis. 2013;13334.
Stockman LJ, Curns AT, Anderson LJ, Fischer-Langley G. Respiratory syncytial virus-
associated hospitalizations among infants and young children in the United States, 1997-2006.
Pediatr Infect Dis J. 2012;31(1):5-9.
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Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J et al. A highly
potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci
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Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it
occurred or it is suspected that use or continued use of the product would result in the
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an ER is not in itself a serious AE, although the reasons for it may be
(eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations planned
before or during a study are not considered AEs if the illness or disease existed before the
subject was enrolled in the study, provided that it did not deteriorate in an unexpected way
during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in
situations where important medical events may not be immediately life threatening or result in
death, hospitalization, disability or incapacity but may jeopardize the subject or may require
medical intervention to prevent one or more outcomes listed in the definition of serious. These
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical
judgment must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring intravenous
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with
N-acetylcysteine

Intensive treatment in an ER or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions
that do not result in hospitalization
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of
AEs and SAEs. The determination of severity should be made by the investigator based upon
medical judgment and the severity categories of Grade 1 to 5 as defined below.
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Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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An event of mild intensity that is usually transient and may
require only minimal treatment or therapeutic intervention. The
event does not generally interfere with usual activities of daily
living.
An event of moderate intensity that is usually alleviated with
additional specific therapeutic intervention. The event interferes
with usual activities of daily living, causing discomfort but
poses no significant or permanent risk of harm to the subject.
A severe event that requires intensive therapeutic intervention.
The event interrupts usual activities of daily living, or
significantly affects the clinical status of the subject.
An event, and/or its immediate sequelae, that is associated with
an imminent risk of death.
Death as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists
for several hours may not meet the regulatory definition of an SAE and would be considered a
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be
considered an SAE.
Assessment of Relationship
A Guide to Interpreting the Causality Question
The investigator is required to provide an assessment of relationship of AEs and SAEs to the
investigational product. The following factors should be considered when deciding if there is a
“reasonable possibility” that an AE may have been caused by the investigational product.

Time Course. Exposure to suspect investigational product. Has the subject actually
received the suspect investigational product? Did the AE occur in a reasonable temporal
relationship to the administration of the suspect investigational product?

Consistency with known investigational product profile. Was the AE consistent with the
previous knowledge of the suspect investigational product (pharmacology and toxicology)
or products of the same pharmacological class? OR could the AE be anticipated from its
pharmacological properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose
of the suspect investigational product?
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
 No alternative cause. The AE cannot be reasonably explained by another etiology such as
the underlying disease, other drugs, or other host or environmental factors.

 Re-challenge experience. Did the AE reoccur if the suspected investigational product was
reintroduced after having been stopped? MedImmune would not normally recommend or
support a re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the
relationship?
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the investigational product?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a
‘reasonable possibility’ of a causal relationship for the individual case. The expression
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough
information to make an informed judgment. With limited or insufficient information in the
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of
effect should be classified as no reasonable possibility.
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol
procedures on the SAE Report Form. This includes non-TESAEs (ie, SAEs that occur prior to
the administration of investigational product) as well as TESAEs. A protocol-related SAE
may occur as a result of a procedure or intervention required during the study (eg, blood
collection, washout of an existing medication). The following guidelines should be used by
investigators to assess the relationship of SAEs to the protocol:
Protocol related:
Not 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.
The event is related to an etiology other than the procedure/
intervention that was described in the protocol (the alternative etiology
must be documented in the study subject’s medical record).
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Appendix B
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National Institute of Allergy and Infectious Diseases and
Food Allergy and Anaphylaxis Network Guidance for
Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from
80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 categories).
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg,
hypotonia [collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope,
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in
systolic BP
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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: d5290c00005-csp-version-2
Document Title:
Document ID:
Version Label:
D5290C00005 Clinical Study Protocol Version 2
Doc ID-003966319
2.0 CURRENT LATEST APPROVED
Server Date
Signed by
(dd-MMM-yyyy HH:mm ‘UTC’Z)
31-Mar-2021 17:16 UTC
31-Mar-2021 19:25 UTC
31-Mar-2021 18:21 UTC
31-Mar-2021 19:25 UTC
31-Mar-2021 19:49 UTC
Meaning of Signature
Author Approval
Content Approval
Content Approval
Content Approval
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.