Conditions: Pseudomonas Aeruginosa
Keywords: Pseudomonas aeruginosa, Pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 188
Healthy volunteers: no

Brief summary:
Clinical trial looking to evaluate the efficacy and safety of MEDI3902 in mechanically ventilated participants for the prevention of nosocomial pneumonia caused by Pseudomonas aeruginosa.

Detailed description:

Arms:
arm 1: Participants will receive a single intravenous (IV) dose of 500 mg MEDI3902. arm 2: Participants will receive a single IV dose of placebo matched to MEDI3902. arm 3: Participants will receive a single IV dose of 1500 mg MEDI3902.

Interventions: intervention 1: MEDI3902 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a single IV dose of MEDI3902 500 mg and 1500 mg in MEDI3902 500 mg arm and MEDI3902 1500 mg arm, respectively. intervention 2: Participants will receive a single IV dose of placebo matched to MEDI3902.

Protocol document:
Prot_002.pdf: 
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A Phase 2 Proof-of-concept Study to Evaluate the Efficacy 
and Safety of MEDI3902 in Mechanically Ventilated Patients 
for the Prevention of Nosocomial Pneumonia Caused by 
Pseudomonas aeruginosa
Sponsor Protocol Number:
D5470C00004
Study Identifier:
EVADE (Effort to Prevent Nosocomial Pneumonia 
caused by P seudomonas aeruginosa in 
Mechanically Ventilated Subjects)
Application Number:
Investigational Product:
MEDI3902
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC, One MedImmune Way, 
Gaithersburg, Maryland, 20878, USA
Medical Monitor:
 
Coordinating Principal Investigator: 
Contract Research Organization:
Protocol History, Date:
Original Protocol, 16Oct2015
Amendment 1, 15Jul2016
Amendment 2, 22Dec2016
Amendment 3, 06Jun2018
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Primary Analysis
The percent reduction of incidence of nosocomial pneumonia caused by P aeruginosa through 21 days postdose 
will be the primary efficacy endpoint. For subjects with multiple P aeruginosa pneumonia events, only the first 
occurrence will be used in the primary analysis. Subjects with mixed cultured results, which include P 
aeruginosa, will be counted towards the primary endpoint.
The primary analysis of the primary endpoint will be evaluated using the mITT Population. P aeruginosa
pneumonia that occurs prior to discontinuation will contribute to the primary efficacy analysis. If no 
P aeruginosa pneumonia occurs prior to discontinuation, the subject will be considered as having no 
P aeruginosa 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 P aeruginosa
pneumonia through 21 days postdose between the 
mg MEDI3902 and placebo groups, using the term of
treatment group as a covariate. The relative risk reduction, defined as 1 – Relative Risk (RR), and its 
corresponding 2-sided 90% CI will be estimated from the model. In addition, the 2-sided p-value testing the null 
hypothesis that the incidence of having P aeruginosa pneumonia between the 
 mg MEDI3902 and placebo 
groups are the same will also be obtained from the model. The significance testing will be performed against a 
2-sided alpha level of 0.2. 
The Poisson regression with robust variance analysis will be implemented using the SAS PROC GENMOD 
procedure with the REPEATED statement for subject ID and logarithm link. The estimated parameter  [ie, log
(
)], 2-sided 80% confidence interval for , and the 2-sided p-value will be provided from the SAS outputs. 
The estimated relative risk (
) and corresponding confidence interval for the relative risk is given by 
exponentiating  and its confidence limits. Therefore, the percent of relative risk reduction is given by [(1 – exp
()) * 100%]. The confidence interval for the percent of relative risk reduction is given by ([1 – exp (upper 
confidence limit for ) * 100%], [1 – exp (lower confidence limit for ) * 100%]).
Sample Size/Power Calculation
Approximately 286 colonised subjects will be enrolled and randomised (1:1 ratio) to 
mg MEDI3902 (or in 
the case of dose adjustment, 
mg MEDI3902; n = 143) or placebo (n = 143). 
Key assumptions used for sample size/power calculations: placebo group P aeruginosa pneumonia incidence 
20%, relative reduction 50%, at least 80% power, 20% adjustment for attrition. Relative reduction of 50% was 
recommended to Sponsor as a clinically meaningful effect by experts in critical care, pulmonary medicine, and 
infectious diseases. In addition, 50% relative reduction was demonstrated in a study by Francois and colleagues 
(Francois et al, 2012) involving a monoclonal antibody to prevent Pseudomonas pneumonia in mechanically 
ventilated patients, supporting the biological feasibility of such an effect.
Power calculations are based on Poisson regression with robust variance comparing each MEDI3902 treatment 
group separately versus placebo, 2-sided, with α = 0.2. 
The sample size may be modified after approximately 50% of the subjects are enrolled and followed through 
21 days postdose based on blinded assessment of the event rate and/or attrition rate in the overall population. 
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ......................................................................................................2
TABLE OF CONTENTS ......................................................................................................6
LIST OF ABBREVIATIONS..............................................................................................11
1
INTRODUCTION ....................................................................................................13
1.1
Disease Background........................................................................................13
1.2
MEDI3902 Background..................................................................................13
1.4
Summary of Clinical Experience.....................................................................15
1.5
Rationale for Conducting the Study.................................................................16
1.6
Research Hypotheses ......................................................................................17
2
OBJECTIVES...........................................................................................................17
2.1
Objectives.......................................................................................................17
2.1.1Primary Objective ...................................................................................17
2.1.2Secondary Objectives ..............................................................................17
2.2
Study Endpoints..............................................................................................18
2.2.1Primary Endpoint ....................................................................................18
2.2.2Secondary Endpoints...............................................................................18
3
STUDY DESIGN......................................................................................................20
3.1
Description of the Study..................................................................................20
3.1.1Overview……….....................................................................................20
3.1.2Treatment Regimen.................................................................................22
3.1.3Management of Study Medication Related Toxicities..............................22
3.2
Study Design and Dose Rationale ...................................................................23
3.2.1Dose Rationale ........................................................................................23
3.2.3Rationale for Endpoints...........................................................................24
4
MATERIALS AND METHODS...............................................................................24
4.1
Subjects ..........................................................................................................24
4.1.1Number of Subjects.................................................................................24
4.1.2Inclusion Criteria.....................................................................................25
4.1.3Exclusion Criteria....................................................................................26
4.1.4Subject Enrolment and Randomisation ....................................................26
4.1.5Withdrawal from the Study......................................................................27
4.1.6Discontinuation of Investigational Product ..............................................28
4.1.7Replacement of Subjects .........................................................................28
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4.1.8Withdrawal of Informed Consent for Data and Biological Samples .........28
4.2
Schedule of Study Procedures.........................................................................29
4.2.1Enrolment/Screening Period....................................................................29
4.2.2Randomised Treatment Period and Follow-up .........................................31
4.3
Description of Study Procedures .....................................................................39
4.3.1Efficacy………. ......................................................................................39
4.3.1.1
Clinical Signs and Symptoms.................................................39
4.3.1.2
Microbiology .........................................................................39
4.3.1.3
Radiography...........................................................................40
4.3.1.4
Definition of P aeruginosa Pneumonia....................................40
4.3.1.5
Definition of P aeruginosa tracheobronchitis in 
mechanically ventilated Subject ...............................43
4.3.3Medical History and Physical Examination, Weight, and Vital Signs.......44
4.3.4Clinical Laboratory Tests ........................................................................45
4.3.6Anti-drug Antibody Evaluation and Methods ..........................................46
4.3.8P aeruginosa Colonisation Evaluation and Methods.................................47
4.3.9Estimate of Volume of Blood to be Collected..........................................47
4.4
Study Suspension or Termination....................................................................48
4.5
Investigational Products..................................................................................49
4.5.1Identity of Investigational Product(s).......................................................49
4.5.1.1
Investigational Product Dose Preparation ...............................50
4.5.1.2
Treatment Administration ......................................................52
4.5.1.3
Monitoring of Dose Administration........................................53
4.5.1.4
Reporting Product Complaints ...............................................53
4.5.2Additional Study Medications .................................................................54
4.5.3Labeling…… ..........................................................................................54
4.5.4Storage………. .......................................................................................54
4.5.5Treatment Compliance ............................................................................54
4.5.6Accountability.........................................................................................54
4.6
Treatment Assignment and Blinding ...............................................................54
4.6.1Methods for Assigning Treatment Groups ...............................................54
4.6.2Methods for Ensuring Blinding................................................................55
4.6.3Methods for Unblinding ..........................................................................56
4.6.3.1
Unblinding in the Event of a Medical Emergency...................56
4.6.3.2
Unblinding for Interim Pharmacokinetic Analysis Purposes ...56
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4.7
Restrictions During the Study and Concomitant Treatment .............................56
4.7.1Contraception..........................................................................................56
4.7.2Concomitant Medication .........................................................................57
4.7.2.1
Permitted Concomitant Medications.......................................57
4.7.2.2
Prohibited Concomitant Medications......................................58
4.8
Statistical Evaluation.......................................................................................58
4.8.1General Considerations ...........................................................................58
4.8.3Efficacy………. ......................................................................................59
4.8.3.1
Primary Efficacy Analysis......................................................59
4.8.3.2
Additional Analyses of the Primary Endpoint.........................60
4.8.4Safety……… ..........................................................................................62
4.8.4.1
Analysis of Adverse Events....................................................62
4.8.4.2
Analysis of Clinical Laboratory Parameters............................62
4.8.6Pharmacokinetics ....................................................................................63
4.8.7Anti-drug Antibody Response .................................................................63
4.8.10Data Review Committees ......................................................................64
4.8.11Interim Analysis....................................................................................64
4.8.12Planned Analysis...................................................................................65
5
ASSESSMENT OF SAFETY....................................................................................66
5.1
Definition of Adverse Events ..........................................................................66
5.2
Definition of Serious Adverse Events..............................................................66
5.3
Definition of Adverse Events of Special Interest .............................................67
5.3.1Hepatic Function Abnormality ................................................................67
5.3.2Hypersensitivity (Including Anaphylaxis) and Infusion related 
Reactions ...............................................................................67
5.3.3Immune Complex Disease.......................................................................68
5.4
Recording of Adverse Events..........................................................................69
5.4.1Time Period for Collection of Adverse Events.........................................69
5.4.2Follow-up of Unresolved Adverse Events................................................69
5.4.3Recording of Adverse Events of Special Interest .....................................70
5.4.3.1
Hepatic Function Abnormality ...............................................70
5.4.3.2
Hypersensitivity (including Anaphylaxis) and Infusion 
related Reactions......................................................70
5.4.3.3
Immune Complex Disease......................................................70
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5.5
Reporting of Serious Adverse Events ..............................................................70
5.6
Other Events Requiring Immediate Reporting .................................................71
5.6.1Overdose………. ....................................................................................71
5.6.2Pregnancy………....................................................................................72
5.6.3Hepatic Function Abnormality ................................................................72
5.6.4Adverse Events of Special Interest...........................................................73
5.6.4.1
Anaphylaxis and Serious Allergic Reactions (Including 
Hypersensitivity) and Infusion related Reaction .......73
5.6.4.2
Immune Complex Disease......................................................73
6
STUDY AND DATA MANAGEMENT...................................................................73
6.1
Training of Study Site Personnel.....................................................................73
6.2
Monitoring of the Study..................................................................................73
6.2.1Source Data.............................................................................................74
6.2.2Study Agreements ...................................................................................74
6.2.3Archiving of Study Documents................................................................74
6.3
Study Timetable and End of Study..................................................................74
6.4
Data Management ...........................................................................................75
6.5
Medical Monitor Coverage..............................................................................75
7
ETHICAL AND REGULATORY REQUIREMENTS..............................................75
7.1
Ethical Conduct of the Study...........................................................................75
7.2
Subject Data Protection...................................................................................76
7.3
Ethics and Regulatory Review.........................................................................76
7.4
Informed Consent............................................................................................77
7.5
Changes to the Protocol and Informed Consent Form......................................78
7.6
Audits and Inspections ....................................................................................78
8
REFERENCES .........................................................................................................79
9
CHANGES TO PROTOCOL....................................................................................80
9.1
Protocol Amendment 1, 15Jul2016..................................................................80
9.2
Protocol Amendment 2, 22Dec2016................................................................82
9.3
Protocol Amendment 3, 06Jun2018.................................................................83




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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALP
Alkaline phosphatase
ALT
alanine transaminase
APACHE-II
Acute Physiology and Chronic Health Evaluation-II
AST
aspartate transaminase
AUC
area under concentration time curve
AUC
area under the concentration-time curve from time zero to infinity
AUCDay22-Day29
area under concentration time curve from day 22 to day 29
BAL
bronchoalveolar lavage
CCC
Clinical Coordinating Centre
Cmax
mean observed maximum concentration
CPIS
Clinical Pulmonary Infection Score
CRP
C-reactive protein
DMC
data monitoring committee
EC90
effective serum concentration associated with 90% survival
eCRF
electronic case report form
EDC
electronic data capture
EQ-5D-5L
EuroQol - 5 Dimensions - 5 Levels
FAAN
Food, Allergy and Anaphylaxis Network
FiO2
fraction of inspired oxygen
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HIV
human immunodeficiency virus
HL
Hy’s Law
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG1
immunoglobulin G1
IL
interleukin 
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
LLOQ
lower limit of quantification


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Abbreviation or 
Specialized Term
Definition
mAb
monoclonal antibody
mITT
modified intent-to-treat
MMP-9
matrix metalloproteinase 9
MPO
myeloperoxidase
NE
neutrophil elastase
NIAID
National Institute of Allergy and Infectious Diseases
NOAEL
no observed adverse effect level 
O2
oxygen
OPK
opsonophagocytic killing
P aeruginosa
Pseudomonas aeruginosa
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
PD
pharmacodynamic
PK
pharmacokinetics
PSB
protected-specimen brush
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SID
subject identification
SOFA
Sequential Organ Failure Assessment
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TNFα
tumour necrosis factor alpha
ULN
upper limit of normal
VAP
ventilator-associated pneumonia 
Vdss
volume of distribution at steady state
WBC
white blood cell
w/v
weight/volume


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1
INTRODUCTION
1.1
Disease Background
Pseudomonas aeruginosa (P aeruginosa) is an important nosocomial pathogen, and 
pneumonia is one of its most important manifestations. Mechanical ventilation is the most 
important risk factor for nosocomial pneumonia caused by P aeruginosa, with cumulative 
risk increasing with the duration of ventilation (Zahar et al, 2009). In one study, 
P aeruginosa accounted for 13% of cases of microbiologically confirmed pneumonia 
acquired in the intensive care unit (ICU) by patients who were not mechanically ventilated, 
and 24% of cases in those who were (Esperatti et al, 2010). In a review of global 
epidemiology data, P aeruginosa caused approximately 27% of ventilator-associated 
pneumonia (VAP; Jones, 2010). Respiratory tract colonisation with P aeruginosa is another 
important risk factor (Rehm and Kollef, 2014). Despite the existence of antipseudomonal 
antibiotics, pneumonia, particularly VAP, due to P aeruginosa remains associated with
significant mortality and morbidity, increased ICU and hospital length of stay, and 
substantial economic burden. Although general strategies exist to decrease the incidence of 
pneumonia in mechanically ventilated patients, there are no systemic agents approved for the 
prevention of pneumonia caused by P aeruginosa.
1.2
MEDI3902 Background
MEDI3902 is briefly described below. Refer to the current Investigator’s Brochure for 
details. 
P aeruginosa possesses a number of virulence factors that play a role in the severity of 
disease, and MEDI3902 was developed to target two of these factors. 
 
 
 
 
 
 
 
 
 
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1.4
Summary of Clinical Experience
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.1.2
Treatment Regimen
At study start, subjects were to be randomly assigned to receive a single dose of 
mg 
MEDI3902, 
 mg MEDI3902, or placebo administered via IV infusion on Day 1.
However, based on emerging data (see Section 3.1.1), subsequent to Amendment 2, subjects
will be enrolled and randomly assigned (1:1 ratio) to receive a single IV infusion of 
mg MEDI3902 (or in the case of dose adjustment,
 mg MEDI3902) or placebo. 
3.1.3
Management of Study Medication Related Toxicities
All subjects will be premedicated with antihistamine, for example, 
 mg diphenhydramine 
IV, clemastine  mg IV, or dexchlorpheniramine mg IV (or another antihistamine 
preparation utilised in routine clinical practice for management of acute allergic reactions)
within 15 to 30 minutes prior to start of IP administration. The data monitoring committee 
(DMC) will monitor the rate and severity of infusion or allergic reactions observed during the 
study. The DMC may authorise additional premedication of subjects with acetaminophen 
mg orally and/or methylprednisolone
mg IV in combination with the antihistamine, or 
the antihistamine together with famotidine 
 mg orally with or without acetaminophen 
and/or methylprednisolone prior to start of investigational product infusion.
In the event of any infusion related reactions observed, the following options should be 
considered:
1. Administer antihistamine, for example, diphenhydramine
 mg IV, clemastine mg IV, 
or dexchlorpheniramine  mg IV, or another antihistamine preparation utilised in routine 
clinical practice for management of acute allergic reactions.
2. Administer methylprednisolone 
mg IV
3. Stop the infusion, and reassess the signs and symptoms as well as the overall condition of 
the patient in about 30 to 60 minutes
a.
If the signs and symptoms abate, consider restarting the study drug at an infusion 
rate, approximately half of the baseline infusion rate
b. If the signs and symptoms of infusion related reaction do not show resolution, or 
there is worsening of the symptoms or in subject’s general condition, permanently 
discontinue the study drug, and consider additional symptomatic treatment, 
including but not limited to antihistamines, epinephrine, and or systemic 
corticosteroids
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 mg MEDI3902, approximately 143 subjects will be randomised to receive the 
 mg 
MEDI3902 dose to maintain 1:1 ratio with the placebo group. Subjects who have been 
enrolled in the 
mg and 
 mg MEDI3902 groups will be followed until the end of the 
study period (Day 50).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male or female 18 years of age or older at the time of study entry 
2. Written informed consent and any locally required authorisation obtained from the 
subject/legal representative prior to performing any protocol-related procedures, 
including screening evaluations
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 
a.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral oophorectomy, or complete hysterectomy) or those who are not 
premenarchal or postmenopausal (defined as 12 months with no menses without an 
alternative medical cause).
4. Currently intubated and on mechanical ventilation in the ICU
5. Tracheal sample collected and positive by polymerase chain reaction (PCR) for 
P aeruginosa within 36 hours prior to randomisation
6. Expected to remain intubated and mechanically ventilated for ≥ 72 hours 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 through 49 days postdose
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4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Acute confirmed or suspected pseudomonal disease at study enrolment and 
investigational product dosing (endotracheal colonisation is acceptable and required 
[see inclusion criterion 5])
2. CPIS of ≥ 6 based on contributing parameters measured within past 24 hours, prior to 
investigational product dosing (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 are tracheostomy-dependent prior to current hospital admission
5. Receipt of anti-P aeruginosa antibiotics (as listed below) for > 72 hours within 96 hours 
prior to randomisation or anticipated ongoing receipt of the anti-P aeruginosa antibiotics:
◦
Systemic colistin
◦
Aerosolized colistin
6. Burns > 40% body surface area
7. Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score ≥ 25 or SOFA 
score ≥ 12 at time of randomisation (Appendix 5 and Appendix 6). Vasopressors only 
used to improve cerebral perfusion pressure (eg, subarachnoid hemorrhage) should not be 
used in the calculation of the cardiovascular component of the SOFA score.
8. Receipt of any investigational drug therapy within 30 days prior to investigational 
product dosing 
9. Previous receipt of a mAb 
10. 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.
11. Lymphoma not in complete remission and on chemotherapy
12. Recipients of bone marrow, stem cell, or solid organ transplant who are not currently in 
complete remission
13. Receipt of chemotherapy or other immunosuppressive drugs including glucocorticoid 
therapy (prednisone 20 mg or equivalent, daily or every other day for 30 days) in the past 
2 months
14. History of known hypersensitivity to any component of the investigational product 
15. Pregnant or nursing female
4.1.4
Subject Enrolment and Randomisation
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
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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, interactive web response system [IWRS]), and the screening evaluations 
may begin to assess study eligibility (inclusion/exclusion) criteria. The SID number will be 
used to identify the subject during the screening process and throughout study participation, 
if applicable. 
A 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 
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 number. 
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. AEs will be followed up. If a subject withdraws 
from further participation in the study, then no further study visits or data collection should 
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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 and collection of AEs will not be performed. Unless consent for follow-up is 
withdrawn, subjects discontinued after receiving a partial dose of investigational product will 
be followed for the full study period (through 49 days postdose) with all laboratory and 
clinical evaluations collected as defined in the protocol.
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 unless the subject specifically requests that the samples are destroyed.
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 15 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 at the screening visit. Assessments 
should be performed in the order shown in the table.
Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Up to 7 days prior to randomisationa
Eligibility
Written informed consent b
X
Assignment of SID number
X
Medical history, comorbidities, and risk factors
X
Physical examination
X
Weight, height
X


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Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Up to 7 days prior to randomisationa
Serum βhCG
X c
Verify eligibility criteria
X
Safety Assessments
Vital signs
X
Serum chemistry
X d
Hematology
X d
Assessment of AEs/SAEs
X
Concomitant medications
X
Disease Assessments
Evaluate for clinical symptoms/signs of pneumonia/serious 
P aeruginosa infection (eg, physical exam, vital signs, CPIS 
assessment, SOFA, APACHE-II, GCS, PaO2/FiO2 ratio, as 
clinically indicated)
X
Tracheal aspirate for P aeruginosa colonisation by PCR
X e
Chest x-ray
X
Tracheal aspirate for Gram stain and culture
X f
AE = adverse event; APACHE II = Acute Physiology and Chronic Health Evaluation II; βhCG = beta human 
chorionic gonadotropin; CPIS = Clinical Pulmonary Infection Score; FiO2 = fraction of inspired oxygen; 
GCS = Glasgow Coma Scale; PaO2 = partial pressure of oxygen; PCR = polymerase chain reaction; 
P aeruginosa = Pseudomonas aeruginosa; SAE = serious adverse event; SID = subject identification; 
SOFA = Sequential Organ Failure Assessment; V = Visit.
a
Rescreening of the same eligible subject is permitted if the subject was eligible but randomisation did not 
occur within 7 days of screening.
b
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. 
c
Female subjects of childbearing potential only; must be negative prior to randomisation.
d
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.
e
Tracheal sample collected and positive by PCR for P aeruginosa within 36 hours prior to randomisation.
f
Tracheal aspirate Gram stain and culture should be assessed on the sample obtained for determination of 
colonisation by PCR.


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4.2.2
Randomised Treatment Period and Follow-up
Table 4.2.2-1 shows all procedures to be conducted during the treatment and follow-up 
periods for subjects who are not suspected of having a P aeruginosa infection. Table 4.2.2-2
shows procedures to be conducted for subjects who are suspected or confirmed of having a 
P aeruginosa infection.
Assessments should be performed in the order shown in the table. Whenever vital signs and 
blood draws are scheduled for the same nominal time, vital signs should be assessed first. 
The timing of the first two assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the exact nominal time. 


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Table 4.2.2-1
Schedule of Investigational Product Administration and Follow-up Study Procedures
Study Period
Investigational Product 
Dosing
Follow-up
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
Procedure / 
Study Day
Day 1
Day 2
Day 4
Day 8
(± 2 days)
Day 15
(± 2 days)
Day 22
(± 2 days)
Day 29
(± 3 days)
Day 50
(± 4 days)
Predosea
Dose
Postdose
Eligibility
Medical history, comorbidities, 
and risk factors
X b
Physical examination
X b
Serum βhCG c
X
X
Verify eligibility criteria d
X
Randomisation
X
Premedication e
X
Investigational Product 
Administration
X
Efficacy Assessments
Monitor for clinical 
symptoms/signs of pneumonia/ 
serious P aeruginosa infection 
(eg, physical exam, vital signs, 
oxygen status f, CPIS , SOFA, as 
indicated) 
X
X
X
Daily while in hospital g; in accordance with symptoms after hospital 
discharge 
For subjects with suspected or confirmed pneumonia, tracheobronchitis or 
bacteremia, see Table 4.2.2-2
Microbiology
Blood for culture
X
Tracheal aspirate for Gram stain
X h
X h
Tracheal aspirate for culture 
(intubated subjects only)
X h
X h
Chest X-ray
X






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Table 4.2.2-1
Schedule of Investigational Product Administration and Follow-up Study Procedures
Study Period
Investigational Product 
Dosing
Follow-up
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
Procedure / 
Study Day
Day 1
Day 2
Day 4
Day 8
(± 2 days)
Day 15
(± 2 days)
Day 22
(± 2 days)
Day 29
(± 3 days)
Day 50
(± 4 days)
Predosea
Dose
Postdose
 
i
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be obtained at screening, on the day of dosing prior to the start of infusion 
(2 recordings of blood pressure and pulse rate, 5 minutes apart), every 30 (± 5) minutes during investigational product infusion, at completion of infusion 
(± 5 minutes), every 30 (± 5) minutes after completion of infusion for 2 hours, and 24 hours (± 30 minutes) after completion of infusion.
j
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 at 24 hours after the end of infusion.
l
To be conducted if subject is extubated and able to complete the form. For subjects who remain intubated on Day 15, initial assessment to be conducted 
within 48 hours of extubation
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Table 4.2.2-2
Schedule of Procedures for Subjects With Suspected or Confirmed Pneumonia, 
Tracheobronchitis 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 P aeruginosa bacteremia
Repeat every other day until blood culture negative for 
P aeruginosa
Tracheal/bronchial aspirate e; intubated subjects only (Gram stain and culture) 
All subjects
X
X
X
Subjects positive for P aeruginosa pneumonia or 
tracheobronchitis
As clinically indicated through clinical resolution c
Expectorated sputum e (unless bronchoscopy performed for clinical management and BAL or PSB sample available); nonintubated subjects only (includes
follow-up assessments through clinical resolution in subjects who were initially intubated at the onset of suspected infection, but were subsequently extubated 
prior to clinical resolution)
(Gram stain and culture) 
All subjects
X
X
X
Subjects positive for P aeruginosa pneumonia or 
tracheobronchitis
As clinically indicated through clinical resolution c
Chest X-ray
Subjects with suspected pneumonia or tracheobronchitis
X 
Subjects with confirmed pneumonia
As clinically indicated through clinical resolution c
PK/ADA/Other
Serum PK 
X
Serum ADA
X
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4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Clinical Signs and Symptoms
Subjects will be monitored for clinical signs and symptoms of pneumonia and other serious 
bacterial infections 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 29. For subjects with suspected or 
confirmed pneumonia, tracheobronchitis or bacteremia, clinical symptoms will continue to be 
monitored through clinical resolution (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 partial pressure of oxygen (PaO2) and fraction 
of inspired oxygen (FiO2) is provided in Appendix 7.
4.3.1.2
Microbiology
The schedule of follow-up procedures is shown in Table 4.2.2-1. Additional procedures for 
subjects who have suspected or confirmed pneumonia, tracheobronchitis or bacteremia are 
shown in Table 4.2.2-2 and are described below. 
All subjects with onset of suspected or confirmed pneumonia, tracheobronchitis or
bacteremia through Day 29 (irrespective of anatomical location) of the follow-up period, will 
have blood and respiratory specimens collected at onset (Day 1) of the suspected or 
confirmed infection. The first set of blood and respiratory specimens will be collected on 
Day 1 of infection before the start of any new antibiotic therapy and will continue on Days 2 
and 3 of infection. Blood samples will be sent for culture and respiratory samples will be sent 
for Gram stain and culture. 
Only subjects who are positive for P aeruginosa bacteremia, P aeruginosa pneumonia or P 
aeruginosa tracheobronchitis will have additional samples taken for microbiological 
assessment after Day 3 of infection. For subjects who are positive for P aeruginosa
bacteremia, blood samples will continue to be collected every other day beginning at Day 4 
of infection until blood culture is negative for P aeruginosa. For subjects who are positive for 
P aeruginosa pneumonia or P aeruginosa tracheobronchitis, respiratory samples will 
continue to be collected as clinically indicated until clinical resolution. 
For respiratory specimens, tracheal aspirate will be collected if the subject is intubated. If the 
subject is not intubated at onset of suspected or confirmed pneumonia, tracheobronchitis or 


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bacteremia or is extubated thereafter, expectorated sputum samples will be collected (unless 
bronchoscopy was performed for clinical management and a bronchoalveolar lavage [BAL] 
or protected-specimen brush [PSB] sample is available). 
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. 
Qualitative respiratory culture results will be recorded by all study sites. Quantitative and 
semi-quantitative respiratory culture results will be recorded by study sites when available.
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. A chest X-ray will 
be conducted in subjects at onset of suspected pneumonia or tracheobronchitis and as 
indicated through clinical resolution if pneumonia is confirmed (see Table 4.2.2-2). Chest X-
rays performed as part of routine medical care can be used when available.
4.3.1.4
Definition of P aeruginosa Pneumonia
P aeruginosa Pneumonia Criteria for Subjects Who Are Mechanically 
Ventilated 
A mechanically ventilated subject is intubated with an endotracheal or nasotracheal tube and 
receiving positive pressure ventilation support, or 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, etc) within the past 24 hours.
Subjects should demonstrate the following new onset of symptoms/signs deemed not due to 
any overt noninfectious causes. All 3 criteria (ie, radiographic, clinical, AND microbiologic) 
must be met in order to meet the P aeruginosa pneumonia endpoint.


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1. Radiographic criteria:
a.
New or worsening infiltrate consistent with pneumonia on chest x-ray obtained within 
24 hours of the event (diagnosed by a qualified radiologist)
AND
2. Clinical criteria: At least 2 of the following minor or 1 major respiratory sign or 
symptom of new onset:
Minor criteria:
a.
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 count (WBC 
count > 10,000 cells/mm3, WBC count < 4,500 cells/mm3, or > 15% band 
neutrophils)
b. Production of new purulent endotracheal secretions
c.
New physical examination findings consistent with pneumonia/pulmonary 
consolidation such as auscultatory findings (eg, rales, rhonchi, bronchial breath 
sounds) or dullness to percussion
Major criteria:
a.
Acute changes made in the ventilatory support system to enhance oxygenation, as 
determined by:
i.
PaO2/FiO2 ratio < 240 mm Hg maintained for at least 4 hours OR 
ii. A decrease in PaO2/FiO2 by ≥ 50 mm Hg maintained for at least 4 hours
AND
3. Microbiologic confirmation (obtained within 24 hours of onset of the event): At least 1
of the following:
a.
Respiratory specimen positive for P aeruginosa by culture includes a specimen of 
respiratory secretion 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.
b. Blood culture positive for P aeruginosa (and no apparent primary source of infection 
outside the lung)
c.
Pleural fluid aspirate or lung tissue culture positive for P aeruginosa during episode 
of pneumonia (only if obtained as part of the subject’s necessary clinical 
management)


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P aeruginosa Pneumonia Criteria for Subjects Who Are No Longer Mechanically 
Ventilated
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.
Subjects 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 P aeruginosa pneumonia endpoint. 
1. Radiographic criteria:
a.
New or worsening infiltrate consistent with pneumonia on chest x-ray obtained within 
24 hours of the event (diagnosed by qualified radiologist)
AND
2. Clinical criteria: At least 2 of the following minor or 1 major respiratory sign or 
symptom of new onset:
Minor criteria:
a.
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 count (WBC 
count > 10,000 cells/mm3, WBC count < 4,500 cells/mm3, or > 15% band 
neutrophils)
b. A new onset of cough (or worsening of cough)
c.
Production of purulent sputum
d. New 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
e.
Dyspnea, tachypnea (respiratory rate > 30 breaths/minute), or hypoxemia defined as:
i.
Oxygen (O2) saturation < 90% or PaO2 < 60 mm Hg on room air if lower than 
baseline, OR
ii. A need to initiate or increase sustained (≥ 3 hours) supplemental O2 to maintain 
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Major criteria:
a.
A need to initiate non-invasive mechanical ventilation or re-initiate invasive 
mechanical ventilation because of respiratory failure or worsening of respiratory 
status
AND
3. Microbiologic confirmation (obtained within 72 hours of onset of the event): At least 1
of the following:
a.
Respiratory specimen positive for P aeruginosa 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
b. Blood culture positive for P aeruginosa (and no other apparent primary source of 
infection outside the lung)
c.
Pleural fluid aspirate or lung tissue culture positive for P aeruginosa (only if obtained 
as part of the subject’s necessary clinical management)
During study execution, a blinded independent endpoint adjudication committee will review 
the data for adjudication of efficacy endpoints.
In addition to the primary endpoint, the Phase 2 study includes key secondary and 
exploratory endpoints, which will be used to guide Phase 3 development for MEDI3902.
4.3.1.5
Definition of P aeruginosa tracheobronchitis in mechanically ventilated 
Subject
A subject will be considered for a tracheobronchitis event if he/she is intubated with an 
endotracheal or nasotracheal tube; or, if the subject has a tracheostomy tube in place and 
requires ≥ 8 hours of positive pressure ventilation. 
Subjects should demonstrate the following new onset of symptoms/signs deemed not due to 
any overt noninfectious causes. All 3 criteria (ie, radiographic, clinical, AND microbiologic) 
must be met in order to meet the P aeruginosa tracheobronchitis endpoint.


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1. Radiographic criteria:
a.
No new infiltrate or change from baseline consistent with pneumonia on chest x-ray 
obtained within 24 hours of the event (diagnosed by a qualified radiologist)
AND
2. Clinical criteria: 
a.
Production of new purulent endotracheal secretions
AND
b. Temperature (oral or tympanic temperature) > 38°C or a core temperature ≥ 38.3°C 
AND
3. Microbiologic confirmation (obtained within 24 hours of onset of the event): 
a.
Respiratory specimen positive for P aeruginosa by culture. Includes a specimen of 
respiratory secretions obtained by endotracheal/tracheostomy aspiration or (if 
performed as part of routine clinical care) by bronchoscopy with BAL or PSB 
sampling in intubated subjects
 
 
 
 
 
 
 
 
 
 
 
4.3.3
Medical History and Physical Examination, Weight, and Vital Signs
Medical History, Physical Examination, and Weight
Medical history, comorbidities, and risk factors will be collected at screening. A targeted 
physical examination, including height and weight, will be conducted at screening. Any new 
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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 48 hours.
Table 4.3.9-1
Estimated Blood Volume to be Collected by Visit
Visit Day
Estimated Blood Volume (mL)
Screening
10
Day 1 (Predose and postdose)
30
Day 2
12
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Table 4.3.9-1
Estimated Blood Volume to be Collected by Visit
Visit Day
Estimated Blood Volume (mL)
Day 4
2
Day 8
30
Day 15
15
Day 22
20
Day 29
15
Day 50
10
Total Volume for Scheduled Assessments
144 mL
Subjects With Suspected or Confirmed Pneumonia, Tracheobronchitis or Bacteremia
Day 1 of illness
30
Day 2 of illness
10
Day 3 of illness
10
Day 4 of illness
20
Day 5 of illness and every other day through clinical 
resolution (only for subjects positive for P aeruginosa 
bacteremia)
10
Day of clinical resolution
25
P aeruginosa = Pseudomonas aeruginosa
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 the Sponsor determines that temporary suspension or termination of the study is required, 
the Sponsor will discuss the reasons for taking such action with all participating investigators 
(or head of the medical institution, where applicable). When feasible, Sponsor will provide 
advance notice to all participating investigators (or head of the medical institution, where 
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Investigational product will be supplied to the site as open-labeled cartons, with each carton 
containing one vial. Each carton has a unique number that is printed on the outer carton label 
and the label of the vial within the carton. 
Refer to Section 4.6.2 for information on blinding. 
4.5.1.1
Investigational Product Dose Preparation
Investigational product should not be removed from storage at 2oC to 8oC (36oF to 46oF) 
until all other procedures required prior to subject dosing have been completed.
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. MEDI3902 is supplied as a 
sterile lyophilised drug product with a post-reconstitution MEDI3902 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 4.5.1.4 for further instructions.
Dose Preparation Steps
Preparation of MEDI3902 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 MEDI3902 or placebo for 
investigational product preparation to start of administration should not exceed 4 hours at 
room temperature or 24 hours at 2oC to 8oC. If storage time exceeds these limits, a new dose 
must be prepared from new vials and the study monitor must be notified immediately. 
MEDI3902 and placebo do not contain preservatives, and any unused portion must be 
discarded.
Reconstitution Procedure for MEDI3902
Clean the rubber stopper of the investigational product vial with 
% ethanol or equivalent 
and allow to air dry. Tilt the vial containing MEDI3902 and slowly add
mL of sterile water 
for injection such that the liquid stream is directed along the wall of the vial and not directly 
upon the
 The solution must be swirled intermittently until all solids have 
been dissolved. DO NOT SHAKE OR VIGOROUSLY AGITATE THE VIAL. At the end of 
reconstitution, invert the vial to dissolve any product that might be on the cap. Visually 
inspect to ensure that the entire content of the
 is reconstituted. The 
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is empty, the IV tubing should be flushed with at least 
 mL of
% 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.
4.5.1.3
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 on the day of dosing prior to the start 
of infusion (2 recordings of blood pressure and pulse rate, 5 minutes apart), every 30 (± 5) 
minutes during investigational product infusion, at completion of infusion (± 5 minutes), 
every 30 (± 5) minutes after completion of infusion for 2 hours, and 24 hours (± 30 minutes) 
after completion of infusion.
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognise and treat 
anaphylaxis.
4.5.1.4
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
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 products must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
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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 infusion bags will be 
labeled by an unblinded investigational product manager at the time of use according to site 
standard operating procedures and instructions provided by MedImmune. The labels 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.
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 Sponsor. 
All unused investigational product will be returned to a Sponsor-authorised depot or disposed 
of upon authorisation by Sponsor.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An 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 IWRS that the subject meets eligibility criteria and the IWRS
assigns a treatment arm and blinded investigational product vial numbers will be assigned to 
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the subject. The 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.
Subjects will be randomised at a 1:1 ratio to receive either MEDI3902 
mg (or in the 
case of dose adjustment,
 mg MEDI3902) or placebo. Randomisation will be stratified 
by geographic region and by duration of anti-P aeruginosa antibiotic treatment (see 
Appendix 10; no antibiotics use, duration of ≤72 hours, duration of > 72 hours) within the 
96 hours prior to randomisation. Detailed instructions for the randomisation process will be 
provided in the IWRS manual.
Investigational product (MEDI3902 or placebo) infusion must be initiated the same day and 
within 6 hours after investigational product is assigned 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 not exceed 8 hours for 
the
 mg MEDI3902/placebo groups and 12 hours (in case of dose adjustment) for the 
 mg MEDI3902/placebo groups. In the event of a delay, the medical monitor must be 
notified immediately. Details of the administration procedure are presented in Section 
4.5.1.2.
4.6.2
Methods for Ensuring Blinding 
This is a double-blind study in which MEDI3902 and placebo are visually indistinguishable. 
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 (International Council for Harmonisation [ICH] E9). Investigational product will be 
handled by an unblinded investigational product manager at the site. 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 need to be known to treat an individual 
subject for an AE, the investigator must notify the sponsor immediately. The site will 
maintain a written plan detailing which staff members are blinded/unblinded and the process 
of investigational product administration used to maintain the blind.
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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 is encouraged to attempt to contact the 
medical monitor, prior to unblinding the investigational product allocation for an individual 
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 IWRS manual. In 
general, unblinding should only occur if management of the medical emergency would be 
different based on the subject having received investigational product. In the majority of 
cases, the management of a medical emergency would be the same whether or not 
investigational product was received by the subject. If this was the case, the investigational 
product allocation should not be unblinded. 
MedImmune retains the right to unblind the treatment allocation for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities.
4.6.3.2
Unblinding for Interim Pharmacokinetic Analysis Purposes
One interim PK analysis is planned. 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 as outlined 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.
4.7
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 
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1 highly effective method of contraception for 49 days postdose; cessation of contraception 
after this point should be discussed with a qualified health care provider or a 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 = ethnyl estradiol; IUD = intrauterine device
4.7.2
Concomitant Medication
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the electronic case report forms (eCRFs).
4.7.2.1
Permitted Concomitant Medications
All subjects will be premedicated with antihistamine, for example,
 mg diphenhydramine 
IV, clemastine  mg IV, or dexchlorpheniramine  mg IV (or another antihistamine 
preparation utilised in routine clinical practice for management of acute allergic reactions). 
Additional suggested concomitant medications in the event of an infusion reaction are 
summarised in Section 3.1.3.
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.
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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 49 days postdose. The sponsor must be notified in the event that a subject was to 
receive an investigational product during the study.
4.8
Statistical Evaluation
4.8.1
General Considerations
The key efficacy analyses will be based on 
 mg MEDI3902 and placebo subjects, given 
there is no dose adjustment after interim PK analysis. Data will be provided in data listings 
sorted by treatment group and subject identification number (SID). 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 Day 22 will be included in the primary efficacy (ie, 
intent-to-treat [ITT]) population as described in the primary efficacy analysis section below. 
If a dose adjustment is made from 
 mg to
 mg MEDI3902 for this dose group, the 
key efficacy analyses will be based on 3000 mg MEDI3902 and placebo subjects. Subjects 
who received 
mg MEDI3902 will be summarized descriptively. Due to the decision to 
discontinue the lower dose arm, subjects who received 
mg MEDI3902 will also be 
summarized descriptively. Additional details of statistical analyses will be described in the 
statistical analysis plan (SAP).
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 randomised 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 
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The primary analysis of the primary endpoint will be evaluated using the mITT Population. 
P aeruginosa pneumonia that occurs prior to discontinuation will contribute to the primary 
efficacy analysis. If no P aeruginosa pneumonia occurs prior to discontinuation, the subject 
will be considered as having no P aeruginosa 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 P aeruginosa pneumonia through 
21 days postdose between 1500 mg MEDI3902 and placebo groups, using the term of
treatment group as a covariate. The relative risk reduction, defined as 1 – Relative Risk (RR), 
and its corresponding 2-sided 90% CI will be estimated from the model. In addition, the 
2-sided p-value testing null the hypothesis that the incidence of having P aeruginosa 
pneumonia between MEDI3902 and placebo groups are the same will also be obtained from 
the model. The significance testing will be performed against a 2-sided alpha level of 0.2.
The Poisson regression with robust variance analysis will be implemented using the SAS 
PROC GENMOD procedure with the REPEATED statement for subject ID and logarithm 
link. The estimated parameter  [ie, log(
	 )], 2-sided 80% confidence interval for , and the 
2-sided p-value will be provided from the SAS outputs. The estimated relative risk (
	 ) and 
corresponding confidence interval for the relative risk is given by exponentiating  and its 
confidence limits. Therefore, the percent of relative risk reduction is given by [(1 – exp()) * 
100%]. The confidence interval for the percent of relative risk reduction is given by ([1 –
exp(upper confidence limit for ) * 100%], [1 – exp (lower confidence limit for ) * 100%]).
 
 
 
 
 
 
 
 
 
 
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4.8.4
Safety
The safety of MEDI3902 will be analysed through 49 days postdose in the As-treated 
Population.
4.8.4.1
Analysis of Adverse Events
Safety of MEDI3902 will primarily be assessed and measured by the occurrence of all 
TEAEs and TESAEs.
•
Occurrence of AEs through 49 days postdose
•
Occurrence of SAEs through 49 days postdose
•
Occurrence of AESIs to include targeted AEs of hepatic function abnormalities, 
hypersensitivity reactions (including anaphylaxis), infusion related reactions, and 
immune complex disease (eg, vasculitis, endocarditis, neuritis, glomerulonephritis) 
through 49 days postdose
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, and hematology) will be summarised 
from baseline through 21 days postdose.
 
 
 
 
 
 
 
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the target concentration of 
 µg/mL, a dose adjustment to
mg MEDI3902 will be 
considered.
4.8.12
Planned Analysis
A blinded sample size re-estimation will be performed after approximately 50% of subjects 
have been followed through 21 days postdose, as described in Section 4.8.2. A final analysis 
will be performed after all subjects have completed the study.
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5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for Good Clinical Practice E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (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
•
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•
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, 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 may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterise and understand 
them in association with the use of this investigational product.
5.3.1
Hepatic Function Abnormality
Hepatic function abnormality meeting the definition of Hy’s law is considered an AESI. See 
Section 5.4.3.1 for the definition and reporting of AESIs of hepatic function abnormality.
5.3.2
Hypersensitivity (Including Anaphylaxis) and Infusion related 
Reactions
Administration of polyclonal immunoglobulin preparations and mAbs have been associated 
with hypersensitivity (including anaphylaxis) and infusion related reactions that occur during 
or after dosing. A hypersensitivity reaction is defined as an acute onset of an illness with 
involvement of the skin, mucosal tissue, or both, during infusion of investigational product 
(but does not meet the definition of anaphylaxis). 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). 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 
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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 
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 hypersensitivity (including anaphylaxis) 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 edema, bronchospasm, dyspnea, tachypnea, 
cyanosis, respiratory arrest, tachycardia, hypotension, arrhythmia, chest pain, ischemia or 
infarction, cardiac arrest, flushing, erythema, pruritus, urticaria, angioedema, maculopapular 
rash, nausea, vomiting, cramping, and diarrhea (Kang and Saif, 2007).
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.
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. 


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The pathology and clinical manifestations are dependent on the tissues/organs involved, with 
vascular, skin and renal tissues being common sites of injury. Common examples of immune 
complex hypersensitivity reactions are serum sickness (systemic) and Arthus reactions 
(local). The clinical manifestations of serum sickness include skin rash, fever, malaise and
polyarthralgias or polyarthritis. Symptoms typically develop 1 to 2 weeks after first exposure 
to antigen and usually resolve in several weeks after withdrawal of the causative agent. 
Serum sickness needs to be differentiated from other ‘serum-sickness-like’ reactions that 
have a similar clinical presentation (eg, viral infections, anti-seizure drugs), but are believed 
to have different pathogenic mechanisms. Both serum sickness and serum sickness-like 
reactions have been reported with mAbs (eg, rituximab, infliximab). Clinical presentation 
and time to onset should be taken into account for the diagnosis and differentiation of these 
reactions. Diagnosis of these suspected reactions is best confirmed via biopsy of the affected 
tissues. 
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs 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 the sponsor see 
Section 5.4 for the definition of SAEs and Appendix 2 for guidelines for assessment of 
severity and relationship. 
If an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form.
5.4.1
Time Period for Collection of Adverse Events
AEs will be collected from time of signature of informed consent through 49 days postdose 
according to the schedule in Table 4.2.1-1 and Table 4.2.2-1.
All SAEs and AESIs will be recorded from the time of informed consent through 49 days 
postdose according to the schedule in Table 4.2.1-1 and Table 4.2.2-1. Assessment for these 
events after 49 days postdose will be conducted by telephone contact.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 


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eCRF. MedImmune retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
5.4.3
Recording of Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be collected from the period immediately 
following investigational product administration through 49 days postdose according to the 
schedule in Table 4.2.2-1.
5.4.3.1
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 hepatic function abnormality is known (including 
progression of pre-existing disease), the diagnosis should be recorded as an AE or SAE 
per 5.4 or Section 5.5 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 5.4
or Section 5.5, respectively.
Medications used to treat these events should be recorded.
5.4.3.2
Hypersensitivity (including Anaphylaxis) and Infusion related Reactions
Events of hypersensitivity (including anaphylaxis) 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 5.2 respectively). Medications used to treat these events should be 
recorded.
5.4.3.3
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
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the 
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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate Sponsor representative(s) within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated Sponsor representative works with the Investigator to ensure that all the 
necessary information is provided to the Sponsor Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform Sponsor 
representatives of any follow-up information on a previously reported SAE within one 
calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated Sponsor 
representative(s).
If the EDC system is not available, then the Investigator or other study site personnel reports 
an SAE to the appropriate Sponsor representative by telephone. The Sponsor representative 
will advise the Investigator/study site personnel how to proceed.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose for this study is defined as administration of investigational product in excess of 
 mg MEDI3902, the highest dose tested in the Phase 1 FTIH study (
 
).
•
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
•
An overdose without associated symptoms is only reported on the Overdose CRF 
module.
If an overdose of study drug occurs in the course of this study, then the Investigator or other 
site personnel inform appropriate sponsor representatives immediately, or no later than 
24 hours of when he or she becomes aware of it.
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The designated sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see 
Section 5.5. For other overdoses, reporting must occur within 30 days.
5.6.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of this study, then the Investigator or other site 
personnel informs the appropriate sponsor representatives immediately, or no later than 
24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site within 1 calendar day 
(life-threatening events) or 5 calendar days for all other SAEs (see Section 5.2), and within 
30 days for all other pregnancies.
The same timelines apply when pregnancy outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
5.6.3
Hepatic Function Abnormality
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3x upper limit of normal (ULN) together with total 
bilirubin ≥ 2xULN may need to be reported as SAEs. Please refer to Appendix 9 for further 
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If a case of Hy's law occurs in the course of this study, the Investigator or other site personnel 
must inform appropriate sponsor representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it.
5.6.4
Adverse Events of Special Interest
5.6.4.1
Anaphylaxis and Serious Allergic Reactions (Including Hypersensitivity) 
and Infusion related Reaction
If a case of anaphylaxis and serious allergic reactions (including hypersensitivity) and 
infusion related reaction occurs in the course of this study, the Investigator or other site 
personnel must inform appropriate sponsor representatives immediately, or no later than 24 
hours of when he or she becomes aware of it.
5.6.4.2
Immune Complex Disease
If a case of immune complex disease occurs in the course of this study, the Investigator or 
other site personnel must inform appropriate sponsor representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
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


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•
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 eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts)
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each/the 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), 
regardless of the number of doses of investigational product that was received.


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Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. 
6.4
Data Management 
Data management will be performed by 
 LLC
according to the Data Management Plan.
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator 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/Good Clinical Practice, and applicable 
regulatory requirements.
Redacted


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7.2
Subject Data Protection
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
7.3
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IEC, and to the 
study site staff.
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to Sponsor before enrolment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.
Sponsor or designee should approve any modifications to the ICF that are needed to meet 
local requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
Sponsor or designee will handle the distribution of any of these documents to the national 
regulatory authorities.
Sponsor or designee will provide Regulatory Authorities, IRB/IEC and Principal 
Investigators with safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions, where relevant.
Each Principal Investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. Sponsor or designee will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.


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7.4
Informed Consent
In a situation where a subject is unable to provide consent, informed consent will be obtained 
by using one of the following possible options, which must comply with the applicable 
country’s local laws and ethics committees regulating the enrolment of incapacitated adults 
into clinical trials: Verbal consent from a legally appointed individual via telephone, 
confirmed by signed consent form sent by fax or email (at least 2 people from the study site 
are required, one to administer the informed consent and the second as a witness). When 
consent is obtained by fax or email, an original signature must be obtained at the earliest 
opportunity. 
In extreme and urgent circumstances when immediate action is required, an independent 
physician, who is a qualified medical doctor with at least one year of experience in intensive 
care medicine, may sign the independent physician statement to authorize subject enrolment 
into the study, if the local laws, regulations and ethics committees approve this process. The 
presumed will of the subject will be determined by the physician and documented based on 
his/her knowledge of the study subject. 
The study subject must be presented with the informed consent as soon as it is possible and 
reasonable, and informed consent obtained for continued study participation. The legally 
authorized representative may act as an agent on the subject’s behalf once they are available 
to provide informed consent. 
The above process must be expedited to ensure that securing consent from an authorized 
representative does not lead to delays that may result in increased risk to the subject. 
Furthermore, at no time will medical treatment be delayed to secure authorised informed 
consent for study participation.
The Principal Investigator(s) at each centre will:
•
Ensure each subject’s authorised representative is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study
•
Ensure each subject’s authorised representative is notified that they are free to 
discontinue from the study at any time
•
Ensure that each subject’s authorised representative is given the opportunity to ask 
questions and allowed time to consider the information provided
•
Ensure each subject’s authorised representative provides signed and dated informed 
consent before conducting any procedure specifically for the study
•
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File


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•
Ensure a copy of the signed ICF 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 ICF that is approved by an IRB/IEC
•
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 Sponsor.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
Sponsor will distribute any subsequent amendments and new versions of the protocol to each 
Principal Investigator(s). For distribution to IRB/IEC see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, Sponsor and the site’s IRB/IEC 
are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
7.6
Audits and Inspections
Authorised representatives of Sponsor, a regulatory authority, or an IRB/IEC may perform 
audits or inspections at the centre, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the ICH, and any applicable regulatory requirements. The investigator will 
contact Sponsor immediately if contacted by a regulatory agency about an inspection at the 
site.


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8
REFERENCES
DiGiandomenico A, Warrener P, Hamilton M, Guillard S, Ravn P, Minter R, et al. 
Identification of broadly protective human antibodies to Pseudomonas aeruginosa 
exopolysaccharide Ps1 by phenotypic screening. J Exp Med. 2012 Jul 2;209(7):1273-87.
Esperatti M, Ferrer M, Theessen A, Liapikou A, Valencia M, Saucedo LM, et al. Nosocomial 
pneumonia in the intensive care unit acquired by mechanically ventilated versus 
nonventilated patients. Am J Respir Care Med. 2010 Dec 15;182(12):1533-9.
Francois B, Luyt CE, Dugard A, Wolff M, Diehl JL, Jaber S, et al. Safety and 
pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically 
ventilated patients colonised with Pseudomonas aeruginosa: a randomised, double-blind, 
placebo-controlled trial. Crit Care Med. 2012;40(8):2320-6.
Heyen JR, Rojko J, Evans M, Brown TP, Bobrowski WF, Vitsky A, et al. Characterization, 
biomarkers, and reversibility of a monoclonal antibody-induced immune complex disease in 
cynomolgus monkeys (Macca fascicularis). Toxicol Pathol. 2014 Jun10;42(4):765-73.
Innovative Medicines Initiative Joint Undertaking (IMI JU). 8th Call for Proposals 2012. 
Available at: 
http://www.imi.europa.eu/sites/default/files/uploads/documents/8th_Call/IMI_8thCallText_F
INAL.pdf.
Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-
associated bacterial pneumonia. Clin Infect Dis. 2010 Aug 1;51 Suppl 1:S81-7.
Kang SP, Saif MW. Infusion related and hypersensitivity reactions of monoclonal antibodies 
used to treat colorectal cancer--identification, prevention, and management. J Support Oncol. 
2007 Oct;5(9):451-7.
Kollef MH, Chastre J, Fagon JY, François B, Niederman MS, Rello J, et al. Global 
prospective epidemiologic and surveillance study of ventilator-associated pneumonia due to 
Pseudomonas aeruginosa. Crit Care Med. 2014 Oct;42(10):2178-87.
Luna CM, Blanzaco D, Niederman MS, Matarucco W, Baredes NC, Desmery P, Palizas F, 
Menga G, Rios F and Apeztequia C. Resolution of ventilator-associated pneumonia: 
prospective evaluation of the clinical pulmonary infection score as an early clinical predictor 
of outcome. Crit Care Med. 2003 Mar;31(3):676-82


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Rehm C, Kollef M. Prospective multinational observational study of the incidence of 
ventilator associated pneumonia. Poster #367. 43rd Critical Care Congress, Society of 
Critical Care Medicine (SCCM); 9-13 January 2014, San Francisco CA, USA. 
Rojko JL, Evans MG, Price SA, Han B, Waine G, DeWitte M, et al. Formation, clearance, 
deposition, pathogenicity, and identification of biopharmaceutical-related immune 
complexes: review and case studies. Toxicol Pathol. 2014 Jun 3; 42(4):725-764.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7.
Vincent JL, Moreno R, Takala J, Willatts et al. 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 Jul; 22 (7): 707-10
Zahar, JR, Nguile-Makao M, Francais A, Schwebel C, Garrouste-Orgeas M, Goldgran-
Toledano D, et al. Predicting the risk of documented ventilator-associated pneumonia for 
benchmarking: construction and validation of a score. Crit Care Med. 2009 Sep;37(9):2545-
51.
Zou, GY. A modified Poisson regression approach to prospective studies with binary data. 
Am J Epidemiol 2004; 159: 702–706.
9
CHANGES TO PROTOCOL
9.1
Protocol Amendment 1, 15Jul2016
Text revisions resulting from this amendment are incorporated in the body of Protocol
Amendment 1. Major changes to the protocol are summarized below:
1. Protocol Synopsis, Section 2.2.1 (Primary Endpoint), Section 3.2.3 (Rationale for 
Endpoints), Table 4.2.2-1 (Schedule of Investigational Product Administration and 
Follow-up Study Procedures), Section 5.4 (New Onset of Chronic Diseases) and Section 
5.4.1 (Time Period for Collection of Adverse Events): NOCDs as a safety assessment has 
been removed. Since AEs, SAEs and AESIs are being assessed at each study visit 
through the end of study (Day 50), any potential NOCDs will be recorded as AEs, SAEs, 
or AESIs, making it unnecessary to capture NOCDs separately.










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Appendix 1
Signatures








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Signature of Principal Investigator
A Phase 2 Proof-of-concept Study to Evaluate the Efficacy and Safety of MEDI3902 in 
Mechanically Ventilated Patients for the Prevention of Nosocomial Pneumonia Caused by 
Pseudomonas aeruginosa
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/Centre Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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


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


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


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Appendix 3
National Institute of Allergy and Infectious Diseases 
and Food, Allergy and Anaphylaxis Network Guidance 
for Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006; 117:391-7.
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 [PEF], hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline


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Appendix 4
Clinical Pulmonary Infection Score
Simplified version of the 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. GCS (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; APACHE-II = Acute Physiology and Chronic Health Evaluation-II APS = Acute Physiology Score; CHE = Chronic Health 
Evaluation; FiO2 = fraction of inspired oxygen GCS = Glasgow Coma Scale; HCO3 = bicarbonate; PaO2 = partial pressure of oxygen; 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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Appendix 9
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) 
criteria are met.  HL criteria are met if there is no alternative explanation for the elevations in 
liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.


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Identification of potential hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
•
ALT ≥ 3xULN
•
AST ≥ 3xULN
•
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to sponsor 
study representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
•
Notify the sponsor study representative
•
Request a repeat of the test (new blood draw) by the central laboratory
•
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central laboratory results the Investigator will 
without delay:
•
Determine whether the patient meets PHL criteria by reviewing laboratory reports from 
all previous visits (including both central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the 
identification criteria are met will:
•
Notify the sponsor study representative
•
Determine whether the patient meets PHL criteria by reviewing laboratory reports from 
all previous visits
•
Promptly enter the laboratory data into the laboratory CRF


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Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
•
Inform the study representative that the patient has not met PHL criteria.
•
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
•
Notify the sponsor study representative who will then inform the central Study Team
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
•
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated 
•
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. This includes deciding which tests available in the Hy’s law lab 
kit should be used. 
•
Complete the Liver CRF Modules as information becomes available 
•
If at any time (in consultation with the Medical Monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of potential hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Medical 
Monitor will contact the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The Clinical Medical Monitor and Global Safety Physician will also be involved in this 
review together with other subject matter experts as appropriate.  


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According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
•
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
•
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
•
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 
▪
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
▪
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
•
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
•
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review




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References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf

SAP_003.pdf: 


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Statistical Analysis Plan 
 
 
 
 
 
Phase 2 Proof-of-concept Study to Evaluate the Efficacy and 
Safety of MEDI3902 in Mechanically Ventilated Patients for the 
Prevention of Nosocomial Pneumonia Caused by Pseudomonas 
aeruginosa 
 
 
Protocol Number: D5470C00004 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................. 6 
2 
STUDY OVERVIEW ............................................................................................. 6 
2.1 
Study Objectives ..................................................................................................... 6 
2.1.1 
Primary Study Objective(s) .................................................................................... 6 
2.1.2 
Secondary Study Objectives ................................................................................... 6 
 
 
2.2 
Study Design ........................................................................................................... 7 
2.3 
Treatment Assignment and Blinding ...................................................................... 8 
2.4 
Sample Size ............................................................................................................ 8 
 
 
3 
STATISTICAL METHODS ................................................................................. 10 
3.1 
General Considerations ......................................................................................... 10 
3.2 
Analysis Populations ............................................................................................ 10 
3.3 
Strata ..................................................................................................................... 11 
3.4 
Study Subjects ...................................................................................................... 11 
3.4.1 
Subject Disposition and Completion Status ......................................................... 11 
3.4.2 
Demographics and Baseline Characteristics ......................................................... 12 
3.4.3 
Study Drug Exposure ............................................................................................ 14 
3.5 
Efficacy Analyses ................................................................................................. 14 
3.5.1 
Primary Efficacy Endpoint and Analyses ............................................................. 14 
3.5.1.1 
Primary Efficacy Endpoint ................................................................................... 14 
3.5.1.2 
Handling of Dropouts and Missing Data .............................................................. 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.8 
Safety Analyses .................................................................................................... 30 
3.8.1 
Adverse Events and Serious Adverse Events ....................................................... 30 
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3.8.2 
Adverse Events of Special Interest ....................................................................... 30 
3.8.3 
Deaths and Treatment Discontinuations due to Adverse Events .......................... 31 
3.8.4 
Clinical Laboratory Evaluation............................................................................. 31 
3.8.5 
Other Safety Evaluations ...................................................................................... 31 
3.9 
Antidrug antibody Response................................................................................. 31 
3.10 
Pharmacokinetics .................................................................................................. 32 
4 
INTERIM ANALYSIS ......................................................................................... 32 
5 
REFERENCES ..................................................................................................... 34 
6 
VERSION HISTORY ........................................................................................... 35 
 
LIST OF IN-TEXT TABLES 
Table 1 
Analysis Populations ................................................................................... 11 
 
 
Table 3 
Version History ........................................................................................... 36 
 
 
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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ACC-AHA 
American College of Cardiology/American Heart Association classification 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ATP 
according to protocol 
BMI 
body mass index 
CHF 
Congestive heart failure 
COPD 
Chronic obstructive pulmonary disease 
CLSI 
Clinical and Laboratory Standards Institute 
CPIS 
Clinical pulmonary infection score 
CRP 
C reactive protein 
CSR 
clinical study report 
DBL 
database lock 
DMC 
Data Monitoring Committee 
EAC 
endpoint adjudication committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EU 
European Union 
GOLD 
Global initiative for chronic Obstructive Lung Disease classification 
HADS 
hospital anxiety and depression scale 
ICU 
intensive care unit 
Ig 
immunoglobulin 
IM 
immunogenicity 
ITT 
intent-to-treat 
IV 
intravenous 
IXRS 
interactive voice/web response system 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 


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Abbreviation or 
Specialized Term 
Definition 
NYHA 
New York Heart Association functional classification 
P aeruginosa 
Pseudomonas aeruginosa 
PaO2/FiO2 
ratio of partial pressure arterial oxygen and fraction of inspired oxygen 
PT 
preferred term 
PK 
pharmacokinetics 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SID 
subject identification number 
SOC 
system organ class 
SOFA 
sequential organ failure assessment 
SPP 
statistical programming plan 
SSR 
Sample size re-estimation 
TFL 
tables, figures and listings 
VAP 
Ventilator-associated pneumonia 
WBC 
white blood cell 
 
 


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1 
INTRODUCTION 
This document describes the statistical analysis for protocol D5470C00004, a proof-of-
concept study to evaluate the efficacy and safety of MEDI3902 in mechanically ventilated 
patients for the prevention of nosocomial pneumonia caused by Pseudomonas aeruginosa.  
A separate Statistical Programming Plan (SPP) will be created to give details for the planned 
Tables, Figures and Listings for this study.  
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
1 
To evaluate the effect of MEDI3902 in reducing the incidence of nosocomial pneumonia 
caused by P aeruginosa 
2 
To evaluate the safety of a single IV dose of MEDI3902 in mechanically ventilated 
patients 
 
2.1.2 
Secondary Study Objectives 
1 
To evaluate the serum pharmacokinetics (PK) of MEDI3902 
2 
To evaluate the serum ADA responses to MEDI3902 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
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been enrolled and randomized in the 
 mg and 
mg MEDI3902 groups will be followed 
until the end of the study period (Day 50).  
Key assumptions used for sample size/power calculations: placebo group P aeruginosa 
pneumonia incidence 20%, relative reduction 50%, at least 80% power, 20% adjustment for 
attrition. Relative reduction of 50% was recommended to Sponsor as a clinically 
meaningful effect by experts in critical care, pulmonary medicine, and infectious diseases.  
Statistical methods: power calculations are based on Poisson regression with robust variance 
comparing MEDI3902 versus placebo, 2-sided, with α = 0.2.  
2.4.1 
Blinded Sample Size Re-estimation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 
STATISTICAL METHODS 
3.1 
General Considerations 
Data will be provided in data listings sorted by treatment group and subject identification 
number (SID). Tabular summaries will be presented by treatment group. Categorical data will 
be summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics, including mean, standard deviation, 
median, minimum, and maximum. No multiplicity adjustments will be made to any of the 
analyses. In general, unless stated otherwise, baseline will be defined as the last value prior to 
dosing.  
The key efficacy analyses will be based on 
mg MEDI3902 and placebo subjects. 
Subjects who received 
mg MEDI3902 will be summarized descriptively for both efficacy 
and safety. 
All statistical tests will be 2-sided at an alpha = 0.2 significance level unless stated otherwise. 
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS Institute 
Inc., Cary, NC) in a UNIX platform. 
3.2 
Analysis Populations 
The analysis populations are defined in Table 1. 
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Table 1 
Analysis Populations 
Population 
Description 
ITT 
All subjects who are randomized. Subjects will be analyzed according to their randomized 
treatment group. 
modified ITT 
(mITT) population 
Subjects who receive any study investigational product will be included in the mITT 
population and subjects will be analyzed according to their randomized treatment group. 
As-Treated 
population 
Subjects who receive any study investigational product will be included in the As Treated 
population and subjects will be analyzed according to the treatment they actually receive. 
ITT = intent-to-treat 
 
 
3.3 
Strata 
Many analyses are presented by, or adjusted for, the stratification factor ‘anti-P aeruginosa 
antibiotic treatment (no antibiotics use, duration of ≤ 72 hours, duration of > 72 hours) within 
the 96 hours prior to randomization’. For subjects who were assigned to an incorrect stratum 
at randomization, the stratum recorded on the electronic case report form (eCRF) will differ 
from the stratum recorded for the subject in the IXRS database. Unless stated otherwise, the 
stratum on the eCRF will be used. 
3.4 
Study Subjects 
3.4.1 
Subject Disposition and Completion Status 
Subject disposition will summarise the total number of subjects screened and the reasons for 
screen failure: did not meet inclusion/exclusion criteria, lost to follow-up, withdrawal of 
consent, and other. The summary will also include the number of subjects randomized, the 
number of subjects randomized and dosed, and the number of subjects randomized and not 
dosed and the reason the subject was not dosed: AE, or other. The summary of subject status 
at the end of the study will include the number and percentage of subjects who completed the 
study (i.e. completed the Day 50 follow-up visit) and the number and percentage of subjects 
who discontinued the study due to reasons such as: lost to follow-up, withdrawal of consent, 
death, or other. This summary will be presented by treatment group, for MEDI3902 total, and 
for all subjects combined. The denominators for this summary will include all subjects who 
were randomized and dosed.  
A further summary showing eligibility of subjects for each of the study analysis populations 
will be provided. The denominator for this summary will include all subjects who were 
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3.4.2 
Demographics and Baseline Characteristics 
Enrolment will be summarized by site and by country and site for each treatment group, for 
MEDI3902 total, and for all subjects combined. The total number of subjects randomized into 
each treatment group will be used as the denominator.  
Enrolment will also be summarized by country and pre-dose anti-P aeruginosa antibiotic 
stratum for each treatment group, for MEDI3902 total, and for all subjects combined. The 
total number of subjects in the mITT population will be used as the denominator. The number 
of mis-stratified subjects (i.e. the true pre-dose anti-P aeruginosa antibiotic recorded on the 
eCRF does not match the IXRS database) will be noted. This will be done for each country as 
well as for all countries combined. 
Demographic will be summarized in the intent-to-treat (ITT) and the modified intent-to-treat 
(mITT) population by treatment group, for MEDI3902 total, and for all subjects combined. 
Subjects will be excluded from the summary (e.g. means and percentages) of an individual 
parameter if data are missing.  
Demographic information related to gender, age (years), age category (< 65 years, ≥ 65 years), 
ethnicity, race, weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI category 
(≤ 30, > 30) will be summarised. Actual weight will be recorded when available. If actual 
weight is not available, estimated weight will be recorded. BMI will be calculated based on 
the weight (actual or estimated) provided. 
Baseline characteristics (i.e. clinical severity scores, comorbidities, risk factors within the last 
3 months prior to randomization, and ventilator associated pneumonia (VAP) prevention) will 
be summarized for subjects in the mITT population by treatment group, for MEDI3902 total, 
and for all subjects combined. Subjects will be excluded from the summary (e.g. means and 
percentages) of an individual parameter if data are missing. 
Summaries of clinical severity scores at baseline (defined as the last assessment prior to 
dosing) will include Acute Physiology and Chronic Health Evaluation II (APACHE II), 
Sequential Organ Failure Assessment (SOFA), and Clinical Pulmonary Infection Score 
(CPIS). For CPIS and SOFA, the total scores are sums of the individual score components, 
respectively. For any component which is ‘Not Done’, a total score cannot be calculated. For 
APACHE-II, the total score is the sum of A+B+C, where (A) = Acute Physiology Score 
(APS) Points, (B) = Age points, and (C) = Chronic Health Points. The calculation for APS 
Points (A) is below:  
 
Total APS Points = [Temperature + Mean Arterial Pressure + Heart Rate + Respiratory 
Rate + [((A-aDO2 or PaO2) + Arterial pH) or Serum HCO3] + Serum Sodium + Serum 
potassium + Serum creatinine + Hematocrit + WBC + Glasgow Coma Scale Score] 


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 
If Arterial Blood Gas (ABGs) are not performed (ie, no result for Oxygenation (both 
AaDo2 and PaO2 are ‘Not Done’) and Arterial pH is ‘Not Done’), use the serum HCO3 
value in the APS Score calculation. If Oxygenation and Arterial pH are both ‘Not Done’ 
and serum HCO3 is also ‘Not Done’, APS points cannot be calculated and therefore, 
APACHE-II cannot be calculated. 
 
The following comorbidities will be summarized: 
 
Chronic obstructive pulmonary disease (COPD) 
 
Congestive heart failure (CHF) 
 
Severe COPD (GOLD Stage III/IV) without advanced CHF 
 
Advanced CHF (NYHA Class III/IV or ACC-AHA Stage C/D) without severe COPD 
 
Both severe COPD and advanced CHF 
 
Any other comorbidity: 
 
Coronary Artery Disease (including Myocardial Infarction) 
o 
Angina (chest pain/discomfort) 
o 
History of angioplasty 
 
Peripheral vascular disease 
 
Cerebrovascular disease 
 
Hypertension 
 
Chronic liver disease 
 
Diabetes 
 
Pulmonary artery hypertension 
 
Renal insufficiency or renal failure 
 
Thoracic malignancy or any malignancies 
 
Known immunodeficiency  
 
The Minimum Inhibitory Concentration (MIC) Clinical and Laboratory Standards Institute 
(CLSI) susceptibility profile of P aeruginosa strain in tracheal aspirate at baseline will 
summarize multidrug-resistant (MDR), extensively drug-resistant (XDR), pandrug-resistant 
(PDR), and non-MDR. Baseline is defined as the last value prior to dosing. 
Risk factors history within 3 months prior to randomization will summarise supplemental 
oxygen use prior to hospital admission, history of previous staph infections or colonization, 
history of P aeruginosa infections or colonization, history of other infection(s) (which 
required either oral or IV antibiotic) (yes/no), antibiotic usage (yes/no), hospitalized (yes/no), 
and resided in long term care prior to hospitalization (yes/no). 
VAP prevention measures at baseline will summarise elevation of the head of the bed 
(yes/no), daily ‘sedation vacations’ and assessment of readiness to extubate (yes/no), peptic 


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ulcer disease prophylaxis (yes/no), deep venous thrombosis prophylaxis (yes/no), daily oral 
care with chlorhexidine (yes/no), and all 5 measures used (yes/no). 
3.4.3 
Study Drug Exposure 
The amount of investigational product infused will be summarized by milligrams (mg) for 
subjects in the ‘As-Treated’ population by treatment group. The actual total amount of 
investigational product infused will be calculated based on the treatment group to which the 
subject was assigned and the dose intensity. If the entire dose was administered, the dose 
intensity will be assumed to be 100%. If the entire dose was not administered, dose intensity 
will be calculated as a percentage of actual volume of investigational product given (mL) 
against the volume that was intended to be administered (ie, 100 mL). The actual total amount 
of investigational product infused (mg) = dose intensity * treatment group (mg). For this 
study, the IV treatment group is either 
 mg, or
 mg or  mg 
 
An additional table will summarise the number of infusion interruptions and the median length 
of interruptions (minutes).  
3.5 
Efficacy Analyses 
3.5.1 
Primary Efficacy Endpoint and Analyses 
3.5.1.1 
Primary Efficacy Endpoint 
The primary endpoint is the incidence of nosocomial pneumonia caused by P aeruginosa (as 
determined by the Endpoint Adjudication Committee [EAC]) through 21 days postdose. For 
subjects with multiple P aeruginosa pneumonia events, only the first occurrence will be used 
in the primary analysis. Subjects with mixed culture results, which include P aeruginosa, will 
be counted towards the primary endpoint. 
The analysis of P aeruginosa pneumonia rates will be based on the protocol-specified 
definition as described in the Protocol (Section 4.3.1.4). The EAC will determine the onset 
and resolution date and time of the P aeruginosa pneumonia event. In general, the onset will 
be the date and time when the first criteria were met (ie, radiographic, clinical, or 
microbiologic). For clinical criteria, for example, if a subject starts with fever, then the next 
day develops purulent secretions and meets the radiographic and microbiologic criteria later, 
the date of onset would typically be the date of the fever, subject to EAC review. 
3.5.1.2 
Handling of Dropouts and Missing Data 
It is anticipated that the main cause of missing data for the primary analysis will be subjects 
who discontinue early as a result of death due to their underlying disease in the ICU. If no 
P aeruginosa pneumonia occurs prior to discontinuation, the subject will be considered having 
no P aeruginosa pneumonia infection in the primary efficacy analysis. No other imputation 
will be applied to the primary efficacy analysis.  
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3.8 
Safety Analyses 
3.8.1 
Adverse Events and Serious Adverse Events 
Adverse events (AEs) will be coded by MedDRA version 21.0 and the type incidence, 
severity and relationship to study investigational product will be summarized for subjects in 
the As-treated population by treatment group and for MEDI3902 total. Specific AEs will be 
counted once for each subject for calculating percentages. In addition, if the same adverse 
event occurs multiple times within a particular subject, the highest severity and level of 
relationship observed will be reported. All TEAEs will be summarized overall, as well as 
categorized by MedDRA System Organ Class and Preferred Term. 
Serious Adverse Events (SAEs) will be summarized for each treatment group by MedDRA 
System Organ Class (SOC) and Preferred Term (PT). 
The overall summary of AEs will summarise the number and percentage of subjects with at 
least one event, at least one investigational product related event, at least one event with at 
least Grade 3 severity, death due to AEs, at least one SAE, at least one serious and/or at least 
one Grade 3 severity event, at least one investigational product related serious event, at least 
one event leading to discontinuation of investigational product, at least one AESI, at least one 
investigational product related AESI, and at least one AESI >= Grade 3 severity. 
3.8.2 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will include targeted AEs of hypersensitivity 
(including anaphylaxis), infusion-related reactions, hepatic function abnormalities, and 
immune complex disease (eg, vasculitis, endocarditis, neuritis, glomerulonephritis, serum 
sickness, arthralgias) and will be summarized by treatment group and for MEDI3902 total 
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overall, and by SOC and PT based on MedDRA. Additional groupings may be added by the 
Medical Monitor if warranted. 
An additional table will summarise duration and time to onset from dosing start for AESIs 
including hypersensitivity reactions, infusion related reactions and anaphylactic reactions. 
3.8.3 
Deaths and Treatment Discontinuations due to Adverse Events 
AEs that resulted in death and AEs that led to discontinuation of study treatment will be 
summarized for each treatment group by SOC and PT.  
3.8.4 
Clinical Laboratory Evaluation 
Laboratory parameters will be summarized for subjects in the As-treated population by 
treatment group and for MEDI3902 total as observed and change from baseline. Frequencies 
of worst observed toxicity and Grade 3-4 toxicities, as defined by NCI CTCAE, 2010, v4.03, 
will be presented for each laboratory parameter by treatment group and for MEDI3902 total. 
Also, laboratory parameters will be assessed by presenting tables containing information 
related to 2-grade (or greater) laboratory shifts from baseline.  
For laboratory values reported as lower than the lower limit of quantification (LLOQ), a value 
equal to half of the limit of quantification will be imputed in the summaries. However, 
< LLOQ will be reported in the listings. 
3.8.5 
Other Safety Evaluations 
Additional data collected throughout the study include important protocol deviations, screen 
failure data, significant findings in medical history and physical exam, vital signs, chest X-ray, 
oxygenation status, oxygen log, microbiology data, antibiotics, and concomitant medications 
through 49 days post dose.  
Data listings will be provided and no formal analyses will be conducted on these data. Upon 
review of the listings, additional summary tables may be generated as appropriate.  
3.9 
Antidrug antibody Response 
The number and percentage of subjects who develop anti-MEDI3902 antibodies will be 
summarized at each visit by treatment group and for MEDI3902 total. Subjects will be 
excluded from the summary of an individual visit if data to that specific visit are missing. For 
those with a positive assessment or borderline positive assessment, the ADA titer results will 
also be summarized. Antidrug antibody values reported as borderline positive (ie, ≤ LLOQ), a 
value equal to LLOQ will be imputed in the summaries. An additional table will summarise 
the number and percentage of subjects positive for ADA at baseline (ie, ADA prevalence) and 
positive at any post-baseline time point (ie, ADA incidence). For those with a positive post-


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baseline assessment, the percentage who were persistent positive and transient positive will 
also be presented. 
5. Persistent positive is defined as positive at ≥ 2 post-baseline assessments (with ≥ 16 weeks 
between first and last positive) or positive at last post-baseline assessment. 
6. Transient positive is defined as negative at last post-baseline assessment and positive at 
only one post-baseline assessment or at ≥ 2 post-baseline assessments (with < 16 weeks 
between first and last positive). 
 
AEs will be summarized by SOC and PT based on MedDRA for subjects with ADA to 
MEDI3902 at any time post-baseline. The impact of ADA on PK will be included in the PK 
report as mentioned in Section 3.10. 
3.10 
Pharmacokinetics 
Individual MEDI3902 concentrations in serum will be tabulated for all subjects by treatment 
group along with descriptive statistics through 49 days post dose. Individual MEDI3902 
concentrations in tracheal aspirate will be assessed for intubated subjects who are intubated 
for any duration through 21 days post dose as an exploratory endpoint. Noncompartmental PK 
data analysis will be performed for MEDI3902 data obtained from treatment group with 
scheduled PK sample collection where data allows. Relevant descriptive statistics of 
noncompartmental PK parameters for MEDI3902 will be provided and may include area 
under the concentration-time curve, maximum observed concentration, clearance, volume of 
distribution and half-life. 
The details of the analyses and presentation of these data will be included in a separate PK 
Report. 
4 
INTERIM ANALYSIS 
An interim PK data analysis will be performed after at least 10 subjects in each of the 
 
mg MEDI3902 and placebo groups are followed through 21 days postdose. The interim PK 
analysis will allow the determination of serum PK profile of MEDI3902 in mechanically 
ventilated subjects. Enrolment will continue in both the
 mg MEDI3902 and placebo 
groups while the PK interim analysis is conducted. An independent DMC will be responsible 
for recommending dose adjustment as outlined in the following criteria: If the mean serum 
concentration of MEDI3902 on Day 22 in the
 mg MEDI3902 dose group is lower than 
the target concentration of 
 μg/mL, a dose adjustment to 3000 mg MEDI3902 will be 
considered. Details of the interim analyses will be provided in the Interim Analysis Plan.  
A blinded sample size re-estimation will be carried out as described in section 2.4.1. 
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Safety data will be reviewed regularly by the sponsor and an independent data monitoring 
committee (DMC). The independent DMC will review make recommendations regarding 
further study conduct. Additional details will be provided in the DMC charter. 
 


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5 
REFERENCES 
Agresti A, Min Y. On Small-Sample Confidence Intervals for Parameters in Discrete 
Distributions. Biometrics 2001; 57: 963-971. 
 
Gray, R. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing 
Risk. The Annals of Statistics 1988; 16:1141–1154. 
NCI CTCAE, 2010, U.S. Department Of Health And Human Services, National Institutes of 
Health, National Cancer Institute, Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0, Published: May 28, 2009 (v4.03: June 14, 2010). 
Shaw JW, Johnson JA, Coons SJ. US Valuation of the EQ-5D Health States: Development 
and Testing of the D1 Valuation Model. Med Care 2005; 43(3): 203-220. 
Zou, G. A Modified Poisson Regression Approach to Prospective Studies with Binary Data. 
Am J Epidemiol 2004; 159:702–706. 
 
 


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6 
VERSION HISTORY 
A significant number of major and minor updates were completed throughout the document. 
Major updates are included in the table below: 








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