Conditions: Staphylococcus Aureus Pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 213
Healthy volunteers: no

Brief summary:
Clinical trial looking at safety and efficacy of MEDI4893 in prevention of pneumonia caused by Staphylococcus aureus in high-risk patients

Detailed description:

Arms:
arm 1: Participants will receive a single intravenous (IV) dose of MEDI4893 5000 milligrams (mg) on Day 1 of the study. arm 2: Participants will receive a single IV dose of placebo matched to MEDI4893 on Day 1 of the study. arm 3: Participants will receive a single IV dose of MEDI4893 2000 mg on Day 1 of the study.

Interventions: intervention 1: MEDI4893 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a single IV dose of MEDI4893 2000 or 5000 mg on Day 1 of the study. intervention 2: Participants will receive a single IV dose of placebo matched to MEDI4893 on Day 1 of the study.

Protocol document:
Prot_000.pdf: 
NCT02296320


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A Phase 2 Randomised, Double-blind, Placebo-controlled, 
Single-dose, Dose-ranging Study of the Efficacy and 
Safety of MEDI4893, a Human Monoclonal Antibody 
Against Staphylococcus aureus Alpha Toxin in 
Mechanically Ventilated Adult Subjects
Sponsor Protocol Number:
CD-ID-MEDI4893-1139
Study Identifier:
SAATELLITE - MEDI4893, a Human Monoclonal 
Antibody Against Staphylococcus aureus Alpha 
Toxin in Mechanically Ventilated Adult Subjects
Application Number:
Investigational Product:
MEDI4893
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC, One MedImmune Way, 
Gaithersburg, Maryland 20878, USA
Medical Monitor:
Senior Director, Clinical Research and Development
Coordinating Principal Investigator:
Contract Research Organisation:
Protocol History, Date
Original Protocol, 07May2014
Amendment 1, 07Aug2014
Amendment 2, 04Jun2015
Administrative Change 1, 26Jun2015
Amendment 3, 14Aug2015


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Amendment 4, 20Oct2016
Amendment 5, 15Mar2018


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PROTOCOL SYNOPSIS
TITLE
A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study of the Efficacy and 
Safety of MEDI4893, a Human Monoclonal Antibody Against Staphylococcus aureus Alpha Toxin in 
Mechanically Ventilated Adult Subjects
HYPOTHESES
Primary Hypotheses
• The primary efficacy hypothesis of this Phase 2 study is that prophylactic use of MEDI4893 in mechanically 
ventilated subjects in the intensive care unit (ICU) who are colonised with S aureus in the lower respiratory 
tract will reduce the incidence of S aureus pneumonia through 30 days post dose irrespective of mechanical 
ventilation status at time of diagnosis.
• The primary safety hypothesis is that a single intravenous (IV) dose of MEDI4893 (dose range 
 
mg) administered to mechanically ventilated subjects in the ICU will have an acceptable safety profile. 
Secondary Hypothesis 
• Prophylactic use of MEDI4893 in mechanically ventilated subjects in the ICU who are colonised with 
S aureus in the lower respiratory tract will reduce the incidence of S aureus pneumonia (i) while mechanical 
ventilation is required, and (ii) after mechanical ventilation is no longer required.
OBJECTIVES
Primary Objectives 
• To evaluate the effect of MEDI4893 in reducing the incidence of S aureus pneumonia
• To evaluate the safety of a single IV dose of MEDI4893
Secondary Objectives
• To evaluate the serum pharmacokinetics (PK) of MEDI4893
• To evaluate the serum anti-drug antibody (ADA) responses to MEDI4893
Exploratory Objectives
•
  
 
 
STUDY ENDPOINTS
Primary Endpoints
• Efficacy of MEDI4893
◦Incidence of S aureus pneumonia through 30 days post dose 
• Safety of MEDI4893 
◦Treatment-emergent adverse events (TEAEs) through 30 days and 90 days post dose 
◦Treatment-emergent serious adverse events (TESAEs), adverse events of special interest (AESIs), and new 
onset chronic diseases (NOCDs) through 190 days post dose
Secondary Endpoints


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• MEDI4893 concentration and PK parameters in serum through 90 days post dose
• MEDI4893 ADA response in serum through 90 days post dose
Exploratory Endpoints
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DESIGN
This is a Phase 2, randomised, double-blind, placebo-controlled, single-dose study evaluating 2 dosage levels in 
mechanically ventilated subjects in the ICU at high risk for S aureus infections who are currently free of 
S aureus-related disease but are colonised with S aureus in the lower respiratory tract. At study start, 
approximately 462 subjects were to be enrolled from 60 to 80 centers primarily in Europe. Subjects were to be 
randomly assigned in a 1:1:1 ratio to receive a single IV dose of 
 mg MEDI4893, 
 mg MEDI4893, or 


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placebo. A PK interim analysis occurred after at least 10 subjects from each treatment group were dosed and 
followed through 30 days post dose to assess the serum PK profile of MEDI4893 in mechanically ventilated 
subjects in this study compared with the PK profile in healthy adult subjects dosed in the Phase 1 study (Study 
CD-ID-MEDI4893-1133). An independent data monitoring committee (DMC) was responsible for 
recommending dose adjustment or potential study termination as outlined in the following criteria: If the 
 
mg MEDI4893 dose serum concentrations on Day 31 were lower than the MEDI4893 serum target level of 
 
µg/mL in ≥ 2 subjects, a dose adjustment to 
 mg MEDI4893 was to be made; if the 
mg MEDI4893 
dose serum concentrations were lower than the target level of 
 µg/mL in ≥ 2 subjects, further enrolment was 
to be re-evaluated. After the DMC reviewed the interim analysis data (serum PK profiles of 
 and 
 mg 
MEDI4893), the DMC recommended that enrolment in the 
 mg MEDI4893 group be discontinued, and that 
the study proceed with enrolment in the
 mg MEDI4893 and placebo groups instead of making a dose 
adjustment to 
 mg MEDI4893. As of 15 March 2018 approximately 206 subjects will be randomized in a 
1:1 ratio to one of 2 treatment groups, 
 mg MEDI4893 or placebo (N = 103 for each treatment group).
Randomisation will be stratified by country and then by whether or not subjects received anti-S aureus systemic 
antibiotic (treatment for ≤48 hours) within the 72 hours prior to randomisation. As the study is blinded, it is 
estimated that approximately 15 subjects may have already been enrolled and randomised in the 
 mg dose, 
prior to the decision of discontinuing this 
 arm, making the total number of study subjects to be 
approximately 221.
Additionally, the interim PK data analysis indicated that the serum exposure of MEDI4893 following a single 
dose of 
 or 
 mg in ICU patients was lower compared to the serum exposure in healthy adults in the 
Phase 1 study. Based on population PK modeling and simulation, MEDI4893 half-life in ICU patients with 
mechanical ventilation was estimated to be 
 days, shorter than the half-life in healthy adults in the Phase 1 
study (80-112 days). On the basis of this observation, following investigational product administration on 
Day 1, subjects will be followed through Day 191 as part of Protocol Amendment 4, as compared to Day 361 
previously.
This study is being conducted through the Innovative Medicines Initiative Joint Undertaking (IMI JU, 2012),
which is a pan-European public-private partnership between the European Commission and the European 
Federation of Pharmaceutical Industries and Associations (EFPIA), theme Combatting Antimicrobial Resistance 
in Europe (COMBACTE) (New Drugs for Bad Bugs [ND4BB] Subtopic 1C). MedImmune will execute this 
study in conjunction with the COMBACTE consortium of leading academic, clinical, and microbiological 
researchers in the field of antibiotic-resistant bacteria and ventilator-associated and ICU pneumonia.
TARGET SUBJECT POPULATION
Subjects in this study will be male or female adults, 18 years of age or older, requiring mechanical ventilation in 
the ICU, who are currently free of S aureus-related disease but are colonised with S aureus in the lower 
respiratory tract.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
Subjects will be randomly assigned to receive a single dose of 
 mg MEDI4893, 
 mg MEDI4893, or
placebo administered via IV infusion on Day 1.
STATISTICAL ANALYSIS PLAN
Data will be provided in data listings sorted by treatment group and subject identification number. Categorical 
data will be summarised by the number and percentage of subjects falling within each category. Continuous 
variables will be summarised by descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. A Poisson regression model with robust variance will be used as the primary efficacy analysis, to 
compare the incidence of S aureus pneumonia through 30 days post dose between placebo and the MEDI4893 
groups, including treatment group and dichotomous prior anti-S aureus systemic antibiotic use as covariates. If 
the number of subjects in either of the prior anti-S aureus systemic antibiotic use stratum is too small and/or 
convergence cannot be achieved, this covariate may not be included in the model. In addition, the 2-sided 
p-value and corresponding 2-sided 90% confidence interval (CI) around the observed relative risk will be 
provided from the model.
No multiplicity adjustments will be made to any of the analyses. Subjects who discontinue prior to the 30-day 
post-dose follow-up will be included in the primary efficacy (ie, Intent-to-treat) population as described in the 
primary efficacy analysis section below. Further, S aureus pneumonia that occurs prior to discontinuation will 
contribute to the primary efficacy analysis. If no S aureus pneumonia occurs prior to discontinuation, the subject 
will be considered as having no S aureus pneumonia infection in the primary efficacy analysis. Different 


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approaches to handle missing data (ie, early discontinuation and no S aureus pneumonia prior to 
discontinuation) may be considered for sensitivity analyses.
Interim Analyses
One interim analysis was planned. The interim analysis occurred after at least 10 subjects from each treatment 
group were followed through 30 days post dose to compare the serum PK profile of MEDI4893 in mechanically 
ventilated subjects in this study with healthy adult subjects dosed in the Phase 1 study (Study CD-ID-
MEDI4893-1133). An independent DMC was responsible for recommending dose adjustment or potential study 
termination as outlined in the following criteria: If the 
 mg MEDI4893 dose serum concentrations on Day
31 were lower than the MEDI4893 serum target level of
µg/mL in ≥2 subjects, a dose adjustment to 
mg MEDI4893 was to be made; if the 
 mg MEDI4893 dose serum concentrations were lower than the 
MEDI4893 target level of 
µg/mL in ≥2 subjects, further enrolment was to be re-evaluated. After the DMC 
reviewed the PK interim analysis data (serum PK profiles of 
 and 
 mg MEDI4893), the DMC 
recommended that enrolment in the 
mg MEDI4893 group be discontinued, and that the study proceed with 
enrolment in the 
 mg MEDI4893 and placebo groups instead of making a dose adjustment to 
 mg 
MEDI4893.
Primary Analysis
Two formal analyses (Stage 1 and Stage 2) are planned. The Stage 1 analysis will be conducted after the last 
subject has completed follow-up through 30 days post dose and will be the primary analysis for efficacy, for 
which the study is powered. During the Stage 1 analysis, all efficacy (ie, primary, secondary, and exploratory 
efficacy endpoints), serum PK, ADA, and safety data collected through 30 days post dose for the last subject 
enrolled will be analysed. The Stage 2 analysis for long-term safety follow-up will be performed after all 
subjects have completed the study (ie, approximately 190 days post dose). During the Stage 2 analysis, safety, 
serum PK, and ADA through 90 days post dose will be analyzed. In addition, the 
 
 
safety through study completion will be analysed.
Sample Size/Power Calculation
Approximately 206 subjects will be enrolled and randomised in a 1:1 ratio to one of 2 treatment groups: 
mg MEDI4893 (N = 103) or placebo (N = 103). As the study is blinded, it is estimated that approximately 
15 subjects may have already been enrolled and randomised in the 
 mg MEDI4893 dose, prior to the 
decision of discontinuing this lower dose arm, making the total number of study subjects to be approximately 
221.
As 
such, a study with a sample size of 92 per arm will allow a 70% power at 2-sided significance level of α = 0.1 to 
detect a relative risk reduction 50% comparing 
 mg MEDI4893 versus placebo. A Poisson regression with 
robust variance (Zou, 2004) is employed in the calculation. N = 221 is derived when considering 10% attrition 
and adding an estimated 15 subjects in the 
 mg dose.
 
 In addition, 50% relative reduction was demonstrated 
in a study by François and colleagues (François et al, 2012) involving a monoclonal antibody to prevent 
Pseudomonas pneumonia in mechanically-ventilated patients, supporting the biological feasibility of such an 
effect.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................3
LIST OF ABBREVIATIONS........................................................................................12
1
INTRODUCTION ..............................................................................................14
1.1
Disease Background..................................................................................14
1.2
MEDI4893 Background............................................................................15
1.3
Summary of Nonclinical Experience .........................................................16
1.4
Summary of Clinical Experience...............................................................16
1.5
Rationale for Conducting the Study...........................................................18
1.6
Research Hypotheses ................................................................................18
1.6.1Primary Hypotheses ..........................................................................18
2
OBJECTIVES.....................................................................................................19
2.1
Objectives.................................................................................................19
2.1.1Primary Objectives............................................................................19
2.1.2Secondary Objectives ........................................................................19
2.1.3Exploratory Objectives......................................................................19
2.2
Study Endpoints........................................................................................20
2.2.1Primary Endpoints.............................................................................20
2.2.2Secondary Endpoints.........................................................................20
2.2.3Exploratory Endpoints.......................................................................20
3
STUDY DESIGN................................................................................................21
3.1
Description of the Study............................................................................21
3.1.1Overview………...............................................................................21
3.1.2Treatment Regimen...........................................................................24
3.2
Study Design and Dose Rationale .............................................................24
3.2.1Rationale for Study Design................................................................24
3.2.2Dose Rationale ..................................................................................24
3.2.3Rationale for Study Population..........................................................25
3.2.4Rationale for Endpoints.....................................................................26
4
MATERIALS AND METHODS.........................................................................26
4.1
Subjects ....................................................................................................26
4.1.1Number of Subjects...........................................................................26
4.1.2Inclusion Criteria...............................................................................26
4.1.3Exclusion Criteria..............................................................................27
4.1.4Subject Enrolment and Randomisation ..............................................28
4.1.5Withdrawal from the Study................................................................29
4.1.6Discontinuation of Investigational Product ........................................30
4.1.7Replacement of Subjects ...................................................................30


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4.1.8Withdrawal of Informed Consent for Data and Biological Samples ...30
4.2
Schedule of Study Procedures...................................................................31
4.2.1Enrolment/Screening Period..............................................................31
4.2.2Treatment and Follow-up Periods......................................................32
4.3
Description of Study Procedures ...............................................................38
4.3.1Efficacy……….. ...............................................................................38
4.3.1.1
Clinical Symptoms...........................................................38
4.3.1.2
Microbiology ...................................................................38
4.3.1.3
Radiography.....................................................................39
4.3.1.4
Definition of S aureus Pneumonia ....................................39
4.3.3Medical History and Physical Examination, Weight, and Vital Signs.42
4.3.4Clinical Laboratory Tests ..................................................................42
4.3.5Pharmacokinetic Evaluation and Methods .........................................43
4.3.6Anti-drug Antibody Evaluation and Methods ....................................43
4.3.8S aureus Colonisation Evaluation and Methods .................................44
4.3.9Estimate of Volume of Blood to be Collected....................................45
4.4
Study Suspension or Termination..............................................................46
4.5
Investigational Products............................................................................46
4.5.1Identity of Investigational Products ...................................................46
4.5.1.1
Investigational Product Dose Preparation .........................47
4.5.1.2
Investigational Product Inspection....................................47
4.5.1.3
Dose Preparation Steps.....................................................48
4.5.1.4
Treatment Administration ................................................48
4.5.1.5
Monitoring of Dose Administration..................................49
4.5.1.6
Reporting Product Complaints .........................................50
4.5.2Additional Study Medications ...........................................................50
4.5.3Labeling……….................................................................................50
4.5.4Storage…………...............................................................................50
4.5.5Treatment Compliance ......................................................................51
4.5.6Accountability...................................................................................51
4.6
Treatment Assignment and Blinding .........................................................51
4.6.1Methods for Assigning Treatment Groups .........................................51
4.6.2Methods for Ensuring Blinding..........................................................52
4.6.3Methods for Unblinding ....................................................................52
4.6.3.1
Unblinding in the Event of a Medical Emergency.............52


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4.6.3.2
Unblinding for Interim Pharmacokinetic Analysis 
Purposes ............................................................53
4.6.3.3
Unblinding for Stage 1 Analysis Purposes........................53
4.7
Restrictions During the Study and Concomitant Treatment .......................53
4.7.1Contraception....................................................................................53
4.7.2Concomitant Medication ...................................................................54
4.7.2.1
Permitted Concomitant Medications.................................54
4.7.2.2
Prohibited Concomitant Medications................................54
4.8
Statistical Evaluation.................................................................................55
4.8.1General Considerations .....................................................................55
4.8.2Sample Size and Power Calculations .................................................55
4.8.3Efficacy………… .............................................................................56
4.8.3.1
Primary Efficacy Analysis................................................56
4.8.3.2
...................56
4.8.3.3
.........................................57
4.8.4Safety………….................................................................................58
4.8.4.1
Analysis of Adverse Events..............................................58
4.8.4.2
Analysis of Clinical Laboratory Parameters......................58
4.8.5
..........................................................59
4.8.6Pharmacokinetics ..............................................................................59
4.8.7Anti-drug Antibody Response ...........................................................59
4.8.8
........................................................................................59
4.8.9
60
4.8.10Data Review Committees ................................................................60
4.8.11Interim Analyses .............................................................................60
4.8.12Planned Analysis.............................................................................61
5
ASSESSMENT OF SAFETY..............................................................................61
5.1
Definition of Adverse Events ....................................................................61
5.2
Definition of Serious Adverse Events........................................................62
5.3
Definition of Adverse Events of Special Interest .......................................63
5.3.1Hepatic Function Abnormality ..........................................................63
5.3.2Anaphylaxis and Serious Allergic Reactions (Including 
Hypersensitivity) and Infusion-related Reactions..............63
5.3.3Immune Complex Disease.................................................................64
5.4
New Onset Chronic Disease......................................................................65
5.5
Collection of Adverse Events....................................................................65
5.5.1Time Period for Collection of Adverse Events...................................66
5.5.2Follow-up of Unresolved Adverse Events..........................................66
5.5.3Collection of Adverse Events of Special Interest ...............................66


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5.5.3.1
Hepatic Function Abnormality .........................................66
5.5.3.2
Anaphylaxis and Serious Allergic Reactions (Including 
Hypersensitivity) and Infusion-related Reactions67
5.5.3.3
Immune Complex Disease................................................67
5.5.4Collection of New Onset Chronic Disease .........................................67
5.6
Reporting of Serious Adverse Events ........................................................67
5.7
Other Events Requiring Immediate Reporting ...........................................68
5.7.1Overdose……….. .............................................................................68
5.7.2Hepatic Function Abnormality ..........................................................69
5.7.3Pregnancy…………….. ....................................................................69
6
STUDY AND DATA MANAGEMENT.............................................................70
6.1
Training of Study Site Personnel...............................................................70
6.2
Monitoring of the Study............................................................................70
6.2.1Source Data.......................................................................................71
6.2.2Study Agreements .............................................................................71
6.2.3Archiving of Study Documents..........................................................71
6.3
Study Timetable and End of Study............................................................71
6.4
Data Management .....................................................................................71
6.5
Medical Monitor Coverage........................................................................72
7
ETHICAL AND REGULATORY REQUIREMENTS........................................72
7.1
Ethical Conduct of the Study.....................................................................72
7.2
Subject Data Protection.............................................................................72
7.3
Ethics and Regulatory Review...................................................................72
7.4
Informed Consent......................................................................................73
7.5
Changes to the Protocol and Informed Consent Form................................74
7.6
Audits and Inspections ..............................................................................74
8
REFERENCES ...................................................................................................75
9
CHANGES TO THE PROTOCOL......................................................................78
9.1
Protocol Amendment 1, 07Aug2014 .........................................................78
9.2
Protocol Amendment 2, 04Jun2015...........................................................79
9.3
Administrative Change 1, 26Jun2015........................................................81
9.4
Protocol Amendment 3, 14Aug2015 .........................................................81
9.5
Protocol Amendment 4, 20Oct2016 ..........................................................82
9.6
Protocol Amendment 5, 15Mar2018..........................................................85
LIST OF IN-TEXT TABLES
Table 4.2.1-1
Schedule of Screening Procedures ....................................................31
Table 4.2.2-1
Schedule of Treatment and Post-dose Follow-up Procedures.............33


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Table 4.2.2-2
Schedule of Procedures for Subjects With Suspected or Confirmed 
Pneumonia or Bacteremia .................................................................36
Table 4.3.9-1
Estimated Volume of Blood to be Collected per Visit .......................45
Table 4.5.1-1
Identification of Investigational Products..........................................47
Table 4.5.1.3-1
Investigational Product Dose Preparation..........................................48
Table 4.5.1.4-1
Duration of Infusion by Treatment Group and Investigational Product 
Solution Volume...............................................................................49
Table 4.7.1-1
Highly Effective Methods of Contraception......................................54
LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................23
LIST OF APPENDICES
Appendix 1
Signatures.........................................................................................87
Appendix 2
Additional Safety Guidance ..............................................................92
Appendix 3
National Institute of Allergy and Infectious Diseases (NIAID) and 
Food Allergy and Anaphylaxis Network (FAAN) Guidance for 
Anaphylaxis Diagnosis .....................................................................94
Appendix 4
Clinical Pulmonary Infection Score...................................................95
Appendix 5
Acute Physiology and Chronic Health Evaluation-II.........................96
Appendix 6
Sequential Organ Failure Assessment ...............................................99
Appendix 7
Conversion Tables for Estimating PaO2 and FiO2 ...........................100


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LIST OF ABBREVIATIONS
Abbreviation or Specialised Term
Definition
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine transaminase
APACHE
Acute Physiology and Chronic Health Evaluation
AST
aspartate transaminase
AT
alpha toxin
BAL
bronchoalveolar lavage
BUN
blood urea nitrogen
CCC
Clinical Coordinating Centre
CI
confidence interval
CL
serum clearance
COMBACTE
Combatting Antimicrobial Resistance in Europe
CPAP
continuous positive airway pressure
CPIS
Clinical Pulmonary Infection Score
CRP
C-reactive protein
CT
computed tomography
DEHP
di(2-ethylhexyl)phthalate
DMC
Data Monitoring Committee
EC90
effective serum concentration associated with 90% survival
eCRF
electronic case report form
EFPIA
European Federation of Pharmaceutical Industries and Associations
ELISA
enzyme-linked immunosorbent assay
EU
European Union
FAAN
Food Allergy and Anaphylaxis Network
Fc
fragment crystallizable
FcRn
neonatal Fc receptor
FTIH
first-time-in-human (study)
GCP
Good Clinical Practice
GCS
Glasgow Coma Scale
GGT
gamma glutamyl transferase
GMP
Good Manufacturing Practice
hCG
human chorionic gonadotropin
HFP
high-power field
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgG1
immunoglobulin G1 kappa
IMI JU
Innovative Medicines Initiative Joint Undertaking
IL
Interleukin


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Abbreviation or Specialised Term
Definition
ITT
Intent-to-treat
IV
Intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
LC10
non-YTE version of MEDI4893
mAb
monoclonal antibody
MMP-9
matrix metalloproteinase 9
MPO
Myeloperoxidase
MSSA
methicillin-susceptible Staphylococcus aureus
MRSA
methicillin-resistant Staphylococcus aureus
NIAID
National Institute of Allergy and Infectious Diseases
ND4BB
New Drugs for Bad Bugs
NE
neutrophil elastase
NOCD
new onset chronic disease
PD
pharmacodynamics
PK
Pharmacokinetics
PSB
protected-specimen brush
PVC
polyvinyl chloride
RBC
red blood cell
S aureus
Staphylococcus aureus
SAE
serious adverse event
SID
subject identification
SOFA
Sequential Organ Failure Assessment
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TK
Toxicokinetic
TNF
tumor necrosis factor alpha
ULN
upper limit of normal
USA
United States of America
WBC
white blood cell
YTE
M252Y/S254T/T256E


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1
INTRODUCTION
1.1
Disease Background
Staphylococcus aureus Infection
Bacterial pneumonia occurring within the hospitalised or intensive care unit (ICU)
population is a clinically significant and serious disease that contributes significantly to 
morbidity and mortality. This constitutes the second leading type of nosocomial infection and 
the leading cause of death from nosocomial infection in the United States of America (USA; 
Spellberg and Talbot, 2010). Staphylococcus aureus is the primary cause of nosocomial 
pneumonia. A recent study of European ICUs reported that 23% of mechanically ventilated 
ICU patients developed pneumonia caused by S aureus, with over half caused by methicillin-
resistant Staphylococcus aureus (MRSA) (Esperatti et al, 2010). A study of morbidity and 
mortality associated with S aureus pneumonia in ICUs across Europe and Latin America 
found a mean duration for mechanical ventilation of 15.9 days (range 11 to 30.3 days), mean 
ICU mortality of 21.6% (range 10% to 60%), and mean Acute Physiology and Chronic 
Health Evaluation (APACHE) score of 18.6 (range 15.2 to 22) for patients with S aureus
pneumonia (Rello et al, 2013).
S aureus pneumonia among mechanically ventilated intubated ICU patients is associated 
with significant healthcare-associated costs. Restrepo and colleagues (Restrepo et al, 2010) 
reported median incremental hospital costs of S aureus pneumonia compared to 
non-pneumonia controls to be $101,660 when examined between 2002 and 2006. A recent 
analysis of a USA claims database of privately insured patients admitted to an ICU between 
2006 and 2012 suggests that S aureus pneumonia was associated with a mean excess or 
incremental cost of approximately $100,000 compared to the control intubated ICU patients 
(unpublished data). 
Further complicating the morbidity and mortality described above, available therapy for 
treating S aureus pneumonia cases is often limited due to antibiotic-resistant strains or the 
patient’s intolerance to treatment. Even with the introduction of new antibiotics against 
S aureus, continuing emergence of resistance requires new approaches to address the 
existing, and potentially expanding, unmet medical need for preventing S aureus disease.
Two major variables associated with an increased risk of S aureus pneumonia are respiratory 
colonisation with S aureus and the prolonged need for mechanical ventilation with 
endotracheal intubation (> 48 hours). The rate of S aureus pneumonia among intubated 
patients colonised with S aureus has been reported to be up to 35% (Sirvent et al, 2000; 


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Ewig et al, 1999). A recent study by Mullins and colleagues (Mullins et al, 2013) reported a 
62.2% S aureus pneumonia rate among mechanically ventilated intubated patients colonised 
with MRSA.
During infection, S aureus releases a number of toxins, and S aureus alpha toxin (AT) is the 
most prevalent virulence factor causing tissue invasion and necrosis (Wilke and Bubeck 
Wardenburg, 2010). The pivotal role of AT in S aureus pathogenesis is supported by animal 
models (dermonecrosis, pneumonia, sepsis, endocarditis, and mastitis) (Bramley et al, 1989; 
Bayer et al, 1997; Bubeck Wardenburg et al, 2008; Kobayashi et al, 2011; 
Powers et al, 2012) and by observational studies in humans in which the presence of anti-AT 
antibodies during severe infections was associated with improved outcome 
(Adhikari et al, 2012; Jacobsson et al, 2010; Ruotsalainen et al, 2008).
Antibiotics are the only intervention available for treating S aureus diseases. Despite the 
introduction of new antibiotics against S aureus, emergence of resistance requires new 
approaches for combatting S aureus diseases. While prevention of healthcare-associated 
infections caused by S aureus is an important public health goal, no vaccines or passive 
immunisation therapies are available. Prevention currently focuses on infection control 
practices and limited prophylactic use of antibiotics (eg, presurgery). Topical decolonisation 
regimens have been proposed for S aureus carriers, given that nasal carriage is a risk factor 
for hospital-acquired infection (Muñoz et al, 2008; Bode et al, 2010). However, 
decolonisation efforts have not been consistently effective and are not universally 
implemented (Kluytmans et al, 1996; Perl et al, 2002; Kalmeijer et al, 2002).
1.2
MEDI4893 Background
MEDI4893 is briefly described below. Refer to the current Investigator’s Brochure for 
details.
MEDI4893 is being developed for the prevention of nosocomial pneumonia caused by 
S aureus. 
 
 
 
 
 
 
 


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1.3
Summary of Nonclinical Experience
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4
Summary of Clinical Experience
 
 
 


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1.5
Rationale for Conducting the Study
Patients in the ICU are at a high risk for developing serious S aureus infection, such as 
pneumonia, bacteremia, bone and joint infection, meningitis, and endocarditis. Mechanical 
ventilation increases the risk for pneumonia in the ICU, with S aureus being one of the most 
common causes of ICU pneumonia. The emergence of S aureus strains resistant to 
methicillin (MRSA) and glycopeptides (glycopeptide-intermediately resistant S aureus and 
glycopeptide-resistant S aureus) complicates the management of S aureus infection by 
limiting the antimicrobial therapeutic options, which highlights the need to consider new 
approaches, such as immunoprophylaxis. One approach to immunoprophylaxis is the use of a 
mAb that targets the AT of S aureus, a toxin that can induce substantial tissue and organ 
damage. Preemptive targeting of AT may prevent both serious antibiotic-susceptible S aureus
and serious antibiotic-resistant S aureus disease in at-risk patients. 
MEDI4893 was found to be generally safe in the initial Phase 1 study with an extended
antibody half-life and the ability to neutralise AT. Because there is no correlate of protection 
for S aureus disease, the next development step is to evaluate if the PK and PD profile 
translate into clinical efficacy and evaluate the safety profile in the target population.
The current study is designed to determine the efficacy, safety, and PK responses to 
MEDI4893 in adult subjects admitted to the ICU who require mechanical ventilation and 
who are also colonised with S aureus in the lower respiratory tract. Results will also form the 
basis for subsequent studies in adult populations at high risk for S aureus infections. 
1.6
Research Hypotheses
1.6.1
Primary Hypotheses
The primary efficacy hypothesis of this Phase 2 study is that prophylactic use of MEDI4893 
in mechanically ventilated subjects in the ICU who are colonised with S aureus in the lower 
respiratory tract will reduce the incidence of S aureus pneumonia through 30 days post dose
irrespective of mechanical ventilation status at time of diagnosis. 
The primary safety hypothesis is that a single IV dose of MEDI4893 (dose range 
 to 
 mg) administered to mechanically ventilated subjects in the ICU will have an 
acceptable safety profile.


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2
OBJECTIVES
2.1
Objectives
2.1.1
Primary Objectives
1. To evaluate the effect of MEDI4893 in reducing the incidence of S aureus pneumonia 
2. To evaluate the safety of a single IV dose of MEDI4893 
2.1.2
Secondary Objectives
1. To evaluate the serum PK of MEDI4893
2. To evaluate the serum ADA responses to MEDI4893
2.1.3
Exploratory Objectives
 
 
 


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2.2
Study Endpoints
2.2.1
Primary Endpoints
1. Efficacy of MEDI4893
◦
Incidence of S aureus pneumonia through 30 days post dose (see Section 4.3.1.4 for 
definition of S aureus pneumonia)
2. Safety of MEDI4893 
◦
TEAEs through 30 days and 90 days post dose
◦
TESAEs, adverse events of special interest (AESIs), and NOCDs through 190 days 
post dose
2.2.2
Secondary Endpoints
1. MEDI4893 concentration and PK parameters in serum through 90 days post dose
2. MEDI4893 ADA response in serum through 90 days post dose
2.2.3
Exploratory Endpoints
 
 
 
 
 
 
 


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3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview……….
This is a Phase 2, randomised, double-blind, placebo-controlled, single-dose study evaluating 
2 dosage levels in mechanically ventilated subjects in the ICU at high risk for S aureus
infections who are currently free of S aureus-related disease but are colonised with S aureus
in the lower respiratory tract. At study start, approximately 462 subjects were to be enrolled 
from 60 to 80 centers primarily in Europe. Subjects were to be randomly assigned in a 1:1:1 
ratio to receive a single IV dose of 
 mg MEDI4893, 
 mg MEDI4893, or placebo.


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One interim analysis was planned. The interim analysis occurred after at least 10 subjects 
from each treatment group were followed through 30 days post dose to assess the serum PK 
profile of MEDI4893 in mechanically ventilated subjects in this study compared with the PK 
profile in healthy adult subjects dosed in the Phase 1 study (Study CD-ID-MEDI4893-1133). 
An independent data monitoring committee (DMC) was responsible for recommending dose 
adjustment or potential study termination as outlined in the following criteria: If the 
 mg 
MEDI4893 dose serum concentrations on Day 31 were lower than the MEDI4893 serum 
target level of 
 µg/mL in ≥ 2 subjects, a dose adjustment to 
mg MEDI4893 was to 
be made; if the 
 mg MEDI4893 dose serum concentrations were lower than the target 
level of 
 µg/mL in ≥ 2 subjects, further enrolment was to be re-evaluated. After the DMC 
reviewed the interim analysis data (serum PK profiles of 
 and 
 mg MEDI4893), the 
DMC recommended that enrolment in the 
 mg MEDI4893 group be discontinued, and 
that the study proceed with enrolment in the 
 mg MEDI4893 and placebo groups instead 
of making a dose adjustment to 
 mg MEDI4893; resulting in a sample size of 270 
subjects (randomised in a 1:1 ratio to either
 mg MEDI4893 or placebo).Effective 15 
March 2018, approximately 206 subjects will be randomized in a 1:1 ratio to one of 2 
treatment groups, 
 mg MEDI4893 or placebo (N = 103 for each treatment group). 
Randomisation will be stratified by country and then by whether or not subjects received 
anti-S aureus systemic antibiotic (treatment for ≤48 hours) within the 72 hours prior to 
randomisation. Following investigational product administration on Day 1, subjects will be 
followed through Day 191. As the study is blinded, it is estimated that approximately 15 
subjects may have already been enrolled and randomised in the 
 mg dose, prior to the 
decision of discontinuing 
, making the total number of study subjects to 
be approximately 221.
Additionally, on the basis of the interim PK data analysis (see Section 1.4 for details), 
following the investigational product administration on Day 1, subjects will be followed 
through Day 191 as part of Protocol Amendment 4, as compared to Day 361 previously.
Two formal analyses (Stage 1 and Stage 2) are planned. The Stage 1 analysis will be 
conducted after the last subject has completed follow-up through 30 days post dose and will 
be the primary analysis for efficacy, for which the study is powered. During the Stage 1 
analysis, all efficacy (ie, primary, secondary, and exploratory efficacy endpoints), serum PK, 
ADA, and safety data collected through 30 days post dose for the last subject enrolled will be 
analysed. The Stage 2 analysis for long-term safety follow-up will be performed after all 
subjects have completed the study (ie, approximately 190 days post dose). During the Stage 2 
analysis, safety, serum PK, and ADA through 90 days post dose will be analyzed. 
 
 


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.
A high-level flow diagram for this study is shown in Figure 3.1.1-1. The endpoints to be 
measured in this study are described in Section 2.2.
Figure 3.1.1-1
Study Flow Diagram
ADA = anti-drug antibody; N = number of subjects; PK = pharmacokinetics.
Note: This study flow diagram was revised based on the first interim analysis and illustrates how approximately 
206 subjects will be randomised in a 1:1 ratio to one of 2 treatment groups: 
 mg MEDI4893 (N = 103) or 
placebo (N = 103). As the study is blinded, it is estimated that approximately 15 subjects may have already been 
enrolled and randomised in the 
 mg dose, prior to the decision of discontinuing 
, 
making the total number of study subjects to be approximately 221. Stage 1 analysis for efficacy, safety, serum 
PK, and ADA will be assessed through 30 days post dose (Day 31); Stage 2 analysis for long-term safety 
follow-up will be assessed through 190 days post dose (Day 191).
This study is being conducted through the Innovative Medicines Initiative Joint Undertaking 
(IMI JU, 2012), which is a pan-European public-private partnership between the European 
Commission and the European Federation of Pharmaceutical Industries and Associations 
(EFPIA), theme Combatting Antimicrobial Resistance in Europe (COMBACTE) (New 
Drugs for Bad Bugs [ND4BB] Subtopic 1C). MedImmune will execute this study in 
conjunction with the COMBACTE consortium of leading academic, clinical, and 
microbiological researchers in the field of antibiotic-resistant bacteria and ventilator-
associated and ICU pneumonia.


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3.1.2
Treatment Regimen
Effective 15 March 2018, approximately 206 subjects will be enrolled and randomly 
assigned (1:1 ratio) to receive a single IV infusion of 
 mg MEDI4893 (N = 103), or 
placebo (N = 103) on Day 1. Subjects who have been enrolled and randomized into the 
mg MEDI4893 group will continue to be followed through the end of study. 
3.2
Study Design and Dose Rationale
3.2.1
Rationale for Study Design
This study is designed to determine if prophylactic administration of MEDI4893 reduces the 
incidence of S aureus pneumonia when added to standard-of-care therapy. The study is 
randomised, double-blinded, and placebo-controlled. Blinding and random assignment of 
treatment are standard elements that limit the occurrence of intentional or unintentional bias 
arising from knowledge of treatment assignment. There is no established medicinal product 
with proven prophylactic value in this indication with which to compare MEDI4893; 
therefore, placebo will be used in the control arm to maintain the blinded assessment of 
therapeutic effect and adverse events (AEs). All subjects will receive standard-of-care. The
use of placebo will not replace or result in the withholding of a currently proven intervention 
during the study period.
3.2.2
Dose Rationale
Two single doses of MEDI4893, 
 mg and 
 mg, have been selected to be evaluated 
in the Phase 2 study based on the PK/PD data from preclinical pharmacology studies and 
PK data from the clinical Phase 1 study (Study CD-ID-MEDI4893-1133). 
 
 
 
 
 
 
 
 
 
 
 
 


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As described in Section 3.1.1, an interim analysis occurred after at least 10 subjects from 
each treatment group were followed through 30 days post dose to compare the serum PK 
profile of MEDI4893 in mechanically ventilated subjects in this study with healthy adult 
subjects dosed in the Phase 1 study (Study CD-ID-MEDI4893-1133). An independent DMC 
was responsible for recommending dose adjustment or potential study termination as outlined 
in the following criteria: If the 
 mg MEDI4893 dose serum concentrations on Day 31 
were lower than the MEDI4893 serum target level of 
 µg/mL in ≥ 2 subjects, a dose 
adjustment to 
mg MEDI4893 was to be made; if the 
 mg MEDI4893 dose serum 
concentrations were lower than the target level of 
µg/mL in ≥ 2 subjects, further 
enrolment was to be re-evaluated. After the DMC reviewed the interim analysis data (serum 
PK profiles of 
 and
 mg MEDI4893), the DMC recommended that enrolment in the 
 mg MEDI4893 group be discontinued, and that the study proceed with enrolment in the
mg MEDI4893 and placebo groups instead of making a dose adjustment to 
 mg 
MEDI4893. Approximately 206 subjects will be randomised in a 1:1 ratio to one of 2 
treatment groups: 
 mg MEDI4893 (N = 103) or placebo (N = 103).
3.2.3
Rationale for Study Population
Subjects in this study will be ICU patients on mechanical ventilation at the time of enrolment 
who are colonised with S aureus in the lower respiratory tract but without a diagnosis of 
acute pneumonia or S aureus infection. While data are limited on a comprehensive 
understanding of all variables that contribute to the risk of S aureus pneumonia, respiratory 
colonisation with S aureus and the prolonged need for mechanical ventilation with 
endotracheal intubation (> 48 hours) are widely recognised as 2 major contributing factors. 
The rate of S aureus pneumonia among intubated patients colonised with S aureus has been 
reported to be up to 35% (Sirvent et al, 2000; Ewig et al, 1999), and up to 62.2% among 
mechanically ventilated intubated patients colonised with MRSA (Mullins et al, 2013). 
Since the objective of the study is to prevent nosocomial pneumonia in mechanically 
ventilated high-risk patients, patients will be excluded if they have pre-existing confirmed or 
suspected S aureus infections, have an underlying condition that would impede a diagnosis of 
pneumonia, are not expected to have a reasonable probability to survive through the study 
evaluation period, or have received potentially effective systemic antibiotic therapy for 
S aureus for > 48 hours within 72 hours prior to dosing. 
These enrolment criteria are expected to result in a population representative of patients 
encountered in clinical practice with a high risk of developing S aureus pneumonia, and will
minimise confounding factors for the characterisation of efficacy of MEDI4893 in preventing 
pneumonia in mechanically ventilated patients.


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3.2.4
Rationale for Endpoints
The primary efficacy endpoint for this study is the incidence of S aureus pneumonia through 
30 days after a single dose of MEDI4893 in mechanically ventilated subjects at risk for 
S aureus pneumonia. It is anticipated that while a substantial number of mechanically 
ventilated subjects will continue to require mechanical ventilation throughout the 30-day 
post-dose period, a number of subjects will be weaned off the ventilator during this period. 
Since these subjects may develop S aureus pneumonia after they no longer require 
mechanical ventilation, primary efficacy will be evaluated in subjects who were on 
mechanical ventilation at the time of enrolment, regardless of whether they remain on or are 
weaned off mechanical ventilation during the 30-day post-dose period. 
The primary safety endpoint will assess AEs and serious adverse events (SAEs) temporally 
associated with MEDI4893 dosing through 30 days post dose as well as 90 days post dose. 
Given the extended half-life of MEDI4893, longer-term safety evaluation will assess SAEs, 
AESIs, and NOCDs through 190 days post dose (approximately 4 half-lives).    
Secondary endpoints of MEDI4893 serum concentration and PK parameters, and ADA 
response to MEDI4893 are designed to assess the presence of MEDI4893 in vivo. 
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Approximately 206 subjects will be randomised to one of 2 treatment groups: 
 mg 
MEDI4893 (N = 103) or placebo (N = 103). As the study is blinded, it is estimated that 
approximately 15 subjects may have already been enrolled and randomised in the 
 mg 
dose, prior to the decision of discontinuing 
, making the total number of 
study subjects to be approximately 221. 
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Age 18 years or older at the time of study entry 
2. Written informed consent and any locally required authorisation (eg, European Union 
[EU] Data Privacy Directive in the EU) obtained from the subject/legal representative 
prior to performing any protocol-related procedures, including screening evaluations


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3. Females of childbearing potential who are sexually active with a nonsterilised male 
partner must have evidence of not being pregnant upon enrolment and have a negative 
pregnancy test prior to administration of investigational product. 
◦
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral oophorectomy or complete hysterectomy), premenarchal, or
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause).
4. Tracheal or bronchial sample positive by polymerase chain reaction (PCR) for S aureus
within 36 hours prior to randomisation. Note: the 36-hour window will be determined by 
the time of sample collection.
5. Currently intubated, on mechanical ventilation in the ICU
6. Expected to remain intubated and mechanically ventilated for ≥ 3 days based on 
investigator estimate
7. No diagnosis of new-onset pneumonia within 72 hours prior to randomisation (subjects 
with evidence of resolved pneumonia will be eligible)
8. Expected to survive for > 2 weeks based on investigator judgment
9. Expected to participate in the study for 190 days post dose
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Acute confirmed or suspected Staphylococcal disease at study enrolment and 
investigational product dosing (endotracheal colonisation is acceptable and required [see 
Section 4.1.2, Inclusion Criterion 4])
2. CPIS of ≥ 6 based on contributing parameters measured within past 24 hours, prior to 
investigational product dosing (CPIS assessment is provided in Appendix 4)
3. Active pulmonary disease that would impair the ability to diagnose pneumonia, such as 
active tuberculosis or fungal disease, obstructing lung cancer, large pleural effusion or 
empyema, cystic fibrosis, or acute respiratory distress syndrome with lung “white out”
4. Subjects who currently have been on mechanical ventilation for > 2 weeks AND are 
known to be colonised with S aureus in lower respiratory tract for > 2 weeks
5. Subjects who are tracheostomy-dependent prior to current hospital admission
6. Receipt of anti-S aureus systemic antibiotics for > 48 hours within 72 hours prior to 
randomisation that are considered active against the S aureus strain with which the 
subject is colonised, or anticipated ongoing receipt of anti-S aureus systemic antibiotics
7. Burns > 40% body surface area
8. APACHE-II score ≥ 25 (if Glasgow Coma Scale [GCS] score is > 5) or ≥ 30 (if GCS 
score is ≤ 5), or SOFA score ≥ 9 at time of randomisation (APACHE-II and SOFA are 
provided in Appendix 5 and Appendix 6, respectively). Vasopressors only used to 
improve cerebral perfusion pressure (eg, subarachnoid hemorrhage) will not be entered 
in the calculation of the cardiovascular component of the SOFA score.


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9. Receipt of any investigational drug therapy within 30 days prior to investigational 
product dosing
10. Previous receipt of a mAb
11. Subjects with human immunodeficiency virus (HIV) infection, who in the opinion of the 
investigator, do not have well-controlled HIV infection. Subjects with a history of HIV 
infection who have been on highly active antiretroviral therapy and asymptomatic from 
HIV infection for at least 6 months may be enrolled.
12. Lymphoma not in complete remission and on chemotherapy
13. Recipients of bone marrow, stem cell, or solid organ transplant who are not currently in 
complete remission
14. Receipt of chemotherapy or other immunosuppressive drugs including glucocorticoid 
therapy (prednisone 20 mg or equivalent, daily or every other day for 30 days) in past 2 
months 
15. History of allergic disease or reactions likely to be exacerbated by any component of the 
investigational product 
16. Not able to complete follow-up for at least 30 days post dose based on investigator 
judgment
17. Pregnant or nursing female
4.1.4
Subject Enrolment and Randomisation
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained from the potential subject or their guardian/legal representative before any 
study-specific procedures are performed. Those subjects who are unconscious or considered 
by the investigator clinically unable to consent at screening and who are entered into the 
study by the consent of a legally acceptable representative should provide their own written 
informed consent for continuing to participate in the study as soon as possible on recovery, as 
applicable, in accordance with local regulations (see Section 7.4 for description of informed 
consent process). 
Once informed consent is obtained, a subject identification (SID) number will be assigned by 
a central system (eg, an interactive voice/interactive web response system [IVRS/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 Clinical Coordinating Centre (CCC) will be available to the study sites 24 hours/day, 
365 days/year to evaluate subjects for study eligibility. The CCC will review the inclusion 
and exclusion criteria to determine if a subject meets the requirements for randomisation. 
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 


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be randomised or receive investigational product. See Section 4.6.1 for information on 
randomisation and assignment of treatment group.
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 randomised), including the reason(s) for screening failure.
Subjects who have failed screening may be rescreened and will receive a new SID. Subjects 
who are considered for rescreening beyond 7 days from the initial informed consent should 
be reconsented prior to being rescreened.
4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will 
be seen and assessed by an investigator. If a subject withdraws from further participation in 
the study, then no further study visits or data collection should take place.
In the event that a subject notifies the investigator ahead of a scheduled visit that he/she 
would not be able to participate in the study beyond the upcoming study visit, all attempts 
must be made to collect assessments included as part of the Day 91 visit (if the decision is 
made prior to Day 91) and the end-of-study visit (Day 191). Once the subject withdraws 
consent, no additional study assessments will be performed.
Lost to Follow-up
Subjects will be considered lost to follow-up only if no contact has been established through
the time of the subject’s last protocol-specified visit/assessment (as defined in Section 6.3). 
Subjects refusing to abide by the study requirements or to continue participation in the study 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing subjects 
throughout the study period. If contact with a missing subject is re-established, the subject 
should not be considered lost to follow-up and any evaluations should resume according to 
the protocol. For subjects who are unable to attend a study visit in person for unforeseen 
reasons beyond their control, the investigator must utilise all means to perform whatever 
assessments possible, eg, assessing safety by telephone. If contact is lost after hospital 
discharge and not re-established until after Day 91, the Medical Monitor will determine 
whether any Day 91 or other missed assessments should be completed. 


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4.1.6
Discontinuation of Investigational Product
All randomised subjects will receive a single dose of investigational product. An individual 
subject will not receive investigational product if any of the following occur in the subject in 
question:
1. Withdrawal of consent
2. An AE that, in the opinion of the investigator or the sponsor, contraindicates dosing
3. Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation
4. A severe or potentially life-threatening serious systemic, allergic, or local reaction with 
onset after dosing has been initiated. If such a reaction is observed during investigational 
product infusion, the infusion would be immediately stopped, no further investigational 
product will be administered and the medical monitor must be contacted immediately.
Subjects who have not received investigational product, regardless of reason, will not be 
followed. Unless consent for follow-up is withdrawn, subjects discontinued after receiving at 
least a partial dose of investigational product will be followed for the full study period with 
all laboratory and clinical evaluations collected as defined in the protocol (see Section 6.3).
4.1.7
Replacement of Subjects
Once a subject has been randomised the subject will not be replaced, including cases where 
subjects are randomised but not dosed or are randomised but do not complete any study 
evaluation.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor.
Samples Obtained for Future Research
Samples obtained for future research will be labeled with a sample identification number
linked to the SID number but will not be labeled with personal identifiers such as the 


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subject’s name. If the subject withdraws consent for participating in the future research, the 
sponsor will locate the subject’s sample and destroy it. The coding of samples and results is 
to ensure that these research results are kept confidential by keeping the subject’s identity 
and these results separate. 
If the subject consents to have his/her samples used for future research, this additional 
research may not start immediately and may start at any time during the storage period. The 
subject’s sample(s) will be stored by the sponsor with similar samples from other subjects at 
a secure central laboratory. The subject’s samples will not be kept for more than 25 years 
after the end of the study in which they were collected. If the subject chooses not to allow 
his/her study samples to be used for future research, the samples will be destroyed by the 
sponsor once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for future research, the investigator will arrange to have it destroyed. If 
consent is withdrawn after the subject’s sample(s) have been sent to the sponsor for future 
research, the sponsor and the investigator will ensure that these sample(s) are destroyed 
unless the sample identification number has been removed and the subject can no longer be 
linked to any sample(s). However, if the subject’s samples have already been used for 
research, the sponsor is not required to destroy results of this research. In this case, only the 
remaining sample(s) will be destroyed.
4.2
Schedule of Study Procedures
4.2.1
Enrolment/Screening Period
Table 4.2.1-1 shows all procedures to be conducted during the screening period. Assessments 
should be performed in the order shown in the table.
Table 4.2.1-1
Schedule of Screening Procedures 
Assessment
Screening
(up to 7 days prior to 
randomisation)
Written informed consent a
X
Assignment of SID number
X
Medical history
X
Physical examination
X
Height 
X
Weight
X
Serum βhCG b
X c
Disease Assessment


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Table 4.2.1-1
Schedule of Screening Procedures 
Assessment
Screening
(up to 7 days prior to 
randomisation)
Evaluate for clinical symptoms of pneumonia/serious S aureus infection 
(physical exam, vital signs, CPIS assessment, SOFA, APACHE-II, GCS, 
PaO2/FiO2 ratio, as clinically indicated)
X
Chest X-ray
X
Safety Assessments
Vital signs
X
Serum chemistry
X c
Hematology
X c
Urinalysis
X c
AEs and SAEs
X
Concomitant medications
X
Tracheal or bronchial aspirate for S aureus colonisation by PCR
X d
Tracheal/bronchial aspirate for Gram stain
X e
Tracheal/bronchial aspirate for culture
X e
Verify eligibility criteria
X
AE = adverse event; APACHE = Acute Physiology and Chronic Health Evaluation; βhCG = beta human 
chorionic gonadotropin; CPIS = Clinical Pulmonary Infection Score; GCS = Glasgow Coma Scale; S aureus
= Staphylococcus aureus; PCR = polymerase chain reaction; SAE = serious adverse event; SID = subject 
identification; SOFA = Sequential Organ Failure Assessment.
a Subjects enrolled in the study with consent obtained from a legally acceptable representative will provide 
their own informed consent as soon as they are capable during the active course of study participation.
b Female subjects of child-bearing potential only; must be negative prior to randomisation.
c All screening laboratory tests will be performed within 7 days prior to randomisation. Abnormal results 
may be repeated at the investigator’s discretion, preferably within 24-48 hours.
d Tracheal or bronchial aspirate for S aureus colonisation by PCR should be obtained within 36 hours prior to 
randomisation. 
e Tracheal or bronchial aspirate Gram stain and culture should be assessed on the sample obtained for 
determination of colonization by PCR.
4.2.2
Treatment and Follow-up Periods
Table 4.2.2-1 shows all procedures to be conducted on the day of investigational product 
administration (Day 1) and during the post-dose follow-up period. Table 4.2.2-2 shows 
procedures for subjects with suspected serious S aureus infection from onset through 
resolution of illness. Assessments should be performed in the order shown in the tables.


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Table 4.2.2-1
Schedule of Treatment and Post-dose Follow-up Procedures
Assessment
Day (Assessment Window)
1
2
4
6
8
±1
15
±1
22
±1
31
+3
61
±5
91
±5
121
±10
151
±10
191
±10
Pre-
dose a
Dose
Post-
dose
Post-dose Follow-up
Eligibility
Medical history
X b
Physical examination
X b
Serum βhCG c
X
X
Verify eligibility criteria d
X
Randomisation
X
Investigational Product Administration
X
Efficacy Assessments
Monitor for clinical symptoms/signs of 
pneumonia/ serious S aureus infection 
(physical exam, vital signs, oxygen status e, 
CPIS, SOFA, as indicated)
X
X
X
Daily while in hospital; in accordance with 
symptoms after hospital discharge
For subjects with suspected pneumonia or 
bacteremia see Table 4.2.2-2
Microbiology
Blood for culture
X
Chest X-ray 
X
Safety Assessments
Vital signs f
X
X
X
X
Serum chemistry 
X b
X
X
Hematology 
X b
X
X
Urinalysis
X b
X
SAEs, AESIs, and NOCDs
X
X
X
X
X
X
X
X
X
X
X
X
X g
X g
X g


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Table 4.2.2-1
Schedule of Treatment and Post-dose Follow-up Procedures
Assessment
Day (Assessment Window)
1
2
4
6
8
±1
15
±1
22
±1
31
+3
61
±5
91
±5
121
±10
151
±10
191
±10
Pre-
dose a
Dose
Post-
dose
Post-dose Follow-up
AEs
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications for SAEs, AESIs, 
and NOCDs only
X g
X g
X g
PK/ADA/Other
Serum PK 
X h
X h
X h
X
X
X
X
X
X
X
Serum ADA
X
X
X
X


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Table 4.2.2-1
Schedule of Treatment and Post-dose Follow-up Procedures
Assessment
Day (Assessment Window)
1
2
4
6
8
±1
15
±1
22
±1
31
+3
61
±5
91
±5
121
±10
151
±10
191
±10
Pre-
dose a
Dose
Post-
dose
Post-dose Follow-up
Abs = antibodies; ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; AT = alpha toxin; βhCG = beta human 
chorionic gonadotropin; CBC = complete blood count; CPIS = Clinical Pulmonary Infection Score;
 G; min = minutes; 
NOCD = new onset chronic disease; PCR = polymerase chain reaction; PK = pharmacokinetics; S aureus = Staphylococcus aureus; SAE = serious 
adverse event; SOFA = Sequential Organ Failure Assessment.
a Assessments conducted as part of screening within 24 hours prior to randomisation do not need to be repeated.
b Update screening medical history and physical examination (any new findings since screening); baseline serum chemistry, hematology, and 
urinalysis reviewed and found to be within normal limits by site investigator.
c Female subjects of child-bearing potential only.
d ContactClinical Coordinating Centre to confirm the subject meets the requirements for randomisation within the next 6 hours. 
e Examples of oxygen status parameters are as follows: highest minute ventilation (L/min), highest FiO2 (%), lowest PaO2 results (for mechanically 
ventilated subjects); liters of oxygen (L/min), lowest O2 saturation (%), FiO2 (%) (for non-mechanically ventilated subjects).
f Vital signs will be obtained before investigational product dosing; 2 predose blood pressure and heart rate readings should be obtained 5 minutes 
apart. Vital signs will also be obtained every 30 minutes (± 5 minutes) during investigational product infusion, at completion of the infusion 
(± 5 minutes), every 30 minutes (± 5 minutes) for 2 hours after investigational product dosing, and again 24 hours post dose.
g Assessments after Day 91 through end of study may be conducted by telephone contact.
h Blood samples for PK measurement will be collected immediately prior to investigational product dosing, at the end of infusion, 8 hours after the 
end of infusion, and 24 hours after the end of infusion.
i
.
j
 


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Table 4.2.2-2
Schedule of Procedures for Subjects With Suspected or Confirmed Pneumonia or Bacteremia
Assessment a
Duration of Infection
Day 1
(Onset)
Day 2
Day 3
Day 4
Day 5 Through Resolution
Clinical Symptoms
CPIS, SOFA, physical exam, vital signs
X
Daily through clinical resolution b,c
Microbiology d
Blood sample (culture) e
All subjects 
X
X
X
Subjects positive for S aureus bacteremia
Repeat every other day until blood culture negative 
for S aureus
Tracheal/bronchial aspirate; intubated subjects only (Gram stain and culture) e
All subjects
X
X
X
Subjects positive for S aureus pneumonia
Daily through clinical resolution c
Expectorated sputum (unless bronchoscopy performed for clinical management and BAL or PSB sample available); non-intubated subjects only
(Gram stain and culture) e
All subjects
X
X
X
Subjects positive for S aureus pneumonia
Daily through clinical resolution c
Chest X-ray
Subjects with suspected pneumonia
X
Subjects with confirmed pneumonia
As clinically indicated through resolution
PK/ADA/Other f
Serum PK
X
Serum ADA
X


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Table 4.2.2-2
Schedule of Procedures for Subjects With Suspected or Confirmed Pneumonia or Bacteremia
Assessment a
Duration of Infection
Day 1
(Onset)
Day 2
Day 3
Day 4
Day 5 Through Resolution
 
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; CBC = complete blood count; CPIS = Clinical Pulmonary Infection Score; PK = pharmacokinetic; 
PSB = protected-specimen brush; S aureus = Staphylococcus aureus; SOFA = Sequential Organ Failure Assessment; WBC = white blood cell.
a
Assessments conducted as part of a scheduled visit in Table 4.2.2-1 are not to be repeated. For subjects with onset of a suspected pneumonia or bacteremia 
from Days 2 through 31, assessments will be collected at onset and through resolution of disease (even if resolution extends beyond Day 31).
b For both the CPIS assessment and SOFA, the last available chest X-ray, serum chemistry, and/or CBC values obtained within 72 hours may be used in 
determining the score.
c Clinical resolution is defined as all signs and symptoms of acute infection have subsided and the therapeutic antibiotic course has been completed.
d If pleural fluid aspirate or lung tissue is obtained as part of the subject’s necessary clinical management, the sample should also be sent for Gram stain and 
culture.
e First blood sample and/or respiratory specimen are to be collected before start of new antibiotic therapy.
f PK/ADA/Other need to be collected as indicated unless a scheduled sample was already obtained on the same date. 


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4.3
Description of Study Procedures
4.3.1
Efficacy………..
4.3.1.1
Clinical Symptoms
Subjects will be monitored for clinical symptoms of pneumonia and other serious S aureus
infection according to the assessments presented in Table 4.2.1-1 and Table 4.2.2-1 at 
screening, prior to administration of investigational product on Day 1, and from 
administration of investigational product through Day 91. For subjects with a suspected 
pneumonia or bacteremia, clinical symptoms will continue to be monitored through 
resolution of illness (see Table 4.2.2-2). The CPIS assessment, APACHE-II, and SOFA are 
provided in Appendix 4, Appendix 5, and Appendix 6, respectively. Additionally a 
conversion table for estimating PaO2 and FiO2 is provided in Appendix 7.
4.3.1.2
Microbiology
Blood and tracheal aspirate samples will be collected for microbiological assessment of 
pneumonia and other serious S aureus infection during screening and prior to administration 
of investigational product on Day 1 (see Table 4.2.1-1 and Table 4.2.2-1).
For subjects with onset of a suspected pneumonia or bacteremia from Days 2 through 91, 
blood and respiratory specimens will be collected at onset and through resolution of disease 
(even if resolution extends beyond Day 91) according to the schedule in Table 4.2.2-2. The 
first set of blood and respiratory specimens will be collected before the start of any new 
antibiotic therapy. Blood samples will be collected daily for the first 3 days of disease and 
then only for subjects who are positive for S aureus bacteremia every other day until 
resolution. While the subject is intubated, tracheal/bronchial aspirates will be collected for 
the first 3 days of disease and then daily until resolution only for subjects who are positive 
for S aureus pneumonia. If the subject is not intubated, expectorated sputum (unless 
bronchoscopy was performed for clinical management and bronchoalveolar lavage [BAL] or 
protected-specimen brush [PSB] sample is available) will be collected for the first 3 days of 
disease and then only for subjects who are positive for S aureus pneumonia daily until 
resolution. 
Blood and tracheal aspirates will be tested for methicillin-susceptible Staphylococcus aureus
(MSSA) and MRSA using standard clinical microbiological methods.


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4.3.1.3
Radiography
A chest X-ray to assess for pneumonia will be conducted according to the schedule in 
Table 4.2.1-1 and Table 4.2.2-1 and evaluated by a qualified radiologist. For subjects with 
pneumonia, a chest X-ray will be conducted at onset of pneumonia and as clinically indicated 
through resolution of illness (see Table 4.2.2-2).
4.3.1.4
Definition of S aureus Pneumonia
1. S aureus Pneumonia Criteria for Subjects Who are Mechanically Ventilated 
at the Time of Diagnosis 
(Subject will be considered mechanically ventilated if:
▪
Subject is intubated with an endotracheal or nasotracheal tube and 
receiving positive pressure ventilation support, or
▪
Subject is not intubated with an endotracheal or nasotracheal tube, but 
requires ≥8 hours of positive pressure ventilation (eg, subjects with 
tracheostomy, continuous positive airway pressure [CPAP], etc) within 
the past 24 hours)
Subject should demonstrate the following new onset of symptoms/signs deemed not due to 
any overt non-infectious causes. All 3 criteria (ie, radiographic, clinical, AND microbiologic) 
must be met in order to meet the S aureus pneumonia endpoint.
a. Radiographic criteria:
•
New or worsening infiltrate consistent with pneumonia on chest X-ray obtained 
within 24 hours of the event (diagnosed by a qualified radiologist)
AND
b. Clinical criteria:
At least 2 of the following minor or 1 major respiratory signs or symptoms, of new onset:
•
Minor criteria:
◦
Systemic signs of infection (one or more of the following): Abnormal temperature 
(oral or tympanic temperature > 38°C or a core temperature ≥ 38.3°C or 
hypothermia, defined as a core body temperature of < 35°C), and/or abnormal 
WBC (WBC count > 10,000 cells/mm3, WBC count < 4500 cells/mm3, or 
> 15% band neutrophils)
◦
Production of purulent endotracheal secretions
◦
Physical examination findings consistent with pneumonia/pulmonary 
consolidation (eg, rales, rhonchi, bronchial breath sounds), dullness to percussion


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•
Major criteria
◦
Acute changes made in the ventilatory support system to enhance oxygenation, as 
determined by: 
▪
PaO2/FiO2 ratio < 240 mmHg maintained for at least 4 hours, or 
▪
A decrease in PaO2/FiO2 by ≥ 50 mmHg maintained for at least 4 hours
AND
c.
Microbiologic confirmation: 
At least 1 of the following (obtained within 24 hours of onset of the event):
•
Respiratory specimen is positive for S aureus by culture. Includes a specimen of 
respiratory secretions obtained by endotracheal aspiration or by bronchoscopy with 
BAL or PSB sampling in intubated subjects. In subjects who are not intubated but 
meet the protocol definition of mechanical ventilation, a specimen of expectorated 
sputum would be acceptable.
•
Blood culture positive for S aureus (and no apparent primary source of infection 
outside the lung)
•
Pleural fluid aspirate or lung tissue culture positive for S aureus during episode of 
pneumonia (only if obtained as part of the subject’s necessary clinical management)
2. S aureus Pneumonia Criteria for Subjects Who are Not Mechanically 
Ventilated at the Time of Diagnosis
A subject is not considered to be mechanically ventilated when an endotracheal or 
nasotracheal tube is not in place and the subject does not require positive ventilation support 
for at least 8 hours. 
Subject should demonstrate the following new onset of symptoms/signs deemed not due to 
any overt non-infectious causes. All 3 criteria (ie, radiographic, clinical, AND microbiologic) 
must be met in order to meet the S aureus pneumonia endpoint. 
a. Radiographic criteria:
•
New or worsening infiltrate consistent with pneumonia on chest X-ray obtained 
within 24 hours of the event (diagnosed by qualified radiologist)
AND
b. Clinical criteria:
At least 2 of the following minor or 1 major respiratory signs or symptoms:
•
Minor criteria:


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◦
Systemic signs of infection: Abnormal temperature (oral or tympanic temperature 
> 38°C or a core temperature ≥ 38.3°C or hypothermia, defined as a core body 
temperature of < 35°C), and/or abnormal WBC (WBC count > 10,000 cells/mm3, 
WBC count < 4500 cells/mm3, or > 15% band neutrophils)
◦
A new onset of cough (or worsening of cough)
◦
Production of purulent sputum
◦
Physical examination findings consistent with pneumonia/pulmonary 
consolidation such as auscultatory findings (eg, rales, rhonchi, bronchial breath 
sounds), dullness to percussion, or pleuritic chest pain
◦
Dyspnea, tachypnea (respiratory rate > 30 breaths/minute), or hypoxemia defined 
as:
▪
O2 saturation < 90% or PaO2 < 60 mmHg on room air if lower than baseline, 
or
▪
A need to initiate or increase sustained (≥ 3 hours) supplemental oxygen to 
maintain pre-event baseline O2 saturations
•
Major criteria
◦
A need to initiate non-invasive mechanical ventilation or re-initiate invasive
mechanical ventilation because of respiratory failure or worsening of respiratory 
status
AND
c.
Microbiologic confirmation:
At least 1 of the following (obtained within 72 hours of onset of the event):
•
Respiratory specimen is positive for S aureus by culture. Includes either expectorated 
sputum or (only if obtained as part of the subject’s necessary clinical management) a 
specimen of respiratory secretions obtained by bronchoscopy with BAL or PSB 
sampling. Respiratory samples from expectoration must show < 10 squamous 
epithelial cells and > 25 polymorphonuclear neutrophils per 100x field to be suitable.
•
Blood culture positive for S aureus (and no other apparent primary source of infection 
outside the lung)
•
Pleural fluid aspirate or lung tissue culture positive for S aureus (only if obtained as 
part of the subject’s necessary clinical management)
4.3.2
 
 
 


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4.3.3
Medical History and Physical Examination, Weight, and Vital Signs
Medical history and a targeted physical examination, including height and weight, will be 
conducted at screening. Any new findings since screening for medical history and physical 
examination will be updated on Day 1 prior to administration of investigational product. 
Vital signs will include blood pressure, heart rate, respiratory rate, and temperature 
(rectal/core, oral, or tympanic). All vital signs will be collected at screening, Day 1, and 
Day 2 according to the schedule in Table 4.2.1-1 and Table 4.2.2-1. Vital signs will also be 
used to monitor for clinical symptoms of suspected pneumonia and bacteremia as clinically 
indicated through Day 91. 
4.3.4
Clinical Laboratory Tests
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in an
accredited clinical laboratory. Abnormal laboratory results may be repeated at the 
investigator’s discretion, preferably within 24 to 48 hours. 
The following clinical laboratory tests will be performed (see Table 4.2.1-1 and Table 4.2.2-1
for the schedule of tests): 
Serum Chemistry
Calcium
Alkaline phosphatase (ALP)
Chloride
Gamma glutamyl transferase (GGT)
Potassium
Creatinine
Sodium
Blood urea nitrogen (BUN)
Bicarbonate
Glucose (fasting or non-fasting) 
Aspartate transaminase (AST)
Total bilirubin
Alanine transaminase (ALT)
• Creatine kinase
Note for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently.


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Hematology
• WBC count with differential
• Hemoglobin
• RBC count
• Platelet count
• Hematocrit
Urinalysis
• Color
• Glucose
• Appearance
• Ketones
• Specific gravity
• Blood
• pH
• Bilirubin
• Protein
• Leukocytes
• Nitrite
• Microscopy including WBC/high-power field (HPF), 
RBC/HPF
Pregnancy Test (females of childbearing potential only)
Serum beta-hCG (at screening, prior to randomisation [if > 24 hours after screening], and on Day 91)
4.3.5
Pharmacokinetic Evaluation and Methods
Blood 
 samples will be collected to evaluate PK of MEDI4893 
in serum 
, according to the schedule in Table 4.2.2-1. 
For subjects with a suspected pneumonia and bacteremia, blood 
 
 samples will be collected for PK evaluation on the day of onset of illness (see 
Table 4.2.2-2). 
 
. The PK of MEDI4893 in serum 
 will be 
measured using a validated sandwich enzyme-linked immunosorbent assay (ELISA) method.
4.3.6
Anti-drug Antibody Evaluation and Methods
Blood samples will be collected to evaluate ADA responses to MEDI4893 in serum 
according to the schedule in Table 4.2.2-1. For subjects with a suspected pneumonia and 
bacteremia, blood samples will be collected for ADA evaluation on the day of onset of illness
(see Table 4.2.2-2).
Evaluations for ADA will be performed using a set of electrochemiluminescent, solution-
phase, bridging immunoassays. A drug-tolerant electrochemiluminescent assay will be used 


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to detect ADA because it is expected to be less susceptible to interference in the presence of 
residual drug levels 90 days post dose. Tiered analyses will be performed to include 
screening, confirmatory, and titer assay components, and positive-negative cutoff points will 
be employed that were statistically determined from drug-naive validation samples. Samples 
confirmed positive for ADA may be characterised for neutralising antibody activity.
4.3.7
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.3.9
Estimate of Volume of Blood to be Collected
Investigators should ensure that the maximum volume of blood drawn per day meets their 
standard institutional guidelines and that samples are prioritised accordingly. The amount of 
blood to be taken from an individual subject is estimated on a per-day basis across all tests 
combined in Table 4.3.9-1. Many of the study specified blood tests and cultures may replace 
those that would be ordered with routine ICU medical management, therefore the table 
represents a conservative estimate of study specific phlebotomy volume. Additional samples
may be obtained for assessment of safety or as necessary for medical management; for 
example, clinically significant abnormal laboratory values are to be repeated, preferably 
within 24 to 72 hours.
Table 4.3.9-1
Estimated Volume of Blood to be Collected per Visit
Visit
Estimated Volume of Blood (mL)
Screening
10
Day 1
30
Day 2
30
Day 4
10
Day 6
10
Day 8
10
Day 15
10
Day 22
10
Day 31
20
Day 61
10
Day 91
10
Total
160
Subjects with Suspected or Confirmed Pneumonia or Bacteremia
Day 1 of illness
30
Day 2 of illness
10
Day 3 of illness 
10
Day 4 of illness
20
Day 6 of illness and every other day through resolution
(only for subjects positive for S aureus bacteremia)
10
Day of resolution
20
S aureus = Staphylococcus aureus.


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4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. 
The reasons for temporarily suspending or terminating the study may include but are not 
limited to the following: 
1. Death in any subject in which the cause of death is assessed as related to investigational 
product 
2. Anaphylaxis that is related to investigational product 
3. Other events that, in the judgment of the sponsor or the principal investigator, are deemed 
serious enough to warrant immediate review by an independent DMC (see Section 4.8.10
for description of data review committees)
4. Subject enrolment is unsatisfactory
5. Noncompliance that might significantly jeopardise the validity or integrity of the study 
6. Sponsor decision to terminate development
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Independent Ethics Committee (IEC) promptly and provide the reason(s) for the 
suspension/termination. If the study is suspended for safety reasons and it is deemed 
appropriate by the sponsor to resume the study, approval from the relevant regulatory 
authorities (and IECs when applicable) will be obtained prior to resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Products
MedImmune will provide the investigators with investigational product (Table 4.5.1-1) using 
designated distribution centers. 


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Table 4.5.1-1
Identification of Investigational Products
Investigational Product
Manufacturer
Concentration and Formulation as Supplied
MEDI4893
MedImmune
 
 
Placebo
MedImmune
 
Investigational product should be stored at 2°C to 8°C.
Investigational product will be supplied to the site in open-labeled kits. Each kit has a unique 
number printed on all labels within the kit (ie, the outer carton label and the label of each 
vial). 
Refer to Section 4.6.2 for information on coding of the container for blinding purposes.
4.5.1.1
Investigational Product Dose Preparation
Preparation of MEDI4893 or placebo and preparation of the infusion bag are to be performed 
by an unblinded investigational product manager using aseptic technique. Total in-use 
storage time from needle puncture of the first vial of MEDI4893 or placebo for 
investigational product preparation to start of administration should not exceed 4 hours at 
room temperature. If storage time exceeds these limits, a new dose must be prepared from 
new vials and the study monitor must be notified immediately.
4.5.1.2
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. MEDI4893 is supplied as a
solution at a concentration of 
 mg/mL.
If there are any defects noted with the investigational product, the Investigator and Site 
Monitor should be notified immediately. Refer to Section 4.5.1.6 for further instructions.


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4.5.1.3
Dose Preparation Steps
The dose preparation steps are as follows:
1. The required volume of investigational product (MEDI4893 or placebo) will be prepared 
in 
-mL infusion bags. Infusion bags should be composed of polyolefin, polyethylene, 
polypropylene, or ethylene vinyl acetate, and be free of latex, polyvinyl chloride (PVC), 
and di(2-ethylhexyl)phthalate (DEHP). Polypropylene syringes should be used for dose 
preparation.  
2. To prepare investigational product, the investigational product manager should remove 
the tab portion of the vial cap and clean the rubber stopper with 70% ethanol or 
equivalent and allowed to air dry. To avoid foaming, the vial should not be shaken.
3. From a 
-mL infusion bag of 0.9% normal saline, withdraw and discard the entire 
contents of the bag using a syringe with no more than 2 punctures to the IV bag port.
4. To prepare the dose, the required volumes of investigational product and commercially 
available saline (Table 4.5.1.3-1) should be added either through an intermittent 
injection port that would allow multiple needle sticks, to the intermittent injection port, 
or by using a syringe with no more than 2 punctures to the IV bag port. For ease of 
preparation, a 1.5-inch 19-gauge withdrawal needle is recommended. Use a new needle 
for withdrawing investigational product from each vial.  
5. Gently mix the contents of the infusion bag. The resulting mixture should be inspected 
to ensure that the solution is clear.
Table 4.5.1.3-1 Investigational Product Dose Preparation
Treatment Group
Capacity of 
Infusion 
Bag (mL)
Investigational 
Product Dose 
Volume (mL)
Number 
of Vials 
Required
Volume of Saline 
to be Added to 
Infusion Bag (mL)
Total Filled Bag 
Volume (mL)
mg MEDI4893
mg MEDI4893
Placebo
4.5.1.4
Treatment Administration
The day of dosing with investigational product is considered Day 1.
All subjects must receive the 
-mL investigational product (MEDI4893 or placebo) 
solution IV through a dedicated line (either central or peripheral) until the entire 
investigational product solution has been infused. MEDI4893 or placebo must be 
administered through a low-protein binding 0.22-μm inline filter using an IV infusion pump
over a minimum duration of 
 minutes. (Table 4.5.1.4-1). MEDI4893 or placebo must 
never be administered via IV push or bolus.


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Table 4.5.1.4-1 Duration of Infusion by Treatment Group and Investigational 
Product Solution Volume
Treatment Group
Total Investigational Product Solution 
Volume Per Bag (mL)
Minimum Duration a of Infusion 
(min)
mg MEDI4893
mg MEDI4893
Placebo
a If the maximum infusion duration exceeds 8 hours, the medical monitor must be notified immediately in case 
of such a delay.
During preparation of the investigational product infusion, the capacity of the tubing should 
be calculated in order to adjust the volume of investigational product solution needed to 
prime the IV tubing (see example below). This step is necessary because the same volume of 
saline will be needed at completion of the infusion to flush the IV tubing in order to deliver 
the complete volume of investigational product solution. Because the IV tubing contains 
investigational product solution, the flush must be infused using the same infusion rate as 
that used for the investigational product solution in the infusion bag.
Example:
If the IV tubing capacity is 
 mL, the IV tubing should be primed with 
 mL of 
investigational product solution from the investigational product infusion bag before 
initiating the investigational product infusion. Once the investigational product infusion bag 
is empty, the IV tubing should be flushed with at least 
 mL of 0.9% normal saline via 
infusion pump at the same rate as dosing.
The start time of the investigational product infusion will be the time the infusion of the 
investigational product solution from the infusion bag (with IV tubing already primed with 
investigational product solution) is started. The stop time of the infusion should be the time 
the IV tubing has been flushed to administer the residual investigational product solution.
4.5.1.5
Monitoring of Dose Administration
Subjects will be monitored with assessment of vital signs (temperature, respiration rate, heart 
rate, and blood pressure). Vital signs will be obtained before the start of investigational 
product infusion (2 pre-dose blood pressure and heart rate readings should be obtained 
5 minutes apart), every 30 minutes (± 5 minutes) during investigational product infusion, at 
completion of the infusion (± 5 minutes), every 30 minutes (± 5 minutes) for 2 hours after 
infusion of investigational product, and again 24 hours post dose.


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As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylaxis must be immediately 
available, and study personnel must be trained to recognise and treat anaphylaxis.
4.5.1.6
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:
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 (GMP) and local regulatory guidelines. The label will fulfill GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.4
Storage…………
Store investigational product at 2°C to 8°C.


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4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a MedImmune-
authorised depot or disposed of upon authorisation by MedImmune.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IVRS/IWRS will be used for randomisation to a treatment group and assignment of 
blinded investigational product kit number. A subject is considered randomised into the study 
when the investigator notifies the IVRS/IWRS that the subject meets eligibility criteria and 
the IVRS/IWRS assigns a treatment arm and blinded investigational product kit number to 
the subject. The IVRS/IWRS will send confirmation of this information to the unblinded 
investigational product manager who dispenses the investigational product to the subject per 
the response system and records the appropriate information in the subject’s medical records 
and investigational product accountability log.
At study start, subjects were randomly assigned in a 1:1:1 ratio to receive a single IV dose of 
 mg MEDI4893, 
 mg MEDI4893, or placebo. After the DMC reviewed the PK 
interim analysis data, the DMC recommended that enrolment in the 
 mg MEDI4893 
group be discontinued, and that the study proceed with enrolment in the 
 mg MEDI4893 
and placebo groups. Thus, subsequent to Protocol Amendment 4, subjects will be randomised 
at a 1:1 ratio to receive either 
mg MEDI4893 or placebo. Randomisation will be 
stratified by country and then by whether or not subjects received anti-S aureus systemic 
antibiotic (treatment for ≤48 hours) within the 72 hours prior to investigational product 
administration. Detailed instructions for the randomisation process will be provided in the 
IVRS manual.
The subject should be randomised no later than 6 hours after obtaining approval from the 
CCC. In case of a delay, the CCC should be contacted again to confirm that the subject still 
meets the requirements for randomisation.


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Investigational product (MEDI4893 or placebo) infusion must be initiated the same day and 
within 6 hours after randomisation or within 4 hours of first vial puncture for investigational 
product preparation. If there is a delay in the administration of investigational product such 
that it will not be administered within the specified timeframe, the study monitor must be 
notified immediately. The duration between the start of investigational product infusion and 
the completion of infusion must be within 8 hours. In the event of a delay that prevents 
completion of infusion within 12 hours of start of investigational product preparation, the 
medical monitor must be notified immediately. Details of the administration procedure are 
presented in Section 4.5.1.4.
4.6.2
Methods for Ensuring Blinding
This is a double-blind study in which MEDI4893 and placebo are identical in appearance. 
Neither the subject/legal representative nor any of the investigator or sponsor staff who are 
involved in the treatment or clinical evaluation of the subjects will be aware of the treatment 
received (ICH E9) (see Section 4.6.3.2 for unblinding related to interim analysis). 
Investigational product will be handled by an unblinded investigational product manager at 
the site. An independent investigational product monitor will also be unblinded to perform 
investigational product accountability. The unblinded personnel will not reveal the treatment 
allocation to the sponsor or blinded site staff. In the event that the treatment allocation for a 
subject becomes known to the investigator or other study staff involved in the management 
of study subjects, the sponsor must be notified immediately. 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 and, if possible, before unblinding the treatment allocation. 
The site will maintain a written plan detailing which staff members are blinded/unblinded 
and the process of investigational product administration used to maintain the blind.
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. The investigator should first attempt to contact the medical 
monitor, prior to unblinding the investigational product allocation for the subject, to discuss 
the medical emergency and the reason for wanting to unblind, as long as it does not 
jeopardise the safety of the individual subject. Instructions for unblinding an individual 
subject’s investigational product allocation are contained in the IVRS/IWRS manual. In 
general, unblinding should only occur if management of the medical emergency would be 
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cases, the management of a medical emergency would be the same whether or not 
investigational product was received by the subject. If this was the case, the investigational 
product allocation should not be unblinded.
MedImmune retains the right to unblind the treatment allocation for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities.
4.6.3.2
Unblinding for Interim Pharmacokinetic Analysis Purposes
One interim PK analysis is planned and will occur after at least 10 subjects from each 
treatment group are followed through 30 days post dose. Description of this analysis is 
provided in Section 4.8.11. To ensure the blinding of each subject’s treatment assignment 
throughout the study, the interim analysis will be performed by a limited number of sponsor 
personnel who are not involved in the conduct of the study. The PK analysis will be 
performed by a MedImmune pharmacokineticist, who will present the PK interim analysis 
data to the DMC. The DMC will be responsible for recommending dose adjustment or 
potential study termination as outlined in the criteria specified in Section 4.8.11. Site 
investigators and site monitors will remain blinded to the treatment assignment of individual 
subjects until the last subject completes the study and the database is locked. Sponsor 
personnel who will have access to the treatment assignments of individual subjects in order 
to prepare the PK dataset for the analysis will be identified in the unblinding plan. Further 
details will be included in the unblinding plan before the interim analysis is performed.
4.6.3.3
Unblinding for Stage 1 Analysis Purposes
The Stage 1 analysis will be conducted after the last subject has completed follow-up through 
30 days post dose, and will be the primary analysis for efficacy. In this analysis, the safety, 
serum PK and ADA data will be summarised through 30 days post dose. In addition, all 
available data as of the data cut-off date will also be summarised. Description of this analysis 
is provided in Section 4.8.12. Sponsor personnel will be unblinded at this primary analysis. 
Study site personnel and the subjects will remain blinded to the treatment assignment of
individual subjects until the last subject completes the study and the database is locked. 
4.7
Restrictions During the Study and Concomitant Treatment
4.7.1
Contraception
Female subjects of child bearing potential (who are sexually active with a nonsterilised male 
partner) will be advised to avoid becoming pregnant by initiating and continuing at least 
1 effective method of contraception for 190 days after receipt of investigational product; 


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cessation of contraception after this point should be discussed with a responsible physician.
A highly effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of contraception. The 
acceptable methods of contraception are described in Table 4.7.1-1.
Table 4.7.1-1
Highly Effective Methods of Contraception
Nonhormonal Methods
Hormonal Methods
• Vasectomised sexual partner
• Tubal occlusion
• IUD
• Levonorgestrel-releasing intrauterine system
• Medroxyprogesterone injections 
• Etonogestrel implants
• Normal and low-dose combined oral pills
• Norelgestromin/EE transdermal system
• Intravaginal device (eg, EE and etonogestrel)
• Desogestrel
EE = ethinyl estradiol; IUD = intrauterine device
4.7.2
Concomitant Medication
The Investigator must be notified as soon as possible about concomitant medication use. Any 
concomitant medication(s), including herbal preparations, taken from the time of screening 
through Day 91 must be reported to the Investigator and recorded. After Day 91 through end 
of study, only concomitant medication used to treat SAEs, AESIs, or NOCDs must be 
reported to the Investigator and recorded.
4.7.2.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate therapeutic and supportive care. Specifically, subjects should receive full 
medical care during the study, including contraceptives, transfusions of blood and blood 
products, and treatment with antibiotics, anti-emetics, anti-diarrheals, analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines.
4.7.2.2
Prohibited Concomitant Medications
Investigators are reminded to minimise concomitant medication use unless necessary for 
medical management. Any other experimental/investigational products are prohibited 
through Day 91. The sponsor must be notified in the event that a subject was to receive an 
investigational product.


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4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be 
summarised by the number and percentage of subjects in each category. Continuous variables 
will be summarised by descriptive statistics, including mean, standard deviation, median, 
minimum, and maximum. No multiplicity adjustments will be made to any of the analyses
because this is a Phase 2 study. Subjects who discontinue prior to the 30-day post-dose 
follow-up will be included in the primary efficacy (ie, modified Intent-to-treat [mITT]) 
population as described in the primary efficacy analysis section below. Due to the decision to 
discontinue the lower dose arm, no dose adjustment will occur. The key efficacy analyses 
will be based on 
 mg MEDI4893 and placebo subjects. Subjects who received 
 mg 
MEDI4893 will be summarized descriptively.
Analysis Populations
The ITT Population is defined as all subjects who are randomised. Subjects will be analysed 
by the treatment group corresponding to their randomised treatment. 
The mITT Population is defined as all subjects who are randomized into the study and who 
receive any amount of investigational product. Subjects will be analysed by the treatment 
group corresponding to their randomised treatment. All analyses, with the exception of 
safety, will be performed on the mITT Population.
The As-treated Population will include all subjects who are randomised into the study and 
who receive any amount of investigational product. Subjects will be analysed by the 
treatment group corresponding to the treatment actually received. All safety analyses will be 
performed on the As-treated Population.
4.8.2
Sample Size and Power Calculations
Approximately 206 colonised subjects will be enrolled and randomised in a 1:1 ratio to one 
of 2 treatment groups: 
 mg MEDI4893 (N = 103) or placebo (N = 103). As the study is 
blinded, it is estimated that approximately 15 subjects may have already been enrolled and 
randomised in the 
 mg dose, prior to the decision of discontinuing this lower dose arm, 
making the total number of study subjects to be approximately 221.
 
 As such, a study with a sample size of N = 184 (
mg MEDI4893 [N = 92] or 
placebo [N = 92]) will allow 70% power at 2-sided significance level of α = 0.1 to detect a 


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relative risk reduction 50% comparing 
 mg MEDI4893 versus placebo. A Poisson 
regression with robust variance (Zou, 2004) is employed in the calculation. A total of 221 
subjects is derived when considering 10% attrition and adding an estimated 15 subjects in the 
 mg dose.
•
 
In 
addition, 50% relative reduction was demonstrated in a study by Francois and colleagues 
(François et al, 2012) involving a monoclonal antibody to prevent Pseudomonas 
pneumonia in mechanically ventilated patients, supporting the biological feasibility of 
such an effect.
4.8.3
Efficacy…………
4.8.3.1
Primary Efficacy Analysis
The percent reduction of incidence of S aureus pneumonia following administration of 
investigational product through 30 days post dose will be the primary efficacy endpoint. For 
subjects with multiple S aureus pneumonia events, only the first occurrence will be used in 
the primary analysis.
The primary analysis of the primary endpoint will be evaluated using the mITT Population. 
S aureus pneumonia that occurs prior to discontinuation will contribute to the primary 
efficacy analysis. If no S aureus pneumonia occurs prior to discontinuation, the subject will 
be considered as having no S aureus pneumonia infection in the primary efficacy analysis. A 
Poisson regression model with robust variance (Zou, 2004) will be used as the primary 
efficacy analysis, to estimate the relative risk of S aureus pneumonia through 30 days post 
dose between 
 MEDI4893and placebo, using the term of treatment group as a 
covariate. The primary analysis will be implemented using the SAS PROC GENMOD 
procedure with the REPEATED statement for subject ID and logarithm link. The percent of 
relative risk reduction [(1 – relative risk) * 100%], 2-sided p-value and corresponding 2-sided 
90% CI around the estimated percent relative risk reduction will be provided from the model. 
Statistically significant treatment effect will be claimed if the 2-sided p-value ≤0.1.
4.8.3.2
 
 
 
 


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4.8.3.3
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.8.4
Safety………….
In the Stage 1 analysis, the safety data will be summarised by treatment group through 30 
days post dose. In addition, all available data as of the data cut-off date will also be 
summarised. For Stage 2 analysis, safety data through 90 days post dose and through the end 
of the study will be summarised by treatment group. All safety analyses will be conducted 
using the As-treated Population.
4.8.4.1
Analysis of Adverse Events
Safety of MEDI4893 will primarily be assessed and measured by the occurrence of all 
TEAEs and TESAEs.
•
Occurrence of AEs from the period immediately following administration of 
investigational product through 30 days and 90 days post dose 
•
Occurrence of SAEs from the period immediately following administration of 
investigational product through 190 days post dose
•
Occurrence of AESIs to include targeted AEs of hepatic function abnormalities,
anaphylaxis and serious allergic reactions (including hypersensitivity), infusion-related
reactions, and immune complex disease (eg, vasculitis, endocarditis, neuritis, 
glomerulonephritis) from the period immediately following investigational product 
administration through 190 days post dose
•
Occurrence of NOCDs from the period immediately following investigational product 
administration through 190 days post dose
Adverse events and SAEs will be summarised by Medical Dictionary for Regulatory 
Activities system organ class and preferred term, and by severity and relationship to 
investigational product.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Clinical laboratory measurements (ie, serum chemistry, hematology, and urinalysis) will be 
summarised from baseline through 30 days post dose. 


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4.8.5
 
 
 
 
4.8.6
Pharmacokinetics 
Individual MEDI4893 concentrations in serum will be tabulated for all subjects by treatment 
group along with descriptive statistics through 90 days post dose. Individual MEDI4893 
concentrations in tracheal aspirate will be assessed for intubated subjects who are intubated 
for any duration through 90 days post dose as an exploratory endpoint. Noncompartmental 
PK data analysis will be performed for MEDI4893 data obtained from treatment group with 
scheduled PK sample collection where data allows. Relevant descriptive statistics of 
noncompartmental PK parameters for MEDI4893 will be provided and may include area 
under the concentration-time curve, maximum observed concentration, clearance, and
half-life.
4.8.7
Anti-drug Antibody Response
The immunogenic potential of MEDI4893 will be assessed by summarising the number and 
percentage of subjects who develop detectable ADAs in serum through 90 days post dose. 
The impact of ADA on PK will be assessed if data allow. Safety data will also be assessed in 
subjects with ADA.
4.8.8
 
 


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•
 
 
 
 
 
 
 
 
4.8.10
Data Review Committees
Safety data will be reviewed regularly by the sponsor and an independent DMC. Efficacy 
data will be assessed by a blinded independent adjudication committee.
Data Monitoring Committee
An independent DMC will review safety data regularly and make recommendations 
regarding further study conduct.
Adjudication Committee
A blinded independent endpoint adjudication committee will review clinical, radiographic, 
and microbiologic data for adjudication of efficacy endpoints, and may request to review all 
data relevant to a potential case, including any radiographic and imaging studies performed 
for medical management of a subject, and any other clinical and/or microbiologic data as 
deemed relevant by the adjudication committee. 
4.8.11
Interim Analyses
One interim analysis was planned. The interim analysis occurred after at least 10 subjects 
from each treatment group were followed through 30 days post dose to compare the serum 


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PK profile of MEDI4893 in mechanically ventilated subjects in this study with healthy adult 
subjects dosed in the Phase 1 study (Study CD-ID-MEDI4893-1133). An independent DMC 
was responsible for recommending dose adjustment or potential study termination as outlined 
in the following criteria: If the 
 mg MEDI4893 dose serum concentrations on Day 31 
were lower than the MEDI4893 serum target level of 
µg/mL in ≥ 2 subjects, a dose 
adjustment to 
mg MEDI4893 was to be made; if the 
 mg MEDI4893 dose serum 
concentrations were lower than the MEDI4893 target level of 
µg/mL in ≥ 2 subjects, 
further enrolment was to be re-evaluated. After the DMC reviewed the interim analysis data 
(serum PK profiles of 
 and
 mg MEDI4893), the DMC recommended that 
enrolment in the 
 mg MEDI4893 group be discontinued, and that the study proceed with 
enrolment in the 
 mg MEDI4893 and placebo groups instead of making a dose 
adjustment to 
 mg MEDI4893.
4.8.12
Planned Analysis
Two formal analyses (Stage 1 and Stage 2) are planned. The Stage 1 analysis will be 
conducted after the last subject has completed follow-up through 30 days post dose and will 
be the primary analysis for efficacy, for which the study is powered. During the Stage 1 
analysis, all efficacy (ie, primary, secondary, 
 endpoints), serum PK, 
ADA, and safety data collected through 30 days post dose for the last subject enrolled will be 
analysed. The Stage 2 analysis for long-term safety follow-up will be performed after all 
subjects have completed the study (ie, approximately190 days post dose). During the Stage 2 
analysis, safety, serum PK, and ADA through 90 days post dose will be analyzed. In 
addition, 
 
 safety through 
study completion will be analysed.
5
ASSESSMENT OF SAFETY
For this study, AEs, SAEs, AESIs, and NOCDs will be assessed. Definitions, collection, and 
reporting are described in the subsections below. 
5.1
Definition of Adverse Events
The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice
(GCP) E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 


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sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including electrocardiogram finding) 
that requires medical intervention by the investigator, or a finding judged by the investigator 
as medically significant should be reported as an AE. If clinical sequelae are associated with 
a laboratory abnormality, the diagnosis or medical condition should be reported (eg, renal 
failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, urine RBC 
increased). Abnormal laboratory values that are not, in the investigator's opinion, medically 
significant and do not require intervention should not be reported as AEs.
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
•
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 jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above
◦
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 


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blood dyscrasias, or convulsions that do not result in hospitalisations; or development 
of drug dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and requires close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. 
5.3.1
Hepatic Function Abnormality
Hepatic function abnormality meeting the definition of Hy’s law is considered an AESI. 
Adverse events of hepatic function abnormality of special interest to the sponsor are defined 
as any increase in ALT or AST equal to or greater than 3 × upper limit of normal (ULN) and
concurrent increase in bilirubin equal to or greater than 2 × ULN. 
In the event of hepatic function abnormality where the etiology is unknown, timely follow-up 
investigations and inquiries should be initiated by the investigational site, based on medical 
judgment, to make an informed decision regarding the etiology of the event.
5.3.2
Anaphylaxis and Serious Allergic Reactions (Including 
Hypersensitivity) and Infusion-related Reactions
Administration of polyclonal immunoglobulin preparations and mAbs have been associated 
with anaphylaxis and serious allergic reactions (including hypersensitivity) and infusion-
related reactions that occur during or after dosing. Anaphylaxis is an acute onset, potentially 
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 hypersensitivity reaction is defined as an acute onset of an illness with involvement 
of the skin, mucosal tissue, or both, during infusion of investigational product (but does not 
meet the definition of anaphylaxis). An infusion-related reaction is defined as any other 
reaction (other than hypersensitivity or anaphylaxis) occurring during infusion of 
investigational product or felt to be temporally related to the infusion.
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions typically develop within 
30 minutes to 2 hours after the initiation of first drug infusion. However, though less 
frequent, infusion-related reactions can occur later on within first 24 hours from the start of 
infusion, and are less common following subsequent exposures. Infusion-related reactions 
may manifest with single or multiple signs and symptoms. Most of them are mild in 


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intensity, but severe and even fatal reactions have been reported. Unlike infusion-related 
reaction, 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. A 
full definition of anaphylaxis is provided in Appendix 3.
Signs and symptoms of anaphylaxis and serious allergic reactions (including 
hypersensitivity) and infusion-related reactions include, but are not limited to, fever, chills, 
rigors, myalgia, weakness, flushing, sweating, headache, dizziness, lightheadedness, 
syncope, seizure, anxiety, nasal congestion, rhinitis, sneezing, oropharyngeal or laryngeal 
oedema, bronchospasm, dyspnoea, tachypnoea, cyanosis, respiratory arrest, tachycardia, 
hypotension, arrhythmia, chest pain, ischemia or infarction, cardiac arrest,  erythema, 
pruritus, urticaria, angio-oedema, maculopapular rash, nausea, vomiting, cramping, and 
diarrhoea (Kang and Saif, 2007).
It should be noted that all subjects in this study will be mechanically ventilated (and therefore 
intubated) at the time of study drug infusion. Although laryngeal oedema is considered a 
relatively common complication of intubation, it can also be a manifestation of 
hypersensitivity reaction, especially in subjects with prior hypersensitivity reaction to the 
investigational product. Therefore, subjects with prior hypersensitivity reaction to the 
investigational product should be closely monitored for any additional signs and symptoms 
of hypersensitivity, including (but not limited) to post-extubation laryngeal oedema.
5.3.3
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 


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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. 
5.4
New Onset Chronic Disease
New onset chronic disease is a newly diagnosed medical condition that is of a chronic, 
ongoing nature. It is observed after receiving the investigational product and is assessed by 
the investigator as medically significant. Examples of NOCDs include but are not limited to 
diabetes, asthma, autoimmune disease (eg, lupus, rheumatoid arthritis), and neurological 
disease (eg, epilepsy). Events that would not be considered as NOCDs are mild eczema, 
diagnosis of a congenital anomaly present at study entry, or acute illness (eg, upper 
respiratory infection, otitis media, bronchitis).
5.5
Collection of Adverse Events
Adverse events will be recorded using a recognised medical term or diagnosis that accurately 
reflects the event. Adverse events will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to MedImmune Patient 
Safety. See Section 5.2 for the definition of SAEs and Appendix 2 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious”, it will be reported on the SAE Report Form.
Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic mAbs delivered through IV
infusion. These reactions are less common following subsequent exposures. Unlike 
infusion-related reactions, anaphylaxis is a rare event, usually occurring after subsequent 
exposure to an antigen, and it is most commonly accompanied by severe systemic skin and or 
mucosal reactions. The investigator is advised to carefully examine symptoms of adverse 
reactions observed during or shortly after exposure to investigational product, and consider 
the above mentioned facts prior to making a final diagnosis. For the investigator’s 
convenience and in order to facilitate consistency in judgments a copy of the National 
Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis 
Network (FAAN) guidance for anaphylaxis diagnosis is provided in Appendix 3.


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5.5.1
Time Period for Collection of Adverse Events
For any randomised subjects, AEs will be collected from time of signature of informed 
consent through Day 91 according to the schedule in Table 4.2.1-1 and Table 4.2.2-1. For 
screening failure subjects, AEs will be collected from time of signature of informed consent 
until they are a confirmed screen failure in IXRS.  
All SAEs will be recorded from the time of informed consent through Day 191 according to 
the schedule in Table 4.2.1-1 and Table 4.2.2-1. Assessments for SAEs after Day 91 will be 
conducted by telephone contact.
Time period for collection of AESIs and NOCDs is presented in Section 5.5.3 and 
Section 5.5.4, respectively.
5.5.2
Follow-up of Unresolved Adverse Events
Any AEs/SAE(s) that are unresolved at the subject’s last AE/SAE assessment in the study are 
followed up by the investigator until resolution, until the subject returns to baseline status, or 
until the condition has stabilised with the expectation that it will remain chronic, even if this 
extends beyond study participation. 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
Collection of Adverse Events of Special Interest 
Adverse events of special interest (which include hepatic function abnormity, anaphylaxis 
and serious allergic reactions, infusion-related reactions and immune complex disease) will 
be collected from the period immediately following investigational product administration 
through Day 191 according to the schedule in Table 4.2.2-1.
5.5.3.1
Hepatic Function Abnormality
Events of hepatic function abnormality, as defined in Section 5.3.1, should be recorded 
according to the definitions of AE and SAE (Section 5.1 and Section 5.2, respectively):
•
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease), the diagnosis should be recorded as an AE or SAE 
per Section 5.5 or Section 5.6, respectively.
•
If the underlying diagnosis for the hepatic function abnormality remains unknown, the 
term “hepatic function abnormal” should be used to report the AE or SAE per Section 5.5
or Section 5.6, respectively.
Medications used to treat these events should be recorded.


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Events of hepatic function abnormality of unknown etiology or that are considered related to 
investigational product must be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety or designee (see Section 5.7.2).
5.5.3.2
Anaphylaxis and Serious Allergic Reactions (Including Hypersensitivity) 
and Infusion-related Reactions
Events of anaphylaxis and serious allergic reactions (including hypersensitivity) and 
infusion-related reactions (as defined in Section 5.3.2 and Appendix 3) should be recorded 
according to the definitions of AE and SAE (Section 5.1 and Section 5.2, respectively). 
Medications used to treat these events should be recorded.
In order to characterise and understand their association with the investigational product, 
non-serious AESIs of allergic reactions (including hypersensitivity) and infusion-related 
reactions must be recorded within 48 hours of knowledge of the event into the eCRF.
5.5.3.3
Immune Complex Disease
Events associated with immune complex disease (eg, vasculitis, endocarditis, neuritis, and 
glomerulonephritis), as defined in Section 5.3.3, should be recorded according to the 
definitions of AE and SAE (Section 5.1 and Section 5.2, respectively). Medications used to 
treat these events should be recorded.
5.5.4
Collection of New Onset Chronic Disease
New onset chronic disease will be recorded using a recognised medical term or diagnosis that 
accurately reflects the event from the period after investigational product administration 
through Day 191 according to the schedule in Table 4.2.2-1. New onset chronic disease 
events will be assessed by the investigator for relationship to the investigational product. 
Events associated with NOCDs as defined in Section 5.4, should be recorded according to the 
definitions of AE and SAE (Section 5.1 and Section 5.2, respectively). Medications used to 
treat NOCDs should be recorded.
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 procedures. SAEs should not be reported for subjects 
once they have failed screening and are no longer being followed in the study. 


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Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE Report 
Form and fax it to MedImmune Patient Safety or designee.
MedImmune or designee contact information: 
 
The sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in 
accordance with ICH Guidelines and/or local regulatory requirements. The sponsor may be 
required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that investigators submit additional 
information requested by the sponsor as soon as it becomes available.
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document 
the event before notifying MedImmune Patient Safety of an SAE. When additional 
information becomes available, investigators should submit a follow-up SAE Report Form 
(separate from the initial report form) with the new information. Any follow-up information 
to an SAE also needs to be provided to MedImmune Patient Safety within 24 hours of 
learning of the new information. 
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 this protocol (ie, 
 mg MEDI4893).
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety or designee using the Safety Fax Notification Form (see 
Section 5.6 for contact information). If the overdose results in an AE, the AE must also be 
recorded (see Section 5.5). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalisation, the event is 
serious and must be reported as an SAE (see Section 5.6). MedImmune does not recommend 


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specific treatment for an overdose. The investigator will use clinical judgment to treat any 
overdose.
5.7.2
Hepatic Function Abnormality
An AESI of hepatic function abnormality (as defined in Section 5.3.1) of unknown etiology 
or that is considered attributable to investigational product, is required to be reported as 
“hepatic function abnormal” within 24 hours of knowledge of the event to MedImmune 
Patient Safety using the SAE Report Form, even if the event is considered to be non-serious 
(see Section 5.6 for contact information). The investigator will review the data with the 
medical monitor. The investigator should then use clinical judgment to establish the cause 
based on local standard of care and follow the subject by conducting testing as clinically 
indicated.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor. 
5.7.3
Pregnancy……………..
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to MedImmune Patient Safety or 
designee using the Safety Fax Notification Form (see Section 5.6 for contact information).
Subjects who become pregnant during the study period will not be withdrawn from the study. 
If the subject requests to know which treatment she received, this information will be 
provided to her. The pregnancy will be followed for outcome of the mother and child 
(including any premature terminations) and should be reported to MedImmune Patient Safety 
or designee after outcome.
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to MedImmune Patient Safety or designee using the Safety Fax 
Notification Form (see Section 5.6 for contact information). The sponsor will endeavor to 
collect follow-up information on such pregnancies provided the partner of the study subject 
provides consent.


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6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative or designee 
will review and discuss the requirements of the Clinical Study Protocol and related 
documents with the investigational staff and also train them in any study-specific procedures 
and system(s) utilised.
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 or designee will have regular contacts with 
the study site, including visits to:
•
Provide information and support to the investigators
•
Confirm that facilities remain acceptable
•
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded, 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 electronic case report 
forms (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 or designee will be available between visits if the 
investigator(s) or other staff at the centre 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 centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
A Clinical Study Agreement must be in place with the Principal Investigator before any 
study-related procedures take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the last protocol-specified visit/assessment (including telephone contact). 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Sections 4.1.5).
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
 according to the Data Management Plan.
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 


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investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator of the 
applicable site. In addition, each subject will receive a toll-free number intended to provide 
the subject’s physician access to a medical monitor 24 hours a day, 7 days a week in the 
event of an emergent situation where the subject’s health is deemed to be at risk. In this 
situation, when a subject presents to a medical facility where the treating physician or health 
care provider requires access to a physician who has knowledge of the investigational 
product and the clinical study protocol and the principal investigator is not available, the 
treating physician or health care provider can contact a medical monitor through this system, 
which is managed by a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements.
7.2
Subject Data Protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
7.3
Ethics and Regulatory Review
An IEC should approve the final study protocol, including the final version of the Informed 
Consent Form and any other written information and/or materials to be provided to the 
subjects. The investigator will ensure the distribution of these documents to the applicable 
IEC, and to the study site staff.
The opinion of the IEC should be given in writing. The investigator should submit the written 
approval to MedImmune or designee before enrolment of any subject into the study. 
The IEC should approve all advertising used to recruit subjects for the study.


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MedImmune or designee should approve any modifications to the Informed Consent Form 
that are needed to meet local requirements.
If required by local regulations, the protocol should be re-approved by the IEC annually.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
MedImmune or designee will handle the distribution of any of these documents to the 
national regulatory authorities.
MedImmune or designee will provide Regulatory Authorities, IEC, and Principal 
Investigators with safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions, where relevant.
As applicable for each participating centre, the Principal Investigator is responsible for 
providing the IEC with reports of any serious and unexpected adverse drug reactions from 
any other study conducted with the investigational product. MedImmune or designee will 
provide this information to the Principal Investigator so that he/she can meet these reporting 
requirements.
7.4
Informed Consent
The Principal Investigators at each centre will:
•
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk, and benefit of the study
•
Ensure each subject is notified that they are free to discontinue from the study at any time
•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study
•
Ensure the original, signed Informed Consent Form(s) is/are stored in the Investigator’s 
Study File
•
Ensure a copy of the signed Informed Consent Form is given to the subject
•
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an IEC


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•
Ensure that subjects who are unconscious or considered by the investigator clinically 
unable to consent at screening and who are entered into the study by the consent of a 
legally acceptable representative provide their own written informed consent for 
continuing to participate in the study as soon as possible on recovery, as applicable in 
accordance with local regulations.
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IEC and if applicable, also the national 
regulatory authority approval, before implementation. Local requirements are to be followed 
for revised protocols.
MedImmune or designee will distribute any subsequent amendments and new versions of the 
protocol to each Principal Investigator(s). For distribution to IEC see Section 7.3.
If a protocol amendment requires a change to a site’s Informed Consent Form, MedImmune 
or designee and the site’s IEC are to approve the revised Informed Consent Form before the 
revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IEC.
7.6
Audits and Inspections
Authorised representatives of MedImmune, a regulatory authority, or an IEC may perform 
audits or inspections at the centre, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, 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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hospital- and ventilator-associated pneumonia due to Staphylococcus aureus (methicillin-
susceptible and methicillin-resistant) between Europe and Latin America: a comparison of 
the EUVAP and LATINVAP study cohorts. Med Intensiva. 2013;37:241-7.
Restrepo MI, Anzueto A, Arroliga AC, Afessa B, Atkinson MJ, Ho NJ, et al. Economic 
burden of ventilator-associated pneumonia based on total resource utilization. Infect Control 
Hosp Epidemiol. 2010;31:509-15.
Ruotsalainen E, Karden-Lilja M, Kuusela P, Vuopia-Varkila J, Virolainen-Julkunen A, 
Sarna S, et al. Methicillin-sensitive Staphylococcus aureus bacteraemia and endocarditis 
among injection drug users and nonaddicts: host factors, microbiological and serological 
characteristics. J Infect. 2008;56:249-56.
Sampson HA, Furlong AM, Campbell RL, Adkinson NF, 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.
Sirvent JM, Torres A, Vidaur L, Armengol J, de Batlle A, Bonet A. Tracheal colonisation 
within 24 h of intubation in patients with head trauma: risk factor for developing early-onset 
ventilator-associated pneumonia. Intensive Care Med. 2000;26:1369-72.
Spellberg B, Talbot G. Recommended design features of future clinical trials of antibacterial 
agents for hospital-acquired bacterial pneumonia and ventilator-associated bacterial 
pneumonia. Clin Infect Dis. 2010;51(Suppl 1):S150-70.
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H. The SOFA 
(Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On 
behalf of the Working Group on sepsis-related problems of the European Society of Intensive 
Care Medicine. Intensive Care Med. 1996;22:707-10.


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Wilke GA, Bubeck Wardenburg J. Role of a disintegrin and metalloprotease 10 in 
Staphylococcus aureus alpha-hemolysin-mediated cellular injury. Proc Natl Acad Sci USA. 
2010 Jul 27;107(30):13473-8.
Zou, G. A modified Poisson regression approach to prospective studies with binary data. Am 
J Epidem; 2004;159(7): 702-6.
9
CHANGES TO THE PROTOCOL
All changes described below have been incorporated into the current version of the protocol.
9.1
Protocol Amendment 1, 07Aug2014
Text revisions resulting from this amendment are incorporated into the body of Protocol 
Amendment 1. Major changes to the protocol are summarised below.
1. The synopsis was updated to be consistent with the protocol body.
2. Section 3.1.1 (Overview): Text was added to indicate that enrolment will continue in 
only the 
 mg MEDI4893 and placebo arms while the interim analyses are being 
performed. A second interim analysis for futility assessment was added, to be conducted 
when approximately 33-40% of the enrolled subjects are followed through 30 days post 
dose.
3. Section 4.1.2 (Inclusion Criteria): Bilateral tubal ligation was stricken from the 
definition of surgical sterility in order to be consistent with Table 4.7.1-1.
4. Section 4.1.4 (Subject Enrolment and Randomisation): A statement was added to 
indicate that subjects who have failed screening may be rescreened.
5. Section 4.2.2 (Treatment and Follow-up Periods): Assessments of CPIS assessment, 
SOFA, PaO2/FiO2 ratio were removed from Table 4.2.2-1. Serum for biomarkers was 
added to Table 4.2.2-1 and Table 4.2.2-2. A footnote was added to Microbiology to 
clarify that if pleural fluid aspirate or lung tissue is obtained as part of a subject’s 
necessary clinical management, the sample should also be sent for Gram stain and 
culture.
6. Section 4.3.1.4 (Definition of S aureus Pneumonia): Under Microbiologic confirmation, 
it was clarified that at least one of the bulleted confirmations (ie, not just the first bullet) 
should be obtained within 24 hours of onset of the event for mechanically ventilated 
subjects and within 72 hours of onset of the event for non-mechanically ventilated 
subjects.
7. Section 4.3.4 (Clinical Laboratory Tests): Leukocytes and nitrite were added to the list 
of urinalysis assessments.
8.
 
9. Section 4.3.9 (Estimate of Volume of Blood to be Collected): Instructional text was 
deleted.


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10. Section 4.5.1.4 (Treatment Administration): The instruction indicating that MEDI4893 
administration should not exceed a rate of 
 mg/minute was deleted. Footnote a in 
Table 4.5.1.4-1 was modified to note that if the maximum infusion duration exceeds  
hours, the medical monitor must be notified.
11. Section 4.6.3.3 (Unblinding for Futility Analysis Purposes): This section was added to 
indicate that the sponsor site personnel will remain blinded to the treatment assignment 
of individual subjects until the last subject completes the study and the database is 
locked and the sponsor personnel will remain blinded to the treatment assignment of 
individual subjects until the Stage 1 analysis (ie, primary analysis).
12. Section 4.7.2.2 (Prohibited Concomitant Medications): Other 
experimental/investigational drugs were prohibited through Day 91 and the sponsor 
must be notified in the event a subject were to receive an investigational product.
13. Section 4.8.2 (Sample Size and Power Calculations): The point at which the sample size 
may be modified was changed from after 40% to 50% of subjects are enrolled to after 
33% to 40% of subjects are enrolled, and the sample size reassessment was to be 
performed prior to the futility assessment.
14. Section 4.8.3 (Efficacy): Subsections describing efficacy analyses were modified to 
indicate that S aureus systemic antibiotic use will be analyzed.
15.
 
 
 
16. Section 4.8.10 (Data Review Committees): Under Data Monitoring Committee, the 
interim analysis for futility was added.
17. Section 4.8.11 (Interim Analyses): A description of the interim analysis for futility was 
added.
18. Appendix 2 (Additional Safety Guidance): Text was modified to correct the definition of 
Grade 4 (life threatening) AEs/SAEs to remove reference to disabilities, which was 
previously inadvertently added to this definition.
9.2
Protocol Amendment 2, 04Jun2015
Text revisions resulting from this amendment are incorporated into the body of Protocol 
Amendment 2. Major changes to the protocol are summarised below: 
1. Title Page: Information for Contract Research Organisation 
 was deleted.
2. The synopsis was updated to be consistent with the protocol body.
3. Section 1.4 (Summary of Clinical Experience): Text was updated with final clinical 
safety and PK data from the first-time-in-human Study CD-ID-MEDI4893-1133.


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4. Figure 3.1.1.-1 (Study Flow Diagram): Text was modified to indicate that the DMC will 
review PK data and recommend dose adjustment or study termination during the interim 
analysis. 
5. Section 4.1.2 (Inclusion Criteria): Text was modified to clarify the time window for 
positive samples for S aureus, and that the samples will be analyzed by PCR. 
6. Section 4.1.3 (Exclusion Criteria): Criteria for SOFA score based on the GCS score was 
modified. 
7. Section 4.1.4 (Subject Enrolment and Randomisation): Clarification was added 
regarding subjects who are considered for rescreening. 
8. Section 4.1.8 (Withdrawal of Informed Consent for Data and Biological Samples; 
Samples Obtained for Future Research): Text was modified to reflect current practices.
9. Table 4.2.1-1 (Schedule of Screening Procedures): Text was modified to clarify that S 
aureus colonisation in tracheal or bronchial aspirates is evaluated by PCR.
10. Table 4.2.2-1 (Schedule of Treatment and Post-dose Follow-up Procedures): Text was 
modified to clarify that S aureus colonisation is evaluated by PCR. Oxygen status was 
added as a parameter to monitor for clinical symptoms/signs of pneumonia/serious 
S aureus infection, and a new footnote with examples of those parameters was also 
added. 
11. Table 4.2.2-2: Title was changed from “Schedule of Procedures for Subjects with 
Suspected Serious S aureus Infection” to “Schedule of Procedures for Subjects with 
Suspected or Confirmed Pneumonia or Bacteremia.” It was also clarified that the term 
“resolution” refers specifically to “clinical resolution.” A new footnote defining the term 
“clinical resolution” was added.  
12. Section 4.3.1.4 (Definition of S aureus Pneumonia): Text was modified to clarify that 
the criterion of dullness to percussion is not elicited by auscultation and it is a separate 
criterion. It was clarified that the acute changes in PaO2/FiO2 have to be maintained for 
at least 4 hours. 
13. Section 4.3.4 (Clinical Laboratory Tests): Text was modified to include fasting glucose 
test. 
14. Table 4.3.9-1 (Estimate Volume of Blood to be Collected per Visit): “Subjects with 
Suspected Serious S aureus infection” was replaced with “Subjects with Suspected or 
Confirmed Pneumonia or Bacteremia.” 
15. Section 4.5.1.3 (Dose Preparation Steps): Ethylene vinyl acetate was added as an 
infusion bag material. 
16. Section 4.6.3.1 (Unblinding in the Event of a Medical Emergency): It was clarified that 
the investigator should first attempt to contact the medical monitor prior to unblinding 
the investigational product allocation for an individual subject as long as this does not 
jeopardise the safety of the subject. 
17. Section 4.6.3.2 (Unblinding for Interim Pharmacokinetic Analysis Purposes): Details 
regarding the PK analysis and presentation to the DMC were added to further describe 
how the DMC will recommend dose adjustments or potential study termination.
18.
 
 


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19. Section 4.8.4.1 (Analysis of Adverse Events): “hypersensitivity (including anaphylaxis)” 
was replaced with “anaphylaxis and serious allergic reactions (including 
hypersensitivity).” 
20. Section 4.8.11 (Interim Analyses): It was added that the DMC will be responsible for 
recommending dose adjustment or potential study termination.
21. Section 5.3.2: Title changed from “Hypersensitivity (including Anaphylaxis) and 
Infusion-related Reactions” to “Anaphylaxis and Serious Allergic Reactions (including 
Hypersensitivity) and Infusion-related Reactions.” In addition, definitions for 
anaphylaxis and infusion-related reactions, as well as signs and symptoms of 
anaphylaxis and serious allergic reactions (including hypersensitivity) were added. 
Information on the risk of post-extubation laryngeal oedema in subjects with prior 
hypersensitivity reaction to investigational product was also added. 
22. Section 5.5.3.2: Title changed from “Hypersensitivity (including Anaphylaxis) and 
Infusion-related Reactions” to “Anaphylaxis and Serious Allergic Reactions (including 
Hypersensitivity) and Infusion-related Reactions.” Text was also modified accordingly.
23. Section 6.2.2 (Study Agreements): Text was modified to reflect current practices. 
9.3
Administrative Change 1, 26Jun2015
1. Section 4.1.2 (Inclusion Criteria): Text was modified in criterion 7 to correct a 
typographical error. 
9.4
Protocol Amendment 3, 14Aug2015
Text revisions resulting from this amendment are incorporated into the body of Protocol 
Amendment 3. Major changes to the protocol are summarised below: 
1. Table 4.2.1-1(Schedule of Screening Procedures): Table was modified to include 
tracheal/bronchial aspirates for both Gram stain and culture in the screening procedures.
2. Table 4.2.2-1 (Schedule of Treatment and Post-dose Follow-up Procedures): 
Tracheal/bronchial aspirates for Gram stain and for culture were deleted from the post-
dose procedures.
3. Section 4.8.10 (Data Review Committees): Text was added to clarify that the 
adjudication committee may request to review all data relevant to a potential case, 
including radiographic and imaging studies, as well as other clinical and/or 
microbiologic data. 


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9.5
Protocol Amendment 4, 20Oct2016
Text revisions resulting from this amendment are incorporated into the body of Protocol 
Amendment 4. Major changes to the protocol are summarised below:
1. Updated synopsis to be consistent with the protocol body.
2.
 
 
3.
 
 
 
 
4. Section 3.1.1 (Overview) and Section 3.2.2 (Dose Rationale): Modified text to reflect 
that an independent DMC reviewed the PK interim analysis data and per protocol, 
recommended that the 
 mg MEDI4893 group be discontinued and that a dose 
adjustment to 
 mg MEDI4893 should not be made, since the lower dose PK profile 
in mechanically ventilated subjects was well below the target drug exposure, thus 
unlikely to offer efficacy. In addition, modified text to reflect the new number of 
subjects that will be enrolled and randomized to one of 2 treatment groups: 
 mg 
MEDI4893 or placebo.
5. Section 3.1.1 (Overview) and Section 4.6.1 (Methods for Assigning Treatment Groups): 
Modified text to reflect change in terms of stratification by receipt of anti-S aureus
systemic antibiotic (treatment for ≤48 hours [rather than ≤ 24 hours]) within the 
72 hours (rather than within the 48 hours) prior to randomization to align with the 
updated exclusion criterion 6 language. In addition, the restriction to ensure that no more 
than approximately 75% of the study population will consist of subjects in either 
stratification level of prior anti-S aureus systemic antibiotic treatment was removed.
These changes were made in order to facilitate study enrolment and randomisation. 
6. Section 3.1.1 (Overview), Section 4.8.2 (Sample Size and Power Calculations), and 
Section 4.8.11 (Interim Analyses): Modified text to reflect that as the 
 mg 
MEDI4893 will no longer be enrolled and randomized, the overall sample size of the 
study has been reduced. Consequently, due to the smaller overall sample size, futility 
analysis will be performed at a later time point based on the operating characteristics; 
thus, modified text to clarify that futility assessment will be conducted when 100-120 
(40% to 50%) subjects enrolled are followed through 30 days instead of 33% to 40% of 
enrolled patients.  
7. Figure 3.1.1 (Study Flow Diagram): Updated diagram to reflect the recommendations by 
the DMC. The study flow diagram now illustrates how the 2 treatment groups, 
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MEDI4893 and placebo will continue to be enrolled and randomised in a 1:1 ratio 
(N = 135 for each treatment group). Additionally, modified diagram to reflect the new 
follow-up times of 190 days post dose.
8. Section 3.1.2 (Treatment Regimen), Section 4.1.1 (Number of Subjects), and Section 
4.8.2 (Sample Size and Power Calculation): Modified text to reflect the new number of 
subjects who will be enrolled and randomised to one of 2 treatment groups: 
 mg 
MEDI4893 or placebo. For Section 3.1.2 (Treatment Regimen) only, a sentence was also 
added to explain that subjects who were enrolled and randomised into the 
 mg 
MEDI4893 group prior Protocol Amendment 4 will continue to be followed through the 
end of study. For Section 4.1.1 (Number of Subjects), a sentence was added to note the 
approximate number of subjects enrolled in the 
 mg dose.
9. Section 4.1.2 (Inclusion Criteria): Modified criterion 9 to reflect new follow-up times of 
190 days post dose instead of 360 days. 
10. Section 4.1.3 (Exclusion Criteria): Modified criterion 6 to exclude enrolment of subjects 
who receive anti-S aureus antibiotics for > 48 hours (instead of > 24 hours) within 72 
hours (instead of 48 hours) prior to randomisation. Modified criterion 8 to exclude 
enrolment of subjects with SOFA score of ≥ 9 at time of randomisation and to clarify 
that vasopressors only used to improve cerebral perfusion pressure will not be entered in 
the calculation of the cardiovascular component of the SOFA score. Modified criterion 
11 to allow enrolment of subjects with asymptomatic HIV infection. Modified criterion 
14 to change the time frame for exclusion of patients receiving chemotherapy from 6 
months to 2 months. All these changes were introduced to facilitate study enrolment and 
randomisation. 
11. Table 4.2.2-1 (Schedule of Treatment and Post-dose Follow-up Procedures): Modified 
table to reflect the new follow-up times of 190 days post dose. Modified footnote ‘d’ to 
reflect that the call to CCC to confirm requirements for randomisation has to be made 
within 6 hours. A similar change was made to the text in Section 4.6.1 (Methods for 
Assigning Treatment Groups).
12. Table 4.2.2-2 (Schedule of Procedures for Subjects with Suspected or Confirmed 
Pneumonia or Bacteremia): Added a new footnote to the PK/ADA/Other Assessments to 
clarify the handling of samples taken for subjects with suspected pneumonia. 
13. Section 4.3.1.4 (Definition of S aureus Pneumonia): Under S aureus Pneumonia Criteria 
for Subjects Who are Mechanically Ventilated at the Time of Diagnosis, clarified that in 
subjects who are not intubated but meet the protocol definition of mechanical 
ventilation, a specimen of expectorated sputum would be acceptable for microbiologic 
confirmation.
14. Section 4.3.1.4 (Definition of S aureus Pneumonia): Under S aureus Pneumonia Criteria 
for Subjects Who are Not Mechanically Ventilated at the Time of Diagnosis, clarified 
that a subject is not considered to be mechanically ventilated when an endotracheal or 
nasotracheal tube is not in place and that the subject does not require positive ventilation 
support for at least 8 hours. 
15. Table 4.5.1.3-1 (Investigational Product Dose Preparation) and Table 4.5.1.4-1 
(Duration of Infusion by Treatment Group and Investigational Product Solution 
Volume): Modified tables to remove information for the 
 and 
 mg doses, as 
subjects will no longer be enrolled at these dose levels.


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16. Section 4.6.1 (Methods for Assigning Treatment Groups): Modified text to clarify 
DMC’s recommendation to discontinue the 
 mg dose. 
17. Section 4.8.1 (General Considerations): Modified text to clarify that no adjustments 
were made when the 
 mg dose was discontinued. In addition, the 
 mg dose was 
removed from the key efficacy analyses.
18. Section 4.8.2 (Sample Size and Power Calculations) and Section 4.8.3.4 (Exploratory 
Efficacy Analysis): The sample size methodology was modified to use Poisson 
regression with robust variance in order to be consistent with the planned primary 
efficacy analysis. 
19. Section 4.8.3.1 (Primary Efficacy Analysis): Added text to clarify the use of covariates 
if the number of subjects in either stratum is too small. 
20. Section 4.8.11 (Interim Analyses): Removed language mentioning that enrolment will 
resume in the lower dose arm after futility analysis as it is no longer applicable.  
21. Section 5 (Assessment of Safety): Added text to clarify that AEs, SAEs, AESIs, and 
NOCDs are assessed in the study. 
22. Section 5.3 (Definition of Adverse Events of Special Interest): The last sentence 
regarding rapid reporting was removed, in order to avoid confusion with the 
requirements for reporting stated in other sections. 
23. Section 5.3.1 (Hepatic Function Abnormality): Updated text for Hy’s law per new 
protocol template. Text that did not apply to this study was removed. 
24. Section 5.5 (Collection of Adverse Events): Changed title from “Recording of Adverse 
Events” to “Collection of Adverse Events” for added clarity on the process. 
25. Section 5.5.1 (Time Period for Collection of Adverse Events): Modified text to clarify 
the time of collection of AEs for subjects who had failed screening. 
26. Section 5.5.3 (Collection of Adverse Events of Special Interest): Changed title from 
“Recording of Adverse Events of Special Interest” to “Collection of Adverse Events of 
Special Interest” for added clarity.
27. Section 5.5.3.2 (Anaphylaxis and Serious Allergic Reactions (Including 
Hypersensitivity) and Infusion-related Reactions): Update text to clarify when these 
events must be recorded in order to understand their association with the investigational 
product. 
28. Section 5.5.4 (Collection of New Onset Chronic Disease): Changed title from 
“Recording of New Onset Chronic Disease” to “Collection of New Onset Chronic 
Disease” for added clarity. 
29. Section 5.6 (Reporting of Serious Adverse Events): Modified text to clarify that SAEs 
should not be reported for subjects once they have failed screening and are no longer 
being followed in the study. 
30. Appendix 6 (Sequential Organ Failure Assessment): Note added to clarify that 
vasopressors only used to improve cerebral perfusion pressure will not be entered in the 
calculation of the cardiovascular component of the SOFA score.


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9.6
Protocol Amendment 5, 15Mar2018
Text revisions resulting from this amendment are incorporated into the body of Protocol 
Amendment 5. Major changes to the protocol are summarised below:
1. Updated synopsis to be consistent with the protocol body.
2.
 
3.
 
 
4.
 
 
 
. 
5.
 
 
 
6. Section 3.1.1 (Overview), Section 3.1.2 (Treatment Regimen), Section 3.2.2 (Dose 
Rationale), Section 4.1.1 (Number of Subjects), Section 4.8.2 (Sample Size and Power 
Calculations): Due to challenges with enrollment and the need to maintain the 
development timeline for MEDI4893, the total number of subjects planned to be 
enrolled was reduced from 285 to approximately 221.
7. Section 3.1.1 (Overview), Section 4.8.2 (Sample Size and Power Calculations), Section 
4.8.10 (Data Review Committees – Data Monitoring Committee), and Section 4.8.11 
(Interim Analysis): Text was modified to remove mentions of futility analysis, as the 
analysis would not be performed, since it would not be informative due to the smaller 
planned sample size. 
8. Figure 3.1.1-1 (Study Flow Diagram): Figure caption text was updated with new 
enrollment numbers. 
9. Section 4.1.5 (Withdrawal from Study): In the sub-section “Lost to Follow-up” text was 
modified to clarify that subjects will be considered lost to follow-up if no contact has 
been established by the time the subject’s last protocol-specified visit assessment has 
been reached, instead of when the entire study is completed. 
10. Section 4.1.7 (Replacement of Subjects): Text was modified to indicate subjects will not 
be replaced. 
11. Table 4.2.2-1 (Schedule of Treatment and Post-dose Follow-up Procedures): For the 
parameter “Monitor for clinical symptoms/signs of pneumonia/serious S aureus
infection (physical exam, vital signs, oxygen status, as indicated),” the footnote stating 
that the CPIS was to be assessed daily while the subject remained on mechanical 
ventilation, was removed since it was not meant to be a mandatory assessment. 
 


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12. Table 4.2.2-2 (Schedule of Procedures for Subjects With Suspected or Confirmed 
Pneumonia or Bacteremia): In footnote “a” text was added to clarify that for subjects 
with an onset of a suspected pneumonia or bacteremia from Days 2 through 31, 
assessments will be collected at onset and through resolution of disease, even if it 
extends past Day 31. 
13.
 
 
14. Section 4.6.3.3 (Unblinding for Futility Analysis): This section was removed completely 
as no futility analysis will be performed. 
15. Section 4.6.3.4 (Unblinding for Stage 1 Analysis Purposes): Text was modified to 
indicate that Stage 1 analysis will be conducted after the last subject has completed 
follow-up through 30 days post dose (instead of 90 days), and that this analysis will be 
the primary analysis for efficacy only. In addition, it was clarified that the safety, serum 
PK and ADA will be summarized through 30 days post dose. New text regarding the 
Stage 1 analysis was also included in Section 3.1.1 (Overview), Section 4.8.4 (Safety), 
and Section 4.8.12 (Planned Analysis). These changes were introduced to keep with the 
development timelines for MEDI4893. 
16. Section 4.8.1 (General Considerations): The primary analysis population was changed 
from the ITT population to the mITT population to account for those subjects who were 
randomized and not dosed. In addition, under sub-Section Analysis Populations, a 
definition for the mITT population was added. 
17. Section 4.8.2 (Sample Size and Power Calculations): Text was modified to change the 
power calculation number from 80% to 70%, due to the smaller planned sample size. 
Text describing sample size reassessment was removed. 
18. Section 4.8.3.1 (Primary Efficacy Analysis): Per feedback from regulators, text was 
modified to indicate that the stratification factors for country and prior systemic 
antibiotics will not be included in the analysis model. Further clarification regarding the 
analysis was also added. 
19.
 
 
20. Section 4.8.4 (Safety), Section 4.8.12 (Planned Analysis): Text was modified to indicate 
that for Stage 2 analysis safety data will be summarized through 90 days post dose and 
through the end of the study. These changes were introduced to keep with the 
development timelines for MEDI4893. 


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Appendix 1
Signatures


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cSponsor Signature
A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study 
of the Efficacy and Safety of MEDI4893, a Human Monoclonal Antibody Against 
Staphylococcus aureus Alpha Toxin in Mechanically Ventilated Adult Subjects
I agree to the terms of this protocol.
Signature and date: 
Filip Dubovsky, MD
Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA 


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Signature of European Federation of Pharmaceutical Industries and 
Associations (EFPIA) Lead
A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study 
of the Efficacy and Safety of MEDI4893, a Human Monoclonal Antibody Against 
Staphylococcus aureus Alpha Toxin in Mechanically Ventilated Adult Subjects
I agree to the terms of this protocol.
Signature and date: 
Senior Director, Clinical Research and Development
Infectious Disease and Vaccines, MedImmune
One MedImmune Way, Gaithersburg MD, 20878, USA 


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Signature of Coordinating Principal Investigator
A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study 
of the Efficacy and Safety of MEDI4893, a Human Monoclonal Antibody Against 
Staphylococcus aureus Alpha Toxin in Mechanically Ventilated Adult Subjects
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Independent Ethic s Committee (IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and IEC, 
and must be approved by the IEC prior to implementation except when necessary to 
eliminate immediate hazards to the subjects or when the change(s), as deemed by the 
sponsor, involves only logistical or administrative changes. Documentation of IEC approval 
must be sent to the sponsor immediately upon receipt.
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Signature of Principal Investigator
A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study 
of the Efficacy and Safety of MEDI4893, a Human Monoclonal Antibody Against 
Staphylococcus aureus Alpha Toxin in Mechanically Ventilated Adult Subjects
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Independent Ethics Committee (IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and IEC, 
and must be approved by the IEC prior to implementation except when necessary to 
eliminate immediate hazards to the subjects or when the change(s), as deemed by the 
sponsor, involves only logistical or administrative changes. Documentation of IEC approval 
must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Appendix 2
Additional Safety Guidance
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below.
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death.
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.
Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.


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


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Appendix 3
National Institute of Allergy and Infectious Diseases
(NIAID) and Food Allergy and Anaphylaxis Network 
(FAAN) Guidance for Anaphylaxis Diagnosis
This definition was a product of a symposium convened by the National Institute of Allergy 
and Infectious Diseases and Food Allergy and Anaphylaxis Network (Sampson et al, 2006). 
NIAID and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset and 
may cause death. They recognise 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, generalised 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, hypoxemia)
b. Reduced blood pressure (see #3 below for definition) 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 subject (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c.
Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen for that subject (minutes to 
several hours); for adults a systolic blood pressure of less than 90 mm Hg or greater than 
30% decrease from that subject’s baseline blood pressure (taken at or immediately prior 
to start of the infusion), whichever blood pressure is lower.


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Appendix 4
Clinical Pulmonary Infection Score
Simplified version of the Clinical Pulmonary Infection Score (CPIS)
Source: Luna et al, 2003.


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Appendix 5
Acute Physiology and Chronic Health Evaluation-II


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Physiologic Variable
High Abnormal Range
Low Abnormal Range
+4
+3
+2
+1
0
+1
+2
+3
+4
1.Temperature core/rectal (C) a
41
39-40.9
38.5-38.9
36.0-38.4
34-35.9
32-33.9
30-31.9
29.9
2.Mean arterial pressure (mmHg)
160
130-159
110-129
70-109
50-69
49
3.Heart rate (ventricular response)
180
140-179
110-139
70-109
55-69
40-54
39
4.Respiratory rate (non-ventilated or 
ventilated)
50
35-49
25-34
12-24
10-11
6-9
5
5. Oxygenation
A-aDO2 or PaO2 (mmHg)
If FiO2 0.5: record A-aDO2
500
350-499
200-349
< 200
If FiO2 < 0.5: record only PaO2
> 70
61-70
55-60
< 55
6.Arterial pH If no ABGs record serum 
HCO3   below
7.7
7.6-7.69
7.5-7.59
7.33-7.49
7.25-7.32
7.15-7.24
< 7.15
7.Serum sodium
180
160-179
155-159
150-154
130-149
120-129
111-119
110
8.Serum potassium
7
6-6.9
5.5-5.9
3.5-5.4
3-3.4
2.5-2.9
< 2.5
9.Serum creatinine (mg/dL)
Double points for acute renal failure
3.5
2-3.4
1.5-1.9
0.6-1.4
< 0.6
10. Hematocrit (%)
60
50-59.9
46-49.9
30-45.9
20-29.9
< 20
11. White blood count (k/mm3)
40
20-39.9
15-19.9
3-14.9
1-2.9
< 1
12. Glasgow Coma Scale
Score = 15 minus actual GCS)
15-GCS=
A   Total Acute Physiology Score (APS)
Sum of the 12 individual variable points =
* Serum HCO3 (venous-mmol/L)
Not preferred, use if no ABGs
52
41-51.9
32-40.9
22-31.9
18-21.9
15-17.9
< 15


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Glasgow Coma Scale
(Circle appropriate response)
B  Age    Points
C                       Chronic Health Points
Apache-II Score 
(Sum of A+B+C)
Eyes open
4 - spontaneously
3 - to speech
2 - to pain
1 - no response
Motor response
6 - to verbal command
5 - localizes to pain
4 - withdraws to pain
3 - flexion to pain
2 - extension to pain
1 - no response
Verbal - nonintubated
5 - oriented
4 - confused
3 - inappropriate words
2 - incomprehensible sounds
1 - no response
Verbal - intubated
5 - seems able to talk
3 - questionable ability to talk
1 - generally unresponsive
Age         Points
44 0
45-54
2
55-64
3
65-74
5
75 6
Age points =
Liver
CV
Pulmonary
Kidney
Immune
If any of the 5 CHE categories is answered yes
give +5 points for non-operative or emergency
postoperative subject and give +2 points if 
elective postoperative subject
Cirrhosis with PHT or encephalopathy
Class IV angina or at rest or with minimal 
self-care activities
Chronic hypoxemia or hypercapnia or
polycytaemia of PHT > 40 mmHg
Chronic peritoneal or hemodialysis
Immune compromised host
Chronic Health Points =
  A APS points
+B Age points
+C Chronic Health Points
___________
=Total APACHE II
ABG = arterial blood gas; APS = Acute Physiology Score; CHE = Chronic Health Evaluation; GCS = Glasgow Coma Scale; PHT = portal hypertension.
a A core temperature (rectal, esophageal, central venous catheter monitor urinary bladder thermistor) must be used when available. If a core temperature is not 
available for that subject, use non-core temperature with the following adjustments: (i) axillary temperature reading, add 1.0C; (ii) oral temperature reading, 
add 0.5C.


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Appendix 6
Sequential Organ Failure Assessment
Source: Vincent et al, 1996.
Note: Vasopressors only used to improve cerebral perfusion pressure (eg, subarachnoid hemorrhage) will not be 
entered in the calculation of the cardiovascular component of the SOFA score.


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Appendix 7
Conversion Tables for Estimating PaO2 and FiO2


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SAP_001.pdf: 
NCT02296320 


I .. IMedlmmune 
A member of the AstraZeneca Group 
Statistical Analysis Plan Approval 
Date: 
07SEP2018 
To: 
From: 
Re: 

YPlan Approval for Study CD-ID-MEDI4893-l 139 
The Statistical Analysis Plan, version 4, for Study CD-ID-MEDI4893-l 139 has been reviewed 
and approved. 
Name: 
Role: 
Statistician 
Date: 
Name: -
Signature: 
Role: 
Statistical Programmer 
Date: 
Name: 
-
Signature: 
Role: 
Clinical Development Lead 
Date: 
Name: 
Signature: 
Role: 
Clinical Biostatistics Therapeutic 
Date: 
Area Head 
Name: 
Role: 
Head of Clinical Biostatistics & 
Data Management 
Signature: 
Date: 
09 September 2018 
10 September 2018 
10 September 2018 
10 September 2018 
SAP approval template version 2.0