Clinical trial NCT02940626
Conditions: Pneumonia, Ventilator-associated Pneumonia, Staphylococcal
Keywords: Pneumonia S. aureus Mechanically ventilated
Sponsor: Arsanis, Inc.
Start date: 2016-11-01; Completion date: 2018-09-28
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is the prevention of Staphylococcus aureus pneumonia in mechanically ventilated subjects heavily colonized with S. aureus. Staphylococcus aureus is a human pathogenic bacterium that causes severe infections, including pneumonia and sepsis. Hospital-acquired bacterial pneumonia (HABP) caused by S. aureus, including ventilator-associated bacterial pneumonia (VABP) in mechanically ventilated subjects, is a significant public health threat despite efforts to optimize antibiotic treatment. ASN100 is an investigational monoclonal antibody product that targets the toxins produced by S. aureus to protect subjects from developing S. aureus pneumonia.

Detailed description:
This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for the prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized with S. aureus. This will be a global study conducted at approximately 65 sites to assess the safety, tolerability, and efficacy of ASN100.

Eligible subjects who meet all of the inclusion criteria and none of the exclusion criteria will be screened by semi-quantitative culture of an endotracheal aspirate (ETA) to identify those who are heavily colonized with S. aureus (3+ to 4+). Upon determination of eligibility, subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups, ASN100 or placebo.

Arms: arm 1: Placebo administered as 2 separate intravenous (IV) infusions arm 2: ASN100 administered as 2 separate intravenous (IV) infusions
Interventions: intervention 1: ASN100 intervention 2: Placebo
Intervention descriptions: intervention 1: monoclonal antibody combination of ASN-1 and ASN-2 intervention 2: Placebo

Protocol documents:
SAP_002.pdf: 
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Addendum to SAP, Version 1.0
Protocol No. ASN100-201
ADDENDUM
STATISTICAL ANALYSIS PLAN
(Protocol No. ASN100-201)
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to
Determine the Safety and Efficacy of a Single Dose of ASN100 for
the Prevention of Staphylococcus aureus Pneumonia in Heavily
Colonized, Mechanically Ventilated Subjects
DEVELOPMENT PHASE: 2
Sponsor:
Arsanis, Inc.
890 Winter Street, Suite 230
Waltham, MA
02451-1472
SAP Addendum Version: 1.0
Date: October 25, 2018
CONFIDENTIAL
This material is the proprietary property of Arsanis, Inc. The information is confidential
and is to be used only in connection with matters authorized by Arsanis, Inc.
No
unpublished information presented in this document is to be disclosed to others without
prior written permission from Arsanis, Inc.




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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................3
1.
LIST OF ABBREVIATIONS ....................................................................4
2.
INTRODUCTION......................................................................................6
3.
STUDY METHODS ..................................................................................7
3.1.
Analysis Populations..................................................................................7
3.1.1.
Intent-to-Treat Population (ITT) ................................................................7
3.1.2.
Modified Intent-to-Treat Population (MITT).............................................7
3.1.3.
Per Protocol (PP) Population......................................................................7
3.1.4.
Safety Population .......................................................................................8
3.2.
Subject Disposition ....................................................................................8
3.3.
Demographic and Baseline Characteristics................................................8
3.4.
Prior and Concomitant Medications/Procedures........................................9
3.5.
Analysis of Efficacy...................................................................................9
3.5.1.
Primary Efficacy Endpoint.........................................................................9
3.5.2.
Additional Analyses for S. aureus Pneumonia.........................................10
3.5.3.
Secondary Efficacy Endpoints .................................................................11
3.5.4.
Exploratory Efficacy Endpoints...............................................................11
3.6.
Subgroup Analyses...................................................................................12
3.7.
Analysis of Safety Data............................................................................13
3.7.1.
Adverse Events.........................................................................................13
3.7.2.
Vital Signs................................................................................................14
3.7.3.
Clinical Laboratory Tests .........................................................................14
4.
GENERAL INFORMATION ..................................................................15
4.1.
Statistical Software...................................................................................15
4.2.
Format of Tables, Listings, and Figures...................................................15
5.
APPENDIX ..............................................................................................16


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1.
LIST OF ABBREVIATIONS
AE
Adverse event
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
ASN-1
Broadly cross-reactive anti-toxin monoclonal antibody that targets alpha-hemolysin
(Hla) and 3 F-components (HlgB, LukF, LukD) involved in forming 4 of the 5 bi-
component leukocidins of Staphylococcus aureus
ASN-2
Anti-toxin monoclonal antibody that targets the fifth bi-component leukocidin of
Staphylococcus aureus, LukGH
ASN100
A combination of the 2 fully human monoclonal antibodies ASN-1 and ASN-2
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
BMI
Body mass index
CSR
Clinical study report
ETA
Endotracheal aspirate
HABP
Hospital-acquired bacterial pneumonia
ICF
Informed consent Form
ICU
Intensive care unit
ITT
Intent-to-Treat
LLN
Lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MITT
Modified Intent-to-Treat
POP
Population and outcome plan
PP
Per Protocol
PT
Preferred term
S. aureus
Staphylococcus aureus
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDO
Sponsor-defined outcome
SOC
System organ class
TEAE
Treatment-emergent adverse event
TFLs
Tables, figures, and listings
ULN
Upper limit of normal


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VABP
Ventilator-associated bacterial pneumonia
WHO
World Health Organization


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2.
INTRODUCTION
This Addendum to the Statistical Analysis Plan (SAP) describes the final selected analyses
and reporting based on the final SAP (dated June 25, 2018, Version 1.0), and as outlined
in appendix Section 5, the final tables, figures, and listings (TFLs) shells. The purpose of
this Addendum is to outline the subset of analyses to support the completion of the Clinical
Study Report (CSR) for Protocol ASN100-201.


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3.
STUDY METHODS
3.1.
Analysis Populations
The following analysis populations will be used for analyses.
3.1.1.
Intent-to-Treat Population (ITT)
The ITT Population includes all subjects who are randomized to receive study drug.
3.1.2.
Modified Intent-to-Treat Population (MITT)
The MITT Population includes all subjects in the ITT Population who receive study drug
and who are heavily colonized with S. aureus as determined by quantitative or semi-
quantitative culture of an ETA specimen. Exclusion from the MITT Population will be
determined programmatically for each ITT subject. Programmatically determined
assignment into the MITT Population will be evaluated for confirmation or Sponsor
Override as applicable during a Review Meeting of the Population and Outcome Plan
(POP) Review Group, as described in the POP.
Review Meetings will be held on a regular basis throughout the conduct of the study.  The
number of subjects included in each Review Meeting will vary depending on the number
of subjects included in a data review cycle per the Medpace Rolling Data Lock Plan.
The final MITT Population classification will be performed in a blinded fashion and prior
to final database lock and unblinding. After the Review Groups review, any Sponsor
overrides of the MITT Population flags will be finalized and documented. The MITT
Population flags will be included in the analysis datasets.
3.1.3.
Per Protocol (PP) Population
The PP Population includes all subjects in the MITT Population who also meet the
following criteria:

Did not have any major protocol violations that would affect assessment of efficacy
based on medical review of available data;

Randomized in a timely manner following collection of an ETA specimen showing
heavy S. aureus colonization;

Was mechanically ventilated at randomization;

Had an appropriate chest image performed at randomization;

Did not have a change of oxygenation and onset of purulent secretions at
randomization;

Was not diagnosed with pneumonia at randomization or within 24 hours of
receiving study drug;

Received an adequate dose of study drug administered in a timely manner following
study drug preparation,


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
Did not die within 24 hours of receiving study drug;

Did not have Investigator Diagnosis of Pneumonia within 24 hours of receiving
study drug; and

Complete an adequate number of Monitoring Period assessments through Day 22
based on medical review of available data.
Exclusion from the PP Population will be determined programmatically for each MITT
subject. Programmatically determined assignment into the PP Population will be evaluated
for confirmation or Sponsor Override as applicable during a Review Meeting.
The final PP Population classification will be performed in a blinded fashion and prior to
final database lock and unblinding. After the Review Groups review, any Sponsor
Overrides of the PP Population flags will be finalized and documented. The PP Population
flags will be included in the analysis datasets.
3.1.4.
Safety Population
The Safety Population includes all subjects who receive any amount of study drug and have
at least 1 post-treatment safety assessment.
3.2.
Subject Disposition
Subject disposition will be summarized for the ITT Population for each treatment group
and in total. The following subject disposition categories will be included in the summary
for the ITT Population:

Subjects who randomized in primary prevention study,

Subjects who randomized in treatment sub-study,

Subjects who received any study drug,

Subjects who completed the study assessments through Day 22,

Subjects who did not complete the study assessments through Day 22,

Subjects who completed the study assessments through Day 90,

Subjects who did not complete the study assessments through Day 90, and

Subjects who completed assessments through Day 22, but did not complete the
study assessments through Day 90.
For subjects who did not complete the study assessments through Day 90, a summary will
be provided by reason of discontinuation. In addition, the total number of subjects for each
defined population will be tabulated.
3.3.
Demographic and Baseline Characteristics
Demographic information including sex, race, ethnicity, corrected randomization
stratification factor (receipt or non-receipt of concomitant anti-staphylococcal antibiotics
at the time of randomization that are potentially active against S. aureus pneumonia), age


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(as a continuous variable and categorized as <55, 55 - <65, 65 - <75 and ≥75 years, and
categorized as <50, 50 - <65, and ≥65 years), height, weight, and BMI (as a continuous
variable, categorized as <25, 25 - <30, 30 - <35, and ≥35 kg/m2), type of hospital unit at
time of ICF (ICU and non-ICU), type of ICU, Length of stay (total days) in ICU post‑
treatment, Length of stay in ICU post‑treatment category (<5, 5-12, >12 - 22, and >22
days), Acute kidney injury status at Day 2 visit, baseline creatinine (as a continuous
variable and categorized as <2 and ≥2 mg/dL), and reason for mechanical ventilation
(trauma, cardiovascular impairment, neurological impairment, pulmonary impairment, and
other) will be summarized by treatment group for the ITT, MITT, PP, and Safety
Populations.
3.4.
Prior and Concomitant Medications/Procedures
Prior and concomitant medications will be coded using the World Health Organization
(WHO) Drug Dictionary (Sept 2016E B2). Concomitant procedures will be coded using
the Medical Dictionary for Regulatory Activities (MedDRA, Version 19.1).
Prior medications are medications used before the initiation of study drug administration.
Any medications used on or after the initiation of study drug administration will be
included as concomitant medications. Hence medications ongoing at start of study
medication will be counted as both prior and concomitant medication.
The number and percentage of subjects taking concomitant medications will be
summarized for the ITT Population by anatomic therapeutic chemical (ATC) class and
preferred term for each treatment group and overall.
Prior and concomitant medications/procedures will be listed by subject.
3.5.
Analysis of Efficacy
For all efficacy analyses, subjects will be analyzed in the treatment group to which they
were randomized.
Sponsor defined outcomes were determined based on the review of microbiology results
from samples tested at the central laboratory.  In cases where a sample was not sent to the
central laboratory, the determination was based on results from samples tested at the local
microbiology laboratory.  In all cases where both a local and central result were available,
concordance was confirmed in terms of Staphylococcus aureus. Therefore, the study
analysis utilized local microbiology data in order to utilize a more complete dataset.
3.5.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is whether the subject has or has not developed S. aureus
pneumonia up to, but not including, Day 22 in the MITT Population. For the primary
analysis, whether the subject has or has not developed S. aureus pneumonia will be based
on sponsor defined outcome (SDO1).
The primary analysis is based on comparing two proportions of subjects who develop S.
aureus pneumonia by SDO1 up to, but not including, Day 22. For each arm, the empirical
proportion is defined by a ratio, which is the number of S. aureus pneumonia events divided


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by the total number of subjects in the arm. The inference about the difference of two
population rates is based on the empirical counterpart. Specifically, the point estimate, 95%
confidence interval and p-value for the rate difference. If subjects discontinued from the
study due to any cause prior to Day 22, it will be considered as not developing S. aureus
pneumonia by SDO1 for the primary efficacy analysis.
3.5.2.
Additional Analyses for S. aureus Pneumonia
Analyses of the primary efficacy endpoint will also be performed based on the
PP Populations.
The following additional analyses will be performed in the MITT and PP Populations:

The primary efficacy analysis, based on comparing two proportions of subjects who
develop S. aureus pneumonia by SDO2 up to, but not including, Day 22. If subjects
discontinued from the study due to any cause prior to Day 22 it will be considered
as not developing S. aureus pneumonia for this analysis by SDO2.

The additional analysis is based on comparing two proportions of subjects who
develop S. aureus pneumonia by SDO1 and SDO2 up to, but not including, Day
22. For each arm, the empirical proportion is defined by a ratio, which is the number
of S. aureus pneumonia events divided by the total number of subjects in the arm.
The inference about the difference of two population rates is based on the empirical
counterpart. Specifically, the point estimate, 95% confidence interval and p-value
for the rate difference. If subjects discontinued from the study due to any cause
prior to Day 22, data will be analyzed both as assumed to have developed S. aureus
pneumonia and not having developed S. aureus pneumonia by SDO1 and SDO2.

The Kaplan-Meier analysis will be performed for the proportion of subjects who
develop S. aureus pneumonia by Day 21 as determined by SDO1 and SDO2. The
proportion of subjects who develop S. aureus pneumonia up to but not including
Day 22 will be obtained from Kaplan-Meier estimates for each treatment group.
The number and percentage of subjects who developed S. aureus pneumonia or
were censored will be summarized. The Kaplan-Meier estimate of event rates
evaluated at Day 21 and the corresponding 95% confidence intervals will be
presented for each treatment group. Subjects who did not develop S. aureus
pneumonia, discontinued from the study, or died prior to Day 22 will be considered
censored.  For the censored subjects, the last assessment date on which the subject
did not develop S. aureus pneumonia based on the Investigators assessment will
be used as the date of censoring.

The additional Kaplan-Meier analysis will be performed for the proportion of
subjects who develop S. aureus pneumonia by Day 21 as determined by SDO1 and
SDO2. The proportion of subjects who develop S. aureus pneumonia up to but not
including Day 22 will be obtained from Kaplan-Meier estimates for each treatment
group. The number and percentage of subjects who developed S. aureus pneumonia
or were censored will be summarized. The Kaplan-Meier estimate of event rates
evaluated at Day 21 and the corresponding 95% confidence intervals will be


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presented for each treatment group. Discontinuation from the study due to any
cause up to but not including Day 22 will be considered as an Event.

The Kaplan-Meier analysis will be performed for the proportion of subjects who
develop S. aureus pneumonia up to but not including Day 22 as determined by the
Investigators judgement and the Review Meetings determination of S. aureus as
a causative pneumonia pathogen.
The number and percentage of subjects with SDO1 and SDO2 of S. aureus pneumonia, no
S. aureus pneumonia, indeterminate, and censored in each treatment group will be
summarized descriptively.
3.5.3.
Secondary Efficacy Endpoints
Duration of mechanical ventilation and length of hospital ICU stay during the first 21 days
post-randomization will be summarized descriptively and compared between treatment
groups using a Wilcoxon rank sum test in the MITT and PP Populations.
The other secondary endpoint, 28-day all-cause mortality in the MITT and PP Population,
will be descriptively summarized by treatment group. All-cause mortality rate at Day 28
based on Kaplan-Meier estimates along with the 95% confidence interval will also be
presented for each treatment group. Subjects whose survival status are unknown due to
early termination or who are lost to follow up will be censored at the last day the subject
was known to be alive.
3.5.4.
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include:

Proportion of subjects in the MITT and PP Populations with a diagnosis of HABP
48 hours post-extubation up to, but not including, Day 22 in extubated subjects;

Proportion of subjects in the MITT and PP Populations with development of VABP
up to, but not including, Day 22;

Incidence of all pneumonias (SDO1 and SDO2) up to, but not including, Day 22 in
the MITT and PP Populations, data will be analyzed both as assumed to have
developed pneumonia and not having developed pneumonia by SDO1 and SDO2;

Incidence of all bacterial pneumonias (SDO1 and SDO2) up to, but not including,
Day 22 in the MITT and PP Populations, data will be analyzed both as assumed to
have developed bacterial pneumonia and not having developed bacterial
pneumonia by SDO1 and SDO2;

Incidence of other non-S. aureus pneumonias (SDO1 and SDO2) up to, but not
including, Day 22 in the MITT and PP Populations, data will be analyzed both as
assumed to have developed non-S. aureus pneumonia and not having developed
non-S. aureus pneumonia by SDO1 and SDO2 ;

Incidence of Gram negative pneumonias (SDO1 and SDO2) up to, but not
including, Day 22 in the MITT and PP Populations, data will be analyzed both as


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assumed to have developed Gram negative pneumonia and not having developed
Gram negative pneumonia by SDO1 and SDO2;

Incidence of other S. aureus (Non-Pulmonary S. aureus) infections acquired up to,
but not including, Day 22 in the MITT and PP Populations.

Summary of all-cause mortality rate through entire study period (through Day 90)
in the MITT and PP Populations.
All exploratory efficacy endpoints will be descriptively summarized by treatment group.
3.6.
Subgroup Analyses
The following subgroups will be used for subgroup analyses for the primary efficacy
endpoint in the MITT Population, i.e. whether the subject has or doesnt have of S. aureus
pneumonia up to, but not including, Day 22 for both SDO1 and SDO2 populations.

Corrected randomization stratification (Receipt or Non-Receipt of concomitant
anti-staphylococcal antibiotics at the time of randomization that are potentially
active against S. aureus pneumonia.)

Type of ICU (e.g., SICU, MICU, Neuro ICU, Trauma ICU)

Length of stay in the intensive care unit (ICU) post-treatment (<5, 5-12, >12-22,
and >22 days)

Reason for mechanical ventilation

BMI categories:  <25, 25-<30, 30-<35, and ≥35

Age: <50, 50-<65, and >65

Male vs. female

Acute kidney injury defined by an absolute increase in serum creatinine of 0.3
mg/dL or a 50% increase (viz., 0.3 mg/dL increase if baseline ≥0.6 mg/dL and 50%
increase if baseline is ≤0.6 mg/dL) within 48 hours from receipt of study drug

Presence of renal disease at Baseline:  serum creatinine <2 mg/dL and ≥2 mg/dl.
The subgroup analyses for all-cause mortality rate at Day 28 and mortality rate through
entire study period (through Day 90) will be performed by country in the MITT Population.
In addition, duration of mechanical ventilation and length of hospital ICU stay during the
first 21 days post-randomization will be performed by the following subgroups in the MITT
Population. Data will be analyzed both as assumed to have developed the following
pneumonia and not having developed the following pneumonia by SDO1 and SDO2:

All pneumonia (SDO1)

All pneumonia (SDO2)

S. aureus pneumonia (SDO1)

S. aureus pneumonia (SDO2)


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
All bacterial pneumonia (SDO1)

All bacterial pneumonia (SDO2)

Non-S. aureus pneumonia (SDO1)

Non-S. aureus pneumonia (SDO2)

Gram negative pneumonia (SDO1)

Gram negative pneumonia (SDO2)
3.7.
Analysis of Safety Data
All subjects in the Safety Population will be included in the safety analyses and analyzed
based on the actual treatment received.
3.7.1.
Adverse Events
Verbatim descriptions of Adverse Events (AEs) will be coded using Version 19.1 of
MedDRA.  Summary tables will be provided for all Treatment-Emergent Adverse Events
(TEAEs). A TEAE is defined as an AE with a start date and time on or after the initiation
of study drug administration. If the time of an AE is missing, it is considered treatment
emergent if it starts on the same date as the initiation of study drug administration. All AEs
(including non-TEAEs), Serious AEs (SAEs), and AEs leading to study drug
discontinuation will be provided in listings by treatment group, subject ID, verbatim term,
MedDRA system organ class (SOC) and preferred term (PT), start and end date,
seriousness flag, severity, relationship to study drug, and action taken with study drug.
An overall summary of AEs will include the number and percentage of subjects in each
treatment group who experienced at least one AE/TEAE in the following categories: any
AE, any TEAE, any drug-related TEAE, any severe TEAE, any SAE, any drug-related
SAE, any SAE leading to death, any TEAE leading to discontinuation of study drug, and
any SAE leading to study drug discontinuation. Subjects with multiple events will be
counted only once within each category. Severity grade and relationship will be counted
using the maximum severity and the strongest relationship respectively for a subject with
multiple TEAEs.
The number and percentage of subjects reporting a TEAE in each treatment group will be
tabulated by SOC and PT; by SOC, PT, and severity; and by SOC, PT, and relationship
(unrelated or related to study drug). For all analyses of TEAEs, if the same AE (based on
PT) is reported for the same subject more than once, the AE is counted only once for that
PT and at the highest severity and strongest relationship to study drug.
The number and percentage of subjects reporting a treatment-emergent SAE in each
treatment group will be summarized by SOC and PT.
Listings will be provided for SAEs and AEs leading to drug discontinuation. In addition,
all AEs will be listed.


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3.7.2.
Vital Signs
Vital sign measurements will include temperature, systolic and diastolic blood pressure,
pulse, respiratory rate, and oxygenation status (as measured by pulse oximetry or arterial
blood gas).
Descriptive statistics will be used to summarize vital signs measurements and change from
baseline by each scheduled time point.
All vital sign assessments will be listed by subject.
3.7.3.
Clinical Laboratory Tests
Descriptive statistics will be provided for hematology, chemistry, urinalysis, and
coagulation parameters and change from baseline by each scheduled time point.
Shift tables from baseline to the worst post-baseline value will be provided for selected
chemistry parameters (Alanine aminotransferase, Aspartate aminotransferase, Total
Bilirubin, Creatinine, and Alkaline phosphatase) and hematology parameters (Hematocrit,
Hemoglobin, Platelets, White blood cell count and differential).
Both scheduled and
unscheduled visits will be considered. For chemistry parameters, the following categories
will be used: <LLN, normal, >ULN and ≤3×ULN, >3×ULN to ≤5×ULN, >5×ULN, and
missing. For hematology parameters, the following categories will be used: low, normal,
high, and missing.
The number and percentage of subjects with the following PCS abnormal liver function
test will be summarized:

ALT ≥3×ULN and ≥5×ULN

AST ≥3×ULN and ≥5×ULN

ALT or AST ≥3×ULN and ≥5×ULN

Total bilirubin ≥1.5×ULN and ≥2×ULN

ALP ≥1.5×ULN and ≥3×ULN

ALT or AST ≥3×ULN and Total bilirubin ≥2×ULN

Potential Hys Law cases: ALT or AST ≥3×ULN, Total bilirubin ≥2×ULN, and
ALP ≤ 2×ULN
A listing of subjects with any post-baseline abnormal liver function tests will be presented.
All clinical laboratory data will be listed. Values outside the normal ranges will be flagged.


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4.
GENERAL INFORMATION
4.1.
Statistical Software
The creation of analysis datasets and statistical analyses will be done using SAS® version
9.3 or higher. The Medpace standard operating procedures (Medpace documents GL-DS-
02-S2.1 and GL-DS-03-S1) will be followed for the validation of all SAS programs and
outputs.
4.2.
Format of Tables, Listings, and Figures
The format of tables, listings, and figures will be described in a stand-alone programming
specifications document and will be finalized before database lock for the study.


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5.
APPENDIX


Table Mock-Ups
TABLE 14.1.1.1 ............................................................................................................................33
Subject Disposition
Intent-to-Treat Population
TABLE 14.1.1.2 ............................................................................................................................35
Analysis Populations
Intent-to-Treat Population
TABLE 14.1.2.1 ............................................................................................................................36
Summary of Demographic and Baseline Characteristics
Intent-to-Treat Population
TABLE 14.1.2.2 ............................................................................................................................41
Summary of Demographic and Baseline Characteristics
Modified Intent-to-Treat Population
TABLE 14.1.2.3 ............................................................................................................................41
Summary of Demographic and Baseline Characteristics
Per Protocol Population
TABLE 14.1.2.4 ............................................................................................................................41
Summary of Demographic and Baseline Characteristics
Safety Population
TABLE 14.1.3 ...............................................................................................................................42
Summary of Concomitant Medications
Intent-to-Treat Population
TABLE 14.2.1.1 ............................................................................................................................43
Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not
Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.1.2 ............................................................................................................................44
Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not
Including Day 22
Per Protocol Population


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TABLE 14.2.1.3 ............................................................................................................................45
Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not
Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.1.4 ............................................................................................................................46
Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not
Including Day 22
Per Protocol Population
TABLE 14.2.1.5 ............................................................................................................................47
Additional Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But
Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.1.6 ............................................................................................................................48
Additional Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But
Not Including Day 22
Per Protocol Population
TABLE 14.2.1.7 ............................................................................................................................49
Additional Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But
Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.1.8 ............................................................................................................................50
Additional Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But
Not Including Day 22
Per Protocol Population
TABLE 14.2.2.1 ............................................................................................................................51
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to
But Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.2.2 ............................................................................................................................52
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to
But Not Including Day 22
Per Protocol Population


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TABLE 14.2.2.3 ............................................................................................................................52
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to
But Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.2.4 ............................................................................................................................52
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to
But Not Including Day 22
Per Protocol Population
TABLE 14.2.2.5 ............................................................................................................................53
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus
Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.2.6 ............................................................................................................................54
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus
Pneumonia Up to But Not Including Day 22
Per Protocol Population
TABLE 14.2.2.7 ............................................................................................................................54
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus
Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.2.8 ............................................................................................................................54
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus
Pneumonia Up to But Not Including Day 22
Per Protocol Population
TABLE 14.2.2.9 ............................................................................................................................55
Kaplan-Meier Analysis of S. aureus Pneumonia Up to But Not Including Day 22
Determined by Investigators Judgement of S. aureus as a Causative Pneumonia Pathogen
Modified Intent-to-Treat Population
TABLE 14.2.2.10 ..........................................................................................................................56
Kaplan-Meier Analysis of S. aureus Pneumonia Up to But Not Including Day 22
Determined by Investigators Judgement of S. aureus as a Causative Pneumonia Pathogen
Per Protocol Population


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TABLE 14.2.3.1.1 .........................................................................................................................57
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Corrected Randomization Stratification
TABLE 14.2.3.1.2 .........................................................................................................................58
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Corrected Randomization Stratification
TABLE 14.2.3.2.1 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Type of ICU at Baseline
TABLE 14.2.3.2.2 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Type of ICU at Baseline
TABLE 14.2.3.3.1 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Length of Stay in ICU Post-Treatment
TABLE 14.2.3.3.2 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Length of Stay in ICU Post-Treatment


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TABLE 14.2.3.4.1 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline BMI Category
TABLE 14.2.3.4.2 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline BMI Category
TABLE 14.2.3.5.1 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Age Group
TABLE 14.2.3.5.2 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Age Group
TABLE 14.2.3.6.1 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Gender
TABLE 14.2.3.6.2 .........................................................................................................................59
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Gender


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TABLE 14.2.3.7.1 .........................................................................................................................60
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Acute Kidney Injury Status within 48 hours from receipt of study drug
TABLE 14.2.3.7.2 .........................................................................................................................60
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Acute Kidney Injury Status within 48 hours from receipt of study drug
TABLE 14.2.3.8.1 .........................................................................................................................60
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline Creatinine Category
TABLE 14.2.3.8.2 .........................................................................................................................60
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline Creatinine Category
TABLE 14.2.3.9.1 .........................................................................................................................60
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Reason for Mechanical Ventilation at Baseline
TABLE 14.2.3.9.2 .........................................................................................................................60
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia
Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Reason for Mechanical Ventilation at Baseline
TABLE 14.2.4.1.1 .........................................................................................................................61
Summary of Pneumonia Infection Rate Up to But Not Including Day 22
Modified Intent-to-Treat Population


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TABLE 14.2.4.1.2 .........................................................................................................................62
Additional Summary of Pneumonia Infection Rate Up to But Not Including Day 22
Modified Intent-to-Treat Population
TABLE 14.2.4.2.1 .........................................................................................................................63
Summary of Pneumonias Infection Rates Up to But Not Including Day 22
Per Protocol Population
TABLE 14.2.4.2.2 .........................................................................................................................63
Additional Summary of Pneumonias Infection Rates Up to But Not Including Day 22
Per Protocol Population
TABLE 14.2.5.1 ............................................................................................................................64
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
TABLE 14.2.5.2 ............................................................................................................................65
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Per Protocol Population
TABLE 14.2.5.3.1A.......................................................................................................................66
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
TABLE 14.2.5.3.1B.......................................................................................................................67
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
TABLE 14.2.5.3.2A.......................................................................................................................68
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)


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TABLE 14.2.5.3.2B.......................................................................................................................68
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
TABLE 14.2.5.4.1A.......................................................................................................................68
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
TABLE 14.2.5.4.1B.......................................................................................................................68
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
TABLE 14.2.5.4.2A.......................................................................................................................68
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
TABLE 14.2.5.4.2B.......................................................................................................................68
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
TABLE 14.2.5.5.1A.......................................................................................................................68
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)


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TABLE 14.2.5.5.1B.......................................................................................................................68
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
TABLE 14.2.5.5.2A.......................................................................................................................68
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO2)
TABLE 14.2.5.5.2B.......................................................................................................................69
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial pneumonia (SDO2)
TABLE 14.2.5.6.1A.......................................................................................................................69
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
TABLE 14.2.5.6.1B.......................................................................................................................69
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
TABLE 14.2.5.6.2A.......................................................................................................................69
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)


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TABLE 14.2.5.6.2B.......................................................................................................................69
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
TABLE 14.2.5.7.1A.......................................................................................................................69
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
TABLE 14.2.5.7.1B.......................................................................................................................69
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
TABLE 14.2.5.7.2A.......................................................................................................................69
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-
Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)
TABLE 14.2.5.7.2B.......................................................................................................................69
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days
Post-Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)
TABLE 14.2.6.1 ............................................................................................................................70
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
TABLE 14.2.6.2 ............................................................................................................................71
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Per Protocol Population


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TABLE 14.2.6.3.1A.......................................................................................................................72
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
TABLE 14.2.6.3.1B.......................................................................................................................73
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
TABLE 14.2.6.3.2A.......................................................................................................................74
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
TABLE 14.2.6.3.2B.......................................................................................................................74
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
TABLE 14.2.6.4.1A.......................................................................................................................74
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
TABLE 14.2.6.4.1B.......................................................................................................................74
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
TABLE 14.2.6.4.2A.......................................................................................................................74
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)


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TABLE 14.2.6.4.2B.......................................................................................................................74
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
TABLE 14.2.6.5.1A.......................................................................................................................74
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
TABLE 14.2.6.5.1B.......................................................................................................................74
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
TABLE 14.2.5.6.2A.......................................................................................................................74
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO2)
TABLE 14.2.5.6.2B.......................................................................................................................75
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial pneumonia (SDO2)
TABLE 14.2.6.6.1A.......................................................................................................................75
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
TABLE 14.2.6.6.1B.......................................................................................................................75
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)


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TABLE 14.2.6.6.2A.......................................................................................................................75
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
TABLE 14.2.6.6.2B.......................................................................................................................75
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
TABLE 14.2.6.7.1A.......................................................................................................................75
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
TABLE 14.2.6.7.1B.......................................................................................................................75
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
TABLE 14.2.6.7.2A.......................................................................................................................75
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)
TABLE 14.2.6.7.2B.......................................................................................................................75
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days
Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)
TABLE 14.2.7.1 ............................................................................................................................76
Analysis of 28-Day All-Cause Mortality Rate
Modified Intent-to-Treat Population
TABLE 14.2.7.2 ............................................................................................................................77
Analysis of 28-Day All-Cause Mortality Rate
Per Protocol Population


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TABLE 14.2.7.3 ............................................................................................................................77
Analysis of All-Cause Mortality Rate Through Entire Study Period (Through Day 90)
Modified Intent-to-Treat Population
TABLE 14.2.7.4 ............................................................................................................................77
Analysis of All-Cause Mortality Rate Through Entire Study Period (Through Day 90)
Per Protocol Population
TABLE 14.2.7.5 ............................................................................................................................78
Subgroup Analysis: Analysis of 28-Day All-Cause Mortality Rate
Modified Intent-to-Treat Population
By Country
TABLE 14.2.7.6 ............................................................................................................................79
Subgroup Analysis: Analysis of All-Cause Mortality Rate Through Entire Study Period
(Through Day 90)
Modified Intent-to-Treat Population
By Country
TABLE 14.2.8.1 ............................................................................................................................80
Summary of Proportion of Subjects with Diagnosis of HABP >48 Hours Post-extubation Up to
But Not Including Day 22
Modified Intent-to-Treat Population
Extubated Subjects
TABLE 14.2.8.2 ............................................................................................................................81
Summary of Proportion of Subjects with Diagnosis of HABP >48 Hours Post-extubation Up to
But Not Including Day 22
Per Protocol Population
Extubated Subjects
TABLE 14.2.9.1 ............................................................................................................................82
Summary of Proportion of Subjects with Development of VABP Up to But Not Including Day
22
Modified Intent-to-Treat Population
TABLE 14.2.9.2 ............................................................................................................................83
Summary of Proportion of Subjects with Development of VABP Up to But Not Including Day
22
Per Protocol Population


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TABLE 14.3.1.1 ............................................................................................................................84
Overview of Adverse Events
Safety Population
TABLE 14.3.1.2 ............................................................................................................................85
Subjects with Treatment-Emergent Adverse Events (TEAEs)
By System Organ Class and Preferred Term
Safety Population
TABLE 14.3.1.3 ............................................................................................................................86
Subjects with Treatment-Emergent Serious Adverse Events (TESAEs)
By System Organ Class and Preferred Term
Safety Population
TABLE 14.3.1.4 ............................................................................................................................86
Subjects with Drug-Related Treatment-Emergent Adverse Events
By System Organ Class and Preferred Term
Safety Population
TABLE 14.3.1.5 ............................................................................................................................87
Subjects with Treatment-Emergent Adverse Events (TEAEs)
By System Organ Class, Preferred Term and Maximum Severity
Safety Population
TABLE 14.3.1.6 ............................................................................................................................88
Subjects with Treatment-Emergent Adverse Events (TEAEs)
By System Organ Class, Preferred Term and Relationship to Study Drug
Safety Population
TABLE 14.3.2.1 ............................................................................................................................89
Listing of Serious Adverse Events
Safety Population
TABLE 14.3.2.2 ............................................................................................................................90
Listing of Adverse Events Leading to Discontinuation of Study Drug
Safety Population
TABLE 14.3.3.1 ............................................................................................................................91
Summary of Laboratory Chemistry Parameters
Safety Population


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TABLE 14.3.3.2 ............................................................................................................................92
Summary of Laboratory Hematology Parameters
Safety Population
TABLE 14.3.3.3 ............................................................................................................................92
Summary of Laboratory Coagulation Parameters
Safety Population
TABLE 14.3.3.4 ............................................................................................................................92
Summary of Laboratory Urinalysis Parameters
Safety Population
TABLE 14.3.3.5 ............................................................................................................................93
Shift Table for Hematology Parameters
Safety Population
TABLE 14.3.3.6 ............................................................................................................................94
Shift Table for Chemistry Parameters
Safety Population
TABLE 14.3.3.7 ............................................................................................................................95
Number (%) of Subjects with Prespecified Potentially Clinically Significant Abnormal Post-
Baseline Liver Function Tests
Safety Population
TABLE 14.3.3.8 ............................................................................................................................97
Listing of Subjects with Prespecified Potentially Clinically Significant Abnormal Post-
Baseline Liver Function Findings
Safety Population
TABLE 14.3.4 ...............................................................................................................................98
Summary of Vital Signs
Safety Population


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 2
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.1.1.1
Subject Disposition
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100
Placebo            Total
(N=###)
(N=###)           (N=###)
n    (%)          n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
Subjects who randomized in primary prevention study
### (###.#)
### (###.#)
### (###.#)
Subjects who randomized in treatment sub-study [1]
### (###.#)
### (###.#)
### (###.#)
Subjects who received study drug
### (###.#)
### (###.#)
### (###.#)
Subjects who completed the study assessments through Day 22
### (###.#)
### (###.#)
### (###.#)
Subjects who did not complete the study assessments through Day 22
### (###.#)
### (###.#)
### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] A single subject 268-002-118 was enrolled and randomized into the treatment sub-study. This subject is only included in
tabulations presenting disposition and safety data.


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 2 of 2
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.1.1.1
Subject Disposition
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100
Placebo            Total
(N=###)
(N=###)           (N=###)
n    (%)          n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
Subjects who completed the study assessments through Day 90
### (###.#)
### (###.#)
### (###.#)
Subjects who did not complete the study assessments through Day 90
### (###.#)
### (###.#)
### (###.#)
Adverse event                                                            ### (###.#)
### (###.#)
### (###.#)
Death
### (###.#)
### (###.#)
### (###.#)
Lost to follow-up
### (###.#)
### (###.#)
### (###.#)
Non-compliance with study drug                                           ### (###.#)       ### (###.#)       ### (###.#)
Physician decision
### (###.#)
### (###.#)
### (###.#)
Protocol deviation
### (###.#)
### (###.#)
### (###.#)
Withdrawal of consent by LAR
### (###.#)
### (###.#)
### (###.#)
Withdrawal of consent by subject
### (###.#)
### (###.#)
### (###.#)
Discontinuation by subject
### (###.#)
### (###.#)
### (###.#)
Discontinuation by LAR
### (###.#)
### (###.#)
### (###.#)
Other
### (###.#)
### (###.#)
### (###.#)
Subjects who completed assessments through Day 22, but did not complete
### (###.#)
### (###.#)
### (###.#)
the study assessments through Day 90
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] A single subject 268-002-118 was enrolled and randomized into the treatment sub-study. This subject is only included in
tabulations presenting disposition and safety data.


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Page 1 of 1
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Table 14.1.1.2
Analysis Populations
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100
Placebo            Total
(N=###)
(N=###)           (N=###)
n    (%)          n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
Intent-to-Treat (ITT) Population [1]                                        ### (###.#)       ### (###.#)       ### (###.#)
Modified Intent-to-Treat (MITT) Population [2]                              ### (###.#)       ### (###.#)       ### (###.#)
Per Protocol (PP) Population [3]                                            ### (###.#)       ### (###.#)       ### (###.#)
Safety Population [4]                                                       ### (###.#)       ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] Intent-to-Treat Population includes all subjects who are randomized to receive study drug.
[2] Modified Intent-to-Treat Population includes subjects in the ITT Population who receive study drug and who are heavily colonized
with S. aureus as determined by quantitative or semi-quantitative culture of an ETA specimen.
[3] Per Protocol Population includes all subjects in the MITT Population who also meet the criteria specified in the SAP.
[4] Safety Population includes all subjects who receive any amount of study drug and have at least 1 post-treatment safety assessment.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 5
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Table 14.1.2.1
Summary of Demographic and Baseline Characteristics
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Demographics/Characteristics                                     ASN100             Placebo            Total
Category/Statistic
(N=###)
(N=###)           (N=###)
______________________________________________________________________________________________________________________________________
Age (years)
n                                                            ###                 ###               ###
Mean                                                          ##.#                ##.#              ##.#
Standard Deviation                                            ##.##               ##.##             ##.##
Minimum                                                       ##                  ##                ##
Median
##.#                ##.#              ##.#
Maximum                                                       ##                  ##                ##
Age group 1 (n, %)
<55 years                                                 ### (###.#)         ### (###.#)       ### (###.#)
55 - <65 years                                            ### (###.#)         ### (###.#)       ### (###.#)
65 - <75 years
### (###.#)         ### (###.#)       ### (###.#)
>=75 years                                                ### (###.#)         ### (###.#)       ### (###.#)
Age group 2 (n, %)
<50 years
### (###.#)         ### (###.#)       ### (###.#)
50 - <65 years                                            ### (###.#)         ### (###.#)       ### (###.#)
>=65 years
### (###.#)         ### (###.#)       ### (###.#)
Gender (n, %)
Male                                                      ### (###.#)         ### (###.#)       ### (###.#)
Female
### (###.#)         ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[1] Acute kidney injury is defined as an absolute increase in serum creatinine of 0.3 mg/dL or a 50% increase (i.e., 0.3 mg/dL
Increase if baseline >=0.6 mg/dL and 50% increase if baseline is <=0.6 mg/dL) within 48 hours from receipt of study drug.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 2 of 5
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Table 14.1.2.1
Summary of Demographic and Baseline Characteristics
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Demographics/Characteristics                                     ASN100             Placebo            Total
Category/Statistic
(N=###)
(N=###)           (N=###)
______________________________________________________________________________________________________________________________________
Race (n, %)
American Indian or Alaska Native                          ### (###.#)         ### (###.#)       ### (###.#)
Asian
### (###.#)         ### (###.#)       ### (###.#)
Black or African American                                 ### (###.#)         ### (###.#)       ### (###.#)
Native Hawaiian or other Pacific Islander                 ### (###.#)         ### (###.#)       ### (###.#)
White                                                     ### (###.#)         ### (###.#)       ### (###.#)
Other
### (###.#)         ### (###.#)       ### (###.#)
Ethnicity (n, %)
Hispanic or Latino                                        ### (###.#)         ### (###.#)       ### (###.#)
Not Hispanic or Latino
### (###.#)         ### (###.#)       ### (###.#)
Not reported                                              ### (###.#)         ### (###.#)       ### (###.#)
Unknown                                                   ### (###.#)         ### (###.#)       ### (###.#)
Weight (kg)
n                                                            ###                 ###               ###
Mean                                                          ##.##
##.##             ##.##
Standard Deviation                                            ##.###              ##.###            ##.###
Minimum                                                       ##.#
##.#              ##.#
Median                                                        ##.##               ##.##             ##.##
Maximum                                                       ##.#                ##.#              ##.#
Height (cm)
n                                                            ###                 ###               ###
Mean                                                          ##.#
##.#              ##.#
Standard Deviation                                            ##.##               ##.##             ##.##
Minimum                                                       ##                  ##
##
Median                                                        ##.#                ##.#              ##.#
Maximum                                                       ##                  ##                ##
____________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[1] Acute kidney injury is defined as an absolute increase in serum creatinine of 0.3 mg/dL or a 50% increase (i.e., 0.3 mg/dL
Increase if baseline >=0.6 mg/dL and 50% increase if baseline is <=0.6 mg/dL) within 48 hours from receipt of study drug.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 3 of 5
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.1.2.1
Summary of Demographic and Baseline Characteristics
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Demographics/Characteristics                                     ASN100
Placebo            Total
Category/Statistic
(N=###)
(N=###)           (N=###)
______________________________________________________________________________________________________________________________________
Body Mass Index (kg/m^2)
n                                                            ###                 ###
###
Mean                                                          ##.##               ##.##             ##.##
Standard Deviation                                            ##.###              ##.###
##.###
Minimum                                                       ##.#                ##.#              ##.#
Median                                                        ##.##               ##.##             ##.##
Maximum                                                       ##.#                ##.#              ##.#
Body Mass Index category (n, %)
<25 kg/m^2
### (###.#)
### (###.#)       ### (###.#)
25-<30 kg/m^2
### (###.#)         ### (###.#)       ### (###.#)
30-<35 kg/m^2
### (###.#)         ### (###.#)
### (###.#)
>=35 kg/m^2
### (###.#)         ### (###.#)       ### (###.#)
Corrected randomization stratification (Receipt of concomitant anti-staphylococcal antibiotics at time of randomization
that are potentially active against S. aureus pneumonia (n, %)
Yes                                                       ### (###.#)         ### (###.#)       ### (###.#)
No
### (###.#)         ### (###.#)       ### (###.#)
Type of Hospital Unit at Time of ICF (n, %)
ICU
### (###.#)         ### (###.#)       ### (###.#)
MICU – Medical ICU
### (###.#)         ### (###.#)       ### (###.#)
SICU - Surgical ICU
### (###.#)         ### (###.#)       ### (###.#)
TICU - Trauma ICU
### (###.#)         ### (###.#)       ### (###.#)
NICU - Neuro ICU
### (###.#)         ### (###.#)       ### (###.#)
CCU - Coronary Care Unit
### (###.#)         ### (###.#)       ### (###.#)
Other ICU                                                 ### (###.#)         ### (###.#)       ### (###.#)
Non-ICU                                                     ### (###.#)
### (###.#)       ### (###.#)
____________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[1] Acute kidney injury is defined as an absolute increase in serum creatinine of 0.3 mg/dL or a 50% increase (i.e., 0.3 mg/dL
Increase if baseline >=0.6 mg/dL and 50% increase if baseline is <=0.6 mg/dL) within 48 hours from receipt of study drug.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 4 of 5
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.1.2.1
Summary of Demographic and Baseline Characteristics
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Demographics/Characteristics
ASN100             Placebo            Total
Category/Statistic
(N=###)
(N=###)           (N=###)
______________________________________________________________________________________________________________________________________
Length of stay (total days) in ICU post‑treatment
n                                                           ###                ###              ###
Mean                                                         ##.##              ##.##            ##.##
Standard Deviation                                           ##.###             ##.###           ##.###
Minimum
##.#               ##.#             ##.#
Median                                                       ##.##              ##.##            ##.##
Maximum
##.#               ##.#             ##.#
Length of stay in ICU post‑treatment category (n, %)
<5 days                                                   ### (###.#)         ### (###.#)       ### (###.#)
5-12 days                                                 ### (###.#)         ### (###.#)       ### (###.#)
>12-22 days                                               ### (###.#)         ### (###.#)       ### (###.#)
>22 days
### (###.#)         ### (###.#)       ### (###.#)
Acute kidney injury status at Day 2 visit (n, %) [1]
Yes                                                       ### (###.#)         ### (###.#)       ### (###.#)
No                                                        ### (###.#)         ### (###.#)       ### (###.#)
Baseline creatinine (mg/dL)
n                                                            ###
###               ###
Mean                                                          ##.###              ##.###            ##.###
Standard Deviation                                            ##.####
##.####           ##.####
Minimum                                                       ##.##               ##.##             ##.##
Median                                                        ##.###              ##.###            ##.###
Maximum                                                       ##.##               ##.##             ##.##
Baseline creatinine category (n, %)
<2 mg/dL
### (###.#)         ### (###.#)       ### (###.#)
>=2 mg/dL
### (###.#)         ### (###.#)       ### (###.#)
____________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[1] Acute kidney injury is defined as an absolute increase in serum creatinine of 0.3 mg/dL or a 50% increase (i.e., 0.3 mg/dL
Increase if baseline >=0.6 mg/dL and 50% increase if baseline is <=0.6 mg/dL) within 48 hours from receipt of study drug.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 5 of 5
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.1.2.1
Summary of Demographic and Baseline Characteristics
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Demographics/Characteristics                                     ASN100             Placebo
Total
Category/Statistic
(N=###)
(N=###)           (N=###)
______________________________________________________________________________________________________________________________________
Reason for mechanical ventilation at baseline (n, %)
Cardiovascular impairment
### (###.#)         ### (###.#)       ### (###.#)
Neurological impairment
### (###.#)
### (###.#)       ### (###.#)
Pulmonary impairment
### (###.#)         ### (###.#)       ### (###.#)
Trauma
### (###.#)         ### (###.#)       ### (###.#)
Other
### (###.#)         ### (###.#)       ### (###.#)
____________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[1] Acute kidney injury is defined as an absolute increase in serum creatinine of 0.3 mg/dL or a 50% increase (i.e., 0.3 mg/dL
Increase if baseline >=0.6 mg/dL and 50% increase if baseline is <=0.6 mg/dL) within 48 hours from receipt of study drug.


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The layouts of the following tables will be the same as Table 14.1.2.1:
Table 14.1.2.2
Summary of Demographic and Baseline Characteristics
Modified Intent-to-Treat Population
Table 14.1.2.3
Summary of Demographic and Baseline Characteristics
Per Protocol Population
Table 14.1.2.4
Summary of Demographic and Baseline Characteristics
Safety Population


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.1.3
Summary of Concomitant Medications
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100            Placebo
Total
ATC Classification
(N=###)
(N=###)           (N=###)
Preferred Term
n    (%)          n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
Any concomitant medications                                         ### (###.#)       ### (###.#)       ### (###.#)
ATC Classification 1                                                ### (###.#)       ### (###.#)       ### (###.#)
Preferred Term 1                                                 ### (###.#)       ### (###.#)       ### (###.#)
Preferred Term 2                                                 ### (###.#)       ### (###.#)       ### (###.#)
ATC Classification 2                                                ### (###.#)       ### (###.#)       ### (###.#)
Preferred Term 1                                                 ### (###.#)
### (###.#)       ### (###.#)
Preferred Term 2                                                 ### (###.#)       ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Coding is based on WHO Drug Dictionary Sept 2016E.
Percentage is calculated using the number of subjects in the column heading as the denominator.
Concomitant medications are medications used on or after the initiation of study drug administration.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.1.1
Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100
Placebo
(N=###)           (N=###)
----------- Treatment Comparison [1] ------------
SDO1
n    (%)          n    (%)
Difference (%)
95% CI          P-value
______________________________________________________________________________________________________________________________________
Yes
### (###.#)       ### (###.#)           ##.#            (##.##, ##.#)       #.####
No                                               ### (###.#)       ### (###.#)
Censored                                         ### (###.#)       ### (###.#)
Indeterminate                                    ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] Treatment difference (ASN100 - Placebo) is the estimate of the difference in the S. aureus pneumonias rate based on SDO1 between
the two treatment arms. The difference estimates, the 95% CIs, and P-values are obtained based on Wald test on equality of
proportions.
Note: In subjects who are not confirmed as having S. aureus pneumonia and who are discontinued from the study due to any cause prior
to Day 22, they are considered as not developing S. aureus pneumonia.


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The layout of the following table will be the same as Table 14.2.1.1:
Table 14.2.1.2
Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.1.3
Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100           Placebo
(N=###)           (N=###)
----------- Treatment Comparison [1] ------------
SDO2
n    (%)          n    (%)
Difference (%)          95% CI
P-value
______________________________________________________________________________________________________________________________________
Yes
### (###.#)       ### (###.#)           ##.#            (##.##, ##.#)       #.####
No                                               ### (###.#)       ### (###.#)
Censored                                         ### (###.#)       ### (###.#)
Indeterminate                                    ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] Treatment difference (ASN100 - Placebo) is the estimate of the difference in the S. aureus pneumonias rate based on SDO2 between
the two treatment arms. The difference estimates, the 95% CIs, and P-values are obtained based on Wald test on equality of
proportions.
Note: In subjects who are not confirmed as having S. aureus pneumonia and who are discontinued from the study due to any cause prior
to Day 22, they are considered as not developing S. aureus pneumonia.


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The layout of the following table will be the same as Table 14.2.1.3:
Table 14.2.1.4
Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.1.5
Additional Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100           Placebo
(N=###)           (N=###)
----------- Treatment Comparison [1] ------------
Category
n    (%)          n    (%)
Difference (%)          95% CI          P-value
______________________________________________________________________________________________________________________________________
SDO1=Yes + Presumed S. aureus Pneumonia [2]
### (###.#)       ### (###.#)           ##.#            (##.##, ##.#)       #.####
SDO1=Yes                                         ### (###.#)
### (###.#)
Presumed S. aureus Pneumonia [2]                 ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] Treatment difference (ASN100 - Placebo) is the estimate of the difference in the S. aureus pneumonias rate based on SDO1 and
Presumed S. aureus pneumonia between the two treatment arms. The difference estimates, the 95% CIs, and P-values are obtained
based on Wald test on equality of proportions.
[2] In subjects who are not confirmed as having S. aureus pneumonia and who are discontinued from the study due to any cause prior
to Day 22, they are considered as developing S. aureus pneumonia, i.e., Presumed S. aureus pneumonia.


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The layout of the following table will be the same as Table 14.2.1.5:
Table 14.2.1.6
Additional Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population


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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.1.7
Additional Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100           Placebo
(N=###)           (N=###)
----------- Treatment Comparison [1] ------------
Category
n    (%)          n    (%)
Difference (%)          95% CI          P-value
______________________________________________________________________________________________________________________________________
SDO2=Yes + Presumed S. aureus Pneumonia [2]
### (###.#)       ### (###.#)           ##.#            (##.##, ##.#)       #.####
SDO2=Yes                                         ### (###.#)       ### (###.#)
Presumed S. aureus Pneumonia [2]                 ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
[1] Treatment difference (ASN100 - Placebo) is the estimate of the difference in the S. aureus pneumonias rate based on SDO2 and
Presumed S. aureus pneumonia between the two treatment arms. The difference estimates, the 95% CIs, and P-values are obtained
based on Wald test on equality of proportions.
[2] In subjects who are not confirmed as having S. aureus pneumonia and who are discontinued from the study due to any cause prior
to Day 22, they are considered as developing S. aureus pneumonia, i.e., Presumed S. aureus pneumonia.


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The layout of the following table will be the same as Table 14.2.1.7:
Table 14.2.1.8
Additional Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.2.1
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)               (N=###)
n    (%)              n    (%)
______________________________________________________________________________________________________________________________________
Subjects with S. aureus pneumonia up to but not including Day 22
### (###.#)             ### (###.#)
Subjects censored                                                              ### (###.#)             ### (###.#)
Kaplan-Meier Estimate (95% CI)
##.# (##.#, ##.#)       ##.# (##.#, ##.#)
__________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Note: Subjects who did not develop S. aureus pneumonia, discontinued from the study, or died prior to Day 22 will be considered
censored.


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The layouts of the following tables will be the same as Table 14.2.2.1:
Table 14.2.2.2
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population
Table 14.2.2.3
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
Table 14.2.2.4
Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.2.5
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)               (N=###)
n    (%)              n    (%)
______________________________________________________________________________________________________________________________________
Subjects with S. aureus pneumonia up to but not including Day 22
### (###.#)             ### (###.#)
Subjects censored                                                              ### (###.#)             ### (###.#)
Kaplan-Meier Estimate (95% CI)
##.# (##.#, ##.#)       ##.# (##.#, ##.#)
__________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Note: Discontinuation from the study due to any cause up to but not including Day 22 will be considered as an event.


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The layouts of the following tables will be the same as Table 14.2.2.5:
Table 14.2.2.6
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population
Table 14.2.2.7
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
Table 14.2.2.8
Additional Kaplan-Meier Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Per Protocol Population


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.2.9
Kaplan-Meier Analysis of S. aureus Pneumonia Up to But Not Including Day 22
Determined by Investigators Judgement of S. aureus as a Causative Pneumonia Pathogen
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)               (N=###)
n    (%)              n    (%)
______________________________________________________________________________________________________________________________________
Subjects with S. aureus pneumonia up to but not including Day 22
### (###.#)             ### (###.#)
Subjects censored                                                              ### (###.#)             ### (###.#)
Kaplan-Meier Estimate (95% CI)
##.# (##.#, ##.#)       ##.# (##.#, ##.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Determination of S. aureus as causative pathogen was confirmed and accepted by Sponsor at review meeting.


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The layouts of the following tables will be the same as Table 14.2.2.9
Table 14.2.2.10
Kaplan-Meier Analysis of S. aureus Pneumonia Up to But Not Including Day 22
Determined by Investigators Judgement of S. aureus as a Causative Pneumonia Pathogen
Per Protocol Population


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Protocol No. ASN100-201
25OCTOBER2018
Page 57 of 144
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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.3.1.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Corrected Randomization Stratification
______________________________________________________________________________________________________________________________________
Subgroup
ASN100             Placebo
-------- Treatment Comparison [1] ---------
SDO1
n/N    (%)        n/N    (%)
Difference (%)        95% CI        P-value
______________________________________________________________________________________________________________________________________
Receipt of concomitant anti-staphylococcal antibiotics at the time of randomization
that are potentially active against S. aureus pneumonia
Yes
### (###.#)       ### (###.#)           ##.#
(##.##, ##.#)       #.####
No                                             ### (###.#)       ### (###.#)
Censored                                       ### (###.#)       ### (###.#)
Indeterminate                                  ### (###.#)
### (###.#)
Non-Receipt of concomitant anti-staphylococcal antibiotics at the time of randomization
that are potentially active against S. aureus pneumonia
Yes
### (###.#)       ### (###.#)
##.#            (##.##, ##.#)       #.####
No                                             ### (###.#)       ### (###.#)
Censored                                       ### (###.#)       ### (###.#)
Indeterminate
### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using N' which is the number of subjects in each subgroup as the denominator.
[1] Treatment difference (ASN100 - Placebo) is the estimate of the difference in the S. aureus pneumonias rate based on SDO1 at
specified subgroup between the two treatment arms. The difference estimates, the 95% CIs, and P-values are obtained based on Wald
test on equality of proportions.
Note: In subjects who are not confirmed as having S. aureus pneumonia and who are discontinued from the study due to any cause prior
to Day 22, they are considered as not developing S. aureus pneumonia.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.3.1.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Corrected Randomization Stratification
______________________________________________________________________________________________________________________________________
Subgroup
ASN100             Placebo
-------- Treatment Comparison [1] ---------
SDO2
n/N    (%)        n/N    (%)
Difference (%)        95% CI        P-value
______________________________________________________________________________________________________________________________________
Receipt of concomitant anti-staphylococcal antibiotics at the time of randomization
that are potentially active against S. aureus pneumonia
Yes
### (###.#)       ### (###.#)           ##.#            (##.##, ##.#)       #.####
No                                             ### (###.#)       ### (###.#)
Censored
### (###.#)       ### (###.#)
Indeterminate                                  ### (###.#)       ### (###.#)
Non-Receipt of concomitant anti-staphylococcal antibiotics at the time of randomization
that are potentially active against S. aureus pneumonia
Yes
### (###.#)       ### (###.#)           ##.#            (##.##, ##.#)       #.####
No                                             ### (###.#)       ### (###.#)
Censored
### (###.#)       ### (###.#)
Indeterminate                                  ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using N' which is the number of subjects in each subgroup as the denominator.
[1] Treatment difference (ASN100 - Placebo) is the estimate of the difference in the S. aureus pneumonias rate based on SDO2 at
specified subgroup between the two treatment arms. The difference estimates, the 95% CIs, and P-values are obtained based on Wald
test on equality of proportions.
Note: In subjects who are not confirmed as having S. aureus pneumonia and who are discontinued from the study due to any cause prior
to Day 22, they are considered as not developing S. aureus pneumonia.


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25OCTOBER2018
Page 59 of 144
The layouts of the following tables will be the same as Tables 14.2.3.1.1 and 14.2.3.1.2:
Table 14.2.3.2.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Type of ICU at Baseline
Table 14.2.3.2.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Type of ICU at Baseline
Table 14.2.3.3.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Length of Stay in ICU Post-Treatment
Table 14.2.3.3.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Length of Stay in ICU Post-Treatment
Table 14.2.3.4.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline BMI Category
Table 14.2.3.4.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline BMI Category
Table 14.2.3.5.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Age Group
Table 14.2.3.5.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Age Group
Table 14.2.3.6.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Gender
Table 14.2.3.6.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Gender


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25OCTOBER2018
Page 60 of 144
The layouts of the following tables will be the same as Tables 14.2.3.1.1 and 14.2.3.1.2:
<<Programing note: for tables 14.2.3.7.1 and 14.2.3.7.2, add footnote “Acute kidney injury is defined as an absolute increase in serum creatinine of 0.3 mg/dL
or a 50% increase (i.e., 0.3 mg/dL increase if baseline >=0.6 mg/dL and 50% increase if baseline is <=0.6 mg/dL) within 48 hours from receipt of study
drug.”>>
Table 14.2.3.7.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Acute Kidney Injury Status within 48 hours from receipt of study drug
Table 14.2.3.7.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Acute Kidney Injury Status within 48 hours from receipt of study drug
Table 14.2.3.8.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline Creatinine Category
Table 14.2.3.8.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Baseline Creatinine Category
Table 14.2.3.9.1
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO1) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Reason for Mechanical Ventilation at Baseline
Table 14.2.3.9.2
Subgroup Analysis - Analysis of Sponsor-Defined Outcome (SDO2) of S. aureus Pneumonia Up to But Not Including Day 22
Modified Intent-to-Treat Population
By Reason for Mechanical Ventilation at Baseline


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.4.1.1
Summary of Pneumonia Infection Rate Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100           Placebo
(N=###)           (N=###)
Category
n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
All pneumonia (SDO1)                            ### (###.#)        ### (###.#)
All pneumonia (SDO2)
### (###.#)        ### (###.#)
S. aureus pneumonia (SDO1)                      ### (###.#)        ### (###.#)
S. aureus pneumonia (SDO2)                      ### (###.#)        ### (###.#)
All bacterial pneumonia rate (SDO1)
### (###.#)        ### (###.#)
All bacterial pneumonia rate (SDO2)
### (###.#)        ### (###.#)
Non-S. aureus pneumonia rate (SDO1)
### (###.#)        ### (###.#)
Non-S. aureus pneumonia rate (SDO2)
### (###.#)        ### (###.#)
Gram negative pneumonia rate (SDO1)             ### (###.#)        ### (###.#)
Gram negative pneumonia rate (SDO2)             ### (###.#)        ### (###.#)
Non-pulmonary S. aureus infection rate
### (###.#)        ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Note: In subjects who are not confirmed as having the specific category and who are discontinued from the study due to any cause prior
to Day 22, they are considered as not developing that category.


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.4.1.2
Additional Summary of Pneumonia Infection Rate Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100           Placebo
(N=###)           (N=###)
Category
n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
All pneumonia (SDO1)                            ### (###.#)        ### (###.#)
All pneumonia (SDO2)                            ### (###.#)        ### (###.#)
S. aureus pneumonia (SDO1)                      ### (###.#)        ### (###.#)
S. aureus pneumonia (SDO2)                      ### (###.#)        ### (###.#)
All bacterial pneumonia rate (SDO1)
### (###.#)        ### (###.#)
All bacterial pneumonia rate (SDO2)
### (###.#)        ### (###.#)
Non-S. aureus pneumonia rate (SDO1)
### (###.#)        ### (###.#)
Non-S. aureus pneumonia rate (SDO2)
### (###.#)        ### (###.#)
Gram negative pneumonia rate (SDO1)             ### (###.#)        ### (###.#)
Gram negative pneumonia rate (SDO2)             ### (###.#)        ### (###.#)
Non-pulmonary S. aureus infection rate
### (###.#)        ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
Note: In subjects who are not confirmed as having the specific category and who are discontinued from the study due to any cause prior
to Day 22, they are considered as developing that category.


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Protocol No. ASN100-201
25OCTOBER2018
Page 63 of 144
The layouts of the following tables will be the same as Table 14.2.4.1.1 and 14.2.4.1.2:
Table 14.2.4.2.1
Summary of Pneumonias Infection Rates Up to But Not Including Day 22
Per Protocol Population
Table 14.2.4.2.2
Additional Summary of Pneumonias Infection Rates Up to But Not Including Day 22
Per Protocol Population


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Protocol No. ASN100-201
25OCTOBER2018
Page 64 of 144
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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.5.1
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
Statistics
(N=###)               (N=####)
______________________________________________________________________________________________________________________________________
n                                             ##                    ##
Mean                                          ##.#                  ##.#
Standard Deviation                            ##.##
##.##
Minimum                                       ##                    ##
Median                                        ##.#                  ##.#
Maximum                                       ##                    ##
----- Treatment Comparison (ASN100 vs. Placebo) [1]-----
P-value                                       #.####
______________________________________________________________________________________________________________________________________
[1] P-value is obtained from a Wilcoxon rank sum test.
Total duration (days) of mechanical ventilation is defined as total number of days on mechanical ventilation during the first 21 days
post-randomization.


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The layout of the following table will be the same as Table 14.2.5.1:
Table 14.2.5.2
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Per Protocol Population


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Page 66 of 144
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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.5.3.1a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
______________________________________________________________________________________________________________________________________
ASN100               Placebo
Statistics
(N=###)               (N=####)
______________________________________________________________________________________________________________________________________
n                                             ##                    ##
Mean                                          ##.#                  ##.#
Standard Deviation                            ##.##                 ##.##
Minimum                                       ##                    ##
Median
##.#                  ##.#
Maximum                                       ##                    ##
----- Treatment Comparison (ASN100 vs. Placebo) [1]-----
P-value                                       #.####
______________________________________________________________________________________________________________________________________
[1] P-value is obtained from a Wilcoxon rank sum test.
Total duration (days) of mechanical ventilation is defined as total number of days on mechanical ventilation during the first 21 days
post-randomization.
Note: In subjects who are not confirmed as having pneumonia (SDO1) and who are discontinued from the study due to any cause prior to
Day 22, they are considered as not developing pneumonia (SDO1).


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.5.3.1b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
______________________________________________________________________________________________________________________________________
ASN100
Placebo
Statistics
(N=###)               (N=####)
______________________________________________________________________________________________________________________________________
n
##                    ##
Mean                                          ##.#                  ##.#
Standard Deviation                            ##.##                 ##.##
Minimum
##                    ##
Median                                        ##.#                  ##.#
Maximum                                       ##                    ##
----- Treatment Comparison (ASN100 vs. Placebo) [1]-----
P-value                                       #.####
______________________________________________________________________________________________________________________________________
[1] P-value is obtained from a Wilcoxon rank sum test.
Total duration (days) of mechanical ventilation is defined as total number of days on mechanical ventilation during the first 21 days
post-randomization.
Note: In subjects who are not confirmed as having pneumonia (SDO1) and who are discontinued from the study due to any cause prior to
Day 22, they are considered as developing pneumonia (SDO1).


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Protocol No. ASN100-201
25OCTOBER2018
Page 68 of 144
The layouts of the following tables will be the same as Table 14.2.5.3.1a and 14.2.5.3.1b:
Table 14.2.5.3.2a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
Table 14.2.5.3.2b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
Table 14.2.5.4.1a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
Table 14.2.5.4.1b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
Table 14.2.5.4.2a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
Table 14.2.5.4.2b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
Table 14.2.5.5.1a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
Table 14.2.5.5.1b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
Table 14.2.5.5.2a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO2)


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Table 14.2.5.5.2b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial pneumonia (SDO2)
Table 14.2.5.6.1a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
Table 14.2.5.6.1b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
Table 14.2.5.6.2a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
Table 14.2.5.6.2b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
Table 14.2.5.7.1a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
Table 14.2.5.7.1b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
Table 14.2.5.7.2a
Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)
Table 14.2.5.7.2b
Additional Analysis of Total Duration (Days) of Mechanical Ventilation During First 21 Days Post-Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.6.1
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
Statistics
(N=###)               (N=####)
______________________________________________________________________________________________________________________________________
n
##                    ##
Mean                                          ##.#                  ##.#
Standard Deviation                            ##.##                 ##.##
Minimum                                       ##
##
Median                                        ##.#                  ##.#
Maximum                                       ##                    ##
----- Treatment Comparison (ASN100 vs. Placebo) [1]-----
P-value                                       #.####
______________________________________________________________________________________________________________________________________
[1] P-value is obtained from a Wilcoxon rank sum test.
Total length of ICU stay (days) is defined as the total number of days of ICU stay during the first 21 days post-randomization.


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The layout of the following table will be the same as Table 14.2.6.1:
Table 14.2.6.2
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Per Protocol Population


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Protocol No. ASN100-201
25OCTOBER2018
Page 72 of 144
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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.6.3.1a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
______________________________________________________________________________________________________________________________________
ASN100               Placebo
Statistics
(N=###)               (N=####)
______________________________________________________________________________________________________________________________________
n                                             ###                   ###
Mean
##.#                  ##.#
Standard Deviation                            ##.##                 ##.##
Minimum                                       ##                    ##
Median                                        ##.#
##.#
Maximum                                       ##                    ##
----- Treatment Comparison (ASN100 vs. Placebo) [1]-----
P-value                                       #.####
______________________________________________________________________________________________________________________________________
[1] P-value is obtained from a Wilcoxon rank sum test.
Total length of ICU stay (days) is defined as the total number of days of ICU stay during the first 21 days post-randomization.
Note: In subjects who are not confirmed as having pneumonia (SDO1) and who are discontinued from the study due to any cause prior to
Day 22, they are considered as not developing pneumonia (SDO1).


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.6.3.1b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO1)
______________________________________________________________________________________________________________________________________
ASN100               Placebo
Statistics
(N=###)               (N=####)
______________________________________________________________________________________________________________________________________
n                                             ##                    ##
Mean                                          ##.#                  ##.#
Standard Deviation                            ##.##                 ##.##
Minimum                                       ##                    ##
Median
##.#                  ##.#
Maximum                                       ##                    ##
----- Treatment Comparison (ASN100 vs. Placebo) [1]-----
P-value                                       #.####
______________________________________________________________________________________________________________________________________
[1] P-value is obtained from a Wilcoxon rank sum test.
Total length of ICU stay (days) is defined as the total number of days of ICU stay during the first 21 days post-randomization.
Note: In subjects who are not confirmed as having pneumonia (SDO1) and who are discontinued from the study due to any cause prior to
Day 22, they are considered as developing pneumonia (SDO1).


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The layouts of the following tables will be the same as Table 14.2.6.3.1a and 14.2.6.3.1b:
Table 14.2.6.3.2a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
Table 14.2.6.3.2b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Pneumonia (SDO2)
Table 14.2.6.4.1a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
Table 14.2.6.4.1b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO1)
Table 14.2.6.4.2a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
Table 14.2.6.4.2b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with S. aureus Pneumonia (SDO2)
Table 14.2.6.5.1a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
Table 14.2.6.5.1b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO1)
Table 14.2.5.6.2a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial Pneumonia (SDO2)


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Table 14.2.5.6.2b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with All Bacterial pneumonia (SDO2)
Table 14.2.6.6.1a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
Table 14.2.6.6.1b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO1)
Table 14.2.6.6.2a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
Table 14.2.6.6.2b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Non-S. aureus Pneumonia (SDO2)
Table 14.2.6.7.1a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
Table 14.2.6.7.1b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO1)
Table 14.2.6.7.2a
Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)
Table 14.2.6.7.2b
Additional Analysis of Total Length of ICU Stay (Days) During First 21 Days Post‑Randomization
Modified Intent-to-Treat Population
Subjects with Gram Negative Pneumonia (SDO2)


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.7.1
Analysis of 28-Day All-Cause Mortality Rate
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)              (N=###)
n    (%)              n    (%)
______________________________________________________________________________________________________________________________________
28-Day all-cause mortality rate
### (###.#)           ### (###.#)
Subjects censored                                ### (###.#)           ### (###.#)
Kaplan-Meier Estimate (95% CI)
##.# (##.#, ##.#)     ##.# (##.#, ##.#)
__________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.


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The layouts of the following tables will be the same as Table 14.2.7.1:
Table 14.2.7.2
Analysis of 28-Day All-Cause Mortality Rate
Per Protocol Population
Table 14.2.7.3
Analysis of All-Cause Mortality Rate Through Entire Study Period (Through Day 90)
Modified Intent-to-Treat Population
Table 14.2.7.4
Analysis of All-Cause Mortality Rate Through Entire Study Period (Through Day 90)
Per Protocol Population


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Table 14.2.7.5
Subgroup Analysis: Analysis of 28-Day All-Cause Mortality Rate
Modified Intent-to-Treat Population
By Country
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)              (N=###)
Subgroup                                         n/N
(%)           n/N    (%)
______________________________________________________________________________________________________________________________________
Country 1
28-Day all-cause mortality rate
###/### (###.#)      ###/### (###.#)
Subjects censored                            ###/### (###.#)      ###/### (###.#)
Kaplan-Meier Estimate (95% CI)
###/### (###.#)      ###/### (###.#)
Country 2
…
__________________________________________________________________________________________________________________________________
Percentage is calculated using N' which is the number of subjects in each subgroup as the denominator.


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The layout of the following table will be the same as Table 14.2.7.5:
Table 14.2.7.6
Subgroup Analysis: Analysis of All-Cause Mortality Rate Through Entire Study Period (Through Day 90)
Modified Intent-to-Treat Population
By Country


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Run Date: MM/DD/YYYY HH:MM
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Table 14.2.8.1
Summary of Proportion of Subjects with Diagnosis of HABP >48 Hours Post-extubation Up to But Not Including Day 22
Modified Intent-to-Treat Population
Extubated Subjects
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)              (N=###)
n    (%)              n    (%)
______________________________________________________________________________________________________________________________________
Subjects with diagnosis of HABP >48 hours
### (###.#)           ### (###.#)
Post-extubation up to but not including Day 22
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.


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The layout of the following table will be the same as Table 14.2.8.1:
Table 14.2.8.2
Summary of Proportion of Subjects with Diagnosis of HABP >48 Hours Post-extubation Up to But Not Including Day 22
Per Protocol Population
Extubated Subjects


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Table 14.2.9.1
Summary of Proportion of Subjects with Development of VABP Up to But Not Including Day 22
Modified Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
ASN100               Placebo
(N=###)              (N=###)
n    (%)             n    (%)
______________________________________________________________________________________________________________________________________
Subjects with development of VABP up to but not including Day 22
### (###.#)           ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.


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The layout of the following table will be the same as Table 14.2.9.1:
Table 14.2.9.2
Summary of Proportion of Subjects with Development of VABP Up to But Not Including Day 22
Per Protocol Population


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of 1
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.1.1
Overview of Adverse Events
Safety Population
______________________________________________________________________________________________________________________________________
ASN100             Placebo           Total
(N=###)            (N=###)          (N=###)
Category
n    (%)
n    (%)          n    (%)
______________________________________________________________________________________________________________________________________
Any Adverse Event (AE)
### (###.#)        ### (###.#)       ### (###.#)
Any Treatment-Emergent Adverse Event (TEAE)
### (###.#)        ### (###.#)       ### (###.#)
Mild TEAEs
### (###.#)        ### (###.#)       ### (###.#)
Moderate TEAEs
### (###.#)        ### (###.#)       ### (###.#)
Severe TEAEs
### (###.#)        ### (###.#)       ### (###.#)
Drug-Related TEAEs [1]
### (###.#)        ### (###.#)       ### (###.#)
Serious AEs
### (###.#)        ### (###.#)       ### (###.#)
Drug-Related Serious AEs
### (###.#)        ### (###.#)       ### (###.#)
Serious AEs Leading to Death
### (###.#)        ### (###.#)       ### (###.#)
TEAEs Leading to Discontinuation of Study Drug
### (###.#)        ### (###.#)       ### (###.#)
Serious TEAEs Leading to Discontinuation of Study Drug
### (###.#)        ### (###.#)       ### (###.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using the number of subjects in the column heading as the denominator.
A treatment-emergent adverse events (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the time of an AE is missing, it is considered treatment emergent if it starts on the same date as the initiation
of study drug administration.
[1] Drug-Related is based on the Investigators assessment.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
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Table 14.3.1.2
Subjects with Treatment-Emergent Adverse Events (TEAEs)
By System Organ Class and Preferred Term
Safety Population
______________________________________________________________________________________________________________________________________
ASN100                   Placebo                   Total
System Organ Class
(N=###)
(N=###)                  (N=###)
Preferred Term
n    (%)                  n    (%)
n    (%)
______________________________________________________________________________________________________________________________________
Subjects with any TEAEs
### (###.#)
### (###.#)
### (###.#)
System Organ Class 1
### (###.#)
### (###.#)
### (###.#)
Preferred Term 1
### (###.#)
### (###.#)
### (###.#)
Preferred Term 2
### (###.#)
### (###.#)
### (###.#)
Preferred Term 3
### (###.#)
### (###.#)
### (###.#)
System Organ Class 2
### (###.#)
### (###.#)
### (###.#)
Preferred Term 1
### (###.#)
### (###.#)
### (###.#)
Preferred Term 2
### (###.#)
### (###.#)
### (###.#)
Preferred Term 3
### (###.#)
### (###.#)
### (###.#)
______________________________________________________________________________________________________________________________________
Coding is based on MedDRA Version 19.1.
Percentage is calculated using the number of subjects in the column heading as the denominator.
A treatment-emergent adverse events (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the time of an AE is missing, it is considered treatment emergent if it starts on the same date as the initiation
of study drug administration.
Subjects with multiple adverse events will be counted only once per system organ class and preferred term.


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The layouts of the following tables will be the same as Table 14.3.1.2:
Table 14.3.1.3
Subjects with Treatment-Emergent Serious Adverse Events (TESAEs)
By System Organ Class and Preferred Term
Safety Population
Table 14.3.1.4
Subjects with Drug-Related Treatment-Emergent Adverse Events
By System Organ Class and Preferred Term
Safety Population


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Table 14.3.1.5
Subjects with Treatment-Emergent Adverse Events (TEAEs)
By System Organ Class, Preferred Term and Maximum Severity
Safety Population
______________________________________________________________________________________________________________________________________
System Organ Class
ASN100         Placebo          Total
Preferred Term
(N=###)
(N=###)
(N=###)
Maximum Grade
n    (%)        n    (%)        n    (%)
______________________________________________________________________________________________________________________________________
Subjects with any TEAEs
### (###.#)     ### (###.#)     ### (###.#)
Mild                                     ### (###.#)     ### (###.#)     ### (###.#)
Moderate                                 ### (###.#)     ### (###.#)     ### (###.#)
Severe                                   ### (###.#)     ### (###.#)     ### (###.#)
System Organ Class 1
### (###.#)     ### (###.#)     ### (###.#)
Mild                                     ### (###.#)     ### (###.#)     ### (###.#)
Moderate                                 ### (###.#)     ### (###.#)     ### (###.#)
Severe                                   ### (###.#)     ### (###.#)     ### (###.#)
Preferred Term 1
### (###.#)     ### (###.#)     ### (###.#)
Mild                                     ### (###.#)     ### (###.#)     ### (###.#)
Moderate                                 ### (###.#)     ### (###.#)     ### (###.#)
Severe
### (###.#)     ### (###.#)     ### (###.#)
Preferred Term 2
### (###.#)     ### (###.#)     ### (###.#)
______________________________________________________________________________________________________________________________________
Coding is based on MedDRA Version 19.1.
Percentage is calculated using the number of subjects in the column heading as the denominator.
A treatment-emergent adverse events (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the time of an AE is missing, it is considered treatment emergent if it starts on the same date as the initiation
of study drug administration.
If the same TEAE (based on preferred term) is reported for the same patient more than once, the TEAE is counted only once for that
preferred term and at the highest severity.


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Table 14.3.1.6
Subjects with Treatment-Emergent Adverse Events (TEAEs)
By System Organ Class, Preferred Term and Relationship to Study Drug
Safety Population
______________________________________________________________________________________________________________________________________
System Organ Class
ASN100         Placebo          Total
Preferred Term
(N=###)
(N=###)         (N=###)
Strongest Relationship
n    (%)        n    (%)        n    (%)
______________________________________________________________________________________________________________________________________
Subjects with any TEAEs
### (###.#)     ### (###.#)     ### (###.#)
Not Related
### (###.#)     ### (###.#)
### (###.#)
Related
### (###.#)     ### (###.#)     ### (###.#)
System Organ Class 1
### (###.#)     ### (###.#)     ### (###.#)
Not Related
### (###.#)     ### (###.#)     ### (###.#)
Related
### (###.#)
### (###.#)     ### (###.#)
Preferred Term 1
### (###.#)     ### (###.#)     ### (###.#)
Not Related
### (###.#)     ### (###.#)     ### (###.#)
Related
### (###.#)     ### (###.#)     ### (###.#)
Preferred Term 2
### (###.#)     ### (###.#)     ### (###.#)
______________________________________________________________________________________________________________________________________
Coding is based on MedDRA Version 19.1.
Percentage is calculated using the number of subjects in the column heading as the denominator.
A treatment-emergent adverse events (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the time of an AE is missing, it is considered treatment emergent if it starts on the same date as the initiation
of study drug administration.
If the same TEAE (based on preferred term) is reported for the same patient more than once, the TEAE is counted only once for that
preferred term and at the strongest relationship to study drug.
Drug-Related is based on the Investigators assessment.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.2.1
Listing of Serious Adverse Events
Safety Population
Treatment
Subject
VT: Verbatim Term/
PT: Preferred Term/
SOC:System Organ Class
Start Date/Time/Day
Stop Date/Time/Day
Duration (days)
TEAE?/
Severity
Related to
Study Drug
Action Taken/
Other Action Taken/
Outcome
ASN100
###-###-###
VT: XXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
Yes/
NOT RELATED
DOSE NOT CHANGED/
PT: XXXXXXXXXXXXXXX/
Continuing
SEVERE
MEDICATION REQUIRED/
SOC:XXXXXXXXXXXXXXXX
NOT RECOVERED/NOT RESOLVED
###-###-###
VT: XXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
Yes/
RELATED
XXXXXXXXXX/
PT: XXXXXXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
XXXXXXX
XXXXXXXXXX/
SOC:XXXXXXXXXXXXXXX
##
XXXXXX
###-###-###
VT: XXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
Yes/
XXXXXXXXXX
XXXXXXXXXXX/
PT: XXXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
XXXXXXXX
XXXXXX/
SOC:XXXXXXXXXXXXXXX
##
XXXXXXXXX
Placebo
Coding is based on MedDRA Version 19.1.
Day = Study day and is based on the first dose of study drug which is day 1.
Duration is calculated using stop date of adverse event - start date of adverse event + 1.
A treatment-emergent adverse events (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the time of an AE is missing, it is considered treatment emergent if it starts on the same date as the initiation
of study drug administration.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.2.2
Listing of Adverse Events Leading to Discontinuation of Study Drug
Safety Population
Treatment
Subject
VT: Verbatim Term/
PT: Preferred Term/
SOC:System Organ Class
Start Date/Time/Day
Stop Date/Time/Day
Duration (days)
SAE?/
TEAE?/
Severity
Related to
Study Drug
Action Taken/
Other Action Taken/
Outcome
ASN100
###-###-###
VT: XXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
Yes/
NOT RELATED
DOSE NOT CHANGED/
PT: XXXXXXXXXXXXXXX/
Continuing
Yes/
MEDICATION REQUIRED/
SOC:XXXXXXXXXXXXXXXX
SEVERE
NOT RECOVERED/NOT RESOLVED
###-###-###
VT: XXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
Yes/
RELATED
XXXXXXXXXX/
PT: XXXXXXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
Yes/
XXXXXXXXXX/
SOC:XXXXXXXXXXXXXXX
##
XXXXX
XXXXXX
###-###-###
VT: XXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
No/
XXXXXXXXXX
XXXXXXXXXXX/
PT: XXXXXXXXXXXX/
YYYY-MM-DD/HH:MM/##
XXX/
XXXXXX/
SOC:XXXXXXXXXXXXXXX
##
XXXXXX
XXXXXXXXX
Placebo
Coding is based on MedDRA Version 19.1.
Day = Study day and is based on the first dose of study drug which is day 1.
Duration is calculated using stop date of adverse event - start date of adverse event + 1.
A treatment-emergent adverse events (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the time of an AE is missing, it is considered treatment emergent if it starts on the same date as the initiation
of study drug administration.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Table 14.3.3.1
Summary of Laboratory Chemistry Parameters
Safety Population
______________________________________________________________________________________________________________________________________
Parameter (unit)
ASN100                        Placebo                         Total
Visit
(N=###)                        (N=###)                        (N=###)
Statistics          Baseline  Post    Change       Baseline  Post    Change       Baseline  Post    Change
______________________________________________________________________________________________________________________________________
Parameter 1 (unit)
Baseline [1]
n
###
###
###
Mean
##.##
##.##
##.##
SD
##.###
##.###
##.###
Minimum
##.#
##.#
##.#
Median
##.##
##.##
##.##
Maximum
##.#
##.#
##.#
Day 2
n [2]               ###       ###
###          ###       ###     ###          ###       ###     ###
Mean
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
SD
##.###    ##.###  ##.###
##.###    ##.###  ##.###
##.###    ##.###  ##.###
Minimum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
Median
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
Maximum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
Day 4
n [2]               ###       ###     ###          ###       ###     ###          ###
###     ###
Mean
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
SD
##.###    ##.###  ##.###
##.###    ##.###  ##.###
##.###    ##.###  ##.###
Minimum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
Median
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
Maximum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
<< Programming note: Repeat for all scheduled visits. Parameters to be included: Alanine aminotransferase (ALT), Albumin, Alkaline phosphatase, Aspartate
aminotransferase (AST), Bicarbonate, Blood urea nitrogen, Calcium, Chloride, Creatinine, Direct bilirubin, Glucose, Phosphorus, Potassium, Sodium, Total
bilirubin, and Total protein>>
______________________________________________________________________________________________________________________________________
[1] Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[2] n is the number of subjects with both baseline and post-baseline measurements.


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The layouts of the following tables will be the same as Table 14.3.3.1:
Table 14.3.3.2
Summary of Laboratory Hematology Parameters
Safety Population
<<Parameters to be included: Absolute neutrophil count, Hematocrit, Hemoglobin, Platelet count, Red blood cell (RBC) count, White blood cell (WBC) count
with differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) , RBC indices mean corpuscular volume (MCV), mean corpuscular
hemoglobin (MCH), and %Reticulocytes.>>
Table 14.3.3.3
Summary of Laboratory Coagulation Parameters
Safety Population
<< Parameters to be included: Prothrombin time and Partial thromboplastin time (PTT)>>
Table 14.3.3.4
Summary of Laboratory Urinalysis Parameters
Safety Population
<< Parameters to be included: pH and Specific Gravity>>


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.3.5
Shift Table for Hematology Parameters
Safety Population
______________________________________________________________________________________________________________________________________
---------------------- Worst Post-baseline Value ---------------------
Parameter (unit)
Low
Normal
High
Missing
Total
Treatment
Baseline [1]
n    (%)       n    (%)       n    (%)       n    (%)       n    (%)
______________________________________________________________________________________________________________________________________
Parameter 1 (unit)
ASN100 (N=###)
Low
### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)
Normal
### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)
High
### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)
Missing
### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)    ### (###.#)
Total
### (###.#)    ### (###.#)    ### (###.#)
### (###.#)    ### (###.#)
Placebo (N=###)
<< Programming note: Parameters to be included: Hematocrit, Hemoglobin, Platelets, White blood cell count and differential including Basophils, Neutrophils,
Lymphocytes, Monocytes, and Eosinophils>>
______________________________________________________________________________________________________________________________________
[1] Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.3.6
Shift Table for Chemistry Parameters
Safety Population
______________________________________________________________________________________________________________________________________
-------------------------------- Worst Post-baseline Value -----------------------------
>ULN and    >3xULN and
Parameter (unit)
<LLN         Normal      <=3xULN      <=5xULN      >5xULN       Missing       Total
Treatment
Baseline [1]         n    (%)     n    (%)
n    (%)     n    (%)     n    (%)     n    (%)     n    (%)
______________________________________________________________________________________________________________________________________
Parameter 1 (unit)
ASN100 (N=###)
<LLN
### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
Normal             ### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
>ULN and <=3xULN   ### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
>3xULN and <=5xULN ### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
>5xULN
### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
Missing            ### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
Total              ### (###.#)  ### (###.#)  ### (###.#)  ### (###.#)
### (###.#)
### (###.#)  ### (###.#)
Placebo (N=###)
<< Programming note: Parameters to be included: ALT, AST, Total Bilirubin, Creatinine, and ALP>>
______________________________________________________________________________________________________________________________________
[1] Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of 2
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.3.7
Number (%) of Subjects with Prespecified Potentially Clinically Significant Abnormal Post-Baseline Liver Function Tests
Safety Population
______________________________________________________________________________________________________________________________________
ASN100
Placebo                Total
Parameter
(N=###)
(N=###)
(N=###)
Category
n/N    (%)           n/N    (%)           n/N    (%)
______________________________________________________________________________________________________________________________________
Subjects with a valid post-baseline value, N       ###                   ###                   ###
ALT
>=3xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
>=5xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
AST
>=3xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
>=5xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
ALT or AST
>=3xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
>=5xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
______________________________________________________________________________________________________________________________________
Percentage is calculated using N, the number of subjects with a valid post-baseline assessment as the denominator.
* Potential Hys Law case is defined as ALT or AST >=3xULN, Total bilirubin >=2xULN and ALP <= 2xULN.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 2 of 2
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.3.7
Number (%) of Subjects with Prespecified Potentially Clinically Significant Abnormal Post-Baseline Liver Function Tests
Safety Population
______________________________________________________________________________________________________________________________________
ASN100
Placebo                Total
Parameter
(N=###)
(N=###)
(N=###)
Category
n/N    (%)           n/N    (%)           n/N    (%)
______________________________________________________________________________________________________________________________________
Total bilirubin
>=1.5xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
>=2xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
ALP
>=1.5xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
>=3xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
ALT or AST >=3xULN and Total bilirubin >=2xULN
###/### (##.#)        ###/### (##.#)
###/### (##.#)
Potential Hy's Law case *
###/### (##.#)        ###/### (##.#)
###/### (##.#)
____________________________________________________________________________________________________________________________________
Percentage is calculated using N, the number of subjects with a valid post-baseline assessment as the denominator.
* Potential Hys Law case is defined as ALT or AST >=3xULN, Total bilirubin >=2xULN and ALP <= 2xULN.


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Protocol No. ASN100-201
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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.3.8
Listing of Subjects with Prespecified Potentially Clinically Significant Abnormal Post-Baseline Liver Function Findings
Safety Population
______________________________________________________________________________________________________________________________________
Treatment
Date and Time
Subject
Parameter (Unit)   Normal Range     Visit
of Collection/Day
Result
Met Criteria
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
XXXXXXXX (XXXX)    ##.#-##.#        Day 1 Pre-dose
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
ALT >= 3xULN
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXX (XXXX)    ##.#-##.#
Day 1 Pre-dose
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
AST >= 3xULN
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
###-###-###
XXXXXXXX (XXXX)    ##.#-##.#
Day 1 Pre-dose
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
ALP >= 1.5xULN
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
##.#
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on the first dose of study drug which is day 1.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Table 14.3.4
Summary of Vital Signs
Safety Population
______________________________________________________________________________________________________________________________________
Parameter (unit)
ASN100                        Placebo                         Total
Visit
(N=###)                        (N=###)                        (N=###)
Statistics            Baseline  Post    Change       Baseline
Post    Change       Baseline  Post    Change
______________________________________________________________________________________________________________________________________
Parameter 1 (unit)
Baseline [1]
n
###
###
###
Mean
##.##
##.##
##.##
SD
##.###
##.###
##.###
Minimum
##.#
##.#
##.#
Median
##.##
##.##
##.##
Maximum
##.#
##.#
##.#
Day 1
n [2]                 ###       ###     ###          ###       ###     ###          ###       ###     ###
Mean
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
SD
##.###    ##.###  ##.###
##.###    ##.###  ##.###
##.###    ##.###  ##.###
Minimum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
Median
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
Maximum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
Day 2
n [2]                 ###       ###     ###          ###       ###     ###          ###       ###     ###
Mean
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##
##.##   ##.##
SD
##.###    ##.###  ##.###
##.###    ##.###  ##.###
##.###    ##.###  ##.###
Minimum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
Median
##.##     ##.##   ##.##
##.##     ##.##   ##.##
##.##     ##.##   ##.##
Maximum
##.#      ##.#    ##.#
##.#      ##.#    ##.#
##.#      ##.#    ##.#
<< Program note: Repeat for all scheduled visits; Parameters also to be included: Systolic BP (mmHg), Diastolic Blood Pressure (mmHg), Pulse (bpm),
Respiratory Rate (rpm), Temperature (C), pH, PaO2 (mmHg), PaCO2 (mmHg), and SpO2 (%)>>
______________________________________________________________________________________________________________________________________
[1] Baseline is defined as the last measurement or assessment prior to the first and only dose of study drug.
[2] n is the number of subjects with both baseline and post-baseline measurements.


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Addendum to SAP, Version 1.0
Protocol No. ASN100-201
25OCTOBER2018
Page 99 of 144
Figure Mock-Ups
FIGURE 14.2.1.1 .........................................................................................................................100
Kaplan-Meier Plot of Overall Survival (Days) by Treatment
Modified Intent-to-Treat Population
FIGURE 14.2.2.1 .........................................................................................................................101
Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22
Based on Sponsor-Defined Outcome (SDO1)
Modified Intent-to-Treat Population
FIGURE 14.2.2.2 .........................................................................................................................102
Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22
Based on Sponsor-Defined Outcome (SDO2)
Modified Intent-to-Treat Population
FIGURE 14.2.2.3 .........................................................................................................................102
Additional Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including
Day 22 Based on Sponsor-Defined Outcome (SDO1)
Modified Intent-to-Treat Population
FIGURE 14.2.2.4 .........................................................................................................................102
Additional Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including
Day 22 Based on Sponsor-Defined Outcome (SDO2)
Modified Intent-to-Treat Population
FIGURE 14.2.2.5 .........................................................................................................................102
Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22
Determined by Investigators Judgement and Review Meetings Determination of S.
aureus as a Causative Pneumonia Pathogen
Modified Intent-to-Treat Population


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Figure 14.2.1.1
Kaplan-Meier Plot of Overall Survival (Days) by Treatment
Modified Intent-to-Treat Population


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Figure 14.2.2.1
Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22 Based on Sponsor-Defined Outcome (SDO1)
Modified Intent-to-Treat Population
Note: Subjects who did not develop S. aureus pneumonia, discontinued from the study, or died prior to Day 22 will be considered
censored.


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The layouts of the following tables will be the same as Figure 14.2.2.1:
Figure 14.2.2.2
Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22 Based on Sponsor-Defined Outcome (SDO2)
Modified Intent-to-Treat Population
<< Programming note: For figures 14.2.2.3 and 14.2.2.4, footnote will use “Note: Discontinuation from the study due to any cause up to but not including Day
22 will be considered as an event.”>>
Figure 14.2.2.3
Additional Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22 Based on Sponsor-Defined Outcome (SDO1)
Modified Intent-to-Treat Population
Figure 14.2.2.4
Additional Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22 Based on Sponsor-Defined Outcome (SDO2)
Modified Intent-to-Treat Population
<< Programming note: For figure 14.2.2.5, no footnote will be used>>
Figure 14.2.2.5
Kaplan-Meier Plot of Time to S. aureus Pneumonias Up to But Not Including Day 22
Determined by Investigators Judgement and Review Meetings Determination of S. aureus as a Causative Pneumonia Pathogen
Modified Intent-to-Treat Population


103
Listings Mock-ups
LISTING 16.2.1.1........................................................................................................................107
Screen Failures
All Subjects
LISTING 16.2.1.2........................................................................................................................108
Subject Disposition
Intent-to-Treat Population
LISTING 16.2.1.3........................................................................................................................109
Subject Randomization
All Subjects
LISTING 16.2.1.4........................................................................................................................110
Sub-Study for Subjects Diagnosed with Pneumonia
All Subjects
LISTING 16.2.2...........................................................................................................................111
Protocol Deviations
Intent-to-Treat Population
LISTING 16.2.3.1........................................................................................................................112
Subject Population
Intent-to-Treat Population
LISTING 16.2.4.1........................................................................................................................113
Demographics
Intent-to-Treat Population
LISTING 16.2.4.2........................................................................................................................114
Smoking Medical History
Intent-to-Treat Population
LISTING 16.2.4.3........................................................................................................................115
Medical History
Intent-to-Treat Population
LISTING 16.2.4.4........................................................................................................................116
Prior and Concomitant Medications
Intent-to-Treat Population


104
LISTING 16.2.4.5........................................................................................................................117
Concomitant Procedure and Non-Drug Therapies
Intent-to-Treat Population
LISTING 16.2.4.6........................................................................................................................118
Ventilator Status
Intent-to-Treat Population
LISTING 16.2.4.7........................................................................................................................119
Risk Factors for Ventilator - Associated Pneumonia
Intent-to-Treat Population
LISTING 16.2.4.8........................................................................................................................120
VAP Prevention
Intent-to-Treat Population
LISTING 16.2.5.1........................................................................................................................121
Study Drug Administration
Intent-to-Treat Population
LISTING 16.2.5.2........................................................................................................................122
Pharmacokinetic Serum Sampling
Intent-to-Treat Population
LISTING 16.2.5.3........................................................................................................................123
Pharmacokinetic BAL Sampling
Intent-to-Treat Population
LISTING 16.2.6.1........................................................................................................................124
ETA Specimen Culture
Intent-to-Treat Population
LISTING 16.2.6.2........................................................................................................................125
Respiratory Culture from Local Laboratory
Intent-to-Treat Population
LISTING 16.2.6.3........................................................................................................................126
Blood Culture from Local Laboratory
Intent-to-Treat Population
LISTING 16.2.6.4........................................................................................................................127
Other Cultures from Local Laboratory
Intent-to-Treat Population


105
LISTING 16.2.6.5........................................................................................................................128
Nasal Swab Specimen
Intent-to-Treat Population
LISTING 16.2.6.6........................................................................................................................129
Microbiological Results from Central Laboratory
Intent-to-Treat Population
LISTING 16.2.6.7........................................................................................................................130
Radiograph and Imaging
Intent-to-Treat Population
LISTING 16.2.6.8........................................................................................................................131
Clinical Signs and Symptoms - Pneumonia
Intent-to-Treat Population
LISTING 16.2.6.9........................................................................................................................132
Clinical Signs and Symptoms and Pneumonia Progression
Pilot Rx Arm Amendment
Intent-to-Treat Population
LISTING 16.2.6.10......................................................................................................................133
Investigator Clinical Outcome of Pneumonia
Pilot Rx Arm Amendment
Intent-to-Treat Population
LISTING 16.2.6.11......................................................................................................................134
Hospitalization Course and Discharge
Intent-to-Treat Population
LISTING 16.2.6.12......................................................................................................................135
Anti-Drug Antibodies Sample Collection
Intent-to-Treat Population
LISTING 16.2.6.13......................................................................................................................136
Survival Status
Intent-to-Treat Population
LISTING 16.2.7.1........................................................................................................................137
Adverse Events
Intent-to-Treat Population


106
LISTING 16.2.7.2........................................................................................................................138
Serious Adverse Events
Intent-to-Treat Population
LISTING 16.2.8.1........................................................................................................................139
Central Laboratory Parameters - Chemistry
Intent-to-Treat Population
LISTING 16.2.8.2........................................................................................................................140
Central Laboratory Parameters - Hematology
Intent-to-Treat Population
LISTING 16.2.8.3........................................................................................................................140
Central Laboratory Parameters - Urinalysis
Intent-to-Treat Population
LISTING 16.2.8.4........................................................................................................................140
Central Laboratory Parameters - Coagulation
Intent-to-Treat Population
LISTING 16.2.8.5........................................................................................................................140
Central Laboratory Parameters - Procalcitonin
Intent-to-Treat Population
LISTING 16.2.8.6........................................................................................................................141
Urine Pregnancy Test from Local Laboratory
Intent-to-Treat Population
LISTING 16.2.8.7........................................................................................................................142
Vital Signs
Intent-to-Treat Population
LISTING 16.2.8.8........................................................................................................................143
12-Lead Electrocardiogram
Intent-to-Treat Population
LISTING 16.2.8.9........................................................................................................................144
Physical Examination
Intent-to-Treat Population


107
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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.1.1
Screen Failures
All Subjects
______________________________________________________________________________________________________________________________________
Subject
Date of Screen Failure
Reason for Screen Failure
______________________________________________________________________________________________________________________________________
###-###-###
YYYY-MM-DD
XXXXXXXXXXXXXXXXXXXXXXXX
###-###-###
YYYY-MM-DD
XXXXXXXXXXXXXXXXXXXXXXXX
###-###-###
YYYY-MM-DD
Other: XXXXXXXXXXXXXXXX
###-###-###
YYYY-MM-DD
XXXXXXXXXXX
###-###-###
YYYY-MM-DD
XXXXXXXXXXXXXXXXXXXXXXXX
______________________________________________________________________________________________________________________________________
Note: A subject was considered a screen failure if they were enrolled in the trial and underwent daily screening of endotracheal
aspirates for the presence of S. aureus.


108
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Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.1.2
Subject Disposition
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Complete Study?/
Treatment
Reason Study
Date/Study Day of Completion
Subject
Not Completed [1]
or Early Termination [2]
Prematurely Unblinded?
______________________________________________________________________________________________________________________________________
ASN100
###-###-###   No/XXXXXXXXXXXXXXX       YYYY-MM-DD/##
No
###-###-###   No/Other:XXXXXXXXX       YYYY-MM-DD/##
Yes
###-###-###   Yes
YYYY-MM-DD/##
No
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] Study considered complete if subject completed the study through the Day 90 Safety Visit.
[2] If a subject completed the study, date of completion is displayed. Otherwise, date of early termination is displayed.


109
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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.1.3
Subject Randomization
All Subjects
______________________________________________________________________________________________________________________________________
Heavily
Met All Inclusion and
Colonized    Remain
Treatment
Protocol
No Exclusion Criteria?/
with         Mechanically   Probable
Date/Time of
Receiving
Subject
Version
Criteria Not Satisfied
S. aureus?   Ventilated?*   Survival?**
Randomization
Kit ID   Antibiotic? [1]
______________________________________________________________________________________________________________________________________
ASN100
###-###-### 02May2017  Yes
Yes
Yes            Yes
YYYY-MM-DD/HH:MM  ######     Yes
###-###-### DDMMMYYYY  No/INCL##, EXCL##
Yes             No
YYYY-MM-DD/HH:MM  ######     No
Placebo
Screen Failure
______________________________________________________________________________________________________________________________________
*  In investigators opinion, subject will require ongoing ventilator support for at least 48 hrs.
** In Investigators opinion, survival beyond 72 hrs post-randomization is expected.
[1] Is the subject receiving concomitant anti-staphylococcal antibiotics at the time of randomization that are potentially active
against S. aureus pneumonia?


110
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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.1.4
Sub-Study for Subjects Diagnosed with Pneumonia
All Subjects
______________________________________________________________________________________________________________________________________
Treatment
Presumed S.aureus Pneumonia               Previous and/or Current Anti-staphylococcal
Subject
at Randomization?
Antibiotic Exposure*
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Yes
<24 hours
###-###-###
Yes
>= 24 hours
###-###-###
No
< 72 hours
###-###-###
Yes
>= 72 hours
###-###-###
XXX
############
Placebo
Screen Failure
______________________________________________________________________________________________________________________________________
* Previous and/or current anti-staphylococcal antibiotic exposure that is potentially effective against S. aureus pneumonia.


111
Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.2
Protocol Deviations
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment        Occurrence
Deviation
CSR
Subject        Date/Day
Type
Protocol Deviation
Action                Reportable?
______________________________________________________________________________________________________________________________________
ASN100
###-###-###    YYYY-MM-DD/##
XXXXXXXX
XXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXX         Yes
XXXXXXXX
XXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXX         No
XXXXXXXX
XXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXX
XXX
###-###-###    YYYY-MM-DD/##
XXXXXXXX
XXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXX         XXX
###-###-###    YYYY-MM-DD/##
XXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXX       XXX
XXXXXXXX
XXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXX
###-###-###    YYYY-MM-DD/##
XXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXX      XXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.3.1
Subject Population
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
ITT
MITT
Per Protocol
Safety
Subject
Population
Population
Population
Population
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Yes
Yes
No
No
###-###-###
Yes
Yes
Yes
Yes
###-###-###
Yes
Yes
Yes
Yes
###-###-###
Yes
Yes
Yes
Yes
###-###-###
Yes
No
Yes
Yes
###-###-###
Yes
Yes
Yes
Yes
Placebo
______________________________________________________________________________________________________________________________________


113
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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.1
Demographics
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Age at
Treatment
Date of
Protocol
Date of   Enrollment
Subject
Informed Consent
Version
Birth      (Years)    Sex     Ethnicity [1]
Race
______________________________________________________________________________________________________________________________________
ASN100
###-###-###   YYYY-MM-DD
02MAY2017
YYYY-MM
##        F      HT              XXXXXXXX
###-###-###
YYYY-MM-DD           16NOV2016
YYYY-MM
##        M
NHT
Other: XXXXXXXX
###-###-###
YYYY-MM-DD           DDMMMYYYY
YYYY-MM
##        M      NR              XXXXXXXX
###-###-###
YYYY-MM-DD           DDMMMYYYY
YYYY-MM
##        M      UNK             XXXXXXXX
###-###-###   YYYY-MM-DD
DDMMMYYYY
YYYY-MM
##        F      NHT             XXXXXXXX
###-###-###   YYYY-MM-DD
DDMMMYYYY
YYYY-MM
##        M      NHT             XXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
[1] Ethnicity: HT = Hispanic or Latino, NHT = Not Hispanic or Latino, NR = Not Reported, UNK = Unknown.


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.2
Smoking Medical History
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
History of
Packs Smoked
Duration of
Subject
Smoking?
Per Week
Smoking (Years)
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Never
###-###-###
Current
#
##
###-###-###
Former
#
##
Placebo
______________________________________________________________________________________________________________________________________


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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.3
Medical History
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Event/
Subject
Diagnosis
Start Date/Day
End Date/Day
______________________________________________________________________________________________________________________________________
ASN100
###-###-###     XXXXXXXXXXXX
YYYY-MM-DD/##
YYYY-MM-DD/##
XXXXXX
YYYY-MM-DD/##
Ongoing
XXXXXXXXXXXXXXXXXXXXX
YYYY-MM-DD/##
###-###-###     XXXXXXXXXXXX
YYYY-MM-DD/##
YYYY-MM-DD/##
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


116
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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.4
Prior and Concomitant Medications
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
VT: Medication Name
Treatment
PT: Preferred Term
Dose/
Frequency/
Start Date/Time/Day/
Subject
ATC:Medication Class
Indication
Unit
Route
Stop Date/Time/Day
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
VT: XXXXXXXXXXXXXXXX
XXXXXXXXX
YXXXXXXXXXX/
XXXXXXXXX/
YYYY-MM-DD/HH:MM/##/
PT: XXXXXXXXXXXXXXXX
YXXXXXXXX
XXXXXXXXX
YYYY-MM-DD/HH:MM/##
ATC:XXXXXXXXXXXXXXXX
###-###-###
VT: XXXXXXXXXXXXXXXX
XXXXXXX
XXXXXXXXXX/
Other: XXX/
YYYY-MM-DD/HH:MM/##
PT: XXXXXXXXXXXXXXXX
Other: XXXXX
Other: XXXX
Ongoing
ATC:XXXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Coding is based on WHO Drug Dictionary Sept 2016E B2.
Day = Study day and is based on first dose of study drug which is Day 1.


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.5
Concomitant Procedure and Non-Drug Therapies
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
VT: Procedure/Non-Drug Therapy
Treatment
PT: Preferred Term
Start Date/Time/Day
Subject
SOC:System Organ Class
Indication
Stop Date/Time/Day
______________________________________________________________________________________________________________________________________
ASN100
###-###-###    VT: XXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXX
YYYY-MM-DD/HH:MM/##
PT: XXXXXXXXXXXXXXXXXXXXXXXXXX
YYYY-MM-DD/HH:MM/##
SOC:XXXXXXXXXXXXXXXXXXXXXXXXXX
VT: XXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXX
YYYY-MM-DD/HH:MM/##
PT: XXXXXXXXXXXXXXXXXXXXXXXXXX
YYYY-MM-DD/HH:MM/##
SOC:XXXXXXXXXXXXXXXXXXXXXXXXXX
###-###-###
VT: XXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXX
YYYY-MM-DD/HH:MM/##
PT: XXXXXXXXXXXXXXXXXXXXXXXXXX
Ongoing
SOC:XXXXXXXXXXXXXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Coding is based on MedDRA Version 19.1.
Day = Study day and is based on first dose of study drug which is Day 1.


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Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.6
Ventilator Status
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Underlying
Mechanically
Is Subject Currently
Treatment
Condition
Start Date/Time of            Ventilated at  Type  FiO2* PEEP**   Extubated or Since    Date/Time of
Subject
[1]
Initial Intubation   Visit    This Visit?    [2]   (%)  (cm H2O)  Previous Assessment?  Extubation
______________________________________________________________________________________________________________________________________
ASN100
###-###-###     T, CI, NI   YYYY-MM-DD/HH:MM     XXXXX    Yes
E      ##   #####    Yes                   YYYY-MM-DD/HH:MM
XXXXX    No
Yes                   YYYY-MM-DD/HH:MM
XXXXX    Yes            T      ##   #####    No
###-###-###
Other: XXXXX YYYY-MM-DD/HH:MM     XXXXX    Yes            OTH    ##   #####    Yes                   YYYY-MM-DD/HH:MM
XXXXX    No
Yes                   YYYY-MM-DD/HH:MM
XXXXX    Yes            E      ##   #####    No
Placebo
______________________________________________________________________________________________________________________________________
[1] T = Trauma, CI = Cardiovascular Impairment, NI = Neurological Impairment, PI = Pulmonary Impairment, Other.
[2] E = Endotracheal, T = Tracheotomy, OTH = Other.
* Predominant FiO2 setting (%) in the past 24 hours.
** Predominant PEEP setting (cm H2O) in the past 24 hours.


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Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.7
Risk Factors for Ventilator - Associated Pneumonia
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Intubated              Is Subject Receiving
Subject
Risk Factors
Previously?            Enteral Tube Feeding?
______________________________________________________________________________________________________________________________________
ASN100
###-###-###     COPD, Coma, ARDS           Unknown
Yes
###-###-###
None                       Yes                    No
###-###-###
ARDS, ICP monitor          Yes                    Yes
###-###-###
COPD
No                     Yes
Placebo
______________________________________________________________________________________________________________________________________


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Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.4.8
VAP Prevention
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment                 VAP
Silver Impregnated
Subject
Visit     Prevention?    Techniques Applied                                                   Endotracheal Tube Used?
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
XXXXXX    Yes            Elevation of head of the bed;
No
Daily sedation vacations and assessment of readiness to extubate;
Peptic ulcer disease prophylaxis;
Deep vein thrombosis prophylaxis;
Daily oral care with chlorhexidine or equivalent;
###-###-###
XXXXXX    No
Unknown
###-###-###
XXXXXX    Yes            Elevation of head of the bed;
Yes
Peptic ulcer disease prophylaxis;
###-###-###
XXXXXX    No
Yes
Placebo
______________________________________________________________________________________________________________________________________


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Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.5.1
Study Drug Administration
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Total Volume
----- Infusion ----
Infused (mL)/                      True Stop Time of Flush Known?/
Treatment
Date/Time/Day of
Start Date/Time/Day/    Entire Bag      Line Flushed?/     Est. Stop Time of Flush Aval.?*/
Subject       Drug Preparation     Bag   End Date/Time/Day       Infused?        Reason Not Done    Stop Time
___________________________________________________________________________________________________________________________________
ASN100
###-###-###
YYYY-MM-DD/HH:MM/##   A    YYYY-MM-DD/HH:MM/##/    ######/
Yes                Yes/-/HH:MM
YYYY-MM-DD/HH:MM/##     Yes
B    YYYY-MM-DD/HH:MM/##/    ######/
No/XXXXXXX
YYYY-MM-DD/HH:MM/##
No
###-###-###   YYYY-MM-DD/HH:MM/##   A    YYYY-MM-DD/HH:MM/##/    ######/
Yes
No/Yes/HH:MM
YYYY-MM-DD/HH:MM/##     Yes
B    YYYY-MM-DD/HH:MM/##/    ######/
Yes
No/No/
YYYY-MM-DD/HH:MM/##     Yes
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
* Only collected if line was flushed and if the true stop time of flush not known.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.5.2
Pharmacokinetic Serum Sampling
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Date/Time/Day of
Treatment
Collection/
Subject
Visit    Time Point
Not performed – Reason Not Done
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Day 1     +15 min
YYYY-MM-DD/HH:MM/##
6 hrs
Site Error
24 hrs
Other: XXXXXXXX
Day 2
+/- 1 hr relative to BAL fluid collection
YYYY-MM-DD/HH:MM/##
Day 3
+/- 1 hr relative to BAL fluid collection
YYYY-MM-DD/HH:MM/##
Day 4
YYYY-MM-DD/HH:MM/##
Day 7
YYYY-MM-DD/HH:MM/##
Day 14
YYYY-MM-DD/HH:MM/##
Day 22
YYYY-MM-DD/HH:MM/##
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


123
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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.5.3
Pharmacokinetic BAL Sampling
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Collected?/
Collection
Subject
Visit    Reason Not Done
Date/Time/Day
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Day 2
Yes
YYYY-MM-DD/HH:MM/##
Day 3
No/Other: XXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.1
ETA Specimen Culture
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Identified?/                                              Isolate
Number of
Stored for
Treatment
ETA Collected?/    Date/Time/Day       Unique                              MRSA or               Shipment?/
Subject       Visit    Reason Not Done    of Collection       Organisms   Genus and Species       MSSA? [1]
Result
Local Lab ID
______________________________________________________________________________________________________________________________________
ASN100
###-###-###   XXXXXX   Yes                YYYY-MM-DD/HH:MM/##   Yes/3
Staphylococcus aureus
MRSA       1+           Yes/###
XXXXXXXXXXXXXXXXX                  >10^5        No
Other: XXXXXXXXXX                  3+           No
###-###-###   XXXXXX   Yes                YYYY-MM-DD/HH:MM/##   No
###-###-###   XXXXXX   No/Other: XXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] MRSA or MSSA: MRSA, MSSA, or ND = Not Determined. Collected only if Staphylococcus aureus specified.


125
Arsanis, Inc.
Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.2
Respiratory Culture from Local Laboratory
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Pathogen
Isolated?/
Date/Time/Day        Type[1]/     Number of      Semi-quantitative                              Stored for
Treatment
Sample Collected     Squ.[2]/
Unique
or Quantitative?/    MRSA or
Shipment?/
Subject      Visit   or Reason Not Done   PMNs[3]      Pathogens
Specify Pathogen
MSSA? [4]    Result       Local Lab ID
______________________________________________________________________________________________________________________________________
ASN100
###-###-###  XXXXXX   YYYY-MM-DD/HH:MM/   XXXX/         Yes/3         Quantitative/        MRSA         >##x10^6     Yes/###
##                  Yes/                        Staphyloccus
No
aureus
Semi-quantitative/
Escherichia coli                  #+           Yes/####
XXXXXXX/                          ##           No
Other:XXXXXXXXXXXX
XXXXXXX   YYYY-MM-DD/HH:MM/    Oth:XXXXX    No
##                   XXXXXXX/
Yes/
Yes
###-###-### XXXXXXX   No/Subject Refused
XXXXXXX   No/Other: XXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] NBB = Non-Bronchoscopic BAL, PBS = Protected brush specimen, ES = Expectoracted or induced sputum, Oth = Other.
[2] Did the specimen contain <10 squamous epithelial cells/100 x field? Collected if type is expectorated or induced sputum.
[3] Did the specimen contain >25 PMNs/100 x field? Collected if type is expectorated or induced sputum.
[4] MRSA or MSSA: MRSA, MSSA, or ND = Not Determined. Collected ony if Staphylococcus aureus specified.


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.3
Blood Culture from Local Laboratory
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Pathogen
Isolated?/
Stored for
Treatment
Collected?/
Date/Time/Day
Number of
MRSA or
Shipment?/
Subject
Visit
Reason Not Done   of Collection
Unique
Genus and Species              MSSA? [1]    Local Lab ID
______________________________________________________________________________________________________________________________________
ASN100
###-###-### XXXXXX   Yes
YYYY-MM-DD/HH:MM/##   Yes/2
Staphylococcus aureus         MRSA          No
Other: XXXXXXXXXXXXXXXXXX
Enterococcus faecium
XXXXXXX  Yes
YYYY-MM-DD/HH:MM/##   Yes/1
XXXXXXXXXXXXXXXXXXXXXXXX
###-###-### XXXXXXX  No/Other: XXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] MRSA or MSSA: MRSA, MSSA, or ND = Not Determined. Collected ony if Staphylococcus aureus specified.


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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.4
Other Cultures from Local Laboratory
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Other
Specimen
Number of
Isolate Stored
Local
Treatment
Collected?/
S. aureus
Date/Time/Day          Unique
MRSA or
for Shipment to
Lab
Subject
Visit
Reason Not Done  Isolated?   Source      of Collection
S. aureus
MSSA? [1]   Central Lab
ID
______________________________________________________________________________________________________________________________________
ASN100
###-###-### XXXXXX    Yes
Yes
Urine       YYYY-MM-DD/HH:MM/##       2
MRSA           Yes            ####
XXXXXX      YYYY-MM-DD/HH:MM/##       0                      No
Other:XXXX  YYYY-MM-DD/HH:MM/##       1       MRSA           Yes            ####
XXXXXXX   Yes
No
###-###-### XXXXXXx   No/Other: XXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] MRSA or MSSA: MRSA, MSSA, or ND = Not Determined.


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Program Name: XXXX.sas
Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.5
Nasal Swab Specimen
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment      Swab Collected         Date/Time/Day of Right    Swab Collected        Date/Time/Day of Left    Reason Not
Subject
from Right Nostril?    Nostril Collection        from Left Nostril?    Nostril Collection       Collected*
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Yes
YYYY-MM-DD/HH:MM/##       No                                             XXXXXXXXXXXXXXX
###-###-###  Yes                    YYYY-MM-DD/HH:MM/##       Yes                   YYYY-MM-DD/HH:MM/##
###-###-###  Yes
YYYY-MM-DD/HH:MM/##       Yes                   YYYY-MM-DD/HH:MM/##
###-###-###
No
No                                             XXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
* Applies to swab collection from either right or left nostril.


129
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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.6
Microbiological Results from Central Laboratory
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Local                           Inducible
Treatment
Specimen Collection   Source of   Specimen  Central               Clindamycin
--- MIC(ug/mL)---
Subject     Visit   Date/Time/Day         Specimen    Number
Genus and Species     Resistance   Antimicrobial  Result    Interp.
______________________________________________________________________________________________________________________________________
ASN100
###-###-### XXXXXX  YYYY-MM-DD/HH:MM/##    ETA         ####
Staphylococcus aureus
Negative   Ampicillin       0.120     S
Ceftaroline     20.000     I
XXXXXXXXXX      ##.###     R
XXXXXXXXXX      <#####     NA
XXXXXX  YYYY-MM-DD/HH:MM/##    Respiratory ####      Klebsiella pneumoniae  Positive   XXXXXXXXXX      ##.###     I
XXXXXXXXXX      ##.###     I
XXXXXXXXXX      ##.###     R
XXXXXXXXXX      ##.###     I
NASAL SWAB
####
Staphylococcus aureus
Negative   XXXXXXXXXX      ##.###     I
XXXXXXXXXX      ##.###     I
XXXXXXXXXX      ##.###     NA
XXXXXXXXXX      ##.###     I
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
MIC Interpretation: S = Susceptible, I = Intermediate, R = Resistant, NA = Not Available.


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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.7
Radiograph and Imaging
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Infiltrates Present?/
Treatment                  Imaging Preformed?/                     Date/Time/Day          Consistent with          Description of
Subject
Visit    Reason Not Done        Type             Performed              Pneumonia?               Infiltrates
___________________________________________________________________________________________________________________________________
ASN100
###-###-###
XXXXX    Yes                    XXXXXXX          YYYY-MM-DD/HH:MM/##    Yes/Yes                  Other: XXXXXXX
XXXXX    Yes                    Other: XXXXXXXX  YYYY-MM-DD/HH:MM/##    No
XXXXX    No/Other: XXXXX
###-###-###
XXXXX    No/XXXXXXXXXXXXX
XXXXX    Yes                    XXXXXXXXX        YYYY-MM-DD/HH:MM/##    Yes/No                   XXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug day which is Day 1.


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Program Name: XXXX.sas
Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.8
Clinical Signs and Symptoms - Pneumonia
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Subject      Visit
Item
Result
______________________________________________________________________________________________________________________________________
ASN100
###-###-###  XXXXXX
Was a chest assessment performed?/Reason if not assessed
Yes
Date/Time/Day performed
YYYY-MM-DD/HH:MM/##
Does chest x-ray show new or progressive infiltrates suggestive of pneumonia?
No
Has the subject been hospitalized for > 48 hours?
Yes
Has the subject received mechanical ventilation via an
endotracheal or nasotracheal tube for >= 48 hours?
Yes
Has the subject developed clinical signs and symptoms within 7 days
following hospital discharge?
No
Has the subject developed new onset or worsening pulmonary signs or symptoms
or the requirement for mechanical ventilation?
No
Was there a need for acute changes in ventilator support to enhance oxygenation
or to the amount of PEEP?
No
Was there new onset of suctioned respiratory secretions?
No
Was temperature > 38°C or < 35°C? No
Was WBC count >= 10,000 cell/mm3 or <= 4500 cell/mm3?
No
Was > 15% immature neutrophils (bands) seen on peripheral blood smear?
No
Was diagnosis of pneumonia made?
No
Was an antibiotic started for treatment of pneumonia?
No
Concomitant antibiotic medication #
N/A
XXXXXX
Was a chest assessment performed?/Reason if not assessed
Yes
Date/Time/Day performed
YYYY-MM-DD/HH:MM/##
Does chest x-ray show new or progressive infiltrates suggestive of pneumonia?
No
Has the subject been hospitalized for > 48 hours?
Yes
Has the subject received mechanical ventilation via an
endotracheal or nasotracheal tube for >= 48 hours?
Yes
…
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.9
Clinical Signs and Symptoms and Pneumonia Progression
Pilot Rx Arm Amendment
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Date/Time/Day
Cough?/Rales?/ Bronchial
Treatment
of Assessment/    Percussion     Sounds?/   Suctioning?/   Fever     Purulent     Dyspnea?/     Hypoxemia?/
Subject      Visit
Reason Not Done   Dullness?
Egophony?  Ventilator?   (>=38 C)   Secretions   Tachypnea     Supplemental O2
______________________________________________________________________________________________________________________________________
ASN100
###-###-###  XXXXXX  YYYY-MM-DD/HH:MM/  Yes/Yes/       Yes/          Yes/
Yes
No
Yes/          Yes/
##                 Yes            No            Yes
No
Yes
XXXXXX  YYYY-MM-DD/HH:MM/  Yes/Yes/       Yes/          Yes/
Yes
No
Yes/          Yes/
##                 Yes            No            Yes
No
Yes
XXXXXX  No/XXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.10
Investigator Clinical Outcome of Pneumonia
Pilot Rx Arm Amendment
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Date/Time/Day
Treatment
of Assessment/
Continued Antibiotic           Antibiotic Therapy
Subject        Visit
Reason Not Done
Pneumonia Status       Therapy Required?
Changed?*
______________________________________________________________________________________________________________________________________
ASN100
###-###-###    XXXXXX   YYYY-MM-DD/HH:MM/##
Continues                Yes
XXXXXX   YYYY-MM-DD/HH:MM/##
Continues                Yes
Day 3    YYYY-MM-DD/HH:MM/##
Continues                Yes
Yes
XXXXXX   YYYY-MM-DD/HH:MM/##
Resolved                 No
XXXXXX   YYYY-MM-DD/HH:MM/##
###-###-###
XXXXXX   YYYY-MM-DD/HH:MM/##
Continues                Yes
XXXXXX   YYYY-MM-DD/HH:MM/##
XXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
* Was antibiotic therapy changed within the first 48 hours based on insufficient therapeutic effect?


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.11
Hospitalization Course and Discharge
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Date/Time/Day          Type of
ICU                          Date/Time/Day
Type of
Subject
of Admission           Admission
Specify [1]    Discharged?   of Discharge
Discharge
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
YYYY-MM-DD/HH:MM/##    ICU           XXXXXXX        Yes          YYYY-MM-DD/HH:MM/##     XXXXXXXXXXXXXXXXXXXXXX
YYYY-MM-DD/HH:MM/##    Non-ICU                      No
###-###-###
YYYY-MM-DD/HH:MM/##    ICU
Other: XXX     Yes          YYYY-MM-DD/HH:MM/##     Other: XXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] MIC = Medical ICU, SICU = Surgical ICU, TICU = Trauma ICU, NICU = Neuro ICU, CCU = Coronary Care Unit, Other.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.12
Anti-Drug Antibodies Sample Collection
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Subject
Visit      Collected?          Reason Sample Not Collected
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Day 1        Yes
Day 22       No                 Other: XXXXXX
Day 90       Yes
###-###-###
XXXXX        No                 XXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________


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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.6.13
Survival Status
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Subject
Visit    Date of Visit/Day    Survival Status   Date of Death/Day   Reason for Status Unknown
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Day ##    YYYY-MM-DD/##        Alive
###-###-###
Day ##    YYYY-MM-DD/##        Alive
###-###-###
Day ##                         Dead            YYYY-MM-DD/##
###-###-###
Day ##                         Unknown                               XXXXXXXXXXXXXXXXXXXXXX
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Protocol Number: ASN100-201
Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.7.1
Adverse Events
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
VT: Verbatim Term                   Start Date/Time/Day    SAE?/                      Action Taken/
Treatment       PT: Preferred Term
Stop Date/Time/Day     TEAE?/     Related to      Other Action Taken/
Subject       SOC:System Organ Class              Duration (days)        Severity   Study Drug      Outcome
_____________________________________________________________________________________________________________________________________
ASN100
###-###-###
VT: XXXXXXXXXXXXXXXXXXXXXXXX        YYYY-MM-DD/HH:MM/##/   No/         NOT RELATED     XXXXXX/
PT: XXXXXXXXXXXXXXXXXXXXXXXX        YYYY-MM-DD/HH:MM/##/   Yes/                        XXXXXXXX/
SOC:XXXXXXXXXXXXXXXXXXXXXXXX        ##
SEVERE                      FATAL
###-###-###
VT: XXXXXXXXXXXXXXXXXXXXXXXX        YYYY-MM-DD/HH:MM/##/   No/         RELATED         XXXXXXXX/
PT: XXXXXXXXXXXXXXXXXXXXXXXX                               No/                         XX /
SOC:XXXXXXXXXXXXXXXXXXXXXXXX
MILD                        NOT RECOVERED/NOT RESOLVED
VT: XXXXXXXXXXXXXXXXXXXXXXXX        YYYY-MM-DD/HH:MM/##/   No/         NOT RELATED     XXXXXXXXX/
PT: XXXXXXXXXXXXXXXXXXXXXXXX
YYYY-MM-DD/HH:MM/##/   Yes/                        XXX
SOC:XXXXXXXXXXXXXXXXXXXXXXXX
##
MODERATE
RECOVERED/RESOLVED WITH SEQUALE
Placebo
______________________________________________________________________________________________________________________________________
Coding is based on MedDRA Version 19.1.
Day = Study day and is based on the first dose of study drug which is day 1.
Duration is calculated using stop date of adverse event - start date of adverse event + 1.
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date and time on or after the initiation of study drug
administration. If the start time of an AE is missing, it is considered treatment emergent if it starts on the same date as the
initiation
of study drug administration.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.7.2
Serious Adverse Events
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Hospitalization/
VT: Verbatim Term
Birth Defect/ Death/               Life Threatening/ Other
Treatment    AE
PT: Preferred Term
Significant   Autopsy/             Other Medically   Possible          Event
Subject
Num  SOC:System Organ Class
Disability    Date/Day of Death    Important Event   Causes            Description
______________________________________________________________________________________________________________________________________
ASN100
###-###-### #   VT: XXXXXXXXXXXXXXXXXXXX
No/           No/                  No                XXXXXXXXXXXX      XXXXXXXXXXXXXXXXX
PT: XXXXXXXXXXXXXXXXXXXX
No            No/                  Yes/
SOC:XXXXXXXXXXXXXXXXXXXX
YYYY-MM-DD/##        Yes
#
VT: XXXXXXXXXXXXXXXXXXXX
No/           No                   Yes/              XXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXX
PT: XXXXXXXXXXXXXXXXXXXX
No                                 No/
SOC:XXXXXXXXXXXXXXXXXXXX
Yes
Placebo
______________________________________________________________________________________________________________________________________
Coding is based on MedDRA Version 19.1.
Day = Study day and is based on first dose of study drug which is Day 1.


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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.8.1
Central Laboratory Parameters - Chemistry
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment                                                        Date/Time/Day                       Reference
Subject
Parameter (Unit)      Normal Range    Visit     Collection              Result      Range [1]     Comments
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
XXXXXXX (XX)          ## - ###        XXXXX     YYYY-MM-DD/HH:MM/##      ###
LN
XXXXX     YYYY-MM-DD/HH:MM/##      ###
LN
XXXXX     YYYY-MM-DD/HH:MM/##      ###
N
XXXXXXX (XX)          ## - ###        XXXXX     YYYY-MM-DD/HH:MM/##      ###
N
XXXXX     YYYY-MM-DD/HH:MM/##      ###
N
XXXXX     YYYY-MM-DD/HH:MM/##      ###
###-###-###
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
[1] LN = Low Normal, LP = Low Panic, N = Normal, HN = High Normal, HP = High Panic, AB = Abnormal, SC = See Comment.


140
The layouts of the following listings will be the same as listing 16.2.8.1:
Listing 16.2.8.2
Central Laboratory Parameters - Hematology
Intent-to-Treat Population
Listing 16.2.8.3
Central Laboratory Parameters - Urinalysis
Intent-to-Treat Population
Listing 16.2.8.4
Central Laboratory Parameters - Coagulation
Intent-to-Treat Population
Listing 16.2.8.5
Central Laboratory Parameters - Procalcitonin
Intent-to-Treat Population


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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.8.6
Urine Pregnancy Test from Local Laboratory
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Treatment
Date/Time/Day of Urine Sample/
Subject
Visit       Reason Not Done
Result
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
XXXXX       Other: XXXXXXXXXXXXXXXXXXX
###-###-###
XXXXX       YYYY-MM-DD/HH:MM/##
Negative
###-###-###
XXXXX       YYYY-MM-DD/HH:MM/##
Negative
###-###-###
XXXXX       Female not of childbearing potential
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.8.7
Vital Signs
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Date/Time/Day                                               Respiratory   Temp
Treatment
of Collection/       Height  Weight  SBP     DBP    Pulse       Rate      (C)/          PaO2    PaCO2   SpO2
Patient
Visit  Reason Not Done       (cm)   (kg)   (mmHg)  (mmHg)  (bpm)  (breaths/min)  Time    pH   (mmHg)   (mmHg)   (%)
______________________________________________________________________________________________________________________________________
ASN100
###-###-### SCR    YYYY-MM-DD/HH:MM/##    ##     ##     ###     ###     ##
###      ##/HH:MM  ##    ###      ###     ##
XXXXX
YYYY-MM-DD/HH:MM/##                  ###     ###     ##
###      ##/HH:MM
##
XXXXX
YYYY-MM-DD/HH:MM/##                  ###     ###     ##
###      ##/HH:MM  ##    ###      ###
XXXXX
YYYY-MM-DD/HH:MM/##                  ###     ###     ##
###      ##/HH:MM  ##    ###      ###
###-###-### SCR    Site Error
XXXXX  Other: XXXXXXXXXXXX
XXXXX
YYYY-MM-DD/HH:MM/##                  ###     ###     ##
###      ##/HH:MM  ##    ###      ###     ##
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.


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Protocol Number: ASN100-201                                                                                 Run Date: MM/DD/YYYY HH:MM
Page 1 of #
Data Last Modified: MM/DD/YYYY HH:MM
Listing 16.2.8.8
12-Lead Electrocardiogram
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Date/Time/Day
Treatment
of Measurement/                                      Overall              Clinically
Subject
Visit
Reason Not Done
HR    PR   QRS   QT   RR      Interpretation       Significant?
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Screening       YYYY-MM-DD/HH:MM/##
###   ###  ###   ###  ###     Abnormal             No
Day 1
YYYY-MM-DD/HH:MM/##    ###   ###  ###   ###  ###     Normal
Day ##          Other: XXXX
Day ##          Subject Refused
###-###-###  Screening       Site Error
Day 1
YYYY-MM-DD/HH:MM/##    ###   ###  ###   ###  ###     Normal
Day ##          YYYY-MM-DD/HH:MM/##    ###   ###  ###   ###  ###     Normal
Day ##
YYYY-MM-DD/HH:MM/##    ###   ###  ###   ###  ###     Not Evaluable
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
Note: Unit of HR is bpm, and units of other measurements are msec.


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Listing 16.2.8.9
Physical Examination
Intent-to-Treat Population
______________________________________________________________________________________________________________________________________
Date/Time/Day
Treatment
Performed/                    Overall               Specify
Subject
Visit
Reason Not Done
Assessment*           Abnormalities
______________________________________________________________________________________________________________________________________
ASN100
###-###-###
Screening
YYYY-MM-DD/HH:MM/##
Normal
Day 1
YYYY-MM-DD/HH:MM/##
Abnormal and CS
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
Day ##
YYYY-MM-DD/HH:MM/##
Abnormal but NCS
XXXXXX
Other: XXXXXXX
###-###-###  Screening
Site Error
Day 1
YYYY-MM-DD/HH:MM/##
Abnormal and CS
XXXXXXXXXXXXXXXXXXXXXXXX
XXXXXX
Subject Refused
Placebo
______________________________________________________________________________________________________________________________________
Day = Study day and is based on first dose of study drug which is Day 1.
* CS = Clinically Significant, NCS = Not Clinically Significant.

SAP_003.pdf: 
Arsanis, Inc.
CONFIDENTIAL                Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
STATISTICAL ANALYSIS PLAN
(Protocol No. ASN100-201)
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to
Determine the Safety and Efficacy of a Single Dose of ASN100 for
the Prevention of Staphylococcus aureus Pneumonia in Heavily
Colonized, Mechanically Ventilated Subjects
DEVELOPMENT PHASE: 2
Sponsor:
Arsanis, Inc.
890 Winter Street, Suite 230
Waltham, MA
02451-1472
SAP Version: 1.0
Date: June 25, 2018
CONFIDENTIAL
This material is the proprietary property of Arsanis, Inc. The information is confidential
and is to be used only in connection with matters authorized by Arsanis, Inc.
No
unpublished information presented in this document is to be disclosed to others without
prior written permission from Arsanis, Inc.




Arsanis, Inc.
CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
Page 3 of 41
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................3
1.
LIST OF ABBREVIATIONS ....................................................................5
2.
INTRODUCTION......................................................................................7
3.
PURPOSE OF THE ANALYSES..............................................................7
4.
STUDY SUMMARY.................................................................................8
4.1.
Study Objectives ........................................................................................8
4.1.1.
Primary Objective ......................................................................................8
4.1.2.
Secondary Objectives.................................................................................8
4.1.3.
Exploratory Objectives...............................................................................8
4.2.
Overall Study Design and Plan ..................................................................9
4.3.
Study Procedures......................................................................................11
4.4.
Selection of Study Population..................................................................16
4.5.
Randomization and Blinding....................................................................16
5.
STUDY METHODS ................................................................................18
5.1.
Analysis Populations................................................................................18
5.1.1.
Intent-to-Treat Population (ITT) ..............................................................18
5.1.2.
Modified Intent-to-Treat Population (MITT)...........................................18
5.1.3.
Per Protocol (PP) Population....................................................................18
5.1.4.
Pharmacokinetic (PK) Population............................................................19
5.1.5.
Safety Population .....................................................................................19
5.2.
Study Endpoints .......................................................................................19
5.2.1.
Microbiological and Clinical Assessments ..............................................19
5.2.2.
Sponsor-Defined Outcome of S. aureus Pneumonia................................21
5.2.3.
Pharmacokinetic Assessments..................................................................22
5.2.4.
Primary Efficacy Endpoint.......................................................................23
5.2.5.
Secondary Efficacy Endpoints .................................................................23
5.2.6.
Exploratory Efficacy Endpoints...............................................................23
5.2.7.
Safety Endpoints ......................................................................................23
6.
SAMPLE SIZE DETERMINATION.......................................................25
7.
STATISTICAL ANALYSIS....................................................................26
7.1.
General Statistical Considerations ...........................................................26


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Protocol No. ASN100-201
25JUNE2018
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7.2.
Treatment Misallocations.........................................................................26
7.3.
Handling of Missing Data ........................................................................26
7.3.1.
Missing Dates...........................................................................................26
7.3.2.
Missing Assessment .................................................................................26
7.3.3.
Other Missing Data ..................................................................................27
7.4.
Baseline Definition...................................................................................27
7.5.
Relative Day.............................................................................................27
7.6.
Interim Analysis .......................................................................................27
7.7.
Subject Disposition ..................................................................................27
7.8.
Demographic and Baseline Characteristics..............................................28
7.9.
Medical History........................................................................................28
7.10.
Prior and Concomitant Medications/Procedures......................................28
7.11.
Analysis of Efficacy.................................................................................29
7.11.1.
Primary Efficacy Endpoint.......................................................................29
7.11.2.
Additional Analyses for S. aureus Pneumonia.........................................29
7.11.3.
Secondary Efficacy Endpoints .................................................................31
7.11.4.
Exploratory Efficacy Endpoints...............................................................32
7.11.5.
Pharmacokinetic Endpoints......................................................................32
7.12.
Subgroup Analyses...................................................................................32
7.13.
Analysis of Safety Data............................................................................34
7.13.1.
Adverse Events.........................................................................................34
7.13.2.
Vital Signs................................................................................................34
7.13.3.
Electrocardiograms...................................................................................35
7.13.4.
Clinical Laboratory Tests .........................................................................35
7.13.5.
Physical Examinations .............................................................................37
7.13.6.
Radiographs and Imaging.........................................................................37
7.13.7.
Immunogenicity .......................................................................................38
8.
GENERAL INFORMATION ..................................................................39
8.1.
Statistical Software...................................................................................39
8.2.
Format of Tables, Listings, and Figures...................................................39
9.
CHANGES FROM PROTOCOL SPECIFIED ANALYSIS...................40


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CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
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1.
LIST OF ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
ASN-1
Broadly cross-reactive anti-toxin monoclonal antibody that targets alpha-hemolysin
(Hla) and 3 F-components (HlgB, LukF, LukD) involved in forming 4 of the 5 bi-
component leukocidins of Staphylococcus aureus
ASN-2
Anti-toxin monoclonal antibody that targets the fifth bi-component leukocidin of
Staphylococcus aureus, LukGH
ASN100
A combination of the 2 fully human monoclonal antibodies ASN-1 and ASN-2
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
AUC
Area under the serum concentration-time curve
BAL
Bronchoalveolar lavage
BMI
Body mass index
Cmax
Maximum serum concentration
CRA
Clinical research associate
CRO
Contract research organization
CSR
Clinical study report
ECG
Electrocardiogram
eCRF
Electronic case report form
ELF
Epithelial lining fluid
ET
Early Termination
ETA
Endotracheal aspirate
HABP
Hospital-acquired bacterial pneumonia
ICU
Intensive care unit
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IV
Intravenous
LLN
Lower limit of normal
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities


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CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
Page 6 of 41
MITT
Modified Intent-to-Treat
PK
Pharmacokinetic
POP
Population and outcome plan
PP
Per Protocol
PT
Preferred term
PTT
Partial thromboplastin time
RBC
Red blood cell
S. aureus
Staphylococcus aureus
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SDO
Sponsor-defined outcome
SOC
System organ class
SUSARS
Serious unexpected suspected adverse reactions
t1/2
Terminal elimination half-life
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum serum concentration
ULN
Upper limit of normal
VABP
Ventilator-associated bacterial pneumonia
WBC
White blood cell
WHO
World Health Organization


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CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
Page 7 of 41
2.
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analyses and reporting for
Protocol ASN100-201: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
to Determine the Safety and Efficacy of a Single Dose of ASN100 for the Prevention of
Staphylococcus aureus Pneumonia in Heavily Colonized, Mechanically Ventilated
Subjects. The SAP is based on the protocol dated May 2, 2017 (Version 4.0).
3.
PURPOSE OF THE ANALYSES
The purpose of this SAP is to outline the planned analyses to support the completion of the
Clinical Study Report (CSR) for Protocol ASN100-201. This SAP may be modified and
finalized before the study data are unblinded.


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CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
Page 8 of 41
4.
STUDY SUMMARY
4.1.
Study Objectives
4.1.1.
Primary Objective
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of a
single dose of ASN100 (administered as a 1:1 ratio of the ASN-1 and ASN-2 components)
versus placebo for the prevention of Staphylococcus aureus (S. aureus) pneumonia in
mechanically ventilated subjects who are heavily colonized with S. aureus.
4.1.2.
Secondary Objectives
The secondary objectives of this study are the following:

To compare the duration of mechanical ventilation post-treatment in subjects
treated with ASN100 versus placebo;

To compare the length of stay in the intensive care unit (ICU) post-treatment for
subjects treated with ASN100 versus placebo;

To determine the serum pharmacokinetics (PK) (i.e. maximum serum concentration
[Cmax], time to maximum serum concentration [Tmax], area under the serum
concentration-time curve [AUC], and terminal elimination half-life [t1/2]) of ASN-
1 and ASN-2 in mechanically ventilated subjects heavily colonized with S. aureus;
and

To compare 28-day all-cause mortality in subjects treated with ASN100 versus
placebo.
4.1.3.
Exploratory Objectives
The exploratory objectives of this study are the following:

To compare the incidence of hospital-acquired bacterial pneumonia (HABP)
occurring >48 hours post-extubation up to, but not including, Day 22 in extubated
subjects treated with ASN100 versus placebo;

To compare the incidence of ventilator-associated bacterial pneumonia (VABP) up
to, but not including, Day 22 in intubated subjects treated with ASN100 versus
placebo;

To determine the immunogenicity of a single dose of ASN100;

To compare the incidence of other S. aureus-associated infections which occur after
dosing up to, but not including, Day 22 in subjects treated with ASN100 versus
placebo; and

To assess ASN-1 and ASN-2 levels in bronchoalveolar lavage (BAL) fluid and to
calculate a blood to epithelial lining fluid (ELF) ratio in those subjects participating
in the BAL fluid PK sub-study.


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CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
Page 9 of 41
4.2.
Overall Study Design and Plan
This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for
the prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily
colonized with S. aureus.
This will be a global study conducted at approximately 70 sites. Subjects will be screened
for eligibility; once an Informed Consent Form is signed (or, in countries where it is
applicable, a decision is made by a council of independent physicians), and all entry criteria
are met, a subject is considered to be enrolled in the study. All enrolled subjects will
undergo an observational stage evaluating endotracheal colonization. Subjects who are
randomized will undergo a treatment, monitoring, and follow-up period. A schematic of
the study is presented in Figure 1.
Figure 1. Study Schematic
1.
Subjects do not need to be colonized to be enrolled.
2.
For the purposes of this study, heavy colonization with S. aureus will be defined as a quantitative threshold of 105 CFU/mL or
3+ to 4+ by semi-quantitative culture from endotracheal aspirates.
3.
Once a subject has an ETA culture result signifying heavy colonization with S. aureus, they must be randomized within 48 hours
(or up to 60 hours with Medical Monitor approval) of specimen collection or be discontinued from the study.
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; ETA = endotracheal aspirate; ICF = Informed Consent Form;
I/E = inclusion/exclusion; PK = pharmacokinetic; S. aureus = Staphylococcus aureus.
Approximately 2250 eligible subjects who meet all of the inclusion criteria and none of the
exclusion criteria will be screened daily (while mechanically ventilated) for up to 8 days
to identify those subjects who are heavily colonized with S. aureus.
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and
Day 14 provided the subject remains mechanically ventilated, for a total Screening Period
of up to 14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the
discretion of the Investigator and provided the subject remains mechanically ventilated.
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or
semi-quantitative methods as required by the protocol. Sites are encouraged to perform
semi-quantitative cultures using a chromogenic media selective for all S. aureus
(e.g., CHROMagarTM Staph aureus) for more rapid and specific detection of S. aureus.


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CONFIDENTIAL                             Statistical Analysis Plan Version 1.0
Protocol No. ASN100-201
25JUNE2018
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Semi-quantitative cultures using chromogenic media are preferred for determination of
eligibility for randomization; however, any quantitative or semi-quantitative culture
performed that indicates that a subject is heavily colonized with S. aureus is permitted if
the culture results are available to randomize the subject within 48 hours (or up to 60 hours
with Medical Monitor approval) from the time the ETA specimen was collected.
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus
colonization and meets all of the inclusion and none of the exclusion criteria, they are
eligible for randomization. If they are not randomized on this occasion according to the
protocol, they are no longer eligible for continued ETA sampling or randomization, and
will be discontinued from the study; however, if subjects are extubated and subsequently
re-intubated/mechanically ventilated, they are eligible for re-screening as a new subject
enrollment, provided all entry criteria continue to be met. Subjects who were previously
randomized are not eligible to be re-consented and re-screened.
At the time of randomization, if a subject’s screening ETA culture also shows heavy
colonization of a Gram-negative organism (i.e. heavy co-colonization of both Gram-
positive and Gram-negative organisms), the subject will not be randomized into the study;
however, randomization should not be delayed while waiting for Gram-negative results if
heavy colonization with S. aureus has been confirmed. Testing for Gram-negative
colonization is however not a requirement of the study protocol and would apply to centers
that routinely test for both Gram-positive and Gram-negative organisms as part of standard
of care.
Nasal swab specimens (one from each nostril) will be obtained at the Randomization Visit
and will be cultured by the central microbiology laboratory. Results from the nasal swab
specimen cultures will be used to assess correlation with results of the qualifying ETA
culture.
Upon determination of eligibility, approximately 354 subjects will be randomized in a 1:1
ratio to 1 of 2 treatment groups:

ASN100 administered as 2 separate intravenous (IV) infusions of ASN-1 and ASN-2
either sequentially or simultaneously, or

Placebo administered as 2 separate IV infusions either sequentially or simultaneously.
To ensure balance among the treatment groups, randomization for this study will be
stratified by receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the
time of randomization that are potentially active against S. aureus pneumonia, including,
but not limited to, nafcillin, oxacillin, vancomycin, linezolid, telavancin, ceftaroline,
ceftobiprole, and teicoplanin.
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg
of ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-
2) or matching placebos, per their assigned randomization scheme.
If, as part of routine standard of care, additional respiratory and/or other microbiological
specimens are collected for culture during the study, results will be documented within the
electronic Case Report Form (eCRF). As described within the study laboratory manual,
bacterial isolates recovered from these specimens that are deemed pathogens by the


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Investigator (if retained and available at the study site’s local microbiology laboratory) will
be sent to the central microbiology laboratory for confirmation of pathogen identification
(all isolates) and susceptibility testing (S. aureus isolates only).
Randomized subjects will be monitored daily for the signs and symptoms of pneumonia
and other S. aureus-associated infections while hospitalized up to up to but not including
Day 22.
All randomized subjects will undergo a study visit on Day 22 (+2 days) for treatment
efficacy evaluation. A follow-up visit will occur on Day 28 (+2 days) to assess mortality.
This visit may be conducted via telephone if the subject is no longer hospitalized.
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where
they received study treatment, a follow-up safety visit will be performed on the day of
discharge from the hospital during this period.
All randomized subjects will return for a Safety Visit on Day 90 (±7 days) (if the subject
is unable to return to the site, this visit may be conducted by telephone). Subjects who
discontinue the study prior to Day 22 will undergo an Early Termination Visit. The end of
the study will occur upon completion of the last Day 90 visit by the last subject.
Safety assessments for this study will include adverse event monitoring, clinical laboratory
assessments (including chemistry, hematology, coagulation, and urinalysis), physical
examinations, vital sign measurements, 12-lead ECGs, chest X-rays and/or thoracic CT
scans, and the determination of the presence of ASN-1 and ASN-2 anti-drug antibodies
(ADAs). Additional safety assessments may be performed throughout the duration of the
study if clinically indicated.
4.3.
Study Procedures
Table 1 presents the visit schedule and procedures to be conducted at each visit.


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Table 1:  SCHEDULE OF PROCEDURES
Study Period
Screening/
Enrollment
Randomization
Treatment
Monitoring Period
Follow-Up Period
ET
Study Day
Up to
Day -14a
Day 1 pre-dose
Day 1
Day 2/3b
(BAL PK
sub-study)
Day 2 to
Day 21c
Day 22
(+2 days)
Day 28
(+2 days)d
Day 40
to
Day 89e
Day 90
(7 days)
Safety
Visitf
Unschedg
Study Procedures
Informed consent
X
Inclusion/exclusion/
randomization criteria
Xh,i
Xj
Medical history
Xh
Xk
Demographics
Xh
Antibiotic/medication historyl
X
X
Height/weight
Xh
Physical examinationm
Xh
X
X
X
X
X
X
Vital signsn
Xh
X
X
X
X
X
X
X
X
Pregnancy testo
Xh
X
X
Clinical laboratory
assessments (chemistry,
hematology, and coagulation)
X
Xp
X
Xq
Urinalysis
X
Xr
X
Xq
Procalcitonin (analysis
performed at central lab)
X
Xs
X
X
Ventilator device status
X
X
X
X
Xt
Xt
Xt
Xt
Xt
Xt
Chest X-ray/thoracic CT scan
Xu
Xv
X
Xw
Xw
Nasal swab specimens for
culture
X
ETA for culturex
X
Collection/culture of
additional microbiological
specimensy
X
X
X
Clinical assessment of
signs/symptoms of pneumonia
X
X
X
X
X
X
Other S. aureus infection
assessment
X
X
X
X
X
X
X
Footnotes begin on the next page.


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Table 1:  SCHEDULE OF PROCEDURES (Continued)
Study Period
Screening/
Enrollment
Randomization
Treatment
Monitoring Period
Follow-Up Period
ET
Study Day
Up to
Day -140
Day 1 pre-dose
Day 1
Day 2/3b
(BAL PK
sub-study)
Day 2 to
Day 21c
Day 22
(+2 days)
Day 28
(+2 days)d
Day 40
to
Day 89e
Day 90
(7 days)
Safety
Visitf
Unschedg
Study Procedures
Randomization
X
Blood collection for ADA and
anti-S. aureus toxin antibodies
X
Xz
X
X
X
X
12-lead ECG
X
X
X
X
X
Assess survival and discharge
disposition
X
X
X
X
X
Study drug administrationaa
X
BAL for PKbb
X
Blood collection for PK
sampling and anti-S. aureus
toxin antibodies
Xcc
Xdd
Xee
Xee
Xee
X
X
Track days on ventilator from
randomization
X
X
X
X
X
X
X
Track days in ICU (or other
observation area)
X
X
X
X
X
X
X
Concomitant medicationsl
X
X
X
X
X
X
X
X
Adverse event assessment
Xff
X
X
X
X
X
X
X
X
a.
Eligible subjects will be screened daily (while mechanically ventilated) for up to 8 days to identify those subjects who are heavily colonized with S. aureus (see Protocol Section
3.1). Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 provided the subject remains mechanically ventilated, for a total Screening
Period of up to 14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator and providing the subject remains mechanically
ventilated.
b.
Procedures are to be performed 48 hours (36 hours) post-dose on approximately Day 2 or Day 3, depending on time of study drug administration, for those subjects participating
in the BAL fluid PK sub-study only or if BAL fluid is collected as part of a standard of care procedure for any subject at any other time post-randomization for any other reason.
c.
Procedures are to be performed daily (unless otherwise indicated) from Day 2 to Day 21 while the subject is hospitalized. For subjects participating in the BAL fluid PK
sub-study, procedures noted for the Day 2 visit only need to be performed 1 time.
d.
A follow-up visit will occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the subject is no longer hospitalized.
e.
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they receive study treatment, a follow-up safety visit will be performed on the day of
discharge.
f.
If the subject is unable to return to the site, this visit may be conducted by telephone, with procedures performed as appropriate (i.e., concomitant medications and adverse
events collected).
g.
An ET visit will be conducted for subjects who are withdrawn from the study prior to Day 22.


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h.
To be performed at the initial Screening Visit only.
i.
At the Screening Visit, subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to be eligible to return for the Randomization Visit.
j.
At the Randomization Visit, subjects must continue to meet all of the inclusion criteria and none of the exclusion criteria. Subjects must also meet all randomization criteria to
be eligible to be randomized into the study.
k.
Review and record medical history (if changes occurred since the Screening Visit).
l.
All prior medications received by the subject within 14 days prior to study drug administration and any concomitant medications used throughout the duration of the study will
be recorded in the source documents and on the appropriate eCRF.
m.
A complete physical examination will be performed at the Screening Visit and as deemed necessary by the Investigator and will include, at a minimum, a pulmonary examination
(including auscultation) and assessments of the skin, abdomen, cardiovascular, gastrointestinal, and neurological systems. A limited physical examination will be performed at
the Randomization Visit, daily during the Monitoring Period (if the subject is hospitalized), on Day 22 (if the subject is hospitalized), at the time of hospital discharge (if
discharge occurs between Day 40 and Day 90), at the Safety Visit (Day 90) if the visit occurs onsite, and at ET (if applicable). The limited physical examination will include,
at a minimum, a pulmonary examination (including auscultation).
n.
Vital sign measurements will include temperature, systolic and diastolic blood pressure, pulse, respiratory rate, and oxygenation status. Blood pressure and pulse will be assessed
via an automated device. Manual techniques are only to be used if an automated device is not available. Oxygenation status will be determined via measurement of arterial
blood gas, provided the subject has an arterial line placed. If no arterial line is present, pulse oximetry may be used.
o.
Female subjects of childbearing potential must have a documented negative pregnancy test at the Screening Visit. Female subjects may be enrolled on the basis of a negative
urine pregnancy test, pending the result of a negative serum pregnancy test prior to randomization. A pregnancy test will also be performed on Day 22 or ET (if applicable).
Additional pregnancy testing may occur throughout the duration of the study, per applicable country requirements.
p.
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1 day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, and twice weekly during
Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through Day 21) of the Monitoring Period while the subject remains hospitalized.
q.
To be obtained if clinically indicated.
r.
Urinalysis to be obtained on Day 6 (±1 day) of the Monitoring Period only.
s.
Procalcitonin testing to occur on the day of diagnosis of pneumonia, if applicable.
t.
If applicable.
u.
A chest X-ray or thoracic CT scan is to be obtained 1 time at the initial Screening Visit. A chest X-ray or thoracic CT scan obtained as part of standard of care within 24 hours
prior to the initial Screening Visit is sufficient provided there are no changes in the subject’s clinical status (e.g., no change in ventilation status, secretions, or signs/symptoms
that may be suggestive of pneumonia) within the 24 hours following imaging.
v.
A chest X-ray or thoracic CT scan obtained within 24 hours of the Randomization Visit is sufficient, provided there are no changes in the subject’s clinical status (e.g., no
change in ventilation status, secretions, or signs/symptoms that may be suggestive of pneumonia) since the time of imaging.
w.
A chest X-ray or thoracic CT scan is required during the Monitoring Period for those subjects presenting with signs and symptoms of a respiratory infection such as dyspnea,
tachypnea, fever, or cough.
x.
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or semi-quantitative methods as required by the protocol. Sites are encouraged to perform
semi-quantitative cultures using a chromogenic media that tests for both the presence of MSSA and MRSA (e.g., CHROMagarTM Staph aureus) for more rapid and specific
detection of S. aureus. If the site is not able to obtain chromogenic media for S. aureus, appropriate chromogenic media may be supplied by the Sponsor. Semi-quantitative
cultures using chromogenic media are preferred for determination of eligibility for randomization; however, any quantitative or semi-quantitative culture performed that indicates
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to randomize the subject within 48 hours (or up to 60 hours with Medical Monitor
approval) from the time the ETA sample was collected. If subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible for re-screening as a
new subject enrollment. Subjects who were previously randomized are not eligible to be re-consented and re-screened. Subjects with a screening ETA culture that also shows
heavy colonization of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and Gram-negative organisms), will not be randomized into the study;
however, randomization should not be delayed while waiting for Gram-negative results if heavy colonization with S. aureus has been confirmed.
y.
Adequate respiratory specimen or other microbiological specimens to be obtained if clinically indicated. If, as part of routine standard of care, additional respiratory and/or other
microbiological specimens are collected for culture during the study, results will be documented within the eCRF.
z.
Obtain sample for ADA (to be obtained only upon discharge from the ICU, if discharge occurs prior to Day 22).


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aa.
Study drug will be administered in a double-blind manner. Subjects will receive ASN100 or matching placebo via 2 IV infusions over a duration of approximately 50 to
60 minutes per infusion. Both ASN100 and placebo will be administered as 2 separate infusions (either sequentially or simultaneously). The last infusion will be completed
within 5 hours from initiation of drug preparation in the pharmacy.
bb. Obtain BAL fluid 48 hours (36 hours) post-dose to determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid is collected as part of a standard of care procedure
from any subject enrolled in the sub-study at any other time post-randomization for any other reason, if possible, a sample for PK analysis will also be obtained.
cc.
Blood samples for PK analysis will be collected immediately following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 24 hours (±6 hours)
post-dose.
dd. Obtain a blood sample for PK measurement 1 hour relative to BAL fluid collection (including scheduled BAL fluid collection or if BAL fluid is collected as part of a standard
of care procedure from any subject enrolled in the sub-study at any time post-randomization).
ee.
A PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected
on the day of discharge (if discharge occurs between Day 40 and Day 90).
ff.
Adverse events that occur between the time the subject signs the ICF and the Randomization Visit will only be recorded if related to a study-specific procedure.
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; CT = computed tomography; ECG = electrocardiogram; eCRF = electronic Case Report Form; ELF = epithelial lining
fluid; ET = Early Termination; ETA = endotracheal aspirate; ICF = Informed Consent Form; ICU = intensive care unit; IV = intravenous; MRSA = methicillin-resistant S. aureus;
MSSA = methicillin-susceptible S. aureus; PK = pharmacokinetic; S. aureus = Staphylococcus aureus; Unsched = unscheduled.


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4.4.
Selection of Study Population
Male and female subjects ≥18 years of age who are heavily colonized with S. aureus as
determined by either quantitative or semi-quantitative culture of an ETA specimen,
mechanically ventilated, and, in the Investigator’s opinion, will require ongoing ventilator
support for at least 48 hours, will be enrolled.
4.5.
Randomization and Blinding
Randomization will occur at the Randomization Visit following determination of the
subject’s eligibility. Subjects will be randomized via a centralized Interactive Response
Technology (IRT) system in a 1:1 ratio to receive a single dose (2 infusions) of either
ASN100 or matching placebo. Randomization will be stratified by receipt or non-receipt
of concomitant anti-staphylococcal antibiotics at the time of randomization that are
potentially effective for the treatment of S. aureus pneumonia.
The study follows a double-blind, placebo-controlled design. All study personnel,
including investigators, site personnel, site pharmacist, Sponsor and contract research
organization (CRO) staff involved in the conduct of the study (e.g., clinical research
associate [CRA]/monitor), and subjects will be blinded to treatment assignment, except as
described below. ASN100 and placebo will be identical in appearance to preserve blinding.
Randomization data will be kept strictly confidential until the time of unblinding and will
not be accessible by subjects, Investigators, or anyone performing assessments and having
access to study data until unblinding occurs. An independent Data Review Committee (as
described in Section 7.6) will conduct a single interim analysis of futility assessment and
will receive unblinded study data.  Sponsor and CRO staff who are involved in the conduct
of the study will not have access to unblinded Data Review Committee materials. The
details of the interim analysis are described in the Data Review Committee Charter dated
8-June-2018. Individual subject unblinding will only occur in the case of subject
emergencies or as required by regulations when reporting serious unexpected suspected
adverse reactions (SUSARs), with complete unblinding at the conclusion of the study.
Emergency breaking of the assigned treatment code should only be undertaken when it is
essential that knowledge of the treatment assignment is necessary to treat the subject’s
emergency safely and effectively. Emergency treatment code breaks will be performed
using the IRT. When the Investigator contacts the system to break a treatment code for a
subject, he/she must provide the requested subject’s identifying information and confirm
the necessity to break the treatment code for the subject. The Investigator will then receive
details of the investigational drug treatment for the specified subject and a fax or email
confirming this information. The system will automatically inform the Sponsor and
Medpace study personnel that the code has been broken.
Should the assignment of the subject be needed to fulfill regulatory reporting requirements
for SUSARs as noted above, the person designated at the CRO/Sponsor for unblinding
needed to fulfill regulatory reporting requirements should contact IRT, for the study drug
information. The IRT documentation indicating the blind break at the site, must be retained


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with the subject’s source documentation in such a way as to avoid unblinding the treatment
assignment to other site or Sponsor blinded personnel.


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5.
STUDY METHODS
5.1.
Analysis Populations
The following analysis populations will be used for analyses.
5.1.1.
Intent-to-Treat Population (ITT)
The ITT Population includes all subjects who are randomized to receive study drug.
5.1.2.
Modified Intent-to-Treat Population (MITT)
The MITT Population includes all subjects in the ITT Population who receive study drug
and who are heavily colonized with S. aureus as determined by quantitative or semi-
quantitative culture of an ETA specimen. Exclusion from the MITT Population will be
determined programmatically for each ITT subject. Programmatically determined
assignment into the MITT Population will be evaluated for confirmation or Sponsor
Override as applicable during a Review Meeting of the Population and Outcome Plan
(POP) Review Group, as described in the POP.
Review Meetings will be held on a regular basis throughout the conduct of the study.  The
number of subjects included in each Review Meeting will vary depending on the number
of subjects included in a data review cycle per the Medpace Rolling Data Lock Plan.
The final MITT Population classification will be performed in a blinded fashion and prior
to final database lock and unblinding. After the Review Group’s review, any Sponsor
overrides of the MITT Population flags will be finalized and documented. The MITT
Population flags and the reasons for Sponsor Override will also be included in the analysis
datasets.
5.1.3.
Per Protocol (PP) Population
The PP Population includes all subjects in the MITT Population who also meet the
following criteria:

Did not have any major protocol violations that would affect assessment of efficacy,

Randomized in a timely manner following collection of an ETA specimen showing
heavy S. aureus colonization;

Was mechanically ventilated at randomization;

Had an appropriate chest image performed at randomization;

Did not have a change of oxygenation and onset of purulent secretions at
randomization;

Was not diagnosed with pneumonia at randomization or within 24 hours of
receiving study drug;

Received an adequate dose of study drug administered in a timely manner following
study drug preparation,


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
Did not die within 24 hours of receiving study drug,

Did not have Investigator Diagnosis of Pneumonia within 24 hours of receiving
study drug, and

Complete an adequate number of Monitoring Period assessments through Day 22
based on medical review of available data.
Exclusion from the PP Population will be determined programmatically for each MITT
subject. Programmatically determined assignment into the PP Population will be evaluated
for confirmation or Sponsor Override as applicable during a Review Meeting.
The final PP Population classification will be performed in a blinded fashion and prior to
final database lock and unblinding. After the Review Group’s review, any Sponsor
Overrides of the PP Population flags will be finalized and documented. The PP Population
flags and the reasons for Sponsor Override will also be included in the analysis datasets.
5.1.4.
Pharmacokinetic (PK) Population
The PK Population includes all subjects in the MITT Population with at least 1 serum PK
sample collected post-dose.
5.1.5.
Safety Population
The Safety Population includes all subjects who receive any amount of study drug and have
at least 1 post-treatment safety assessment.
5.2.
Study Endpoints
5.2.1.
Microbiological and Clinical Assessments
ETA specimens will be collected for culture during Screening/Enrollment to determine
randomization eligibility, including identification of heavy S. aureus colonization.
Additional respiratory specimens may be collected for culture throughout the Monitoring
Period or at Early Termination (if applicable) if clinically indicated according to routine
standard of care.
If, as part of routine standard of care, additional respiratory and/or other microbiological
specimens are collected for culture during the study, results will be documented within the
eCRF. As described within the study lab manual, bacterial isolates recovered from these
specimens that are deemed pathogens by the Investigator (if retained and available at the
study site local microbiology laboratory) will be sent to the central microbiology laboratory
for confirmation of pathogen identification (all isolates) and susceptibility testing (S.
aureus isolates only).
During the Monitoring Period, a diagnosis of S. aureus pneumonia will be determined if
subjects have S. aureus identified at any level from an adequate respiratory specimen by
the local microbiology laboratory or central microbiology laboratory if the local
microbiological sample was either not done, cultured improperly, or no growth. For a
diagnosis of S. aureus pneumonia, the collection of an adequate respiratory specimen
culture that is positive for S. aureus must occur within ±2 days from the time of the


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development of clinical signs and symptoms of pneumonia or chest imaging results
indicative of pneumonia:

A respiratory specimen obtained by BAL, non-bronchoscopic BAL, or protected
specimen brush will be considered an adequate respiratory specimen; or

For extubated subjects, an adequate expectorated/induced sputum specimen is
defined as one that does not have either ≥10 squamous epithelial cells or ≤25
PMNs/100× field will also be an adequate respiratory specimen; and

For both intubated and extubated subjects, adequate respiratory specimens will
undergo either semi-quantitative or quantitative culture in accordance with the local
laboratory’s standard procedure.
Subjects will be assessed daily throughout the Monitoring Period for the following clinical
signs and symptoms:
Clinical Signs and Symptoms
Mechanically Ventilated Subjects
Non-Mechanically Ventilated Subjects

Cough,

Rales,

Dullness on percussion,*

Bronchial breath sounds,

Egophony,*

Need for suctioning,

Need for ventilator support, and

Fever 38C (100.4F).

Cough,

Rales,

Dullness on
percussion,*

Bronchial breath
sounds,

Egophony,*

Dyspnea,

Tachypnea,

Respiratory rate,

Hypoxemia, and

Fever 38C
(100.4F).
*If routinely performed.
A diagnosis of pneumonia will be determined by the Investigator based on their clinical
expertise and experience.
Each pneumonia diagnosis will be categorized programmatically as HABP or VABP using
the definitions below. Programmatically determined assignments as HABP and VABP will
be evaluated for confirmation or Sponsor Override as applicable by the Review Group.
The final categorizations will be performed in a blinded fashion and prior to final database
lock and unblinding. After the Review Group’s review, the decision to override a
programmatic determination will be finalized and documented. The reasons for Sponsor
Overrides will be included in the analysis datasets.


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Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia
Indication
Definition
HABP

A chest image showing new or progressive infiltrates suggestive of pneumonia;

Subject has been off of mechanical ventilation via an endotracheal or nasotracheal
tube for >48 hours;

At least ONE of the following:
o
Has been hospitalized for 48 hours; or
o
Developed clinical signs and symptoms within 7 days following hospital
discharge;

At least ONE of the following:
o
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea,
tachypnea (e.g., respiratory rate 25 breaths per minute), expectorated sputum
production, or the requirement for mechanical ventilation (if subject is not already
ventilated);
o
Need for acute changes in ventilator support to enhance oxygenation or to the
amount of PEEP; or
o
New onset of suctioned respiratory secretions; AND

At least ONE of the following clinical signs/symptoms:
o
Temperature 38°C or 35°C;
o
WBC count 10,000 cell/mm3 or 4500 cell/mm3; or
o
15% immature neutrophils (bands) on peripheral blood smear.
VABP

A chest image showing new or progressive infiltrates suggestive of pneumonia;

Subject has received mechanical ventilation via an endotracheal or nasotracheal tube
for 48 hours;

At least ONE of the following:

Currently receiving mechanical ventilation via an endotracheal or nasotracheal
tube; or

Discontinued
receiving mechanical ventilation
via an endotracheal or
nasotracheal tube within the last 48 hours (i.e. ≤48 hours);

At least ONE of the following:
o
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea,
tachypnea (e.g., respiratory rate 25 breaths per minute), expectorated sputum
production, or the requirement for mechanical ventilation (if subject is not already
ventilated);
o
Need for acute changes in ventilator support to enhance oxygenation or to the
amount of PEEP; or
o
New onset of suctioned respiratory secretions; AND

At least ONE of the following clinical signs/symptoms:
o
Temperature 38°C or 35°C,
o
WBC count 10,000 cell/mm3 or 4500 cell/mm3, or
o
15% immature neutrophils (bands) on peripheral blood smear.
HABP = hospital-acquired bacterial pneumonia; PEEP = positive end-expiratory pressure; VABP = ventilator-
associated bacterial pneumonia; WBC = white blood cell.
5.2.2.
Sponsor-Defined Outcome of S. aureus Pneumonia
Sponsor-Defined Outcome (SDO)
of
S. aureus
pneumonia
will be determined
programmatically based on the data and the manual review conducted at Review Meetings
per the POP.


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Each randomized subject will be evaluated for the occurrence of S. aureus pneumonia
between Randomization and up to, but not including, Day 22. In order to assign a SDO,
the following assessments will be made based on available data:
1. Microbiological Assessment
2. Chest Imaging Assessment
3. Clinical Assessments
a.
Respiratory
b. Signs and Symptoms
4. Operational Assessments
There will be 2 SDO definitions for data analysis:  SDO1 and SDO2.  The 2 definitions
will need to satisfy the 4 assessments above and differ only on the clinical assessments.
SDO1 will meet either respiratory OR signs and symptoms requirements while SDO2 will
meet both respiratory AND signs and symptoms requirements.
The individual assessments for each randomized subject will be collapsed to assign an
SDO1/SDO2 of Yes, No, Indeterminate (i.e. insufficient data to assign a SDO of Yes or
No), or Censored (i.e. subject died prior to the Day 22 assessment) based on the mutually
exclusive, hierarchical rules specified in the POP.
5.2.3.
Pharmacokinetic Assessments
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. Blood
samples for PK analysis will be collected immediately following the completion of the
second infusion (+15 minutes) and at 6 hours (±4 hours) and 24 hours (±6 hours) post-dose
following the second infusion. In addition, a PK sample will be obtained from all subjects
on Days 4 (±1 day), 7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period.
Additional PK samples will be collected on the day of discharge (if discharge occurs
between Day 40 and Day 90), on Day 90 (if hospitalized or if the subject is able to return
to the clinic), or Early Termination (if applicable).
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25
to 35 subjects who volunteer will participate in this sub-study and will have BAL fluid
collected 48 hours (36 hours) post-dose (on approximately Day 2 or Day 3, depending on
time of study drug administration) to determine ASN-1 and ASN-2 levels and blood to
ELF ratio. Subjects participating in the BAL fluid PK sub-study will have a blood sample
collected for PK measurement 1 hour relative to BAL fluid collection.
If BAL fluid is collected as part of a standard of care procedure from any subject enrolled
in the sub-study at any other time post-randomization for any other reason, if possible, a
sample for PK analysis will also be obtained.  Additionally, attempts will be made to collect
a serum sample for PK measurement 1 hour relative to BAL fluid collection.


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5.2.4.
Primary Efficacy Endpoint
The primary efficacy endpoint is whether the subject has developed an SDO1 of S. aureus
pneumonia up to, but not including, Day 22. The summary measure for efficacy is the
proportion of subjects in the MITT Population who develop an SDO1 of S. aureus
pneumonia up to, but not including, Day 22.
Analyses of the primary efficacy endpoint will also be performed separately for the ITT
and PP Populations.
5.2.5.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Duration of mechanical ventilation during the first 21 days post-randomization for
subjects in the MITT, ITT, and PP Populations;

Length of ICU stay during the first 21 days post-randomization for subjects in the
MITT, ITT, and PP Populations;

The Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single
dose of ASN100 in the PK Population; and

28-day all-cause mortality in the MITT, ITT, and PP Population.
5.2.6.
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include:

Proportion of subjects in the MITT and PP Populations with a diagnosis of HABP
48 hours post-extubation up to, but not including, Day 22 in extubated subjects;

Proportion of subjects in the MITT and PP Populations with development of VABP
up to, but not including, Day 22;

Incidence of all bacterial pneumonias in the MITT, ITT, and PP Populations;

Incidence of other non-S. aureus bacterial pneumonias up to, but not including, Day
22 in the MITT, ITT, and PP Populations; and

Incidence of other S. aureus infections acquired up to, but not including, Day 22 in
the MITT, ITT, and PP Populations.
5.2.7.
Safety Endpoints
Safety endpoints are as follows:
1. Treatment-emergent adverse events (TEAEs)
2. Vital signs
3. Electrocardiograms (ECGs)
4. Laboratory parameters
5. Physical examinations


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6. Radiographs and Imaging
7. Immunogenicity and anti-drug antibodies


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6.
SAMPLE SIZE DETERMINATION
The estimated incidence of progression to S. aureus pneumonia in mechanically ventilated
subjects with heavy endotracheal colonization of S. aureus is approximately 25% within
22 days of randomization.
Assuming a 2-sided significance level of 0.05 and a desired power of 80% to detect a
significant difference between S. aureus pneumonia incidence rates of 25% in the placebo
group and 12.5% in the ASN100 treatment group (50% reduction), 152 evaluable subjects
are required in each treatment group. A sample size of 304 subjects (152 subjects per
treatment group) will yield 80% power to detect a 50% reduction in the incidence of S.
aureus pneumonia with ASN100 treatment when assuming a 25% incidence rate of S.
aureus pneumonia in placebo-treated subjects. Assuming a 14% non-evaluable rate,
approximately 354 subjects (177 subjects per treatment group) will be randomized.
Assuming the screen failure rate is about 84%, approximately 2250 subjects will be
screened.


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7.
STATISTICAL ANALYSIS
7.1.
General Statistical Considerations
Summary statistics will be presented by treatment group. For continuous variables, the
number of observations (n), mean, standard deviation (SD), median, minimum, and
maximum will be provided. For categorical variables, the frequency and percentage in each
category will be displayed.
For summary statistics, the mean and median will be displayed to one decimal place greater
than the original value and the measure of variability (e.g., standard deviation) will be
displayed to two decimal places greater than the original value.
All statistical tests will be performed at the 0.05 significance level using 2-sided tests,
except where otherwise noted. All confidence intervals will have a confidence level of
95%.
7.2.
Treatment Misallocations
If subjects were randomized but were not treated, the subjects will be included in the ITT
Population, but not included in the MITT, PP, PK, and Safety Populations consistent with
their definitions.
If subjects were randomized but received incorrect study medication, they will be reported
under their randomized treatment group for all efficacy analyses for the ITT, MITT, and
PP Populations, but will be reported under the treatment they actually received for all safety
analyses for the Safety Population.
7.3.
Handling of Missing Data
7.3.1.
Missing Dates
In cases of missing or incomplete dates (e.g., AE and concomitant medications), the
missing component(s) will be assumed as the most conservative value possible. For
example, AEs with missing start dates, but with stop dates either overlapping into the
treatment period or missing, will be counted as treatment-emergent, taking the worst-case
approach. When partial dates are present in the data, both a partial start date and/or a partial
stop date will be evaluated to determine whether it can be conclusively established that the
AE started prior to the start of study drug or ended prior to the start of study drug. If the
above cannot be conclusively established based on the partial and/or present dates, then the
AE will be considered as treatment-emergent. Actual data values as they appear in the
original case report forms (CRFs) will be presented in the data listings.
7.3.2.
Missing Assessment
Randomized subjects discontinued from the study due to any cause prior to Day 22 will be
considered as not developing S. aureus pneumonia by SDO1 for the primary efficacy
analysis.


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Randomized subjects that are non-informative (i.e. a subject that does not develop SDO1
or SDO2 of S. aureus pneumonia, indeterminate, or dies before Day 22) will be censored
for the Kaplan-Meier analysis unless it is noted otherwise.
7.3.3.
Other Missing Data
Other missing values will not be imputed and only observed values will be used for
reporting of descriptive statistics unless otherwise stated.
7.4.
Baseline Definition
For all efficacy and safety endpoints, baseline is defined as the last measurement or
assessment prior to the first and only dose of study drug.
7.5.
Relative Day
The date of the initiation of study drug administration will be considered relative day 1,
relative days will be calculated as follows only when the full assessment date is known
(i.e., partial dates will have missing relative days):
For days before the initiation of study drug administration:
Relative Day = Date of Assessment – Date of the initiation of study drug administration
For days on or after the initiation of study drug administration:
Relative Day = Date of Assessment – Date of the initiation of study drug administration +
1
7.6.
Interim Analysis
One interim analysis will be conducted during the study, when approximately 125 subjects
have reached Day 22. The interim analysis is for futility assessment of the study, and for a
potential study sample size adjustment.  The futility assessment is based on an unblinded
efficacy evaluation while any sample size adjustment result from a review of blinded data
pooled across the treatment arms.
The interim analysis of futility assessment will be
reviewed by an independent Data Review Committee. The details of the interim analysis
are described in the Data Monitoring Committee Charter dated 25-June-2018.
7.7.
Subject Disposition
Subject disposition will be summarized for the ITT Population for each treatment group
and in total. The following subject disposition categories will be included in the summary
for the ITT Population:

Subjects who randomized,

Subjects who received any study drug,

Subjects who completed the study assessments through Day 22,

Subjects who did not complete the study assessments through Day 22,


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
Subjects who completed the study assessments by Day 28,

Subjects who did not complete the study assessments by Day 28,

Subjects who completed the study assessments through Day 90,

Subjects who did not complete the study assessments through Day 90, and

Subjects who completed assessments through Day 22, but did not complete the
study assessments through Day 90.
For subjects who did not complete the study assessments through Day 90, a summary will
be provided by reason of discontinuation. In addition, the total number of subjects for each
defined population will be tabulated.
7.8.
Demographic and Baseline Characteristics
Demographic information including sex, race, ethnicity, corrected randomization
stratification factor (receipt or non-receipt of concomitant anti-staphylococcal antibiotics
at the time of randomization that are potentially active against S. aureus pneumonia), age
(as a continuous variable and categorized as <55, 55 - <65, 65 - <75 and ≥75 years), height,
weight, and BMI will be summarized by treatment group for the ITT, MITT, PP, PK, and
Safety Populations.
7.9.
Medical History
Medical history will be collected at the screening visit and randomization visit if changes
occurred since the Screening Visit. Only adverse events that were considered to be study
procedure related were to be reported between the first study screening visit and
randomization.  Therefore, any changes in the subject’s medical condition during this
period were captured as medical history.
All reported medical history conditions will be listed by subject.
7.10.
Prior and Concomitant Medications/Procedures
Prior and concomitant medications will be coded using the World Health Organization
(WHO) Drug Dictionary (Sept 2016E B2). Concomitant procedures will be coded using
the Medical Dictionary for Regulatory Activities (MedDRA, Version 19.1).
Prior medications are medications used before the initiation of study drug administration.
Any medications used on or after the initiation of study drug administration will be
included as concomitant medications. Hence medications ongoing at start of study
medication will be counted as both prior and concomitant medication.
The number and percentage of subjects taking prior medications will be summarized for
the ITT Population by anatomic therapeutic chemical (ATC) class and preferred term for
each treatment group and overall.
The number and percentage of subjects taking concomitant medications will be
summarized for the ITT Population by anatomic therapeutic chemical (ATC) class and
preferred term for each treatment group and overall.


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The number and percentage of subjects receiving concomitant procedures will also be
summarized for the ITT Population by system organ class (SOC) and preferred term for
each treatment group and overall.
Prior and concomitant medications/procedures will be listed by subject.
7.11.
Analysis of Efficacy
For all efficacy analyses, subjects will be analyzed in the group to which they were
randomized.
7.11.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is whether the subject has or has not developed S. aureus
pneumonia up to, but not including, Day 22 in the MITT Population. For the primary
analysis, whether the subject has or has not developed S. aureus pneumonia will be based
on sponsor defined outcome (SDO1).
The primary analysis is based on comparing two proportions of subjects who develop S.
aureus pneumonia by SDO1 up to, but not including, Day 22. For each arm, the empirical
proportion is defined by a ratio, which is the number of S. aureus pneumonia events divided
by the total number of subjects in the arm. The inference about the difference of two
population rates is based on the empirical counterpart. Specifically, the point estimate, 95%
confidence interval and p-value for the rate difference. If subjects discontinued from the
study due to any cause prior to Day 22, it will be considered as not developing S. aureus
pneumonia by SDO1 for the primary efficacy analysis.
7.11.2.
Additional Analyses for S. aureus Pneumonia
Analyses of the primary efficacy endpoint will also be performed based on the ITT and
PP Populations.
The following additional analyses will be performed in the MITT and PP Populations:

The primary efficacy analysis, based on comparing two proportions of subjects who
develop S. aureus pneumonia by SDO2 up to, but not including, Day 22. If subjects
discontinued from the study due to any cause prior to Day 22 it will be considered
as not developing S. aureus pneumonia for this analysis by SDO2.

The primary analysis is based on comparing two proportions of subjects who
develop S. aureus pneumonia by SDO1 up to, but not including, Day 22. For each
arm, the empirical proportion is defined by a ratio, which is the number of S. aureus
pneumonia events divided by the total number of subjects in the arm. The inference
about the difference of two population rates is based on the empirical counterpart.
Specifically, the point estimate, 95% confidence interval and p-value for the rate
difference. If subjects discontinued from the study due to any cause prior to Day
22, it will be considered as developing S. aureus pneumonia by SDO1 and SDO2.

The Kaplan-Meier analysis will be performed for the proportion of subjects who
develop S. aureus pneumonia by Day 21 as determined by SDO1. The proportion
of subjects who develop S. aureus pneumonia up to but not including Day 22 will


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be obtained from Kaplan-Meier estimates for each treatment group.  The inference
about the difference of two rates will be made via the Kaplan-Meier estimates and
their corresponding variance estimates in the MITT population. The treatment
difference of two rates, the corresponding 95% confidence intervals and p-value
will be presented. In addition, the number and percentage of subjects who
developed S. aureus pneumonia or were censored will be summarized. The Kaplan-
Meier estimate of event rates evaluated at Day 21 and the corresponding 95%
confidence intervals will be presented for each treatment group. Subjects who did
not develop S. aureus pneumonia, discontinued from the study, or died prior to Day
22 will be considered censored.  For the censored subjects, the last assessment date
on which the subject did not develop S. aureus pneumonia based on the
Investigator’s assessment will be used as the date of censoring.

The Kaplan-Meier analysis will be performed for the proportion of subjects who
develop S. aureus pneumonia up to but not including Day 22 as determined by
SDO1 and the Review Meeting’s determination of S. aureus as a causative
pneumonia pathogen.

The Kaplan-Meier analysis will be performed for the proportion of subjects who
develop S. aureus pneumonia up to but not including Day 22 as determined by
SDO2 and the Review Meeting’s determination of S. aureus as a causative
pneumonia pathogen

The Kaplan-Meier analysis will be performed for the proportion of subjects who
develop S. aureus pneumonia up to but not including Day 22 as determined by the
Investigator’s judgement and the Review Meeting’s determination of S. aureus as
a causative pneumonia pathogen.

An additional Kaplan-Meier analysis will be conducted for subjects with S. aureus
pneumonia and presumed S. aureus pneumonia by SDO1 and SDO2.  The
presumed
S. aureus
pneumonia
population
includes
those
subjects
with
microbiologic results “Not Done” up to and including Day 7 (presumed S. aureus
pneumonia).

A third Kaplan-Meier analysis will be conducted for subjects with S. aureus
pneumonia including those subjects with microbiologic results “Not Done” up to
and including Day 10 (presumed S. aureus pneumonia) for both SDO1 and SDO2
populations.

The proportion of subjects who develop S. aureus pneumonia up to but not
including Day 22 as determined by the Investigator’s judgement and the Review
Meeting’s determination of S. aureus as a causative pneumonia pathogen will be
obtained from Kaplan-Meier estimates for each treatment group. Discontinuation
from the study due to any cause up to but not including Day 22 will be considered
as an ‘Event’.

The proportion of subjects who develop S. aureus pneumonia up to but not
including Day 22 as determined by the Investigator’s judgement and the Review
Meeting’s determination of S. aureus as a causative pneumonia pathogen will be


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obtained from Kaplan-Meier estimates for each treatment group incorporating
censoring. Discontinuation from the study due to any cause up to but not including
Day 22 will be considered censored.

The proportion of subjects who develop either S. aureus pneumonia up to but not
including Day 22 as determined by the Investigator’s judgement and the Review
Meeting’s determination of S. aureus as a causative pneumonia or another S. aureus
infection up to but not including Day 22 will be obtained from Kaplan-Meier
estimates for each treatment group. Discontinuation from the study due to any
cause up to but not including Day 22 will be considered as an ‘Event’.

The proportion of subjects who develop either S. aureus pneumonia as determined
by the Investigator’s judgement and the Review Meeting’s determination of S.
aureus as a causative pneumonia or another S. aureus infection up to but not
including Day 22 will be obtained from Kaplan-Meier estimates for each treatment
group incorporating censoring. Discontinuation from the study due to any cause
up to but not including Day 22 will be considered censored.

The proportion of subjects who develop S. aureus pneumonia by Day 90 as
determined by the Investigator’s judgement will be obtained from Kaplan-Meier
estimates for each treatment group. Discontinuation from the study due to any
cause prior to Day 90 will be considered as an ‘Event’.

The proportion of subjects who develop S. aureus pneumonia by Day 90 as
determined by the Investigator’s judgement will be obtained from Kaplan-Meier
estimates for each treatment group incorporating censoring. Discontinuation from
the study due to any cause prior to Day 90 will be considered censored.

In addition, the two-sided statistical test with 5% false positive rate for the treatment
difference will be conducted based on the difference of two observed proportions
of subjects who develop S. aureus pneumonia before Day 22 by both SDO1 and
SDO2 populations. The treatment difference of two proportions, the corresponding
95% confidence intervals and p-values will also be provided based on a Wald test
on equality of proportions.
The number and percentage of subjects with SDO1 and SDO2 of S. aureus pneumonia, no
S. aureus pneumonia, indeterminate, and censored in each treatment group will be
summarized descriptively.
7.11.3.
Secondary Efficacy Endpoints
Duration of mechanical ventilation and length of hospital ICU stay during the first 21 days
post-randomization will be summarized descriptively and compared between treatment
groups using a Wilcoxon rank sum test in the MITT, ITT, and PP Populations.
The other secondary endpoint, 28-day all-cause mortality in the ITT, MITT and PP
Population, will be descriptively summarized by treatment group. All-cause mortality rate
at Day 28 based on Kaplan-Meier estimates along with the 95% confidence interval will
also be presented for each treatment group. Subjects whose survival status are unknown


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due to early termination or who are lost to follow up will be censored at the last day the
subject was known to be alive.
7.11.4.
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include:

Proportion of subjects in the ITT, MITT and PP Populations with a diagnosis of
HABP 48 hours post-extubation up to, but not including, Day 22 in extubated
subjects;

Proportion of subjects in the ITT, MITT and PP Populations with development of
VABP up to, but not including, Day 22;

Incidence of all bacterial pneumonias up to, but not including, Day 22 in the MITT,
ITT, and PP Populations;

Incidence of other non-S. aureus pneumonias up to, but not including, Day 22 in
the MITT, ITT, and PP Populations; and

Incidence of other S. aureus infections acquired up to, but not including, Day 22 in
the MITT, ITT, and PP Populations.

Mechanical ventilation free days and ICU free days during the first 21 days, or prior
to death, or early termination post randomization will be summarized descriptively
and compared between treatment groups using a Wilcoxon rank sum test in the
MITT, ITT, and PP Populations.

Summary of pneumonia free days for subjects with S. aureus pneumonias, for
subjects with bacterial pneumonias, and for subjects with any pneumonia in the
MITT and PP Populations.

Summary of All-cause mortality rate at Day 28 for subjects with any pneumonia in
the MITT and PP Populations.
All exploratory efficacy endpoints will be descriptively summarized by treatment group.
7.11.5.
Pharmacokinetic Endpoints
A listing of all PK serum sample collection dates and times and the PK BAL sample
collection dates and times in the PK sub-study will be provided.
The statistical analyses for PK concentrations and parameters in serum and in BAL fluid
in the PK sub-study will be performed by another vendor and described in a standalone PK
analysis plan. The results will reside in a separate analytical report, which will be appended
to the CSR.
7.12.
Subgroup Analyses
The following subgroups will be used for subgroup analyses for the primary efficacy
endpoint in the MITT and PP Populations, i.e. whether the subject has or doesn’t have of
S. aureus pneumonia up to, but not including, Day 22 for both SDO1 and SDO2


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populations. The exploratory efficacy endpoints, the incidence of all pneumonias, and the
incidence of other non-S. aureus pneumonias up to, but not including, Day 22 in the MITT
and PP Populations, will also undergo the following subgroup analyses.

Corrected Randomization stratification (Receipt or Non-Receipt of concomitant
anti-staphylococcal antibiotics at the time of randomization that are potentially
active against S. aureus pneumonia.)

Type of ICU (e.g., SICU, MICU, Neuro ICU, Trauma ICU)

Type of mechanical ventilation
(Tracheotomy
or
Non-Tracheotomy)
at
Randomization

Length of stay in the intensive care unit (ICU) post-treatment (<5, 5-12, >12-22,
and >22 days)

Duration of mechanical ventilation before randomization (≤48 vs. >48 hours)

Baseline MRSA/MSSA from qualifying ETA culture

Pneumonia MRSA/MSSA

Reason for mechanical ventilation

BMI categories:  <25, 25-<30, 30-<35, and ≥35

Age: <50, 50-<65, and >65

WBC × 10^9/L at Baseline:  <1, 1 to <2.5, 2.5 to <5, 5 to <10, and >10

Platelet count × 10^9/L at Baseline: <50, 50 to <150; 150 to <400, and > 400

Change in platelet count from Baseline: decrease by 50% or greater, or an increase
by 50% or greater

Male vs. female

Smoker vs. non-smoker

History of COPD vs. non-COPD

History of alcohol use vs. no history of alcohol use

Hospital readmission within 30 days after discharge

Qualifying ETA and Screening ETA cultures: S. aureus only vs. co-colonized S.
aureus and any Gram-negative at any time before randomization vs. co-colonized
S. aureus and any other organism at any time before randomization

Procalcitonin at Baseline for those who develop pneumonia vs. those who don’t
develop pneumonia: <median vs. ≥median

Qualifying ETA culture: S. aureus 3+ vs. 4+ vs. Heavy

Cardiac events yes/no from receipt of study drug to Day 90 or early termination

Multi organ failure yes/no from receipt of study drug to Day 90 or early termination


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
Acute kidney injury defined by an absolute increase in serum creatinine of 0.3
mg/dL or a 50% increase (viz., 0.3 mg/dL increase if baseline ≥0.6 mg/dL and 50%
increase if baseline is ≤0.6 mg/dL) within 48 hours from receipt of study drug

Presence of renal disease at Baseline:  serum creatinine <2 mg/dL and ≥2 mg/dl.
7.13.
Analysis of Safety Data
All subjects in the Safety Population will be included in the safety analyses and analyzed
based on the actual treatment received.
7.13.1.
Adverse Events
Verbatim descriptions of Adverse Events (AEs) will be coded using Version 19.1 of
MedDRA.  Summary tables will be provided for all Treatment-Emergent Adverse Events
(TEAEs). A TEAE is defined as an AE with a start date and time on or after the initiation
of study drug administration. If the time of an AE is missing, it is considered treatment
emergent if it starts on the same date as the initiation of study drug administration. All AEs
(including non-TEAEs), Serious AEs (SAEs), and AEs leading to study drug
discontinuation will be provided in listings by treatment group, subject ID, verbatim term,
MedDRA system organ class (SOC) and preferred term (PT), start and end date,
seriousness flag, severity, relationship to study drug, and action taken with study drug.
An overall summary of AEs will include the number and percentage of subjects in each
treatment group who experienced at least one AE/TEAE in the following categories: any
AE, any TEAE, any drug-related TEAE, any severe TEAE, any SAE, any drug-related
SAE, any SAE leading to death, any TEAE leading to discontinuation of study drug, and
any SAE leading to study drug discontinuation. Subjects with multiple events will be
counted only once within each category. Severity grade and relationship will be counted
using the maximum severity and the strongest relationship respectively for a subject with
multiple TEAEs.
The number and percentage of subjects reporting a TEAE in each treatment group will be
tabulated by SOC and PT; by SOC, PT, and severity; and by SOC, PT, and relationship
(unrelated or related to study drug). For all analyses of TEAEs, if the same AE (based on
PT) is reported for the same subject more than once, the AE is counted only once for that
PT and at the highest severity and strongest relationship to study drug.
The number and percentage of subjects reporting a SAE and reporting a TEAE leading to
discontinuation of study drug in each treatment group will be summarized by SOC and PT.
Listings will be provided for SAEs and AEs leading to drug discontinuation. In addition,
all AEs will be listed.
7.13.2.
Vital Signs
Vital sign measurements will include temperature, systolic and diastolic blood pressure,
pulse, respiratory rate, and oxygenation status (as measured by pulse oximetry or arterial
blood gas).


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Vital sign measurements will be obtained at the Screening Visit, the Randomization Visit
(Day 1 pre-dose), on Day 1 following administration of study drug, daily during the
Monitoring Period (if subject is hospitalized), on Day 22, on the day of hospital discharge
(for subjects who are discharged between Day 40 and Day 90), at the Day 90 Safety Visit
(if the visit occurs onsite), or Early Termination (if applicable). Oxygenation status will
be determined at the Screening and Randomization Visits via measurement of arterial
blood gas, provided the subject has an arterial line placed. If no arterial line is present,
pulse oximetry may be used.
Descriptive statistics will be used to summarize vital signs measurements and change from
baseline by each scheduled time point.
All vital sign assessments will be listed by subject.
7.13.3.
Electrocardiograms
A 12-lead ECG will be performed for all eligible subjects at the Randomization Visit
(Day 1 pre-dose), on Day 22, on the day of hospital discharge (for subjects who are
discharged between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs
onsite), or Early Termination (if applicable).
Quantitative ECG parameters (HR, PR, QRS, QT, and RR) will be summarized with
descriptive statistics for baseline, post-baseline, and change from baseline by each
scheduled time point.
The number and percent of subjects with normal, abnormal not clinically significant, and
abnormal clinically significant ECG assessments will be tabulated.
All 12-lead ECG data will be listed by subject.
7.13.4.
Clinical Laboratory Tests
Standard clinical laboratory profiles for safety assessments (including chemistry,
hematology, coagulation, and urinalysis) will be collected and evaluated at the
Randomization Visit (Day 1 pre-dose).
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1
day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, or Early Termination (if
applicable and if clinically indicated). During Week 2 (Day 8 through Day 14) and/or Week
3 (Day 15 through Day 21) of the Monitoring Period, clinical laboratory assessments of
chemistry, hematology, and coagulation will be performed twice a week while the subject
remains hospitalized.
Urine for urinalysis will be obtained at the Randomization Visit (Day 1 pre-dose), on Day
6 (±1 day) of the Monitoring Period, or Early Termination (if applicable and if clinically
indicated).
Below is a list of clinical laboratory analytes to be assessed:
Chemistry


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Alanine aminotransferase (ALT)
Albumin
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bicarbonate
Blood urea nitrogen
Calcium
Chloride
Creatinine
Direct bilirubin
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin
Total protein
Hematology
Hematocrit
Hemoglobin
Platelet count
Red blood cell (RBC) count
White blood cell (WBC) count
with
differential 
(basophils, 
eosinophils,
lymphocytes, monocytes, and neutrophils)
RBC indices: mean corpuscular volume
(MCV), mean corpuscular hemoglobin
(MCH), %Reticulocytes
Coagulation
Prothrombin time
Partial thromboplastin time (PTT)
Urinalysis
pH
Blood
Ketones
Specific Gravity
Leukocyte esterase
Bilirubin
Glucose
Nitrite
Protein
Other Screening Tests as needed (for female subjects of childbearing potential only)
Urine and/or serum pregnancy test
Descriptive statistics will be provided for hematology, chemistry, urinalysis, and
coagulation parameters and change from baseline by each scheduled time point.
Shift tables from baseline to the worst post-baseline value will be provided for selected
chemistry parameters (Alanine aminotransferase, Aspartate aminotransferase, Total
Bilirubin, Creatinine, and Alkaline phosphatase) and hematology parameters (Hematocrit,
Hemoglobin, Platelets, White blood cell count and differential).
Both scheduled and
unscheduled visits will be considered. For chemistry parameters, the following categories
will be used: <LLN, normal, >ULN and ≤3×ULN, >3×ULN to ≤5×ULN, >5×ULN, and
missing. For hematology parameters, the following categories will be used: low, normal,
high, and missing.
The number and percentage of subjects with the following PCS abnormal liver function
test will be summarized:

ALT ≥3×ULN, ≥5×ULN, ≥10×ULN, and ≥20×ULN

AST ≥3×ULN, ≥5×ULN, ≥10×ULN, and ≥20×ULN

ALT or AST ≥3×ULN, ≥5×ULN, ≥10×ULN, and ≥20×ULN


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
Total bilirubin ≥1.5×ULN and ≥2×ULN

ALP ≥1.5×ULN and ≥3×ULN

ALT or AST ≥3×ULN and Total bilirubin ≥2×ULN

Potential Hy’s Law cases: ALT or AST ≥3×ULN, Total bilirubin ≥2×ULN, and
ALP ≤2×ULN
A listing of subjects with any post-baseline abnormal liver function tests will be presented.
All clinical laboratory data will be listed. Values outside the normal ranges will be flagged.
7.13.5.
Physical Examinations
A complete physical examination will be performed at the Screening Visit and as deemed
necessary by the Investigator and will include, at a minimum, a pulmonary examination
(including auscultation) and assessments of the skin, abdomen, cardiovascular,
gastrointestinal, and neurological systems. Body weight and height will also be measured.
A limited physical examination will be performed at the Randomization Visit, daily during
the Monitoring Period, on Day 22, on the day of hospital discharge (for subjects who are
discharged between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs
onsite), or Early Termination (if applicable).
The limited physical examination will
include, at a minimum, a pulmonary examination (including auscultation).
All abnormal physical examination findings will be listed by subject.
7.13.6.
Radiographs and Imaging
A chest X-ray or thoracic CT scan is required on 4 occasions during the study as defined
below for (1) initial Screening Visit, (2) Randomization Visit, (3) Post-BAL sampling for
those subjects participating in the optional BAL sub-study, and (4) Monitoring Period (Day
2 through Day 22) for those subjects presenting with signs/symptoms suggestive of a
respiratory infection.
Imaging should be conducted per institutional guidelines and assessed by the Investigator.
The results of radiographs or imaging obtained at the Screening Visit and any subsequent
visits should be documented on the appropriate eCRF. Radiograph or imaging reports and
films will be collected for future analysis and will be uploaded within the EDC system.
All Radiographs and Imaging data will be listed by subject.


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7.13.7.
Immunogenicity
Samples to evaluate anti-drug antibody response, including neutralizing antibodies, to
ASN-1 and ASN-2 will be collected from all subjects at the Randomization Visit (Day 1
pre-dose), upon discharge from the ICU (if discharge occurs prior to Day 22), on Day 22,
on the day of hospital discharge (for subjects who are discharged between Day 40 and Day
90), and at the Day 90 Safety Visit (if the visit occurs onsite).
Subjects who discontinue early or are withdrawn from the study should also have samples
collected as part of their Early Termination Visit. These samples will be sent to the central
laboratory for analysis.
Samples will be screened for antibodies binding to ASN-1 and ASN-2 and the titer of
confirmed positive samples will be reported. Other analyses may be performed to verify
the neutralizing ability of antibodies to ASN-1 or ASN-2 and/or to further characterize the
immunogenicity of ASN-1 and ASN-2.
All anti-drug antibody data will be listed by subject.
The statistical analyses for ADA data will be performed by another vendor and described
in a standalone analysis plan. The results will reside in a separate analytical report, which
will be appended to the CSR.


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8.
GENERAL INFORMATION
8.1.
Statistical Software
The creation of analysis datasets and statistical analyses will be done using SAS® version
9.3 or higher. The Medpace standard operating procedures (Medpace documents GL-DS-
02-S2.1 and GL-DS-03-S1) will be followed for the validation of all SAS programs and
outputs.
8.2.
Format of Tables, Listings, and Figures
The format of tables, listings, and figures will be described in a stand-alone programming
specifications document and will be finalized before database lock for the study.


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9.
CHANGES FROM PROTOCOL SPECIFIED ANALYSIS
The following analysis have been added which are not described in the protocol.
The primary efficacy analysis, based on comparing two proportions of subjects who
develop S. aureus pneumonia by SDO2 up to but not including Day 22.
The Kaplan-Meier analysis will be performed for the proportion of subjects who develop
S. aureus pneumonia up to but not including Day 22 as determined by the SDO1.
The Kaplan-Meier analysis will be performed for the proportion of subjects who develop
S. aureus pneumonia by up to but not including Day 22 as determined by the SDO1 and
the Review Meeting’s determination of S. aureus as a causative pneumonia pathogen.
The Kaplan-Meier analysis will be performed for the proportion of subjects who develop
S. aureus pneumonia up to but not including Day 22 as determined by SDO2 and the
Review Meeting’s determination of S. aureus as a causative pneumonia pathogen.
The Kaplan-Meier analysis will be performed for the proportion of subjects who develop
S. aureus pneumonia up to but not including Day 22 as determined by the Investigator’s
judgement and the Review Meeting’s determination of S. aureus as a causative pneumonia
pathogen.
An additional Kaplan-Meier analysis will be conducted for subjects with S. aureus
pneumonia and presumed S. aureus pneumonia by SDO1 and SDO2.  The presumed S.
aureus pneumonia population includes those subjects with microbiologic results “Not
Done” up to and including Day 7 (presumed S. aureus pneumonia).
A third Kaplan-Meier analysis will be conducted for subjects with S. aureus pneumonia
including those subjects with microbiologic results “Not Done” up to and including Day
10 (presumed S. aureus pneumonia) for both SDO1 and SDO2 populations.
The proportion of subjects who develop S. aureus pneumonia up to but not including Day
22 as determined by the Investigator’s judgement and the Review Meeting’s determination
of S. aureus as a causative pneumonia pathogen will be obtained from Kaplan-Meier
estimates for each treatment group.  Discontinuation from the study due to any cause up to
but not including Day 22 will be considered as an ‘Event’.
The proportion of subjects who develop S. aureus pneumonia up to but not including Day
22 as determined by the Investigator’s judgement and the Review Meeting’s determination
of S. aureus as a causative pneumonia pathogen will be obtained from Kaplan-Meier
estimates for each treatment group incorporating censoring. Discontinuation from the study
due to any cause up to but not including Day 22 will be considered censored.
The proportion of subjects who develop either S. aureus pneumonia by Day 21 as
determined by the Investigator’s judgement and the Review Meeting’s determination of S.
aureus as a causative pneumonia or another S. aureus infection up to but not including Day
22
will be obtained from Kaplan-Meier estimates for each treatment group.
Discontinuation from the study due to any cause up to but not includingDay 22 will be
considered as an ‘Event’.


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The proportion of subjects who develop either S. aureus pneumonia as determined by the
Investigator’s judgement and the Review Meeting’s determination of S. aureus as a
causative pneumonia or another S. aureus infection up to but not including Day 22 will be
obtained from Kaplan-Meier estimates for each treatment group incorporating censoring.
Discontinuation from the study due to any cause prior to Day 22 will be considered
censored.
The proportion of subjects who develop S. aureus pneumonia by Day 90 as determined by
the Investigator’s judgement will be obtained from Kaplan-Meier estimates for each
treatment group.  Discontinuation from the study due to any cause prior to Day 90 will be
considered as an ‘Event’.
The proportion of subjects who develop S. aureus pneumonia by Day 90 as determined by
the Investigator’s judgement will be obtained from Kaplan-Meier estimates for each
treatment group incorporating censoring.  Discontinuation from the study due to any cause
prior to Day 90 will be considered censored.
Mechanical ventilation free days and ICU free days during the first 21 days, or prior to
death, or early termination post randomization will be summarized descriptively and
compared between treatment groups using a Wilcoxon rank sum test in the MITT, ITT,
and PP Populations.
Summary of pneumonia free days for subjects with S. aureus pneumonias and for subjects
with all pneumonias in the MITT and PP Populations.
Summary of All-cause mortality rate at Day 28 for subjects with any pneumonia in the
MITT and PP Populations.

Prot_001.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Determine the Safety and Efficacy of a Single Dose of ASN100 for 
the Prevention of Staphylococcus aureus Pneumonia in Heavily 
Colonized, Mechanically Ventilated Subjects  
 
Investigational Product: ASN100 
Protocol Number: ASN100-201 
IND Number: 128766 
EudraCT Number: 2016-002146-23 
 
Sponsor: 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA  
02451-1472 
 Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 
 
Version Number: 4.1 (Site Specific Amendment) 
Date: 23 April 2018 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Arsanis, Inc. except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Arsanis, Inc. You are allowed to 
disclose the contents of this document only to your Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed/notified that the 
protocol content is confidential and proprietary to Arsanis, Inc. and that it may not be further 
disclosed to third parties. 










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Version 4.1, 23 April 2018 (Site Specific Amendment) 
3
INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Arsanis, Inc. (Arsanis) to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study procedures. I will 
let them know that this information is confidential and proprietary to Arsanis and that it may not 
be further disclosed to third parties. I understand that the study may be terminated or enrollment 
suspended at any time by Arsanis, with or without cause, or by me if it becomes necessary to 
protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with the United States Food and Drug 
Administration (FDA) Regulations, Institutional Review Board/Ethic Committee Regulations and 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  


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SYNOPSIS 
TITLE:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Determine the 
Safety and Efficacy of a Single Dose of ASN100 for the Prevention of Staphylococcus aureus 
Pneumonia in Heavily Colonized, Mechanically Ventilated Subjects 
PROTOCOL NUMBER:  ASN100-201 
INVESTIGATIONAL PRODUCT:  ASN100 
PHASE:  2 
INDICATION:  The prevention of Staphylococcus aureus (S. aureus) pneumonia in 
mechanically ventilated subjects who are heavily colonized with S. aureus. 
STUDY DEFINITION:  For the purposes of this study, heavy colonization of S. aureus will be 
defined as a quantitative threshold of ≥105 CFU/mL or 3+ to 4+ by semi-quantitative culture from 
an endotracheal aspirate. 
OBJECTIVES: 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of a single 
dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus. 
The secondary objectives of this study are: 
• To compare the duration of mechanical ventilation post-treatment in subjects treated with 
ASN100 versus placebo;  
• To compare the length of stay in the intensive care unit (ICU) post-treatment for subjects 
treated with ASN100 versus placebo;  
• To determine the serum pharmacokinetics (PK) (i.e., maximum serum concentration 
[Cmax], time to maximum serum concentration [Tmax], area under the serum concentration-
time curve [AUC], and terminal elimination half-life [t1/2]) of ASN-1 and ASN-2 in 
mechanically ventilated subjects heavily colonized with S. aureus; and 
• To compare 28-day all-cause mortality in subjects treated with ASN100 versus placebo. 
The exploratory objectives are: 
• To compare the incidence of hospital-acquired bacterial pneumonia (HABP) occurring 
>48 hours post-extubation up to but not including Day 22 in extubated subjects treated 
with ASN100 versus placebo; 
• To compare the incidence of ventilator-associated bacterial pneumonia (VABP) up to but 
not including Day 22 in subjects treated with ASN100 versus placebo; 


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• To determine the immunogenicity of a single dose of ASN100; 
• To compare the incidence of other S. aureus-associated infections which occur after 
dosing up to but not including Day 22 in subjects treated with ASN100 versus placebo; 
and 
• To assess ASN-1 and ASN-2 levels in bronchoalveolar lavage (BAL) fluid and calculate 
a blood to epithelial lining fluid (ELF) ratio in those subjects participating in the BAL 
fluid PK sub-study. 
POPULATION: 
Inclusion Criteria 
Subjects must meet all of the following criteria at the Screening and Randomization Visits in order 
to be eligible for randomization into the study: 
1. Subject, legally authorized representative, or council of independent physicians (CIP) (if 
applicable) has provided written informed consent; 
2. Subject is ≥18 years of age at the time of enrollment; 
3. Subject is currently hospitalized and is mechanically ventilated endotracheally 
(i.e., orotracheal or nasotracheal) and, in the Investigator’s opinion, will require ongoing 
ventilator support for at least 48 hours; 
NOTE: Subjects with a tracheostomy at the time of enrollment are not eligible. After 
enrollment, conversion to tracheostomy is permitted per standard of care. 
4. Female subjects must not be pregnant or lactating. Female subjects of childbearing potential 
must have a documented negative pregnancy test at the Screening Visit. Female subjects may 
be enrolled on the basis of a negative urine pregnancy test, pending the result of a negative 
serum pregnancy test prior to randomization; and 
5. Female subjects of childbearing potential and non-surgically sterile male subjects who are 
sexually active must agree to use an approved highly effective form of contraception from the 
time of informed consent until 165 days post-dose. Approved forms of contraception include 
hormonal intrauterine devices, hormonal contraceptives (oral birth control pill, depo, patch, or 
injectable) together with supplementary double barrier methods such as condoms or 
diaphragms with spermicidal gel or foam. 
NOTE: The following categories define women who are NOT considered to be of childbearing 
potential: 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy, 
o Documented bilateral salpingectomy, or 
o Documented bilateral oophorectomy, or 
• Postmenopausal female, defined as having amenorrhea for at least 12 months without an 
alternative medical cause.  


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Exclusion Criteria 
Subjects who meet any of the following criteria at the Screening and/or Randomization Visit will 
be excluded from participation in the study: 
1. Subject has received intravenous (IV) immunoglobulin therapy within 4 months prior to the 
Screening Visit; 
2. Subject has a chest X-ray or thoracic computed tomography (CT) scan that is definitive for a 
diagnosis of pneumonia; 
3. Subject demonstrates both of the following: 
a. Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
positive end-expiratory pressure; AND 
NOTE: Changes made in ventilator support due to day-to-day maintenance other than 
those changes made to improve oxygenation will not exclude a subject from participation 
in the study. 
b. New onset of purulent suctioned respiratory secretions; 
4. Subject has a known and documented ETA culture showing heavy colonization with a 
Gram-negative organism at enrollment or at any time during the Screening period; 
NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
5. Subject has been diagnosed with neutropenia (absolute neutrophil count <500/mm3); 
6. Subject has a severe non-pulmonary source of infection which, in the Investigator’s opinion, 
would interfere with the conduct of the study or jeopardize the subject’s safety; 
7. Subject is currently on either continuous veno-venous hemodialysis or extracorporeal 
membrane oxygenation; 
8. Subject has been previously exposed to ASN100 or ASN-1 or ASN-2, individually; 
9. Subject has a known hypersensitivity to ASN100 or any of its excipients; 
10. Subject has received any investigational product within 30 days prior to the Screening Visit 
(or 5 half-lives of the investigational product, whichever is longer); 
11. Subject has, in the opinion of the Investigator, a high probability of death within 72 hours of 
enrollment;  
12. Subject is, in the opinion of the Investigator, not able or willing to comply with the protocol;  
13. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
subject, the potential activity of the study drug, or the quality of the data; or 
14. Subjects with a known history or current (suspected) diagnosis of cytokine release syndrome 
associated with the administration of peptides, proteins, and/or antibodies.20 
NOTE: Subjects with a prior history of sepsis are not excluded. 
 


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Randomization Criteria 
At the Randomization Visit, subjects must meet all of the following requirements to be 
randomized into the study: 
1. Subject continues to meet all of the inclusion criteria and none of the exclusion criteria 
required at the Screening Visit; 
NOTE: Subjects who undergo tracheostomy after enrollment are still eligible for 
randomization, provided they remain mechanically ventilated (see criterion 3 below). 
2. Subject is heavily colonized with S. aureus as determined by either quantitative or 
semi-quantitative culture of an endotracheal aspirate (ETA);  
NOTE: The results of the qualifying ETA culture must allow randomization to occur within 
48 hours (or up to 60 hours with Medical Monitor approval) from the time the ETA sample 
was collected. Subjects with ETA culture results obtained after 60 hours showing heavy 
colonization of S. aureus may not be randomized and will be discontinued from the study. 
3. Subject remains mechanically ventilated and, in the Investigator’s opinion, will require 
ongoing ventilator support for at least 48 hours; and 
4. Subject has, in the opinion of the Investigator, a probability of survival beyond 72 hours 
post-randomization. 
STUDY DESIGN AND DURATION: 
This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus. Subjects will be screened for eligibility; once an Informed Consent Form is signed 
(or, in countries where it is applicable, a decision is made by the CIP), and all entry criteria are 
met, a subject is considered to be enrolled in the study. All enrolled subjects will undergo an 
observational stage evaluating endotracheal colonization. Subjects who are randomized will 
undergo a treatment, monitoring, and follow-up period. 
Approximately 2250 eligible subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be screened daily (while mechanically ventilated) for up to 8 days to 
identify those subjects who are heavily colonized with S. aureus.  
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 
14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the 
Investigator and providing the subject remains mechanically ventilated.  
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or 
semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of 
methicillin-susceptible S. aureus and methicillin-resistant S. aureus (e.g., CHROMagarTM Staph 
aureus) for more rapid and specific detection of S. aureus. If the site is not able to obtain 
chromogenic media for S. aureus, appropriate chromogenic media may be supplied by the 
Sponsor.  


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Semi-quantitative cultures using chromogenic media are preferred for determination of eligibility 
for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to 
randomize the subject within 48 hours (or up to 60 hours with Medical Monitor approval) from 
the time the ETA sample was collected. 
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for 
randomization. If they are not randomized on this occasion according to the protocol, they are no 
longer eligible for continued ETA sampling and randomization, and will be discontinued from the 
study; however, if subjects are extubated and subsequently re-intubated/mechanically ventilated, 
they are eligible for re-screening as a new subject enrollment. Subjects who were previously 
randomized are not eligible to be re-consented and re-screened. 
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into the study; however, 
randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
Nasal swab specimens (one from each nostril) will be obtained at the Randomization Visit and 
will be cultured by the central microbiology laboratory. Results from the nasal swab specimen 
cultures will be used to assess correlation with results of the qualifying ETA culture. 
Upon determination of eligibility, approximately 354 subjects will be randomized in a 1:1 ratio to 
1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate IV infusions of 
ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
To ensure balance among the treatment groups, randomization for this study will be stratified by 
receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the time of randomization 
that are potentially active against S. aureus pneumonia, including, but not limited to, nafcillin, 
oxacillin, vancomycin, linezolid, telavancin, ceftaroline, ceftobiprole, and teicoplanin. 
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg of 
ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-2) or 
matching placebos, per their assigned randomization scheme.  
Randomized subjects will be monitored daily for the signs and symptoms of pneumonia and other 
S. aureus-associated infections while hospitalized up to Day 21. 
All randomized subjects will undergo a study visit on Day 22 (+2 days). A follow-up visit will 
occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the 
subject is no longer hospitalized.  
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they 
receive study treatment, a follow-up safety visit will be performed on the day of discharge. 
All randomized subjects will return for a Safety Visit on Day 90 (±7 days) (if the subject is unable 
to return to the site, this visit may be conducted by telephone). Subjects who discontinue the study 


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prior to Day 22 will undergo an Early Termination Visit. The end of the study will occur upon 
completion of the last Day 90 visit by the last subject. 
Safety assessments for this study will include adverse event monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), chest X-rays and/or 
thoracic CT scans, and the determination of the presence of ASN-1 and ASN-2 anti-drug 
antibodies (ADAs). Additional safety assessments may be performed throughout the duration of 
the study if clinically indicated. 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), on the day 
of diagnosis of pneumonia (if applicable), and on Day 22 or Early Termination (if applicable). 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. Blood 
samples for PK analysis will be collected immediately following the completion of the second 
infusion (+15 minutes) and at 6 hours (± 4 hours) and 24 hours (±6 hours) post-dose following the 
second infusion. In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 
7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will 
be collected on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 
(if hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable). 
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25 to 
35 subjects who volunteer will participate in this sub-study and will have BAL fluid collected 
48 hours (±36 hours) post-dose (on approximately Day 2 or Day 3, depending on time of study 
drug administration) to determine ASN-1 and ASN-2 levels and blood to ELF ratio. Subjects 
participating in the BAL fluid PK sub-study will have a blood sample collected for PK 
measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection 
or if BAL fluid is collected as part of a standard of care procedure from any subject enrolled in 
the sub-study at any time post-randomization). 
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined and no 
genetic information will be extracted from these samples. Samples will be destroyed following 
the completion of all S. aureus anti-toxin antibody analyses. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
ASN100 is a combination product with 2 separate human monoclonal antibody (mAb) 
components of the immunoglobulin G1 isotype. The specific mAbs are formulated separately and 
called ASN-1 and ASN-2. Each component is supplied as a sterile, colorless, clear liquid solution 
formulated ready for injection. 
ASN-1 is a broadly cross-reactive anti-toxin mAb that targets alpha hemolysin and 
3 F-components (gamma hemolysin B, leukocidin F, and leukocidin D) involved in forming 4 of 
the 5 bi-component leukocidins of S. aureus. 
ASN-2 is directed against the fifth bi-component toxin of S. aureus, leukocidin GH. 
ASN-1 and ASN-2 will be supplied in separate 10 mL vials as a sterile solution for infusion with 
an extractable volume of 10 mL and a nominal mAb concentration of 20 mg/mL. Each vial will 


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contain 200 mg of ASN-1 or 200 mg of ASN-2. Matched vials of ASN-1 placebo and 
ASN-2 placebo will also be provided. 
ASN100 will be administered as separate infusions of 1800 mg ASN-1 and 1800 mg ASN-2 
(9 vials of each to be pooled aseptically according to the Pharmacy Manual into separate infusion 
bags) delivered either sequentially within a 3-hour window from the time of initiation of the first 
infusion to the completion of the second infusion, or simultaneously. 
Placebo will be administered as separate infusions of 9 vials of ASN-1 placebo and 9 vials of 
ASN-2 placebo (vials to be pooled aseptically according to the Pharmacy Manual into separate 
infusion bags) delivered either sequentially within a 3-hour window from the time of initiation of 
the first infusion to the completion of the second infusion, or simultaneously. 
ANALYSIS POPULATIONS: 
Intent-to-Treat (ITT) Population 
The ITT Population includes all subjects who are randomized to receive study drug.  
Modified Intent-to-Treat (MITT) Population 
The MITT Population includes all subjects in the ITT Population who receive study drug who are 
heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an 
ETA. 
Per Protocol (PP) Population 
The PP Population includes all subjects in the MITT Population who also meet the following 
criteria: 
• Do not have any major protocol violations that would affect assessment of efficacy, and 
• Complete an adequate number of Monitoring Period assessments through and including 
Day 22. 
Pharmacokinetic (PK) Population 
The PK Population includes all subjects in the MITT Population with at least 1 serum PK sample 
collected post-dose. 
Safety Population 
The Safety Population includes all subjects who receive any amount of study drug and have at 
least 1 post-treatment safety assessment. 
EFFICACY VARIABLES:  
The primary efficacy endpoint is the proportion of subjects in the MITT Population who develop 
S. aureus pneumonia up to but not including Day 22. 
The secondary efficacy endpoints include: 
• Duration of mechanical ventilation during the first 21 days post-randomization for subjects 
in the MITT, ITT, and PP Populations; 


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• Length of ICU stay during the first 21 days post-randomization for subjects in the MITT, 
ITT, and PP Populations;  
• The Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single dose of 
ASN100 in the PK Population; and 
• 28-day all-cause mortality in the MITT, ITT, and PP Populations. 
Exploratory efficacy endpoints include: 
• Proportion of subjects in the MITT and PP Populations with a diagnosis of HABP at 
>48 hours post-extubation up to but not including Day 22 in extubated subjects; 
• Proportion of subjects in the MITT and PP Populations with development of VABP up to 
but not including Day 22; 
• Incidence of all bacterial pneumonias in the MITT, ITT, and PP Populations; 
• Incidence of other non-S. aureus pneumonias up to but not including Day 22 in the MITT, 
ITT, and PP Populations; and  
• Incidence of other S. aureus infections acquired following study drug administration up 
to but not including Day 22 in the MITT, ITT, and PP Populations. 
MICROBIOLOGICAL AND CLINICAL ASSESSMENTS: 
ETA specimens will be collected for culture during Screening/Enrollment to determine the degree 
of S. aureus colonization. Additional respiratory specimens may be collected for culture 
throughout the Monitoring Period or Early Termination (if applicable) if clinically indicated 
according to standard of care. 
If, as part of routine standard of care, additional respiratory and/or other microbiological 
specimens are collected for culture during the study, results will be documented within the 
electronic Case Report Form. As fully described within the study laboratory manual, bacterial 
isolates recovered from these specimens that are deemed pathogens by the Investigator (if retained 
and available at the study site local microbiology laboratory) will be sent to a central microbiology 
laboratory for confirmation of pathogen identification (all isolates) and susceptibility testing 
(S. aureus isolates only). 
During the Monitoring Period, a diagnosis of S. aureus pneumonia will be determined if subjects 
have S. aureus identified from an adequate respiratory specimen and clinical signs and symptoms 
of pneumonia. For a diagnosis of S. aureus pneumonia, clinical signs and symptoms must occur 
±2 days from the time of collection of an adequate respiratory specimen culture that is positive for 
S. aureus.  
• For intubated subjects, a respiratory specimen obtained by BAL, non-bronchoscopic BAL, 
or protected specimen brush will be considered an adequate respiratory specimen; or 
• For extubated subjects, an adequate expectorated/induced sputum specimen is defined as 
<10 squamous epithelial cells and >25 polymorphonuclear cells/100× field; and 


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• For both intubated and extubated subjects, adequate respiratory specimens will undergo 
either semi-quantitative or quantitative culture in accordance with the local laboratory’s 
standard procedure. 
Subjects will be assessed daily throughout the Monitoring Period for the following clinical signs 
and symptoms: 
Clinical Signs and Symptoms 
Mechanically Ventilated Subjects 
Non-Mechanically Ventilated Subjects 
• 
Cough, 
• 
Rales, 
• 
Dullness on percussion,* 
• 
Bronchial breath sounds, 
• 
Egophony,* 
• 
Need for suctioning, 
• 
Need for ventilator support, and 
• 
Fever ≥38°C (≥100.4°F). 
• 
Cough, 
• 
Rales, 
• 
Dullness on 
percussion,* 
• 
Bronchial breath 
sounds, 
• 
Egophony,* 
• 
Dyspnea, 
• 
Tachypnea, 
• 
Respiratory rate, 
• 
Hypoxemia, and 
• 
Fever ≥38°C 
(≥100.4°F). 
*If routinely performed. 
A diagnosis of pneumonia (HABP or VABP) will be determined as defined below: 
Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia 
Indication 
Definition 
HABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed by the 
Investigator);  
• 
At least ONE of the following: 
o 
Has been hospitalized for >48 hours, or 
o 
Developed clinical signs and symptoms within 7 days following hospital discharge; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the requirement for 
mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
VABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed by the 
Investigator);  
• 
Subject has received mechanical ventilation via an endotracheal or nasotracheal tube for ≥48 hours; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the requirement for 
mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
HABP = hospital-acquired bacterial pneumonia; PEEP = positive end-expiratory pressure; VABP = ventilator-associated bacterial 
pneumonia; WBC = white blood cell. 
 


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PHARMACOKINETIC VARIABLES: 
The primary PK endpoints are the Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum 
following a single IV dose of ASN100 in the PK Population. 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. At the 
completion of the second infusion, blood samples for PK analysis will be collected immediately 
following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 
24 hours (±6 hours) post-dose. 
In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 
14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected 
on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 (if 
hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable). 
Subjects participating in the BAL fluid PK sub-study will have a blood sample collected for PK 
measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection 
or if BAL fluid is collected as part of a standard of care procedure from any subject enrolled in 
the sub-study at any time post-randomization). 
In order to maintain the study blind, all subjects, including those randomized to receive placebo, 
will have PK samples obtained at the above time points. 
The levels of ASN-1 and ASN-2 will be measured in BAL fluid in a PK sub-study (to include 
approximately 25 to 35 subjects who volunteer) which will allow the calculation of a blood to ELF 
ratio. Subjects participating in this sub-study will have BAL fluid collected 48 hours (±36 hours) 
post-dose (on approximately Day 2 or Day 3, depending on time of study drug administration) to 
determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid is collected as part of a 
standard of care procedure from any subject enrolled in the sub-study at any other time 
post-randomization for any other reason, if possible, a sample for PK analysis will also be 
obtained.  
SAFETY VARIABLES: 
Safety variables for this study will include adverse event monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead ECGs, chest X-rays and/or thoracic CT scans, and 
the determination of the presence of ASN-1 and ASN-2 (i.e., ASN100) ADAs.  
STATISTICAL ANALYSES: 
Continuous variables will be summarized by using the number of non-missing observations, 
arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive 
statistics. Categorical variables will be summarized by using the frequency count and the 
percentage of subjects in each category as descriptive statistics.  
All statistical tests will be performed at the 0.05 significance level using 2-sided tests, except 
where otherwise noted. 
The primary efficacy endpoint is whether the subject has developed S. aureus pneumonia up to 
but not including Day 22. The summary measure for efficacy is the proportion of subjects in the 
MITT Population who develop S. aureus pneumonia up to but not including Day 22. Analysis for 


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the primary endpoint will compare the proportion of subjects who develop S. aureus pneumonia 
in the ASN100 arm versus the placebo arm in the MITT Population. The statistical test for 
comparing 2 event rates is based on a 2-sided test with a false positive rate of 5%.  
Analyses of the primary efficacy endpoint will also be performed separately for the ITT and 
PP Populations. 
Duration of mechanical ventilation and length of hospital ICU stay during the first 21 days 
post-randomization will be compared between treatment groups using a Wilcoxon rank sum test. 
Other efficacy endpoints will be summarized by treatment group. 
All subjects in the Safety Population will be included in the safety analyses and analyzed based 
on the actual treatment received. 
One interim analysis will be conducted during the study, when approximately 125 subjects have 
reached Day 22. The interim analysis is for futility assessment of the study, and for a potential 
study sample size adjustment based on an overall blinded efficacy evaluation pooled across the 
treatment arms. Based on this assessment, the sample size may be increased. The interim analysis 
of futility assessment will be reviewed by an independent Data Review Committee (DRC).  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
Treatment-emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred term. A TEAE is defined as an adverse event with a start date and time on or after the 
first dose of study treatment. Listings will be provided for serious adverse events and adverse 
events leading to drug discontinuation. In addition, all adverse events will be listed. 
Safety laboratory data and vital signs will be presented by each scheduled time point and for 
change from baseline to each time point. The results of all laboratory tests, physical examination 
findings, vital signs, and ADAs will be presented in data listings. 
Descriptive statistics will be provided for all PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population. Subject PK profiles will be determined using 
parameters such as Cmax, Tmax, AUC, and t1/2 for each of ASN-1 and ASN-2 in serum. Epithelial 
lining fluid PK will also be analyzed and an ELF/serum PK ratio will be calculated. 
SAMPLE SIZE DETERMINATION: 
The estimated incidence of progression to S. aureus pneumonia in mechanically ventilated 
subjects with heavy colonization is approximately 25% within 22 days of randomization.  
Assuming a 2-sided significance level of 0.05 and a desired power of 80% to detect a significant 
difference between S. aureus pneumonia incidence rates of 25% in the placebo group and 12.5% 
in the ASN100 treatment group (50% reduction), 152 evaluable subjects are required in each 
treatment group. A sample size of 304 subjects (152 subjects per treatment group) will yield 
80% power to detect a 50% reduction in the incidence of S. aureus pneumonia with ASN100 
treatment when assuming a 25% incidence rate of S. aureus pneumonia in placebo-treated 
subjects. Assuming a 14% non-evaluable rate, approximately 354 subjects (177 subjects per 
treatment group) will be randomized. Assuming the screen failure rate is about 84%, 
approximately 2250 subjects will be screened. 


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SITES:  Approximately 70 global sites. 
SPONSOR: 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA  
02451-1472 
Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 


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TABLE OF CONTENTS 
 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................. 16 
LIST OF TABLES ........................................................................................................................ 21 
LIST OF FIGURES ...................................................................................................................... 22 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 23 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 25 
1.1 
Background ................................................................................................................. 25 
1.2 
Rationale ..................................................................................................................... 26 
1.3 
Risk/Benefit ................................................................................................................ 27 
2 
STUDY OBJECTIVES ..................................................................................................... 29 
2.1 
Primary Objective ....................................................................................................... 29 
2.2 
Secondary Objectives.................................................................................................. 29 
2.3 
Exploratory Objectives ............................................................................................... 29 
3 
STUDY DESCRIPTION .................................................................................................. 30 
3.1 
Definition of Heavy Colonization ............................................................................... 30 
3.2 
Summary of Study Design .......................................................................................... 30 
Figure 1. Study Schematic ............................................................................................................ 30 
3.3 
Study Indication .......................................................................................................... 33 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 34 
4.1 
Inclusion Criteria ........................................................................................................ 34 
4.2 
Exclusion Criteria ....................................................................................................... 34 
4.3 
Randomization Criteria ............................................................................................... 35 
4.4 
Withdrawal Criteria .................................................................................................... 36 
5 
STUDY TREATMENTS .................................................................................................. 38 
5.1 
Treatment Groups ....................................................................................................... 38 
5.2 
Stratification ................................................................................................................ 38 
5.3 
Rationale for Dosing ................................................................................................... 38 


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5.4 
Randomization and Blinding ...................................................................................... 39 
5.5 
Breaking the Blind ...................................................................................................... 39 
5.6 
Drug Supplies.............................................................................................................. 39 
5.6.1 Formulation and Packaging .................................................................................. 39 
5.6.2 Study Drug Preparation and Dispensing ............................................................... 40 
5.6.3 Study Drug Administration ................................................................................... 40 
5.6.4 Treatment Compliance .......................................................................................... 41 
5.6.5 Storage and Accountability ................................................................................... 41 
5.7 
Prior and Concomitant Medications and/or Procedures ............................................. 41 
5.7.1 Excluded Medications and/or Procedures ............................................................. 41 
5.7.2 Documentation of Prior and Concomitant Medication Use .................................. 41 
6 
STUDY PROCEDURES .................................................................................................. 42 
6.1 
Informed Consent........................................................................................................ 42 
6.2 
Screening/Enrollment (Up to Day -14) ....................................................................... 42 
6.3 
Randomization Visit (Day 1 Pre-Dose) ...................................................................... 43 
6.4 
Treatment Period (Day 1) ........................................................................................... 44 
6.5 
Monitoring Period ....................................................................................................... 44 
6.5.1 Day 2/Day 3 – Bronchoalveolar Lavage Fluid Pharmacokinetic Sub-Study ....... 44 
6.5.2 Day 2 to Day 21 .................................................................................................... 45 
6.5.3 Day 22 ................................................................................................................... 46 
6.6 
Follow-Up Period........................................................................................................ 47 
6.6.1 Day 28 (+2 Days) Follow-Up ............................................................................... 47 
6.6.2 Day 40 to Day 89 (Follow-Up Safety Visit) ......................................................... 47 
6.6.3 Safety Visit (Day 90 [±7 Days]) ........................................................................... 47 
6.7 
Early Termination Visit and Withdrawal Procedures ................................................. 48 
7 
EFFICACY ASSESSMENTS .......................................................................................... 49 
7.1 
Primary Efficacy Endpoint ......................................................................................... 49 
7.2 
Secondary Efficacy Endpoints .................................................................................... 49 
7.3 
Exploratory Efficacy Endpoints .................................................................................. 49 
7.4 
Microbiological and Clinical Assessments ................................................................. 50 
7.4.1 Microbiological Assessment ................................................................................. 50 
7.4.2 Assessment of Clinical Signs and Symptoms ....................................................... 50 


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Table 1. Clinical Signs and Symptoms ......................................................................................... 50 
Table 2. Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia ........ 51 
8 
PHARMACOKINETIC ASSESSMENTS ....................................................................... 52 
8.1 
Pharmacokinetic Endpoint .......................................................................................... 52 
8.2 
Pharmacokinetic Assessments .................................................................................... 52 
8.2.1 Serum Pharmacokinetic Sampling ........................................................................ 52 
8.2.2 Bronchoalveolar Lavage Fluid Pharmacokinetic Sampling ................................. 53 
8.2.3 Analysis of Anti-Staphylococcus aureus Toxin Antibody Titers ......................... 53 
9 
SAFETY ASSESSMENTS ............................................................................................... 54 
9.1 
Adverse Events ........................................................................................................... 54 
9.1.1 Adverse (Drug) Reaction ...................................................................................... 55 
9.1.2 Unexpected Adverse Drug Reaction ..................................................................... 55 
9.1.3 Assessment of Adverse Events by the Investigator .............................................. 55 
9.2 
Serious Adverse Events .............................................................................................. 56 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators.............................. 57 
9.4 
Pregnancy Reporting ................................................................................................... 58 
9.5 
Expedited Reporting ................................................................................................... 58 
9.6 
Clinical Laboratory Evaluations ................................................................................. 58 
9.7 
Radiographs and Imaging ........................................................................................... 59 
9.8 
Vital Signs ................................................................................................................... 59 
9.9 
Electrocardiograms ..................................................................................................... 60 
9.10 
Physical Examinations ................................................................................................ 60 
9.11 
Immunogenicity .......................................................................................................... 60 
10 
STATISTICS .................................................................................................................... 61 
10.1 
Analysis Populations ................................................................................................... 61 
10.2 
Statistical Methods ...................................................................................................... 61 
10.2.1 Disposition ............................................................................................................ 61 
10.2.2 Demographic and Baseline Characteristics .......................................................... 61 
10.2.3 Analysis of Efficacy .............................................................................................. 62 
10.2.4 Analysis of Safety ................................................................................................. 62 
10.2.5 Analysis of Pharmacokinetics ............................................................................... 62 
10.2.6 Sample Size Determination................................................................................... 62 


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10.2.7 Interim Analysis .................................................................................................... 63 
11 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 64 
11.1 
Data Management ....................................................................................................... 64 
11.1.1 Data Handling ....................................................................................................... 64 
11.1.2 Computer Systems ................................................................................................ 64 
11.1.3 Data Entry ............................................................................................................. 64 
11.1.4 Medical Information Coding................................................................................. 64 
11.1.5 Data Validation ..................................................................................................... 64 
11.2 
Record Keeping .......................................................................................................... 64 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 65 
12.1 
Ethical Conduct of the Study ...................................................................................... 65 
12.2 
Institutional Review Board/Independent Ethics Committee....................................... 65 
12.3 
Informed Consent........................................................................................................ 65 
12.4 
Study Monitoring Requirements ................................................................................. 66 
12.5 
Protocol Deviations ..................................................................................................... 66 
12.6 
Disclosure of Data....................................................................................................... 67 
12.7 
Retention of Records................................................................................................... 67 
12.8 
Publication Policy ....................................................................................................... 67 
12.9 
Financial Disclosure.................................................................................................... 67 
12.10 Insurance and Indemnity ............................................................................................. 67 
12.11 Legal Aspects .............................................................................................................. 68 
13 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 69 
13.1 
Protocol Amendments ................................................................................................. 69 
13.2 
Address List ................................................................................................................ 69 
13.2.1 Sponsor ................................................................................................................. 69 
13.2.2 Global Contract Research Organization ............................................................... 69 
13.2.3 Drug Safety ........................................................................................................... 69 
13.2.4 Biological Specimens............................................................................................ 70 
13.2.5 Study Drug Packaging, Labeling, and Distribution .............................................. 70 


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14 
REFERENCES ................................................................................................................. 71 
Appendix A: Schedule of Procedures ........................................................................................... 73 
Appendix B: Clinical Laboratory Analytes .................................................................................. 77 
Appendix C: Site-Specific Sub-Study for Subjects Diagnosed with Pneumonia ......................... 78 
 
 
 
 


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LIST OF TABLES 
Table 1. 
Clinical Signs and Symptoms ..................................................................................... 50 
Table 2. 
Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia .... 51 
 
 


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LIST OF FIGURES  
Figure 1. Study Schematic.......................................................................................................... 30 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ALT 
Alanine aminotransferase 
ASN-1 
Broadly cross-reactive anti-toxin monoclonal antibody that targets
alpha hemolysin (Hla) and 3 F-components (HlgB, LukF, LukD)
involved in forming 4 of the 5 bi-component leukocidins of
Staphylococcus aureus 
ASN-2 
Anti-toxin monoclonal antibody that targets the fifth bi-component
toxin of Staphylococcus aureus, LukGH 
ASN100 
A combination of 2 fully human monoclonal antibodies (ASN-1 and 
ASN-2) 
AST 
Aspartate aminotransferase 
AUC 
Area under the serum concentration-time curve 
BAL 
Bronchoalveolar lavage 
CFR 
Code of Federal Regulations 
CFU 
Colony forming units 
CIP 
Council of independent physicians 
Cmax 
Maximum serum concentration 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CT 
Computed tomography 
CTA 
Clinical trial authorization 
DRC 
Data Review Committee 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ELF 
Epithelial lining fluid 
ET 
Early Termination 
ETA 
Endotracheal aspirate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HABP 
Hospital-acquired bacterial pneumonia 
Hla 
Alpha hemolysin 
HlgAB 
Gamma hemolysin AB 
HlgB 
Gamma hemolysin B 
HlgCB 
Gamma hemolysin CB 
ICF 
Informed Consent Form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous  
LAR 
Legally authorized representative 
LukD 
Leukocidin D 
LukED 
Leukocidin ED 
LukF 
Leukocidin F 
LukGH 
Leukocidin GH 
LukSF 
Leukocidin SF or Panton-Valentine Leukocidin 
mAb 
Monoclonal antibody 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat 
MRSA 
Methicillin-resistant Staphylococcus aureus 
MSSA 
Methicillin-susceptible Staphylococcus aureus 
NIMP 
Non-investigational medical product 
PCT 
Procalcitonin  
PD 
Pharmacodynamic  
PK 
Pharmacokinetic  
PMN 
Polymorphonuclear cell 
PP 
Per Protocol 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PVL 
Panton-Valentine Leukocidin or leukocidin SF 
RBC 
Red blood cell 
S. aureus 
Staphylococcus aureus 
SAE 
Serious adverse event  
t1/2 
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum serum concentration 
VABP 
Ventilator-associated bacterial pneumonia 
WBC 
White blood cell 


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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Staphylococcus aureus (S. aureus) is a human pathogenic bacterium that causes severe infections, 
including pneumonia and sepsis. Hospital-acquired bacterial pneumonia (HABP) caused by 
S. aureus, including ventilator-associated bacterial pneumonia (VABP) in mechanically ventilated 
patients, is a significant public health threat despite efforts to optimize antibiotic treatment. 
The primary exotoxins of S. aureus are alpha hemolysin (Hla), which damages lung epithelial 
cells, facilitating pneumonia and systemic bacterial invasion, and a group of exotoxins known as 
bi-component, pore-forming leukocidins.1,2 Staphylococcus aureus isolates are capable of 
producing up to 5 potent leukocidins: 2 gamma hemolysins (gamma hemolysin AB [HlgAB] and 
gamma hemolysin CB [HlgCB]), the Panton-Valentine Leukocidin (PVL or leukocidin SF 
[LukSF]), leukocidin ED (LukED), and leukocidin GH (LukGH). Alpha hemolysin, the gamma 
hemolysins, and LukGH genes are present in all clinical isolates; however, LukSF and LukED are 
found in approximately 5% to 10% and approximately 60% of strains, respectively. The most 
prevalent community-acquired methicillin-resistant S. aureus (MRSA) strain in the United States 
is the USA300 pulsotype, which possesses genes for all 5 of these potent leukocidins. 
Alpha hemolysin and the bi-component leukocidins bind to various cell surface receptors and this 
leads to cell type specific cytotoxicity. The combined effect of these exotoxins in staphylococcal 
pathogenesis is multifold:  
• Hla destroys the epithelial barrier by direct cytolysis;  
• Leukocidins target phagocytic cells for lysis, reducing the capacity of immune cells to 
eliminate S. aureus; and 
• All cytotoxins induce inflammatory responses that lead to further tissue damage. 
Inflammatory signals further enhance the susceptibility of human polymorphonuclear 
cells (PMNs) to lysis by LukGH rendering this toxin dominant among the S. aureus 
leukocidins in vitro.3 
Counteracting these functions of staphylococcal toxins by means of monoclonal antibodies (mAbs) 
may contribute to or induce the prevention and/or treatment of S. aureus pneumonia. 
ASN100 is a combination of 2 fully human mAbs (ASN-1 and ASN-2, both of the 
immunoglobulin G1 [IgG1] subclass) that target these exotoxins of S. aureus. ASN-1 is a broadly 
cross-reactive anti-toxin mAb that targets Hla and 3 F-components (gamma hemolysin B [HlgB], 
leukocidin F [LukF], and leukocidin D [LukD]) involved in forming 4 of the 5 bi-component 
leukocidins of S. aureus, while ASN-2 is directed against the fifth bi-component toxin of S. aureus, 
LukGH.4,5,6  
The 2 antibodies (i.e., ASN-1 and ASN-2) are dosed in a 1:1 ratio and operate as follows: 
• ASN-1 binds to and neutralizes Hla and 4 bi-component S. aureus cytotoxins 
(leukocidins): HlgAB, HlgCB, LukED, and LukSF (also known as PVL); and 
• ASN-2 binds to and neutralizes the fifth S. aureus leukocidin, LukGH. 
While ASN-1 and ASN-2 each provide partial protection of human phagocytic cells against a 
combination of staphylococcal exotoxins, the 2 mAbs act in synergy to prevent lysis of human 


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phagocytic cells in the presence of Hla and all 5 bi-component leukocidins. By neutralizing Hla 
and inactivating HlgAB, HlgCB, LukED, and LukSF, ASN-1 prevents the lysis of granulocytes 
(PMNs) caused by these leukocidins. ASN-1 demonstrated superior efficacy compared to 
Hla-neutralizing mAbs against S. aureus pneumonia in a rabbit in vivo model.7 By neutralizing 
LukGH, ASN-2 protects PMNs, monocytes, and macrophages from lysis. 
ASN100 (i.e., ASN-1 and ASN-2) has demonstrated potency and efficacy against a wide range of 
S. aureus strains in in vitro studies and in vivo models of S. aureus pneumonia.4,5 Collectively, 
these studies support the synergy of ASN-1 and ASN-2 and the need for both mAbs in ASN100 to 
protect patients in the clinical setting against the full range of S. aureus strains 
(methicillin-susceptible S. aureus [MSSA] and MRSA).  
1.2 
Rationale 
Published studies have demonstrated that microbiologic screening of mechanically ventilated 
patients to determine those who are heavily colonized with S. aureus increases the probability of 
correctly predicting those patients who will eventually develop S. aureus pneumonia.8,9 
Approximately one-third of heavily colonized mechanically ventilated patients progressed to 
S. aureus pneumonia and these same studies demonstrated that patients still develop S. aureus 
pneumonia despite treatment with potentially effective anti-staphylococcal antibiotics. Secondary 
analyses of these studies have shown that antibiotic treatment is ineffective in reducing S. aureus 
colonization in the lower airways and preventing ventilator-associated tracheobronchitis or VABP, 
and S. aureus seems to be in competition for colonization with the normal respiratory flora.10 
Staphylococcus aureus, particularly MRSA, is frequently identified as the causative pathogen of 
pneumonia and the incidence of healthcare-related MRSA pneumonia among hospitalized patients 
is increasing.11,12,13 According to the American Thoracic Society and the Infectious Diseases 
Society of America, MRSA is associated with >50% of intensive care unit (ICU) infections in the 
United States.14  
Despite the availability of microbiologically appropriate antibiotics, mortality in patients with 
S. aureus pneumonia remains high.15 No specific prevention strategies have proven effective 
against S. aureus pneumonia in mechanically ventilated patients. While general pneumonia 
prevention measures demonstrate efficacy in many cases, not all ICU types benefit from these 
efforts.17 Although reported pneumonia rates have decreased over time, the remaining S. aureus 
cases are unlikely to be prevented by non-specific measures.17,18  
Data from retrospective observational studies indicate that mechanically ventilated patients who 
have moderate to heavy colonization with S. aureus as determined by culture of endotracheal 
aspirate (ETA) specimens (i.e., ≥3+ by semi-quantitative culture) have a higher risk of developing 
pneumonia.8,19 As noted above, many of these patients still ultimately develop S. aureus 
pneumonia despite treatment with potentially effective antibiotics.  
The USA300 pulsotype is the most prevalent community-acquired MRSA strain in the 
United States and is known to possess all 5 leukocidins produced by S. aureus. When Hla and the 
bi-component leukocidins bind to various cell surface receptors, cell type specific cytotoxicity 
results. In addition, Hla expression level of colonizing S. aureus MSSA strains have been observed 
as a biomarker for progression to VABP in ventilated patients.19  


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Monoclonal antibodies may counteract these toxin activities and thereby offer benefit in the 
prevention of S. aureus pneumonia. Together, the components of ASN100 (i.e., ASN-1 and 
ASN-2) have demonstrated potency and efficacy against a wide range of S. aureus strains in 
in vitro studies and in vivo models of S. aureus pneumonia, positioning ASN100 to be a needed 
therapy for the prevention of S. aureus pneumonia. The design of this Phase 2 prevention study 
with ASN100 is based on an assumption of a 50% reduction in the incidence of S. aureus 
pneumonia in these subjects, irrespective of the concomitant use of potentially effective 
antibiotics. 
A series of pharmacokinetic (PK) and pharmacodynamic (PD) experiments was conducted using 
the rabbit S. aureus pneumonia model and measured PK in both healthy rabbits and rabbits with 
pneumonia caused by several S. aureus strains. The range of effective doses for preventing 
S. aureus pneumonia in animal models was 2.5 to 10 mg/kg of each component of ASN100. 
The 20 mg/kg dose (10 mg ASN-1 and 10 mg ASN-2) translated into a 1600 mg dose for an 80 kg 
subject. 
ASN100 was well tolerated up to 8000 mg (i.e., 4000 mg ASN-1 and 4000 mg ASN-2) in a single 
ascending dose study conducted in healthy human volunteers. There were no reported related 
serious adverse events (SAEs) and 2 related treatment-emergent adverse events (TEAEs) of 
headache and fatigue were reported in this study. These data and data obtained from the nonclinical 
program determined that ASN100 3600 mg (i.e., 1800 mg ASN-1 and 1800 mg ASN-2) will be an 
appropriate dose to assess safety and efficacy in this first study in mechanically ventilated subjects 
who are heavily colonized with S. aureus. 
The significant unmet need, the lack of existing therapies to prevent S. aureus pneumonia in 
high-risk patients, and the demonstrated in vitro potency and in vivo efficacy of ASN100 provide 
sufficient rationale for this Phase 2 study in the prevention of S. aureus pneumonia in high-risk, 
mechanically ventilated subjects. 
1.3 
Risk/Benefit 
In mechanically ventilated subjects heavily colonized with S. aureus, ASN100 may prevent 
S. aureus pneumonia, a condition associated with significant morbidity and mortality and 
representing a significant unmet clinical need. 
The ASN100 drug components ASN-1 and ASN-2 are fully human mAbs belonging to the IgG1 
immunoglobulin subclass glycoproteins. They share a high degree of sequence homology with 
endogenous IgGs of the same subclass (approximately 90% to 95%) and are manufactured using 
standard mammalian cell expression and purification technologies (including 4 orthogonal viral 
clearance steps); therefore, they are expected to carry mammalian glycosylation pattern and to 
continue to be well tolerated in humans. 
The target toxins recognized by ASN-1 and ASN-2 are bacterial, non-human, and are not 
expressed in human tissues. Lack of off-target reactivity is supported by the results of human tissue 
cross-reactivity studies involving a panel of 33 tissue types that demonstrated no cross-reactivity 
with human tissues. The antibody function of ASN100 is based solely on neutralization; 
complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) 
mechanisms in the mode of action are irrelevant. ASN-1 and ASN-2 cannot bind to toxins already 
bound to human tissues and therefore unwanted ADCC reactions toward human cells and tissues 
is unlikely. 


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A single ascending dose study conducted with ASN100 in doses up to 8000 mg 
(i.e., 4000 mg ASN-1 and 4000 mg ASN-2) demonstrated that ASN100 was well tolerated with 
no reported related SAEs and 2 reported possibly related adverse events of headache and fatigue. 
No dose-limiting toxicity was observed up to the highest dose tested. 
The potential immunogenicity of the antibodies and resulting immune complex formation 
following the production of anti-drug immunoglobulin M and IgG antibodies by the host immune 
system cannot be excluded; however, the risk for this outcome is considered to be low. 
ASN100 belongs to the class of mAbs targeting foreign (bacterial), non-human antigens and is 
expected to yield a low risk of adverse events resulting from immunogenicity due to the 
single-dose administration used in this study. 
Subjects participating in this study will be closely monitored following study drug administration 
via means of adverse event monitoring, clinical laboratory assessments, vital sign measurements, 
physical examinations, 12-lead electrocardiograms (ECGs), chest X-rays and/or thoracic 
computed tomography (CT) scans, and the determination of the presence of ASN-1 and/or ASN-2 
anti-drug antibodies (ADAs). Additional safety assessments may be performed throughout the 
duration of this study if clinically indicated. Concomitant antibiotics are permitted per standard of 
care throughout the duration of this study. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of a single 
dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To compare the duration of mechanical ventilation post-treatment in subjects treated with 
ASN100 versus placebo;  
• To compare the length of stay in the ICU post-treatment for subjects treated with ASN100 
versus placebo;  
• To determine the serum PK (i.e., maximum serum concentration [Cmax], time to maximum 
serum concentration [Tmax], area under the serum concentration-time curve [AUC], and 
terminal elimination half-life [t1/2]) of ASN-1 and ASN-2 in mechanically ventilated 
subjects heavily colonized with S. aureus; and 
• To compare 28-day all-cause mortality in subjects treated with ASN100 versus placebo. 
2.3 
Exploratory Objectives 
The exploratory objectives are: 
• To compare the incidence of HABP occurring >48 hours post-extubation up to but not 
including Day 22 in extubated subjects treated with ASN100 versus placebo; 
• To compare the incidence of VABP up to but not including Day 22 in subjects treated with 
ASN100 versus placebo; 
• To determine the immunogenicity of a single dose of ASN100; 
• To compare the incidence of other S. aureus-associated infections which occur after 
dosing up to but not including Day 22 in subjects treated with ASN100 versus placebo; 
and 
• To assess ASN-1 and ASN-2 levels in bronchoalveolar lavage (BAL) fluid and calculate 
a blood to epithelial lining fluid (ELF) ratio in those subjects participating in the BAL 
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Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 14 days. 
Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator 
and providing the subject remains mechanically ventilated.  
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or 
semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of MSSA 
and MRSA (e.g., CHROMagarTM Staph aureus) for more rapid and specific detection of S. aureus. 
If the site is not able to obtain chromogenic media for S. aureus, appropriate chromogenic media 
may be supplied by the Sponsor.  
Semi-quantitative cultures using chromogenic media are preferred for determination of eligibility 
for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to 
randomize the subject within 48 hours (or up to 60 hours with Medical Monitor approval) from 
the time the ETA sample was collected. 
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for randomization. 
If they are not randomized on this occasion according to the protocol, they are no longer eligible 
for continued ETA sampling and randomization, and will be discontinued from the study; however, 
if subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible 
for re-screening as a new subject enrollment. Subjects who were previously randomized are not 
eligible to be re-consented and re-screened. 
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into the study; however, 
randomization should not be delayed while waiting for Gram-negative results if heavy colonization 
with S. aureus has been confirmed. 
Nasal swab specimens (one from each nostril) will be obtained at the Randomization Visit and will 
be cultured by the central microbiology laboratory. Results from the nasal swab specimen cultures 
will be used to assess correlation with results of the qualifying ETA culture. 
Upon determination of eligibility, approximately 354 subjects will be randomized in a 1:1 ratio to 
1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate intravenous (IV) 
infusions of ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
To ensure balance among the treatment groups, randomization for this study will be stratified by 
receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the time of randomization 
that are potentially active against S. aureus pneumonia (see Section 5.2). 
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg of 
ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-2) or 
matching placebos, per their assigned randomization scheme.  


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If, as part of routine standard of care, additional respiratory and/or other microbiological 
specimens are collected for culture during the study, results will be documented within the 
electronic Case Report Form (eCRF). As fully described within the study laboratory manual, 
bacterial isolates recovered from these specimens that are deemed pathogens by the 
Investigator (if retained and available at the study site local microbiology laboratory) will be 
sent to a central microbiology laboratory for confirmation of pathogen identification (all 
isolates) and susceptibility testing (S. aureus isolates only).   
NOTE: Subjects who are heavily colonized and who would have otherwise qualified for 
randomization, but who are found to have already progressed to pneumonia, may be 
eligible to enroll in a site-specific pilot treatment sub-study.  See Appendix C for criteria. 
Randomized subjects will be monitored daily for the signs and symptoms of pneumonia 
(see Section 7.4.2 and Table 1) and other S. aureus-associated infections while hospitalized up to 
Day 21.  
All randomized subjects will undergo a study visit on Day 22 (+2 days). A follow-up visit will 
occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the 
subject is no longer hospitalized.  
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they 
receive study treatment, a follow-up safety visit will be performed on the day of discharge. 
All randomized subjects will return for a Safety Visit on Day 90 (±7 days) (if the subject is unable 
to return to the site, this visit may be conducted by telephone). Subjects who discontinue the study 
prior to Day 22 will undergo an Early Termination Visit. The end of the study will occur upon 
completion of the last Day 90 visit by the last subject. 
Safety assessments for this study will include adverse event monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead ECGs, chest X-rays and/or thoracic CT scans, and 
the determination of the presence of ASN-1 and ASN-2 ADAs. Additional safety assessments may 
be performed throughout the duration of the study if clinically indicated. 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), on the day 
of diagnosis of pneumonia (if applicable), and on Day 22 or Early Termination (if applicable). 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. Blood 
samples for PK analysis will be collected immediately following the completion of the second 
infusion (+15 minutes) and at 6 hours (± 4 hours) and 24 hours (±6 hours) post-dose following the 
second infusion. In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 
7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will 
be collected on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 
(if hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable).  
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25 to 
35 subjects who volunteer will participate in this sub-study and will have BAL fluid collected 
48 hours (±36 hours) post-dose (on approximately Day 2 or Day 3, depending on time of study 
drug administration) to determine ASN-1 and ASN-2 levels and blood to ELF ratio. Subjects 
participating in the BAL fluid PK sub-study will have a blood sample collected for PK 
measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection 


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or if BAL fluid is collected as part of a standard of care procedure from any subject enrolled in the 
sub-study at any time post-randomization). 
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined and no 
genetic information will be extracted from these samples. Samples will be destroyed following the 
completion of all S. aureus anti-toxin antibody analyses. 
3.3 
Study Indication 
The prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily 
colonized with S. aureus. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria at the Screening and Randomization Visits in order 
to be eligible for randomization into the study: 
1. Subject, legally authorized representative (LAR), or CIP (if applicable) has provided written 
informed consent; 
2. Subject is ≥18 years of age at the time of enrollment; 
3. Subject is currently hospitalized and is mechanically ventilated endotracheally 
(i.e., orotracheal or nasotracheal) and, in the Investigator’s opinion, will require ongoing 
ventilator support for at least 48 hours; 
NOTE: Subjects with a tracheostomy at the time of enrollment are not eligible. After 
enrollment, conversion to tracheostomy is permitted per standard of care. 
4. Female subjects must not be pregnant or lactating. Female subjects of childbearing potential 
must have a documented negative pregnancy test at the Screening Visit. Female subjects may 
be enrolled on the basis of a negative urine pregnancy test, pending the result of a negative 
serum pregnancy test prior to randomization; and 
5. Female subjects of childbearing potential and non-surgically sterile male subjects who are 
sexually active must agree to use an approved highly effective form of contraception from the 
time of informed consent until 165 days post-dose. Approved forms of contraception include 
hormonal intrauterine devices, hormonal contraceptives (oral birth control pill, depo, patch, or 
injectable) together with supplementary double barrier methods such as condoms or 
diaphragms with spermicidal gel or foam. 
NOTE: The following categories define women who are NOT considered to be of childbearing 
potential: 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy, 
o Documented bilateral salpingectomy, or 
o Documented bilateral oophorectomy, or 
• Postmenopausal female, defined as having amenorrhea for at least 12 months without an 
alternative medical cause. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria at the Screening and/or Randomization Visit will 
be excluded from participation in the study: 
1. Subject has received IV immunoglobulin therapy within 4 months prior to the Screening Visit; 
2. Subject has a chest X-ray or thoracic CT scan that is definitive for a diagnosis of pneumonia; 


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3. Subject demonstrates both of the following: 
a. Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
positive end-expiratory pressure; AND 
NOTE: Changes made in ventilator support due to day-to-day maintenance other than those 
changes made to improve oxygenation will not exclude a subject from participation in the 
study. 
b. New onset of purulent suctioned respiratory secretions; 
4. Subject has a known and documented ETA culture showing heavy colonization with a 
Gram-negative organism at enrollment or at any time during the Screening period; 
NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
5. Subject has been diagnosed with neutropenia (absolute neutrophil count <500/mm3); 
6. Subject has a severe non-pulmonary source of infection which, in the Investigator’s opinion, 
would interfere with the conduct of the study or jeopardize the subject’s safety; 
7. Subject is currently on either continuous veno-venous hemodialysis or extracorporeal 
membrane oxygenation; 
8. Subject has been previously exposed to ASN100 or ASN-1 or ASN-2, individually; 
9. Subject has a known hypersensitivity to ASN100 or any of its excipients; 
10. Subject has received any investigational product within 30 days prior to the Screening Visit 
(or 5 half-lives of the investigational product, whichever is longer); 
11. Subject has, in the opinion of the Investigator, a high probability of death within 72 hours of 
enrollment;  
12. Subject is, in the opinion of the Investigator, not able or willing to comply with the protocol; 
13. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
subject, the potential activity of the study drug, or the quality of the data; or 
14. Subjects with a known history or current (suspected) diagnosis of cytokine release syndrome 
associated with the administration of peptides, proteins, and/or antibodies.20 
NOTE: Subjects with a prior history of sepsis are not excluded. 
4.3 
Randomization Criteria 
Following the Screening Visit, eligible subjects who meet all of the inclusion criteria and none of 
the exclusion criteria will be screened daily (while mechanically ventilated) for up to 8 days via 
quantitative or semi-quantitative culture of an ETA to identify those subjects who are heavily 
colonized with S. aureus (see Section 3.1).  
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 14 days. 
Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator 
and providing the subject remains mechanically ventilated.  


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Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for randomization. 
If they are not randomized on this occasion according to the protocol, they are no longer eligible 
for continued ETA sampling and randomization, and will be discontinued from the study; however, 
if subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible 
for re-screening as a new subject enrollment. Subjects who were previously randomized are not 
eligible to be re-consented and re-screened. 
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into the study. 
NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
At the Randomization Visit, subjects must meet all of the following requirements to be randomized 
into the study: 
1. Subject continues to meet all of the inclusion criteria and none of the exclusion criteria required 
at the Screening Visit; 
NOTE: Subjects who undergo tracheostomy after enrollment are still eligible for 
randomization, provided they remain mechanically ventilated (see criterion 3 below). 
2. Subject is heavily colonized with S. aureus as determined by either quantitative or 
semi-quantitative culture of an ETA (see Section 3.1);  
NOTE: The results of the qualifying ETA culture must allow randomization to occur within 
48 hours (or up to 60 hours with Medical Monitor approval) from the time the ETA sample 
was collected. Subjects with ETA culture results obtained after 60 hours showing heavy 
colonization of S. aureus may not be randomized and will be discontinued from the study. 
3. Subject remains mechanically ventilated and, in the Investigator’s opinion, will require 
ongoing ventilator support for at least 48 hours; and 
4. Subject has, in the opinion of the Investigator, a probability of survival beyond 72 hours 
post-randomization. 
4.4 
Withdrawal Criteria 
Participation of a subject in this clinical study may be discontinued for any of the following 
reasons: 
• The subject or LAR withdraws consent from the study for any reason; 
• The subject or LAR requests discontinuation from the study for any reason; 
• Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol; 
• Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the subject; 


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• Pregnancy; 
• Requirement of prohibited concomitant medication; 
• Subject failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by the Sponsor or the regulatory authority. 
If a subject withdraws prematurely from the study due to the above criteria (except in the case of 
withdrawal of consent) or any other reason, study staff should make every effort to complete the 
full panel of assessments scheduled for the Early Termination Visit. The reason for subject 
withdrawal must be documented in the eCRF. 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
Randomized subjects who are withdrawn will not be replaced.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Following Screening/Enrollment and upon determination that a subject is heavily colonized with 
S. aureus as determined by a positive quantitative or semi-quantitative culture of an ETA (see 
Section 3.1), eligible subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate IV infusions of 
ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
Whether ASN-1, ASN-2, or placebo are administered sequentially or simultaneously will be 
determined by operational considerations of IV access at the time of dosing. If 2 IV lines are 
available for simultaneous administration this is preferable; however, if IV access or other 
considerations support sequential administration, this is allowed provided that both infusions are 
completed within 3 hours.  
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg of 
ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-2) or 
matching placebos, per their assigned randomization scheme.  
5.2 
Stratification 
To ensure balance among the treatment groups, randomization for this study will be stratified by 
receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the time of randomization 
that are potentially active against S. aureus pneumonia, including, but not limited to, nafcillin, 
oxacillin, vancomycin, linezolid, telavancin, ceftaroline, ceftobiprole, and teicoplanin. 
5.3 
Rationale for Dosing 
A series of PK and PD experiments was conducted using the rabbit S. aureus pneumonia model 
and measured PK in both healthy rabbits and rabbits with pneumonia caused by several S. aureus 
strains. The range of effective doses for preventing S. aureus pneumonia in animal models was 
2.5 to 10 mg/kg of each component of ASN100. The 20 mg/kg dose (10 mg ASN-1 and 
10 mg ASN-2) translated into a 1600 mg dose for an 80 kg subject. 
ASN100 was well tolerated up to 8000 mg (i.e., 4000 mg ASN-1 and 4000 mg ASN-2) in a 
single-ascending dose study conducted in healthy human volunteers. There were no reported 
related SAEs and 2 related TEAEs of headache and fatigue were reported in this study. These data 
and data obtained from the nonclinical program determined that ASN100 3600 mg (i.e., 1800 mg 
ASN-1 and 1800 mg ASN-2) will be an appropriate dose to assess safety and efficacy in this first 
study in mechanically ventilated subjects who are heavily colonized with S. aureus.  
This study did not identify a maximum tolerated dose. Based on these observations from the single 
ascending dose study, as well as data obtained from the nonclinical program conducted to date, it 
is reasonable to select a dose of ASN100 of 3600 mg (i.e., 1800 mg ASN-1 and 1800 mg ASN-2) 
as an appropriate dose to assess safety and efficacy in this first study in mechanically ventilated 
subjects who are heavily colonized with S. aureus. 


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5.4 
Randomization and Blinding 
Randomization will occur at the Randomization Visit following determination of the subject’s 
eligibility. Subjects will be randomized via a centralized Interactive Response Technology (IRT) 
system in a 1:1 ratio to receive a single dose (2 infusions) of either ASN100 or matching placebo. 
The study follows a double-blind, placebo-controlled design. All study personnel, including 
investigators, site personnel, site pharmacist, Sponsor and contract research organization (CRO) 
staff involved in the conduct of the study (e.g., clinical research associate [CRA]/monitor), and 
subjects will be blinded to treatment assignment. ASN100 and placebo will be identical in 
appearance to preserve blinding. 
5.5 
Breaking the Blind 
Randomization data will be kept strictly confidential until the time of unblinding and will not be 
accessible by subjects, Investigators, or anyone performing assessments and having access to study 
data until unblinding occurs. Individual subject unblinding will only occur in the case of subject 
emergencies, with complete unblinding at the conclusion of the study. 
Emergency breaking of the assigned treatment code should only be undertaken when it is essential 
that knowledge of the treatment assignment is necessary to treat the subject’s emergency safely 
and effectively. Emergency treatment code breaks will be performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject’s identifying information and confirm the necessity to break the treatment code 
for the subject. The Investigator will then receive details of the investigational drug treatment for 
the specified subject and a fax or email confirming this information. The system will automatically 
inform the Sponsor and Medpace study personnel that the code has been broken. 
5.6 
Drug Supplies 
5.6.1 
Formulation and Packaging 
ASN100 is a combination product with 2 separate human mAb components of the IgG1 isotype. 
The specific mAbs are formulated separately and called ASN-1 and ASN-2.  
ASN-1 is a broadly cross-reactive anti-toxin mAb that targets Hla and 3 F-components (HlgB, 
LukF, and LukD) involved in forming 4 of the 5 bi-component leukocidins of S. aureus. 
ASN-2 is directed against the fifth bi-component toxin of S. aureus, LukGH. 
Each component is supplied as a sterile, colorless, clear liquid solution formulated ready for 
injection. 
ASN-1 and ASN-2 will be supplied in separate 10 mL vials as a sterile solution for infusion with 
an extractable volume of 10 mL and a nominal mAb concentration of 20 mg/mL. Each vial will 
contain 200 mg of ASN-1 or 200 mg of ASN-2. Matched vials of ASN-1 placebo and ASN-2 
placebo will also be provided. 
Additional details regarding formulation and packaging will be provided in the Pharmacy Manual 
and the Investigator’s Brochure. 


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5.6.2 
Study Drug Preparation and Dispensing 
Blinded study drug and reference preparations will be delivered to the study site. The site 
pharmacist will prepare the study drug for administration by extracting all volume from each set 
of 9 vials and inserting into an empty IV bag for each set, using aseptic technique according to the 
Pharmacy Manual. These will be delivered to the study site research staff in 2 blinded, ready-to-use 
infusion bags. 
Additional details regarding study drug preparation and dispensing will be provided in the 
Pharmacy Manual. 
5.6.3 
Study Drug Administration 
Subjects will receive ASN100 or matching placebo via 2 IV infusions over a duration of 
approximately 50 to 60 minutes per infusion.  
Both ASN100 and placebo will be administered as 2 separate infusions (either sequentially or 
simultaneously). The last infusion will be completed within 5 hours from initiation of drug 
preparation in the pharmacy. 
Infusions delivered simultaneously must be administered via distinct IV lines (either peripheral or 
central lines; in the instance that a multi-port central line is used, infusions will be delivered 
through separate ports) such that the infusions do not mix before entering the blood stream.  
In the occasion that the 2 infusion bags cannot be hung simultaneously, the blinded IV bags will 
indicate which bag should be infused first and which bag should be infused second. If administered 
sequentially, no more than a 3-hour window should elapse from the time of initiation of the first 
infusion to the completion of the second infusion.  
ASN100 will be administered as separate infusions of 1800 mg ASN-1 and 1800 mg ASN-2 
(9 vials of each to be pooled aseptically according to the Pharmacy Manual into separate infusion 
bags) delivered either sequentially within a 3-hour window from the time of initiation of the first 
infusion to the completion of the second infusion, or simultaneously. 
Placebo will be administered as separate infusions of 9 vials of ASN-1 placebo and 9 vials of 
ASN-2 placebo (vials to be pooled aseptically according to the Pharmacy Manual into separate 
infusion bags) delivered either sequentially within a 3-hour window from the time of initiation of 
the first infusion to the completion of the second infusion, or simultaneously. 
The infusion catheter and tubing will be flushed with sterile saline for injection immediately before 
and following completion of the infusion. 
Either infusion may be discontinued if deemed medically necessary at any time. 
If the first infusion is stopped at any point due to the concern of an adverse event, the second 
infusion will not be administered. 
Refer to the Pharmacy Manual for additional details regarding study drug administration. 


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5.6.4 
Treatment Compliance 
Study drug will be administered at the clinical site by blinded study personnel. The date and time 
of administration, including start and completion times of each infusion, will be accurately logged 
in the source documentation. Due to the single dose design of this study, treatment compliance is 
anticipated to be high. 
5.6.5 
Storage and Accountability 
Study drug (ASN-1, ASN-2, and matching placebos) will be stored at 2°C to 8°C, will be protected 
from light, and will be kept in a secure area with access limited to authorized personnel. The 
primary packaging (vials) is to be kept within the secondary packaging (carton box). 
Investigational site personnel (e.g., study pharmacist) will perform an ongoing inventory of study 
drug products. At the end of the study, a full reconciliation of drug inventory will be performed 
and the results of the inventory will be recorded in the drug accountability log. Any unused vials 
should be returned for destruction.  
Additional details regarding study drug storage and accountability will be provided in the 
Pharmacy Manual. 
5.7 
Prior and Concomitant Medications and/or Procedures 
5.7.1 
Excluded Medications and/or Procedures 
The use of any investigational product within 30 days prior to the Screening Visit (or 5 half-lives 
of the investigational product, whichever is longer) is prohibited. Any immunoglobulin preparation 
for any medical indication is prohibited through follow-up Day 90 of the study. 
Prior use of ASN100, ASN-1, or ASN-2 is prohibited. 
5.7.2 
Documentation of Prior and Concomitant Medication Use 
All prior medications received by the subject within 14 days prior to study drug administration and 
any concomitant medications used throughout the duration of the study will be recorded in the 
source documents and on the appropriate eCRF. The medication name, route of administration, 
dose, frequency, indication, and duration of treatment (start and stop dates) will be recorded. 
 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Written informed consent will be obtained from all subjects prior to any study-specific procedures 
being performed. A separate consent will be obtained from those subjects who participate in the 
BAL fluid PK sub-study. 
See Section 12.3 for additional details regarding informed consent. 
6.2 
Screening/Enrollment (Up to Day -14) 
Screening/Enrollment may be performed up to 14 days prior to randomization. Subjects who meet 
all of the inclusion criteria and none of the exclusion criteria will be screened daily (while 
mechanically ventilated) for up to 8 days to identify those subjects who are heavily colonized with 
S. aureus (see Section 3.1). 
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 14 days. 
Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator 
and providing the subject remains mechanically ventilated.  
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for randomization. 
If they are not randomized on this occasion according to the protocol, they are no longer eligible 
for continued ETA sampling and randomization, and will be discontinued from the study; however, 
if subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible 
for re-screening as a new subject enrollment. Subjects who were previously randomized are not 
eligible to be re-consented and re-screened. 
The following procedures will be performed during Screening/Enrollment: 
• Obtain informed consent; 
• Review inclusion and exclusion criteria; 
• Record medical history;  
• Record demographics; 
• Record antibiotic and other medication history; 
• Obtain height and body weight measurements; 
• Perform complete physical examination; 
• Obtain vital sign measurements, including oxygenation status; 
• Perform pregnancy test for female subjects of childbearing potential only. Female subjects 
may be enrolled on the basis of a negative urine pregnancy test, pending the result of a 
negative serum pregnancy test prior to randomization; 
• Assess ventilator device status; 
• Perform chest X-ray or thoracic CT scan. A chest X-ray or thoracic CT scan obtained as 
part of standard of care within 24 hours prior to the initial Screening Visit is sufficient 


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provided there are no changes in the subject’s clinical status (e.g., no change in ventilation 
status, secretions, or signs/symptoms that may be suggestive of pneumonia) within the 24 
hours following imaging; 
• Obtain ETA for culture;  
• Assess for other S. aureus-associated infections; and 
• Perform adverse event assessment (adverse events that occur between the time the subject 
signs the ICF and the Randomization Visit will only be recorded if related to a study-
specific procedure). 
6.3 
Randomization Visit (Day 1 Pre-Dose) 
The Randomization Visit will occur pre-dose on Day 1. At the time of randomization, if a subject’s 
screening ETA culture also shows heavy colonization of a Gram-negative organism (i.e., heavy 
co-colonization of both Gram-positive and Gram-negative organisms), the subject will not be 
randomized into the study; however, randomization should not be delayed while waiting for 
Gram-negative results if heavy colonization with S. aureus has been confirmed. 
The following procedures will be performed at the Randomization Visit: 
• Review inclusion, exclusion, and randomization criteria; 
• Review and record medical history (if changes occurred since the Screening Visit); 
• Review and record antibiotic and other medication history (if changes occurred since the 
Screening Visit); 
• Perform limited physical examination (to include, at a minimum, a pulmonary 
examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform clinical laboratory assessments, including chemistry, hematology, coagulation, 
and urinalysis; 
• Obtain a blood sample for procalcitonin testing; 
• Assess ventilator device status; 
• Perform chest X-ray or thoracic CT scan. A chest X-ray or thoracic CT scan obtained 
within 24 hours of the Randomization Visit is sufficient, provided there are no changes in 
the subject’s clinical status (e.g., no change in ventilation status, secretions, or 
signs/symptoms that may be suggestive of pneumonia) since the time of imaging; 
NOTE: Subjects who are heavily colonized and who would have otherwise qualified for 
randomization, but who are found to have already progressed to pneumonia, may be 
eligible to enroll in a site-specific pilot treatment sub-study. See Appendix C for criteria. 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain nasal swab specimens for culture (one from each nostril); 


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• Randomize to study treatment; 
• Obtain a blood sample for ADA and assessment of pre-existing anti-S. aureus toxin 
antibodies; 
• Perform 12-lead ECG; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.4 
Treatment Period (Day 1) 
The following procedures will be performed on Day 1 following administration of study drug: 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status; 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
NOTE:  Subjects who had already progressed to pneumonia while being evaluated for 
randomization under the VAP Prevention study, and who met eligibility criteria for the 
pilot treatment sub-study, will have the same study assessments and protocol required 
procedures as outlined in this and subsequent sections of this protocol, however the nature 
of the assessments may vary slightly to accommodate the sub-study endpoint of resolution 
of pneumonia. See Appendix C for criteria. 
• Assess for other S. aureus-associated infections; 
• Administer study drug; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin 
antibodies (to be collected immediately following the completion of the second infusion 
[+15 minutes] and at 6 hours [±4 hours] and 24 hours [±6 hours] post-dose); 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.5 
Monitoring Period 
6.5.1 
Day 2/Day 3 – Bronchoalveolar Lavage Fluid Pharmacokinetic Sub-Study 
The following procedures will be performed 48 hours (±36 hours) post-dose (Day 2 or Day 3 
depending on the time of study drug administration) for those subjects participating in the 
BAL fluid PK sub-study only or if BAL fluid is collected as part of a standard of care procedure 
for any subject at any other time post-randomization for any other reason: 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status; 


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• Perform chest X-ray or thoracic CT scan; 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain BAL fluid to determine ASN-1 and ASN-2 concentrations (48 hours [±36 hours] 
post-dose) for those subjects participating in the BAL fluid PK sub-study (if BAL fluid is 
collected as part of a standard of care procedure from any subject enrolled in the sub-study 
at any other time post-randomization for any other reason, if possible, a sample for PK 
analysis will also be obtained);  
• Obtain a blood sample for PK measurement ±1 hour relative to BAL fluid collection 
(including scheduled BAL fluid collection or if BAL fluid is collected as part of a standard 
of care procedure from any subject enrolled in the sub-study at any time post-
randomization); 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.5.2 
Day 2 to Day 21 
The following procedures will be performed daily (unless otherwise indicated) from Day 2 to 
Day 21 while the subject is hospitalized. For subjects participating in the BAL fluid PK sub-study, 
procedures noted for the Day 2 visit only need to be performed 1 time: 
• Perform limited physical examination (to include, at a minimum, a pulmonary 
examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform clinical laboratory assessments, including chemistry, hematology, coagulation, 
and urinalysis. Blood samples for chemistry, hematology, and coagulation will be obtained 
on Days 2 (+1 day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, and twice weekly 
during Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through Day 21) of the 
Monitoring Period while the subject remains hospitalized. Urine for urinalysis will be 
obtained on Day 6 (±1 day) of the Monitoring Period only; 
• Obtain a blood sample for procalcitonin testing (on day of diagnosis of pneumonia only, 
if applicable); 
• Assess ventilator device status (if applicable); 
• Perform chest X-ray or thoracic CT scan (required during the Monitoring Period for those 
subjects presenting with signs and symptoms of a respiratory infection such as dyspnea, 
tachypnea, fever, or cough); 
• Obtain adequate respiratory specimen for culture (if clinically indicated); 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 


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• Assess for other S. aureus-associated infections; 
• Obtain a blood sample for ADAs (to be obtained only upon discharge from the ICU, if 
discharge occurs prior to Day 22); 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin 
antibodies (Days 4 [±1 day], 7 [±1 day], and 14 [±2 days] only); 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.5.3 
Day 22 
The following procedures will occur on Day 22 (+2 days): 
• Perform limited physical examination (if subject is hospitalized) (to include, at a 
minimum, a pulmonary examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform pregnancy test for female subjects of childbearing potential only (additional 
pregnancy testing may occur throughout the duration of the study, per applicable country 
requirements); 
• Perform clinical laboratory assessments including chemistry, hematology, coagulation, 
and urinalysis; 
• Obtain a blood sample for procalcitonin testing; 
• Assess ventilator device status (if applicable); 
• Perform chest X-ray or thoracic CT scan (required during the Monitoring Period for those 
subjects presenting with signs and symptoms of a respiratory infection such as dyspnea, 
tachypnea, fever, or cough); 
• Obtain adequate respiratory specimen for culture (if clinically indicated); 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin 
antibodies; 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  


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• Record concomitant medications; and 
• Perform adverse event assessment. 
6.6 
Follow-Up Period 
6.6.1 
Day 28 (+2 Days) Follow-Up 
The following procedures will occur during a follow-up telephone call or visit, if the subject 
remains hospitalized, on Day 28 (+2 days): 
• Assess ventilator device status (if applicable); and 
• Assess for survival and discharge disposition. 
6.6.2 
Day 40 to Day 89 (Follow-Up Safety Visit) 
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they 
receive study treatment, a follow-up safety visit will be performed on the day of discharge.  
The following procedures will occur on the day of hospital discharge for subjects who are 
discharged between Day 40 and Day 90: 
• Perform limited physical examination (to include, at a minimum, a pulmonary 
examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status (if applicable); 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin 
antibodies; 
• Track days on ventilator from randomization (if applicable); 
• Track days in ICU (or other observation area) from randomization; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.6.3 
Safety Visit (Day 90 [±7 Days]) 
The following procedures will be performed at the Safety Visit on Day 90 (±7 days). If the subject 
is unable to return to the site, this visit may be conducted by telephone, with procedures performed 
as appropriate (i.e., concomitant medications and adverse events collected): 
• Perform limited physical examination (to include, at a minimum, a pulmonary 
examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 


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• Assess ventilator device status (if applicable); 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin 
antibodies; 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.7 
Early Termination Visit and Withdrawal Procedures 
For subjects who are withdrawn from the study prior to Day 22, the following procedures will be 
performed at an Early Termination Visit: 
• Perform limited physical examination (to include, at a minimum, a pulmonary 
examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform pregnancy test for female subjects of childbearing potential only; 
• Perform clinical laboratory assessments including chemistry, hematology, coagulation, 
and urinalysis (if clinically indicated); 
• Obtain a blood sample for procalcitonin testing; 
• Assess ventilator device status (if applicable); 
• Obtain adequate respiratory specimen for culture (if clinically indicated);  
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin 
antibodies; 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  
• Record concomitant medications; and 
• Perform adverse event assessment. 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects in the MITT Population who develop 
S. aureus pneumonia as defined in Section 7.4 up to but not including Day 22. 
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• Duration of mechanical ventilation during the first 21 days post-randomization for 
subjects in the MITT, Intent-to-Treat (ITT), and Per Protocol (PP) Populations; 
• Length of ICU stay during the first 21 days post-randomization for subjects in the MITT, 
ITT, and PP Populations;  
• The Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single dose of 
ASN100 in the PK Population; and 
• 28-day all-cause mortality in the MITT, ITT, and PP Populations. 
7.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
• Proportion of subjects in the MITT and PP Populations with a diagnosis of HABP at 
>48 hours post-extubation up to but not including Day 22 in extubated subjects; 
• Proportion of subjects in the MITT and PP Populations with development of VABP up to 
but not including Day 22; 
• Incidence of all bacterial pneumonias in the MITT, ITT, and PP Populations; 
• Incidence of other non-S. aureus pneumonias up to but not including Day 22 in the MITT, ITT, 
and PP Populations; and  
• Incidence of other S. aureus infections acquired following study drug administration up 
to but not including Day 22 in the MITT, ITT, and PP Populations. 


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7.4 
Microbiological and Clinical Assessments 
7.4.1 
Microbiological Assessment 
ETA specimens will be collected for culture during Screening/Enrollment to determine the degree 
of S. aureus colonization. Additional respiratory specimens may be collected for culture 
throughout the Monitoring Period or Early Termination (if applicable) if clinically indicated 
according to standard of care. 
If, as part of routine standard of care, additional respiratory and/or other microbiological specimens 
are collected for culture during the study, results will be documented within the eCRF. As fully 
described within the study lab manual, bacterial isolates recovered from these specimens that are 
deemed pathogens by the Investigator (if retained and available at the study site local microbiology 
laboratory) will be sent to a central microbiology laboratory for confirmation of pathogen 
identification (all isolates) and susceptibility testing (S. aureus isolates only). 
During the Monitoring Period, a diagnosis of S. aureus pneumonia will be determined if subjects 
have S. aureus identified from an adequate respiratory specimen (Section 7.4.1) and clinical signs 
and symptoms of pneumonia. For a diagnosis of S. aureus pneumonia, clinical signs and symptoms 
must occur ±2 days from the time of collection of an adequate respiratory specimen culture that is 
positive for S. aureus (Section 7.4.2).  
• 
For intubated subjects, a respiratory specimen obtained by BAL, non-bronchoscopic BAL, 
or protected specimen brush will be considered an adequate respiratory specimen; or 
• 
For extubated subjects, an adequate expectorated/induced sputum specimen is defined as 
<10 squamous epithelial cells and >25 PMNs/100× field; and 
• 
For both intubated and extubated subjects, adequate respiratory specimens will undergo 
either semi-quantitative or quantitative culture in accordance with the local laboratory’s 
standard procedure. 
7.4.2 
Assessment of Clinical Signs and Symptoms 
Subjects will be assessed daily throughout the Monitoring Period for the following clinical signs 
and symptoms presented in Table 1. 
Table 1. Clinical Signs and Symptoms 
Mechanically Ventilated Subjects 
Non-Mechanically Ventilated Subjects 
• 
Cough, 
• 
Rales, 
• 
Dullness on percussion,* 
• 
Bronchial breath sounds, 
• 
Egophony,* 
• 
Need for suctioning, 
• 
Need for ventilator support, and 
• 
Fever ≥38°C (≥100.4°F). 
• 
Cough, 
• 
Rales, 
• 
Dullness on 
percussion,* 
• 
Bronchial breath 
sounds, 
• 
Egophony,* 
• 
Dyspnea, 
• 
Tachypnea, 
• 
Respiratory rate, 
• 
Hypoxemia, and 
• 
Fever ≥38°C 
(≥100.4°F). 
*If routinely performed. 


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A diagnosis of pneumonia (HABP or VABP) will be determined as defined in Table 2. 
Table 2. 
Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia 
Indication 
Definition 
HABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed 
by the Investigator); 
• 
At least ONE of the following: 
o 
Has been hospitalized for >48 hours, or 
o 
Developed clinical signs and symptoms within 7 days following hospital discharge; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the 
requirement for mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
VABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed 
by the Investigator);  
• 
Subject has received mechanical ventilation via an endotracheal or nasotracheal tube for 
≥48 hours; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the 
requirement for mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
HABP = hospital-acquired bacterial pneumonia; PEEP = positive end-expiratory pressure; VABP = ventilator-associated 
bacterial pneumonia; WBC = white blood cell. 


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8 
PHARMACOKINETIC ASSESSMENTS 
8.1 
Pharmacokinetic Endpoint 
The primary PK endpoints are the Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum 
following a single IV dose of ASN100 in the PK Population. 
The levels of ASN-1 and ASN-2 will be measured in BAL fluid in a PK sub-study which will 
allow the calculation of a blood to ELF ratio.  
8.2 
Pharmacokinetic Assessments 
Samples for PK analysis will be obtained to determine the PK of ASN-1 and ASN-2 in serum and 
BAL fluid (for subjects participating in the BAL fluid PK sub-study only). Instructions for the 
collection, handling, and storage of biological samples will be provided in a separate Laboratory 
Manual.  
In order to maintain the study blind, all subjects, including those randomized to receive placebo, 
will have PK samples obtained at the specified time points. The actual date and time of each sample 
will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded Sponsor or CRO personnel until the study has been unblinded. 
8.2.1 
Serum Pharmacokinetic Sampling 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. At the 
completion of the second infusion, blood samples for PK analysis will be collected immediately 
following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 
24 hours (±6 hours) post-dose. 
In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 
14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected 
on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 (if 
hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable). 
The following serum PK parameters will be assessed: 
• Maximum serum concentration (Cmax), 
• Time to maximum serum concentration (Tmax), 
• Area under the serum concentration-time curve (AUC), and 
• Terminal elimination half-life (t1/2). 
Subjects participating in the BAL fluid PK sub-study will have a blood sample collected for 
PK measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid 
collection or if BAL fluid is collected as part of a standard of care procedure from any subject 
enrolled in the sub-study at any time post-randomization). 


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8.2.2 
Bronchoalveolar Lavage Fluid Pharmacokinetic Sampling 
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25 to 
35 subjects who volunteer will participate in this sub-study and will have BAL fluid collected 
48 hours (±36 hours) post-dose (on approximately Day 2 or Day 3, depending on time of study 
drug administration) to determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid 
is collected as part of a standard of care procedure from any subject enrolled in the sub-study at 
any other time post-randomization for any other reason, if possible, a sample for PK analysis will 
also be obtained.  
8.2.3 
Analysis of Anti-Staphylococcus aureus Toxin Antibody Titers 
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined and no 
genetic information will be extracted from these samples. Samples will be destroyed following the 
completion of all S. aureus anti-toxin antibody analyses. 


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9 
SAFETY ASSESSMENTS 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events that occur between the time the subject signs the ICF and the Randomization Visit 
will only be recorded if related to a study-specific procedure. Beginning with randomization all 
adverse events, which include clinical laboratory test and physical examination variables, will be 
monitored and documented until study participation is complete. Subjects should be instructed to 
report any adverse event that they experience to the Investigator. Site personnel will ensure each 
adverse event is recorded on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at the time of randomization should not be reported as an 
adverse event unless the medical condition or signs or symptoms present at baseline change in 
severity or seriousness at any time during the study. In this case, it should be reported as an adverse 
event. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at the time of randomization and significantly worsen 
during the study should be reported as adverse events. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Any abnormal test that is determined to be an error does not 
require reporting as an adverse event. 
Lack of efficacy (i.e., development of pneumonia as defined in Section 7.4) will be captured as an 
efficacy measure and in general will not be considered an adverse event; however, new onset of 
specific pulmonary symptoms that do not meet the study-specific definition of pneumonia or 
worsening of baseline signs and symptoms should be captured as adverse events. Events that meet 
the criteria for an SAE (Section 9.2) should follow the procedures for SAE reporting as detailed in 
Section 9.3. 


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9.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product mean that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
9.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
The reference safety information for ASN100 is included in the current version of the 
Investigator’s Brochure. The reference safety information will be reviewed yearly and the 
periodicity of the review will be harmonized with the reporting period of the Development Safety 
Update Report. 
9.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 


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The following factors should also be considered: 
• The temporal sequence from study drug administration: 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event; 
• Underlying, concomitant, intercurrent diseases: 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have; 
• Concomitant drugs: 
o The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question; 
• Known response pattern for this class of study drug: 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect; 
• Exposure to physical and/or mental stresses: 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event; and 
• The pharmacology and PK of the study drug: 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
o NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in the view 
of either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 


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situational reasons (i.e., no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the 
development of drug dependency. 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
Serious adverse events related to a study-specific procedure that occur between the Screening Visit 
and the Randomization Visit, and all SAEs occurring from the time of randomization until the 
Day 90 Safety Visit, must be reported to Medpace Clinical Safety within 24 hours of the 
knowledge of the occurrence (this refers to any adverse event that meets any of the aforementioned 
serious criteria). All SAEs that the Investigator considers related to study drug occurring after the 
Day 90 Safety Visit must be reported to the Sponsor. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form.  
If the event meets serious criteria and it is not possible to access the EDC system, send an email 
to Medpace Safety at Medpace-safetynotification@medpace.com or call the Medpace SAE hotline 
(phone number listed below), and fax the completed paper SAE form to Medpace (fax number 
listed below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available.  
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, Dial 3 or +1-513-579-9911, Dial 3 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
Email: medpace-safetynotification@medpace.com 
Medpace SAE hotline – Europe: 
Telephone: +49-89-89-55-718-44 
Facsimile: +49-89-89-55-718-104 
Email: medpace-safetynotification@medpace.com 


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Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
9.4 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant from the time of 
randomization until the Day 90 Safety Visit, the Investigator should report the pregnancy to 
Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero form to the Investigator for completion.  
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
9.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the FDA, applicable competent 
authorities in all the Member States concerned, and to the Central Ethics Committee, and in any 
case no later than 7 days after knowledge by the Sponsor of such a case, and that relevant follow-up 
information will subsequently be communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable 
competent authorities concerned, and to the Central Ethics Committee concerned as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all Investigators as required.  
Expedited reporting of suspected unexpected serious adverse reactions related to 
non-investigational medical products (NIMPs) used in this study (and any other NIMPs) will not 
be necessary. Listings of cases related to NIMPs will be included in the Development Safety 
Update Report. 
9.6 
Clinical Laboratory Evaluations 
Standard clinical laboratory profiles for safety assessments (including chemistry, hematology, 
coagulation, and urinalysis) will be collected and evaluated at the Randomization Visit 
(Day 1 pre-dose).  
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1 day), 
4 (±1 day), and 6 (±1 day) of the Monitoring Period, or Early Termination (if applicable and if 


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clinically indicated). During Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through 
Day 21) of the Monitoring Period, clinical laboratory assessments of chemistry, hematology, and 
coagulation will be performed twice a week while the subject remains hospitalized.  
Urine for urinalysis will be obtained at the Randomization Visit (Day 1 pre-dose), on Day 6 
(±1 day) of the Monitoring Period, or Early Termination (if applicable and if clinically indicated). 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), on the day 
of diagnosis of pneumonia (if applicable), and on Day 22 or Early Termination (if applicable). 
Study required laboratory samples will be sent to the central laboratory for analysis. Subject care 
should be directed by local laboratory testing. 
See Appendix B for a list of clinical laboratory analytes to be assessed. 
9.7 
Radiographs and Imaging 
A chest X-ray or thoracic CT scan is required on 4 occasions during the study as defined below 
for (1) initial Screening Visit, (2) Randomization Visit, (3) Post-BAL sampling for those subjects 
participating in the optional BAL sub-study, and (4) Monitoring Period (Day 2 through Day 22) 
for those subjects presenting with signs/symptoms suggestive of a respiratory infection. 
• Initial Screening Visit: A chest X-ray or thoracic CT scan will be obtained at the initial 
Screening Visit to ensure that the subject does not have pneumonia. A chest X-ray or 
thoracic CT scan obtained as part of standard of care within 24 hours of the initial 
Screening Visit is sufficient provided there are no changes in the subject’s clinical status 
(e.g., no change in ventilation status, secretions, or signs/symptoms that may be suggestive 
of pneumonia) within the 24 hours since the imaging procedure. 
• Randomization Visit: A chest X-ray or thoracic CT scan will be obtained at the 
Randomization Visit to ensure that the subject does not have pneumonia. A chest X-ray 
or thoracic CT scan obtained as part of standard of care within 24 hours of the 
Randomization Visit is sufficient provided there are no changes in the subject’s clinical 
status (e.g., no change in ventilation status, secretions, or signs/symptoms that may be 
suggestive of pneumonia) since the time of imaging. 
• BAL sub-study: A chest X-ray or thoracic CT scan will be obtained on Day 2/Day 3 
post-BAL sampling for all subjects participating in the optional BAL fluid PK sub-study. 
• Monitoring Period (Day 2 through Day 22): A chest X-ray or thoracic CT scan is required 
during the Monitoring Period for those subjects presenting with signs and symptoms of a 
respiratory infection such as dyspnea, tachypnea, fever, or cough. 
Imaging should be conducted per institutional guidelines and assessed by the Investigator. 
The results of radiographs or imaging obtained at the Screening Visit and any subsequent visits 
should be documented on the appropriate eCRF. Radiograph or imaging reports and/or films will 
be collected for future analysis and will be captured within the EDC system. 
9.8 
Vital Signs 
Vital sign measurements will be obtained at the Screening Visit, the Randomization Visit (Day 1 
pre-dose), on Day 1 following administration of study drug, daily during the Monitoring Period (if 
subject is hospitalized), on Day 22, on the day of hospital discharge (for subjects who are 


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discharged between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs onsite), or 
Early Termination (if applicable). 
Vital sign measurements will include temperature, systolic and diastolic blood pressure, pulse, 
respiratory rate, and oxygenation status (as measured by pulse oximetry or arterial blood gas). 
Vital sign measurements will be recorded on the appropriate eCRF. 
Blood pressure and pulse will be assessed via an automated device. Manual techniques are only to 
be used if an automated device is not available. 
Oxygenation status will be determined at the Screening and Randomization Visits via 
measurement of arterial blood gas, provided the subject has an arterial line placed. If no arterial 
line is present, pulse oximetry may be used. Oxygenation status may be determined at subsequent 
visits by either measurement of arterial blood gas or pulse oximetry, if no arterial line is present. 
9.9 
Electrocardiograms 
A 12-lead ECG will be performed for all eligible subjects at the Randomization Visit 
(Day 1 pre-dose), on Day 22, on the day of hospital discharge (for subjects who are discharged 
between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs onsite), or 
Early Termination (if applicable). 
9.10 
Physical Examinations 
A complete physical examination will be performed at the Screening Visit and as deemed 
necessary by the Investigator and will include, at a minimum, a pulmonary examination (including 
auscultation) and assessments of the skin, abdomen, cardiovascular, gastrointestinal, and 
neurological systems. Body weight and height will also be measured.  
A limited physical examination will be performed at the Randomization Visit, daily during the 
Monitoring Period, on Day 22, on the day of hospital discharge (for subjects who are discharged 
between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs onsite), or 
Early Termination (if applicable). The limited physical examination will include, at a minimum, a 
pulmonary examination (including auscultation). 
9.11 
Immunogenicity 
Samples to evaluate ADA response including neutralizing antibodies to ASN-1 and ASN-2 will 
be collected from all subjects at the Randomization Visit (Day 1 pre-dose), upon discharge from 
the ICU (if discharge occurs prior to Day 22), on Day 22, on the day of hospital discharge (for 
subjects who are discharged between Day 40 and Day 90), and at the Day 90 Safety Visit (if the 
visit occurs onsite).  
Subjects who discontinue early or are withdrawn from the study should also have samples 
collected as part of their Early Termination Visit. These samples will be sent to the central 
laboratory for analysis. 
Samples will be screened for antibodies binding to ASN-1 and ASN-2 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to ASN-1 or ASN-2 and/or to further characterize the immunogenicity of ASN-1 and 
ASN-2. 
The impact of ADAs on safety, efficacy, and PK will be addressed in the Statistical Analysis Plan.  


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10 
STATISTICS 
10.1 
Analysis Populations 
Intent-to-Treat (ITT) Population 
The ITT Population includes all subjects who are randomized to receive study drug.  
Modified Intent-to-Treat (MITT) Population 
The MITT Population includes all subjects in the ITT Population who receive study drug who are 
heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an 
ETA. 
Per Protocol (PP) Population 
The PP Population includes all subjects in the MITT Population who also meet the following 
criteria: 
• Do not have any major protocol violations that would affect assessment of efficacy, and 
• Complete an adequate number of Monitoring Period assessments through and including 
Day 22. 
Pharmacokinetic (PK) Population 
The PK Population includes all subjects in the MITT Population with at least 1 serum PK sample 
collected post-dose. 
Safety Population 
The Safety Population includes all subjects who receive any amount of study drug and have at 
least 1 post-treatment safety assessment. 
10.2 
Statistical Methods 
All statistical analyses will be provided in the Statistical Analysis Plan. Continuous variables will 
be summarized by using the number of non-missing observations, arithmetic mean, standard 
deviation, median, minimum, and maximum values as descriptive statistics. Categorical variables 
will be summarized by using the frequency count and the percentage of subjects in each category 
as descriptive statistics.  
All statistical tests will be performed at the 0.05 significance level using 2-sided tests, except where 
otherwise noted. All confidence intervals will have a confidence level of 95%. 
10.2.1 
Disposition 
The number of subjects randomized, treated, completed, and discontinued early from the study 
and the reasons for discontinuation will be summarized descriptively. In addition, reasons leading 
to study discontinuation will be summarized for each treatment group. The number and percentage 
of subjects for the randomized subjects included in each analysis population will also be presented. 
10.2.2 
Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment group for demographics (e.g., age, gender, race, 
and ethnicity) and for baseline characteristics. 


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10.2.3 
Analysis of Efficacy 
The primary efficacy endpoint is whether the subject has developed S. aureus pneumonia up to 
but not including Day 22. The summary measure for efficacy is the proportion of subjects in the 
MITT Population who develop S. aureus pneumonia up to but not including Day 22. Analysis for 
the primary endpoint will compare the proportion of subjects who develop S. aureus pneumonia 
in the ASN100 arm versus the placebo arm in the MITT Population. The statistical test for 
comparing 2 event rates is based on a 2-sided test with a false positive rate of 5%.  
Analyses of the primary efficacy endpoint will also be performed separately for the ITT and 
PP Populations. 
Duration of mechanical ventilation and length of hospital ICU stay during the first 21 days 
post-randomization will be compared between treatment groups using a Wilcoxon rank sum test. 
Other efficacy endpoints will be summarized by treatment group.  
10.2.4 
Analysis of Safety 
All subjects in the Safety Population will be included in the safety analyses and analyzed based on 
the actual treatment received.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events will be summarized by system organ class and preferred term. 
A TEAE is defined as an adverse event with a start date and time on or after the first dose of study 
treatment. Listings will be provided for SAEs and adverse events leading to drug discontinuation. 
In addition, all adverse events will be listed.  
Safety laboratory data and vital signs will be presented by each scheduled time point and for 
change from baseline to each time point. The results of all laboratory tests, physical examination 
findings, vital signs, and ADAs will be presented in data listings.  
10.2.5 
Analysis of Pharmacokinetics 
Descriptive statistics will be provided for all PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population. Subject PK profiles will be determined using 
parameters such as Cmax, Tmax, AUC, and t1/2 for each of ASN-1 and ASN-2 in serum. Epithelial 
lining fluid PK will also be analyzed and an ELF/serum PK ratio will be calculated.  
A description of the PK parameter analysis will be included in the Statistical Analysis Plan. 
10.2.6 
Sample Size Determination 
The estimated incidence of progression to S. aureus pneumonia in mechanically ventilated subjects 
with heavy colonization is approximately 25% within 22 days of randomization.  
Assuming a 2-sided significance level of 0.05 and a desired power of 80% to detect a significant 
difference between S. aureus pneumonia incidence rates of 25% in the placebo group and 12.5% 
in the ASN100 treatment group (50% reduction), 152 evaluable subjects are required in each 
treatment group. A sample size of 304 subjects (152 subjects per treatment group) will yield 
80% power to detect a 50% reduction in the incidence of S. aureus pneumonia with ASN100 
treatment when assuming a 25% incidence rate of S. aureus pneumonia in placebo-treated subjects. 
Assuming a 14% non-evaluable rate, approximately 354 subjects (177 subjects per treatment 


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group) will be randomized. Assuming the screen failure rate is about 84%, approximately 
2250 subjects will be screened. 
10.2.7 
Interim Analysis 
One interim analysis will be conducted during the study, when approximately 125 subjects have 
reached Day 22. The interim analysis is for futility assessment of the study, and for a potential 
study sample size adjustment based on an overall blinded efficacy evaluation pooled across the 
treatment arms. Based on this assessment, the sample size may be increased. The interim analysis 
of futility assessment will be reviewed by an independent Data Review Committee (DRC).  


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel with a 
role designated for data entry must log into the system using their secure user name and password 
in order to enter, review, or correct study data. These procedures must comply with Title 21 of the 
Code of Federal Regulations (21 CFR Part 11) and other appropriate international regulations. All 
passwords will be strictly confidential. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• MedDRA for adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
12.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
12.2 
Institutional Review Board/Independent Ethics Committee 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of subjects. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements (if 
applicable), written information given to the subjects, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB/IEC by the Investigator. 
Federal regulations and ICH require that approval be obtained from an IRB/IEC prior to 
participation of subjects in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for subject recruitment, and any other written 
information regarding this study to be provided to a subject or subject’s legal guardian must be 
approved by the IRB/IEC. Where applicable, the requirements of the CIP, as well as the 
decision-making process regarding inclusion of subjects into the study, must be approved by the 
IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor. 
It is the responsibility of the Sponsor or CRO to obtain the approval of the responsible ethics 
committees according to the national regulations.  
The study will only start at the respective sites once the respective committee’s written approval 
has been given. 
12.3 
Informed Consent 
The ICF, the ICF for the BAL fluid PK sub-study, and any changes to the ICFs made during the 
course of the study must be agreed to by the Sponsor or designee and the IRB/IEC prior to use and 
must be in compliance with all ICH GCP, local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each subject or the subject’s legal representative (if applicable) before any 
study-specific activity is performed and should document in the source documentation that consent 
was obtained prior to enrollment in the study. In the case that the subject is not fully conscious, a 
shortened version of informed consent will be signed by the subject and a complete version of 
informed consent will be signed, dependent on the country-specific requirements, by the subject’s 
legal representative or close person (e.g., husband/wife, child, or sibling), or by the CIP (if 
applicable), by an impartial witness, and by the Investigator prior to any study-specific procedure 


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being performed. A subject who is not fully conscious will be required to sign the complete version 
of informed consent once fully conscious. The original signed copy of the ICF must be maintained 
by the Investigator and is subject to inspection by a representative of the Sponsor, their 
representatives, auditors, the IRB/IEC, and/or regulatory agencies. A copy of the signed ICF will 
be given to the subject. 
In countries only where it is applicable, for subjects who are unable to read and sign either version 
of the ICF (i.e., shortened or complete version), decisions regarding the subject’s enrollment will 
be made by the CIP. The decision of the CIP to include the subject in the study must be documented 
in the minutes of the CIP meeting, signed by the members of the CIP, and the decision must be 
entered in the medical records of the subject. The minutes of the CIP meeting should contain the 
names of all physicians included in the composition of the CIP, the subject’s diagnosis, the 
subject’s condition at the time the decision was made, the interpretation of clinical, laboratory, 
instrumental, and other data, and the decision of the CIP. The documents supporting the CIP 
decision must be maintained by the Investigator. 
12.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki (Seoul 2008), and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
12.5 
Protocol Deviations 
Deviations from the protocol are not permitted. If a protocol deviation occurs, the CRA will ensure 
the deviation is appropriately documented. Substantial deviations will be compiled into a listing 
for inclusion in the final clinical study report and minor deviations will be recorded in the source 
documents at the site. Investigators must comply with all applicable IRB/IEC and local 
requirements in the reporting of protocol deviations.  


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12.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable national or regional health authorities, and the IRB/IEC as appropriate. 
Subjects or their legal representatives may request their medical information be given to their 
personal physician or other appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
12.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., CRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
12.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. However, the Investigator will be afforded the right to 
publish their individual results after the end of the trial if no agreement on the publication can be 
achieved within 2 years of database lock. 
12.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR §54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 


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12.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e., initiation of study centers) when the CTA and favorable Ethics 
opinion have been received from those bodies governing those study centers.  


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for subject safety. In this 
case, the situation must be documented and reported to the IRB/IEC within 5 working days. 
13.2 
Address List 
13.2.1 
Sponsor 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA 02451-1472 
Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 
13.2.2 
Global Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-513-579-9911 
Facsimile: +1-513-579-0444 
13.2.3 
Drug Safety 
Medpace Clinical Safety 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-800-730-5779, Dial 3 or +1-513-579-9911, Dial 3 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
Email: Medpace-safetynotification@medpace.com 


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13.2.4 
Biological Specimens 
Clinical and Microbiology Laboratory 
ACM Global 
160 Elmgrove Park 
Rochester, NY 14624 
Telephone: +1-585-429-2374 or +1-866-405-0400 
Pharmacokinetic and Immunogenicity Laboratory 
Eurofins | ADME BIOANALYSES 
75 A, Avenue de Pascalet 
30310 Vergèze, France 
Telephone: +33-(0)4-66-73-17-73 
Facsimile: +33-(0)4-66-73-17-74 
13.2.5 
Study Drug Packaging, Labeling, and Distribution 
ABF Pharmaceutical Services GmbH 
Gastgebgasse 5-13 
1230 Vienna, Austria 
Telephone: +43-1-890-12-00-30 
Facsimile: +43-1-890-12-00-11 
 
 


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14 
REFERENCES 
1. Berube BJ, Bubeck Wardenburg J. Staphylococcus aureus α-toxin: nearly a century of intrigue. 
Toxins (Basel). 2013;5(6):1140-66. 
2. Reyes-Robles T, Torres VJ. Staphylococcus aureus pore-forming toxins. Curr Top Microbiol 
Immunol. 2016. Epub ahead of publication. DOI: 10.1007/82_2016_16. 
3. Janesch P, Rouha H, Weber S, et al. Selective Sensitization of Human Neutrophils to LukGH 
Mediated Cytotoxicity by Staphylococcus aureus and IL-8. J Infect 2017. Epub ahead of 
publication. 
4. Rouha H, Badarau A, Visram ZC, et al. Five birds, one stone: neutralization of 
alpha-hemolysin and 4 bi-component leukocidins of Staphylococcus aureus with a single 
human monoclonal antibody. MAbs. 2015;7(1):243-54. 
5. Badarau A, Rouha H, Malafa S, et al. Context matters: The importance of dimerization-induced 
conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of 
neutralizing antibodies. MAbs. 2016;8(7):1347-60. 
6. Badarau A, Rouha H, Malafa S, et al. Structure-function analysis of heterodimer formation, 
oligomerization, and receptor binding of the Staphylococcus aureus bi-component toxin 
LukGH. J Biol Chem. 2015;290(1):142-56. 
7. Diep BA, Le VT, Visram ZC, et al. Improved Protection in a Rabbit Model of 
Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia 
upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin. Antimicrob Agents 
Chemother. 2016; 60(10):6333-40. 
8. Craven DE, Lei Y, Ruthazer R, Sarwar A, Hudcova J. Incidence and outcomes of 
ventilator-associated tracheobronchitis and pneumonia. Am J Med. 2013;126(6):542-9. 
9. Arsanis, Inc. Data on file. 
10. Stulik L, Hudcova J, Craven DE, Nagy G, Nagy E. Low Efficacy of Antibiotics against 
Staphylococcus aureus Airway Colonization in Ventilated Patients. Clin Infect Dis. 2017. 
Epub ahead of publication. 
11. Smith SB, Ruhnke GW, Weiss CH, Waterer GW, Wunderink RG. Trends in pathogens among 
patients hospitalized for pneumonia from 1993 to 2011. JAMA Intern Med. 
2014;174(11):1837-9. 
12. Lewis SS, Walker VJ, Lee MS, et al. Epidemiology of methicillin-resistant 
Staphylococcus aureus pneumonia in community hospitals. Infect Control Hosp Epidemiol. 
2014;35(12):1452-7. 
13. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator 
associated bacterial pneumonia. Clin Infect Dis. 2010;51(S1):S81-7. 
14. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and 
ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases 
Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. 


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15. Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable mortality of 
ventilator-associated pneumonia from randomized prevention studies. Crit Care Med. 
2011;39(12):2736-42. 
16. Croce MA, Brasel KJ, Coimbra R, et al. National Trauma Institute prospective evaluation of 
the ventilator bundle in trauma patients: does it really work? J Trauma Actue Care Surg. 
2013;74(2):354-60. 
17. Blot S, Lisboa T, Angles R, Rello J. Prevention of VAP: is zero rate possible? Clin Chest Med. 
2011;32(3):591-9. 
18. Klompas M, Kleinman K, Khan Y, et al. Rapid and reproducible surveillance for 
ventilator-associated pneumonia. Clin Infect Dis. 2012;54(3):370-7. 
19. Stulik L, Malafa S, Hudcova J, et al. α-Hemolysin activity of methicillin-susceptible 
Staphylococcus aureus predicts ventilator-associated pneumonia. Am J Respir Crit Care Med. 
2014;190(10):1139-48. 
20. Doessegger L and Banholzer ML. clinical development methodology for infusion-related 
reactions with monoclonal antibodies. Clin Transl Immunology. 2015;4(7):e39. 
 


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Appendix A: Schedule of Procedures 
 
 
Study Period 
Screening/ 
Enrollment 
Randomization 
Treatment 
Monitoring Period 
 
Follow-Up Period 
ET 
Study Day 
 
Up to 
Day -14a 
Day 1 pre-dose 
Day 1 
Day 2/3b 
(BAL PK 
sub-study) 
Day 2 to 
Day 21c 
Day 22 
(+2 days)  
Day 28 
(+2 days)d  
Day 40 
to 
Day 89e 
 
 
Day 90 
(±7 days) 
Safety 
Visitf 
Unschedg 
Study Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion/ 
randomization criteria 
Xh,i 
Xj 
 
 
 
 
 
 
 
 
Medical history 
Xh 
Xk 
 
 
 
 
 
 
 
 
Demographics 
Xh 
 
 
 
 
 
 
 
 
 
Antibiotic/medication historyl 
X 
X 
 
 
 
 
 
 
 
 
Height/weight 
Xh 
 
 
 
 
 
 
 
 
 
Physical examinationm 
Xh 
X 
 
 
X 
X 
 
X 
X 
X 
Vital signsn 
Xh 
X 
X 
X 
X 
X 
 
X 
X 
X 
Pregnancy testo 
Xh 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory 
assessments (chemistry, 
hematology, and coagulation)  
  
X 
 
 
Xp 
X 
 
 
 
Xq 
Urinalysis 
 
X 
 
 
Xr 
X 
 
 
 
Xq 
Procalcitonin (analysis 
performed at central lab) 
 
X 
 
 
Xs 
X 
 
 
 
X 
Ventilator device status 
X 
X 
X 
X 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
Chest X-ray/thoracic CT scan 
Xu 
Xv 
 
X 
Xw 
Xw 
 
 
 
 
Nasal swab specimens for 
culture 
 
X 
 
 
 
 
 
 
 
 
ETA for culturex 
X 
 
 
 
 
 
 
 
 
 
Collection/culture of 
additional microbiological 
specimensy 
 
 
 
 
X 
X 
 
 
 
X 
Clinical assessment of 
signs/symptoms of pneumonia  
 
X 
X 
X 
X 
X 
 
 
 
X 
Other S. aureus infection 
assessment  
X 
X 
X 
X 
X 
X 
 
 
 
X 
Footnotes begin on the next page. 


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Appendix A:  Schedule of Procedures (continued) 
Study Period 
Screening/ 
Enrollment 
Randomization 
Treatment 
Monitoring Period 
 
Follow-Up Period 
ET 
Study Day 
Up to 
Day -14a 
Day 1 pre-dose 
Day 1 
Day 2/3b 
(BAL PK 
sub-study) 
Day 2 to 
Day 21c 
Day 22 
(+2 days)  
Day 28 
(+2 days)d  
Day 40 
to 
Day 89e 
 
 
Day 90 
(±7 days) 
Safety 
Visitf 
Unschedg 
Study Procedures 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Blood collection for ADA and 
anti-S. aureus toxin antibodies 
 
X 
 
 
Xz 
X 
 
X 
X 
X 
12-lead ECG 
 
X 
 
 
 
X 
 
X 
X 
X 
Assess survival and discharge 
disposition 
 
 
 
 
 
X 
X 
X 
X 
X 
Study drug administrationaa 
 
 
X 
 
 
 
 
 
 
 
BAL for PKbb 
 
 
 
X 
 
 
 
 
 
 
Blood collection for PK 
sampling and anti-S. aureus 
toxin antibodies 
 
 
Xcc 
Xdd 
Xee 
Xee 
 
Xee 
X 
X 
Track days on ventilator from 
randomization 
 
 
X 
X 
X 
X 
 
X 
X 
X 
Track days in ICU (or other 
observation area)  
 
 
X 
X 
X 
X 
 
X 
X 
X 
Concomitant medicationsl 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Adverse event assessment 
Xff 
X 
X 
X 
X 
X 
 
X 
X 
X 
a. 
Eligible subjects will be screened daily (while mechanically ventilated) for up to 8 days to identify those subjects who are heavily colonized with S. aureus (see Section 3.1). 
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 provided the subject remains mechanically ventilated, for a total Screening 
Period of up to 14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator and providing the subject remains mechanically 
ventilated.  
b. 
Procedures are to be performed 48 hours (±36 hours) post-dose on approximately Day 2 or Day 3, depending on time of study drug administration, for those subjects participating 
in the BAL fluid PK sub-study only or if BAL fluid is collected as part of a standard of care procedure for any subject at any other time post-randomization for any other reason. 
c. 
Procedures are to be performed daily (unless otherwise indicated) from Day 2 to Day 21 while the subject is hospitalized. For subjects participating in the BAL fluid PK 
sub-study, procedures noted for the Day 2 visit only need to be performed 1 time. 
d. 
A follow-up visit will occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the subject is no longer hospitalized. 
e. 
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they receive study treatment, a follow-up safety visit will be performed on the day of 
discharge. 
f. 
If the subject is unable to return to the site, this visit may be conducted by telephone, with procedures performed as appropriate (i.e., concomitant medications and adverse 
events collected). 
g. 
An ET visit will be conducted for subjects who are withdrawn from the study prior to Day 22. 


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h. 
To be performed at the initial Screening Visit only. 
i. 
At the Screening Visit, subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to be eligible to return for the Randomization Visit. 
j. 
At the Randomization Visit, subjects must continue to meet all of the inclusion criteria and none of the exclusion criteria. Subjects must also meet all randomization criteria to 
be eligible to be randomized into the study. 
k. 
Review and record medical history (if changes occurred since the Screening Visit). 
l. 
All prior medications received by the subject within 14 days prior to study drug administration and any concomitant medications used throughout the duration of the study will 
be recorded in the source documents and on the appropriate eCRF. 
m. A complete physical examination will be performed at the Screening Visit and as deemed necessary by the Investigator and will include, at a minimum, a pulmonary examination 
(including auscultation) and assessments of the skin, abdomen, cardiovascular, gastrointestinal, and neurological systems. A limited physical examination will be performed at 
the Randomization Visit, daily during the Monitoring Period (if the subject is hospitalized), on Day 22 (if the subject is hospitalized), at the time of hospital discharge (if 
discharge occurs between Day 40 and Day 90), at the Safety Visit (Day 90) if the visit occurs onsite, and at ET (if applicable). The limited physical examination will include, 
at a minimum, a pulmonary examination (including auscultation). 
n. 
Vital sign measurements will include temperature, systolic and diastolic blood pressure, pulse, respiratory rate, and oxygenation status. Blood pressure and pulse will be assessed 
via an automated device. Manual techniques are only to be used if an automated device is not available. Oxygenation status will be determined via measurement of arterial 
blood gas, provided the subject has an arterial line placed. If no arterial line is present, pulse oximetry may be used. 
o. 
Female subjects of childbearing potential must have a documented negative pregnancy test at the Screening Visit. Female subjects may be enrolled on the basis of a negative 
urine pregnancy test, pending the result of a negative serum pregnancy test prior to randomization. A pregnancy test will also be performed on Day 22 or ET (if applicable). 
Additional pregnancy testing may occur throughout the duration of the study, per applicable country requirements. 
p. 
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1 day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, and twice weekly during 
Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through Day 21) of the Monitoring Period while the subject remains hospitalized. 
q. 
To be obtained if clinically indicated. 
r. 
Urinalysis to be obtained on Day 6 (±1 day) of the Monitoring Period only. 
s. 
Procalcitonin testing to occur on the day of diagnosis of pneumonia, if applicable. 
t. 
If applicable. 
u. 
A chest X-ray or thoracic CT scan is to be obtained 1 time at the initial Screening Visit. A chest X-ray or thoracic CT scan obtained as part of standard of care within 24 hours 
prior to the initial Screening Visit is sufficient provided there are no changes in the subject’s clinical status (e.g., no change in ventilation status, secretions, or signs/symptoms 
that may be suggestive of pneumonia) within the 24 hours following imaging. 
v. 
A chest X-ray or thoracic CT scan obtained within 24 hours of the Randomization Visit is sufficient, provided there are no changes in the subject’s clinical status (e.g., no 
change in ventilation status, secretions, or signs/symptoms that may be suggestive of pneumonia) since the time of imaging. 
w. A chest X-ray or thoracic CT scan is required during the Monitoring Period for those subjects presenting with signs and symptoms of a respiratory infection such as dyspnea, 
tachypnea, fever, or cough. 
x. 
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of MSSA and MRSA (e.g., CHROMagarTM Staph aureus) for more rapid and specific 
detection of S. aureus. If the site is not able to obtain chromogenic media for S. aureus, appropriate chromogenic media may be supplied by the Sponsor. Semi-quantitative 
cultures using chromogenic media are preferred for determination of eligibility for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to randomize the subject within 48 hours (or up to 60 hours with Medical Monitor 
approval) from the time the ETA sample was collected. If subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible for re-screening as a 
new subject enrollment. Subjects who were previously randomized are not eligible to be re-consented and re-screened. Subjects with a screening ETA culture that also shows 
heavy colonization of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and Gram-negative organisms), will not be randomized into the study; 
however, randomization should not be delayed while waiting for Gram-negative results if heavy colonization with S. aureus has been confirmed. 
y. 
Adequate respiratory specimen or other microbiological specimens to be obtained if clinically indicated. If, as part of routine standard of care, additional respiratory and/or other 
microbiological specimens are collected for culture during the study, results will be documented within the eCRF. 
z. 
Obtain sample for ADA (to be obtained only upon discharge from the ICU, if discharge occurs prior to Day 22). 


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aa. Study drug will be administered in a double-blind manner. Subjects will receive ASN100 or matching placebo via 2 IV infusions over a duration of approximately 50 to 
60 minutes per infusion. Both ASN100 and placebo will be administered as 2 separate infusions (either sequentially or simultaneously). The last infusion will be completed 
within 5 hours from initiation of drug preparation in the pharmacy. 
bb. Obtain BAL fluid 48 hours (±36 hours) post-dose to determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid is collected as part of a standard of care procedure 
from any subject enrolled in the sub-study at any other time post-randomization for any other reason, if possible, a sample for PK analysis will also be obtained. 
cc. Blood samples for PK analysis will be collected immediately following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 24 hours (±6 hours) 
post-dose. 
dd. Obtain a blood sample for PK measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection or if BAL fluid is collected as part of a standard 
of care procedure from any subject enrolled in the sub-study at any time post-randomization). 
ee. A PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected 
on the day of discharge (if discharge occurs between Day 40 and Day 90). 
ff. 
Adverse events that occur between the time the subject signs the ICF and the Randomization Visit will only be recorded if related to a study-specific procedure. 
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; CT = computed tomography; ECG = electrocardiogram; eCRF = electronic Case Report Form; ELF = epithelial lining 
fluid; ET = Early Termination; ETA = endotracheal aspirate; ICF = Informed Consent Form; ICU = intensive care unit; IV = intravenous; MRSA = methicillin-resistant S. aureus; 
MSSA = methicillin-susceptible S. aureus; PK = pharmacokinetic; S. aureus = Staphylococcus aureus; Unsched = unscheduled.


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Appendix B: Clinical Laboratory Analytes 
Chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Direct bilirubin 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Hematology  
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with 
differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
RBC indices: mean corpuscular volume 
(MCV), mean corpuscular hemoglobin 
(MCH), %Reticulocytes 
Coagulation  
Prothrombin time (PT) 
Partial thromboplastin time (PTT) 
Urinalysis  
pH 
Blood 
Ketones 
Specific Gravity 
Leukocyte esterase 
Bilirubin  
Glucose 
Nitrite 
Protein 
 
Other Screening Tests as Needed (for female subjects of childbearing potential only) 
Urine and/or serum pregnancy test 
Other Tests 
Procalcitonin (PCT)  
 
 
 
 


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Appendix C: Site-Specific Sub-Study for Subjects Diagnosed with Pneumonia 


 
CLINICAL STUDY PROTOCOL 
Site-Specific Addendum 
PRIMARY STUDY TITLE:  A Phase 2, Randomized, Double-
Blind, Placebo-Controlled Study to Determine the Safety and 
Efficacy of a Single Dose of ASN100 for the Prevention of 
Staphylococcus aureus Pneumonia in Heavily Colonized, 
Mechanically Ventilated Subjects  
SITE-SPECIFIC SUB-STUDY TITLE:  Safety and Efficacy of a 
Single Dose of ASN100 (versus Placebo) in Heavily Colonized 
Mechanically Ventilated Subjects Who Develop Pneumonia Prior 
to Randomization in Study ASN100-201 
 
Investigational Product: ASN100 
Protocol Number: ASN100-201 
IND Number: 128766 
EudraCT Number: 2016-002146-23 
 
Sponsor: 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA 02451-1472 
 Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 
 
Site-Specific Addendum:  23 April 2018 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written consent of 
Arsanis, Inc. except to the extent that disclosure would be required by law and for the purpose of 
evaluating and/or conducting a clinical study for Arsanis, Inc. You are allowed to disclose the contents of 
this document only to your Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and 
study personnel directly involved with conducting this protocol. Persons to whom the information is 
disclosed must be informed/notified that the protocol content is confidential and proprietary to Arsanis, 
Inc. and that it may not be further disclosed to third parties. 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 81 
1. 
PURPOSE OF THIS SITE-SPECIFIC ADDENDUM ..................................................... 83 
2. 
SUB-STUDY OBJECTIVES............................................................................................ 84 
2.1. 
Primary Objective ....................................................................................................... 84 
2.2. 
Additional Objectives ................................................................................................. 84 
3. 
SUB-STUDY DESIGN AND DURATION ..................................................................... 85 
4. 
SELECTION OF SUB-STUDY SUBJECTS ................................................................... 88 
4.1. 
Inclusion Criteria ........................................................................................................ 88 
4.2. 
Exclusion Criteria ....................................................................................................... 88 
5. 
SUB-STUDY TREATMENTS ......................................................................................... 89 
5.1. 
Study Medication ........................................................................................................ 89 
5.1.1 ASN100................................................................................................................. 89 
5.1.2 Placebo .................................................................................................................. 89 
6. 
SUB-STUDY PROCEDURES ......................................................................................... 90 
7. 
EFFICACY ASSESSMENTS .......................................................................................... 91 
7.1. 
Primary Efficacy Endpoint ......................................................................................... 91 
7.2. 
Additional Efficacy Endpoints .................................................................................... 91 
7.3. 
Microbiological and Clinical Assessments ................................................................. 91 
7.3.1 Microbiological Assessment ................................................................................. 91 
7.3.2 Assessment of Clinical Signs/Symptoms and Pneumonia Progression Status ..... 92 
7.3.3 Evaluation of Pneumonia Outcomes ..................................................................... 92 
8. 
Pharmacokinetics .............................................................................................................. 95 
9. 
STATISTICAL ANALYSES ........................................................................................... 96 
9.1. 
Analysis Populations ................................................................................................... 96 
9.2. 
Sample Size Determination......................................................................................... 96 
9.3. 
Statistical Methods ...................................................................................................... 96 
10. 
APPENDICES .................................................................................................................. 98 
10.1. Schedule of Procedures for Sub-Study ....................................................................... 98 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ASN100 
A combination of 2 fully human monoclonal antibodies (ASN-1 and ASN-2) 
AUC 
Area under the serum concentration-time curve 
BAL 
Bronchoalveolar lavage 
CFU 
Colony forming units 
CIP 
Council of independent physicians 
CT 
Computed tomography 
Cmax 
Maximum serum concentration 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ELF 
Epithelial lining fluid 
E-mMITT 
Expanded Microbiologically Evaluable Modified Intent-to-Treat 
ET 
Early termination 
ETA 
Endotracheal aspirate 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HABP 
Hospital-acquired bacterial pneumonia 
ICF 
Informed consent form 
ICU 
Intensive care unit 
ITT 
Intent-to-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat 
mMITT 
Microbiologically Evaluable Modified Intent-to-Treat 
MRSA 
Methicillin-resistant Staphylococcus aureus 
MSSA 
Methicillin-susceptible Staphylococcus aureus 
PaO2 
Partial pressure of oxygen in arterial blood 
PCT 
Procalcitonin  
PEEP 
Positive end-expiratory pressure 
PK 
Pharmacokinetic  
PSB 
Protected specimen brush 
S. aureus 
Staphylococcus aureus 
t1/2 
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum serum concentration 
VABP 
Ventilator-associated bacterial pneumonia 


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Term 
Definition 
Adequate respiratory specimen 
Intubated Subjects:  A respiratory specimen obtained by BAL, non-
bronchoscopic BAL, or protected specimen brush 
Extubated Subjects:  An expectorated/induced sputum specimen that yields 
<10 squamous cells and >25 polymorphonuclear cells/100× field 
Heavy colonization of S. aureus 
An endotracheal culture result of ≥105 CFU/mL (quantitative culture) or 3+/4+ 
(semi-quantitative culture) 
S. aureus pneumonia 
Pneumonia with the growth of S. aureus from an adequate respiratory sample 


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1. 
PURPOSE OF THIS SITE-SPECIFIC ADDENDUM 
This addendum contains a detailed description of the additions made to the protocol for Study 
ASN100-201. These additions apply to selected sites only. Approximately 50 subjects will 
participate in this site-specific sub-study. The purpose of this addendum is to allow subjects who 
meet the criteria for heavy endotracheal colonization with S. aureus, but who have progressed to 
pneumonia prior to randomization into the primary study, to be randomized and receive ASN100 
(or placebo) as adjunct therapy for treatment of the pneumonia.  (Note: Subjects enrolled in the 
primary ASN100-201 study, who are found to have heavy endotracheal colonization with 
S. aureus, but who have already progressed to pneumonia, are not eligible for randomization into 
the primary study.) 


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2. 
SUB-STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the sub-study is to evaluate the safety, tolerability, and efficacy of a 
single dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo, in 
addition to standard of care, as adjunctive therapy for the treatment of ventilator-associated 
S. aureus pneumonia. 
2.2. 
Additional Objectives  
Additional objectives of this sub-study are to compare ASN100 versus placebo (added to standard 
of care) with regard to the following: 
• The duration of mechanical ventilation post-treatment; 
• The resolution time for S. aureus pneumonia, all bacterial pneumonias, and non-S. aureus 
bacterial pneumonia;  
• The length of stay in the intensive care unit (ICU) and length of hospital stay post-
treatment;  
• 28-day all-cause mortality; 
• The incidence of other S. aureus-associated infections which occur after dosing up to but 
not including Day 22; and 
• Serum pharmacokinetics (PK) (i.e., maximum serum concentration [Cmax], time to 
maximum serum concentration [Tmax], area under the serum concentration-time curve 
[AUC], and terminal elimination half-life [t1/2]) of ASN-1 and ASN-2 in mechanically 
ventilated subjects heavily colonized with S. aureus who developed pneumonia;  
• ASN-1 and ASN-2 levels in bronchoalveolar lavage (BAL) fluid and calculate a blood to 
epithelial lining fluid (ELF) ratio in those subjects who undergo BAL as part of their 
microbiological evaluation of their pneumonia or as part of their standard of care; 
• Immunogenicity (development of anti-drug antibodies) of a single dose of ASN100. 


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3. 
SUB-STUDY DESIGN AND DURATION 
This is a double-blind, randomized, single-dose, placebo-controlled, site-specific, sub-study of 
ASN100 as adjunctive treatment of S. aureus pneumonia. In the primary study, subjects will be 
screened for eligibility; once an informed consent form is signed (or, in countries where it is 
applicable, a decision is made by the council of independent physicians [CIP]), and all entry 
criteria are met, a subject is considered to be enrolled in the study. All enrolled subjects will 
undergo an observational stage evaluating endotracheal colonization. Subjects who are 
randomized will undergo Treatment, Monitoring, and Follow-Up Periods. 
In the parent study, approximately 2250 eligible subjects who meet all of the inclusion criteria and 
none of the exclusion criteria will be screened daily (while mechanically ventilated) for up to 
8 days to identify those subjects who are heavily colonized with S. aureus.  
Screening for heavy S. aureus colonization by endotracheal aspirate (ETA) culture will continue 
on Days 11 and 14 (provided the subject remains mechanically ventilated) for a total Screening 
Period of up to 14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the 
discretion of the Investigator and providing the subject remains mechanically ventilated.  
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or 
semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of 
methicillin-susceptible S. aureus and methicillin-resistant S. aureus (e.g., CHROMagarTM Staph 
aureus) for more rapid and specific detection of S. aureus. If the site is not able to obtain 
chromogenic media for S. aureus, appropriate chromogenic media may be supplied by the 
Sponsor.  
Semi-quantitative cultures using chromogenic media are preferred for determination of eligibility 
for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to 
randomize the subject within 48 hours (or up to 60 hours with Medical Monitor approval) from 
the time the ETA sample was collected. 
If an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization and 
subsequently develops pneumonia, they are ineligible for the primary study but then become 
eligible for this sub-study. If they meet all of the inclusion and none of the exclusion criteria of 
this sub-study, they are eligible for randomization into this sub-study.  
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into this sub-study; however, 
randomization should not be delayed while waiting for Gram-negative or other culture results if 
heavy colonization with S. aureus has been confirmed. 
 
 


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Also, at the time of randomization, subjects will be stratified into 3 groups according to their 
previous and/or current anti-staphylococcal antibiotic exposure that is potentially effective against 
S. aureus pneumonia:   
• Group 1:  <24 hours (for example one dose of a daily antibiotic, 2 doses of a twice-daily 
antibiotic) 
• Group 2:  ≥24 but <72 hours  
• Group 3:  ≥72 hours   
This stratification will ensure balance of prior effective antibiotic treatment between the ASN100 
and placebo groups. 
Nasal swab specimens (one from each nostril) will be obtained at the Randomization Visit and will 
be cultured by the central microbiology laboratory. Results from the nasal swab specimen cultures 
will be used to assess correlation with results of the qualifying ETA culture. 
Upon determination of eligibility, approximately 50 subjects will be randomized in a 1:1 ratio to 
1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate intravenous (IV) 
infusions of ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
Following randomization on Day 1, in addition to any standard-of-care therapy for their 
pneumonia, subjects will receive either a single IV dose of 3600 mg of ASN100 or matching 
placebo. 
An adequate respiratory sample (defined in the primary study) to determine the microbiological 
etiology of the pneumonia is to be collected within 36 hours of randomization, although all 
attempts should be made to obtain the specimen as close as possible to when the diagnosis of 
pneumonia is made.  Note:  Any time a BAL/non-bronchoscopic BAL or protected specimen brush 
(PSB) is performed to collect a respiratory microbiological sample, then a PK sample should also 
be collected to determine ASN-1 and ASN-2 levels to derive blood to ELF ratio, and to measure 
S. aureus toxins. 
While hospitalized, randomized subjects will be monitored daily for up to 21 days for pneumonia 
resolution or recurrence, and the occurrence of other S. aureus-associated infections. If a subject’s 
clinical symptoms of pneumonia improve such that no further antibiotic therapy is required, or if 
the pneumonia persists requiring a change in antibiotic therapy, then all attempts will be made to 
collect an adequate respiratory specimen. 
All randomized subjects will undergo a study visit on Day 22 (+2 days) for assessment of 
pneumonia. An adequate respiratory specimen should be obtained from subjects who remain 
ventilated and non-ventilated subjects who are able to produce sputum. 
A Follow-Up Visit will occur on Day 28 (+2 days) to assess mortality.  This visit may be conducted 
via telephone if the subject is no longer hospitalized.  


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For subjects who remain hospitalized between Days 40 and 90 at the institution where they receive 
study treatment, the Follow-Up Visit will be performed on the day of discharge. 
All randomized subjects will return for a Safety Visit on Day 90 (±7 days) (if the subject is unable 
to return to the site, this visit may be conducted by telephone). Subjects who discontinue the study 
prior to Day 22 will undergo an Early Termination Visit. The end of the study will occur upon 
completion of the last study visit (e.g., Day 90) visit by the last subject. 
Safety assessments for this study will include adverse event (AE) monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), chest X-rays and/or 
thoracic computed tomography (CT) scans, and the determination of the presence of ASN-1 and 
ASN-2 anti-drug antibodies (ADAs).  Additional safety assessments may be performed throughout 
the duration of the study if clinically indicated. 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), and on Day 
22 or Early Termination (if applicable). 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. Blood 
samples for PK analysis will be collected immediately following the completion of the second 
infusion (+15 minutes) and at 6 hours (±4 hours) and 24 hours (±6 hours) post-dose following the 
second infusion. In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 
7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will 
be collected on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 
(if hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable).  
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined, and no 
genetic information will be extracted from these blood samples.  Blood samples will be destroyed 
following the completion of all S. aureus anti-toxin antibody analyses. 
BAL fluid obtained during the procedure to assess the baseline pneumonia pathogen (within 
36 hours of randomization), and in subjects who participate in the BAL PK sub-study, will be 
analyzed for the presence of S. aureus toxins. No genetic information will be extracted from these 
samples, which will be destroyed following the completion of this analysis. 


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4. 
SELECTION OF SUB-STUDY SUBJECTS 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria at the Randomization Visit in order to be eligible 
for randomization into the sub-study: 
1. Subject is currently hospitalized and enrolled in the Arsanis Protocol ASN100-201; 
2. Subject is presumed to have S. aureus pneumonia as determined by heavy S. aureus 
colonization of ETA (defined as quantitative threshold of ≥105 CFU/mL or 3+ to 4+ by 
semi-quantitative culture); 
3. Subject has both signs and symptoms supporting a clinical diagnosis of pneumonia per 
the Investigator and has an imaging study (chest X-ray or thoracic CT) supportive of the 
diagnosis of pneumonia; and 
4. Subject is randomized within 24 hours of the imaging study supporting the diagnosis of 
pneumonia (see Criterion 3 above). 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria at the Randomization Visit will be excluded from 
participation in the sub-study: 
1. Subject has a known and documented ETA culture showing heavy colonization with a 
non-Staphylococcus aureus organism (e.g., a Gram-negative organism)  
NOTE: Randomization should not be delayed while waiting for other culture results if 
heavy colonization with S. aureus has been confirmed. 
2. Subject has been diagnosed with neutropenia (absolute neutrophil count <500/mm3); 
3. Subject has a severe non-pulmonary source of infection which, in the Investigator’s 
opinion, would interfere with the conduct of the study or jeopardize the subject’s safety; 
4. Subject has been previously exposed to ASN100 or ASN-1 or ASN-2, individually; 
5. Subject has a known hypersensitivity to ASN100 or any of its excipients; 
6. Subject has received any investigational product within 30 days prior to the Screening 
Visit (or 5 half-lives of the investigational product, whichever is longer); 
7. Subject has, in the opinion of the Investigator, a high probability of death within 72 hours 
of randomization;  
8. Subject is, in the opinion of the Investigator, not able or willing to comply with the 
protocol;  
9. Subject has any condition that, in the opinion of the Investigator, would compromise the 
safety of the subject, the potential activity of the study drug, or the quality of the data; or 
10. Subjects with a known history or current (suspected) diagnosis of cytokine release 
syndrome associated with the administration of peptides, proteins, and/or antibodies. 
NOTE: Subjects with a prior history of sepsis are not excluded. 


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5. 
SUB-STUDY TREATMENTS 
5.1. 
Study Medication 
Study medication (ASN100 or placebo) will be administered at the same dose and following the 
same preparation and administration procedures as per the primary study. 
5.1.1 
ASN100 
ASN-1 and ASN-2 will be supplied in separate 10-mL vials as a sterile, colorless, clear solution 
for infusion with an extractable volume of 10 mL and a nominal mAb concentration of 20 mg/mL. 
Each vial will contain 200 mg of ASN-1 or 200 mg of ASN-2.  ASN100 will be administered as 
separate infusions of 1800 mg ASN-1 and 1800 mg ASN-2 (9 vials of each to be pooled aseptically 
according to the Pharmacy Manual into separate infusion bags), each delivered over 50-60 minutes 
intravenously, either sequentially within a 3-hour window from the time of initiation of the first 
infusion to the completion of the second infusion, or simultaneously. 
5.1.2 
Placebo 
Matched vials of ASN-1 placebo and ASN-2 placebo will be provided. 
Placebo will be administered as separate infusions of 9 vials of ASN-1 placebo and 9 vials of 
ASN-2 placebo (vials to be pooled aseptically according to the Pharmacy Manual into separate 
infusion bags), each delivered over 50-60 minutes intravenously, either sequentially within a 3-
hour window from the time of initiation of the first infusion to the completion of the second 
infusion, or simultaneously. 


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6. 
SUB-STUDY PROCEDURES 
Following randomization into the sub-study, procedures and assessments will follow those of the 
primary study, with minor modifications given the treatment aims of this sub-study. See 
Section 10.1 for a schedule of procedures for this sub-study. 


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7. 
EFFICACY ASSESSMENTS  
7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the resolution of S. aureus pneumonia in the microbiologically 
evaluable modified intent-to-treat (mMITT) Population up to, but not including, Day 22. 
7.2. 
Additional Efficacy Endpoints 
• The time to resolution of S. aureus pneumonia in the modified intent-to-treat (MITT), 
mMITT, and expanded microbiologically evaluable modified intent-to-treat (E-
mMITT) Populations; 
• The time to resolution of all bacterial pneumonia in the MITT and mMITT Populations; 
• The time to resolution of non-S. aureus pneumonia in the MITT and mMITT 
Populations; 
• Duration of mechanical ventilation during the first 21 days post-randomization for 
subjects in the MITT, mMITT, and E-mMITT Populations; 
• Length of ICU and hospital stay during the first 21 days post-randomization for subjects 
in the MITT, mMITT, and E-mMITT Populations; 
• Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single dose of 
ASN100 in the pharmacokinetic (PK) Population;  
• 28-day all-cause mortality in the MITT, mMITT, and E-mMITT Populations; 
• Development of ADAs to a single dose of ASN100; 
• ASN-1 and ASN-2 levels in BAL fluid and blood to ELF ratio; and 
• Incidence of other non-pulmonary S. aureus infections acquired following study drug 
administration up to the final study visit (e.g., Day 90, Early Termination, etc.) in the 
mMITT and E-mMITT Populations. 
7.3. 
Microbiological and Clinical Assessments 
7.3.1 
Microbiological Assessment 
In the primary study, ETA specimens will be collected for culture during the Screening/Enrollment 
Period to determine the degree of S. aureus colonization. Additional respiratory specimens may 
be collected for culture throughout the Monitoring Period or at Early Termination (if applicable) 
if clinically indicated according to standard of care. 
If, as part of routine standard of care, additional respiratory and/or other microbiological specimens 
are collected for culture during the study, results will be documented within the electronic case 
report form. As described within the study laboratory manual, bacterial isolates recovered from 
these specimens that are deemed pathogens by the Investigator (if retained and available at the 
study site local microbiology laboratory) will be sent to a central microbiology laboratory for 
confirmation of pathogen identification (all isolates) and susceptibility testing (S. aureus isolates 
only). 


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For a Sponsor diagnosis of S. aureus pneumonia, an adequate respiratory specimen culture that is 
positive for S. aureus must be obtained within 36 hours from randomization.   
• For intubated subjects, a respiratory specimen obtained by BAL, non-bronchoscopic BAL, 
or PSB will be considered an adequate respiratory specimen; 
• For extubated subjects, an adequate expectorated/induced sputum specimen is defined as 
<10 squamous epithelial cells and >25 PMNs/100× field; and 
• Adequate respiratory specimens will undergo either semi-quantitative or quantitative 
culture in accordance with the local laboratory standard procedure.  For each subject, the 
sampling and testing method should be consistent for microbiological diagnosis of both 
pneumonia and its resolution. 
7.3.2 
 Assessment of Clinical Signs/Symptoms and Pneumonia Progression Status 
Subjects will be assessed daily throughout the Monitoring Period for the following clinical signs 
and symptoms and pneumonia progression status: 
Clinical Signs and Symptoms and Pneumonia Progression Status 
Mechanically Ventilated Subjects 
Non-Mechanically Ventilated Subjects 
Cough 
Rales 
Dullness on percussion * 
Bronchial breath sounds 
Egophony* 
Need for suctioning 
Need for ventilator support 
Fever ≥38°C (≥100.4°F) 
Presence of purulent secretions 
PaO2 (if measured) 
FiO2 (most representative setting) 
PEEP (most representative setting) 
Cough 
Rales 
Dullness on percussion * 
Bronchial breath sounds 
Egophony * 
Dyspnea 
Tachypnea 
Respiratory rate 
Hypoxemia 
Fever ≥38°C (≥100.4°F) 
Supplemental oxygen (i.e., nasal canula 2L, face mask at 30% O2) 
Presence of purulent secretions 
Fi02 = fraction of inspired oxygen; PaO2 = partial pressure of oxygen in arterial blood; PEEP = Positive end-expiratory 
pressure  
*If routinely performed. 
7.3.3 
 Evaluation of Pneumonia Outcomes 
7.3.3.1. 
Clinical Outcomes of Pneumonia According to Investigator 
In addition to the daily assessment of respiratory signs and symptoms, the Investigator will make 
a determination of pneumonia resolution if the subject meets all four of the following criteria:  
• Complete resolution of all or most of the pneumonia clinical signs and symptoms; 
• No new signs, symptoms, or complications of pneumonia; 
• No additional antibiotic therapy administered for pneumonia; and 
• Subject is alive. 


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7.3.3.2. 
Clinical Outcomes at Day 22 (Test of Cure) 
Clinical outcome will be assessed by the Sponsor as cured, failure, or indeterminate using the 
criteria below.  The classifications will be determined at Study Day 22 based on data collected and 
reported by the Investigator during the monitoring period. 
Cured  
To be classified as cured, subjects must meet all of the following criteria: 
1. Alive 
2. Resolution of signs and symptoms of infection or significant improvement of the index 
infection, including all of the following: 
• Improvement in signs and symptoms since diagnosis of pneumonia; 
• Improvement in oxygenation, as defined by any of the following:  
o Extubation (or removal of tracheostomy tube); 
o Improvement in PaO2:FiO2 by ≥20 mmHg [≥2.7 kPa]; or  
o Reduction in PEEP ≥2 cm for at least 2 consecutive days.  
(Note:  Failure of extubation should not be considered a clinical failure if it is due 
to reasons other than pneumonia; the reason for failure of extubation should be 
documented.) 
• Absence of fever (core temperature of >38.0ºC [>100.4ºF]) or hypothermia (<35ºC 
[<95 ºF]); 
• Absence of purulent sputum or other deep respiratory specimen; and 
• A 25% or more decrease in WBC count from the peak value associated with the 
diagnosis of pneumonia if the WBC was greater than 11,000/mm3 
3. No requirement for new or additional antimicrobial therapy for treatment of pneumonia 
and did not require antibiotic therapy beyond Study Day 14   
Failure 
Subjects meeting either of the following criteria will be classified as failures: 
1. Subject fails to meet any of the criteria for cure (above) or 
2. Subject dies of pneumonia >48 hours post-treatment with study medication 
Indeterminate  
Subjects meeting any the following criteria will be classified as indeterminate: 
1. Subjects lost to follow-up;  
2. Subjects for whom data are unavailable to allow for a determination of clinical cure or 
failure;  
3. Subjects who die within the first 48 hours; or  


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4. Subjects who change antibiotic therapy within the first 48 hours based on insufficient 
therapeutic effect.   
7.3.3.3. 
Microbiological Outcomes at Day 22 (Test of Cure)  
Eradication (documented or presumed) of the baseline pathogen(s) will be considered 
microbiological success while any new pathogen or persistence (documented or presumed) will be 
considered microbiological failure.  Specific microbiological outcomes definitions are as follows: 
 
Eradication: 
Absence of the baseline pathogen in an adequate post-
baseline respiratory specimen. 
Presumed Eradication: 
Absence of an adequate post-baseline respiratory 
specimen to culture in a subject deemed a clinical 
cure.  
Persistence: 
Presence of the baseline pathogen in an adequate 
post-baseline respiratory specimen. 
Presumed Persistence: 
Absence of an adequate post-baseline respiratory 
specimen to culture in a subject deemed a clinical 
failure. 
Indeterminate: 
Non-qualifying growth from the baseline respiratory 
culture or any confounding factors (e.g., early 
discontinuation from study medication) that prevent 
the assignment of an appropriate microbiologic 
outcome. 
Recurrence or Relapse: 
Isolation of a S. aureus strain from an adequate post-
baseline respiratory specimen after documented 
eradication. 
Emergent Infections or Superinfection: 
Isolation of a different pathogen, other than a baseline 
pathogen, from an adequate post-baseline respiratory 
specimen obtained in a subject with signs and 
symptoms of infection, while the subject is still on 
antibiotic therapy for the original infection. 
New Infection: 
Isolation of a different pathogen, other than the 
baseline pathogen, from a culture obtained after 
completion of antibiotic therapy in a subject with 
signs and symptoms of infection.  
 


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8. 
PHARMACOKINETICS 
The PK endpoints are the Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a 
single IV dose of ASN100 in the PK Population. 
Blood samples for the measurement of ASN-1 and ASN-2 in serum will be collected from all 
subjects in the sub-study on the same schedule as for the parent study. Samples will be collected 
at the following timepoints: 
• Immediately following the completion of the second infusion (+15 minutes), and at 
6 hours (±4 hours) and 24 hours (±6 hours) post-dose following the second infusion.  
• Days 4 (±1 day), 7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period.  
• Day of hospital discharge (if discharge occurs between Day 40 and Day 90), on Day 90 
(if hospitalized or if the subject is able to return to the clinic), or Early Termination (if 
applicable).  
Subjects may also participate in an optional BAL fluid PK sub-study as part of the primary study. 
If adequate fluid is obtained and available, lung fluid will be analyzed to measure S. aureus toxins.   
Please refer to Section 8.2 in the primary study protocol for additional specifics regarding the BAL 
sub-study. 
 


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9. 
STATISTICAL ANALYSES 
9.1. 
Analysis Populations 
Intent-to-Treat (ITT) Population 
The ITT Population includes all subjects who are randomized to receive study drug. 
Modified Intent-to-Treat (MITT) Population 
The MITT Population includes all subjects in the ITT Population who receive study drug who are 
heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an 
ETA specimen. 
Microbiologically Evaluable Modified Intent-to-Treat (mMITT) Population 
The mMITT Population includes those subjects in the MITT Population that have confirmation by 
an adequate respiratory sample of a microbiological etiology of pneumonia as S. aureus, either 
MSSA or MRSA, without recovery of any other bacterial pathogens 
Expanded Microbiologically Evaluable Modified Intent-to-Treat (E-mMITT) Population  
The E-mMITT Population includes those subjects in the MITT Population that have confirmation 
by an adequate respiratory sample of a microbiological etiology of pneumonia as S. aureus, either 
MSSA or MRSA, with or without recovery of other bacterial pathogens. 
Pharmacokinetic (PK) Population 
The PK Population includes all subjects in the MITT Population with at least one serum PK sample 
collected post-dose. 
Safety Population 
The Safety Population includes all subjects who receive any amount of study drug and have at 
least one post-treatment safety assessment. 
9.2. 
Sample Size Determination 
This is a sub-study examining the potential benefit of ASN100 as an adjunct therapy to standard 
of care for the treatment of S. aureus pneumonia.  No formal statistical assessment for sample size 
determination has been conducted. The sample size is based on practical considerations. An 
estimated sample size of approximately 50 subjects derived from the observed number of subjects 
to date who have developed pneumonia prior to randomization in the primary study. 
9.3. 
Statistical Methods 
To insure balance among the treatment groups, randomization for the sub-study will be stratified 
by the number of days a subject has received anti-staphylococcal antibiotics on or prior to the time 
of randomization which are potentially effective against S. aureus pneumonia (further described 
in Section 3 of this Site-specific Addendum).  
Continuous variables will be summarized by using the number of non-missing observations, 
arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive 
statistics. Categorical variables will be summarized by using the frequency count and the 
percentage of subjects in each category as descriptive statistics.  


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The primary endpoint reflecting clinical activity is the resolution of S. aureus pneumonia up to but 
not including Day 22. Analysis will include the comparison of the proportion of subjects who 
resolve S. aureus pneumonia in the ASN100 arm versus the placebo arm in the mMITT Population. 
An additional endpoint includes the time to resolution of S. aureus pneumonia. 
Duration of mechanical ventilation and length of hospital and ICU stay up to but not including 
Day 22 post-randomization will be compared between treatment groups. 
Other endpoints will be summarized by treatment group. 
All subjects in the Safety Population will be included in the safety analyses and analyzed based on 
the actual treatment received. 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent adverse events (TEAEs) will be summarized by system organ 
class and preferred term. A TEAE is defined as an adverse event with a start date and time on or 
after the first dose of study treatment. Listings will be provided for serious adverse events and 
adverse events leading to drug discontinuation. In addition, all adverse events will be listed. 
Safety laboratory data and vital sign measurements will be presented by each scheduled time point 
and for change from baseline to each time point. The results of all laboratory tests, physical 
examination findings, vital sign measurements, and ADAs will be presented in data listings. 
Descriptive statistics will be provided for all PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population.  Subject PK profiles will be determined using 
parameters such as Cmax, Tmax, AUC, and t1/2 for each of ASN-1 and ASN-2 in serum. Epithelial 
lining fluid PK will also be analyzed and a serum/ELF PK ratio will be calculated. 
 
 
 


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10. 
APPENDICES 
10.1. 
Schedule of Procedures for Sub-Study 
 
Study Period 
Random-
ization 
Treatment 
Monitoring Period 
Follow-Up Period 
ET 
Study Day 
Day 1  
Pre-dose 
Day 1 
Day 2/3j 
(BAL PK 
Sub-study) 
Days 2 
to 21k 
Day 22 
(+2 days)  
Day 28 
(+2 days)l  
Days 40 
to 89m 
Day 90 
(±7 days) 
Safety Visitn 
Unschedo 
Study Procedures 
Inclusion/exclusion criteria 
Xp 
 
 
 
 
 
 
 
 
Medical history a 
X 
 
 
 
 
 
 
 
 
Antibiotic/medication history a 
X 
 
 
 
 
 
 
 
 
Physical examination b 
X 
 
 
X 
X 
 
X 
X 
X 
Vital signs c 
X 
X 
X 
X 
X 
 
X 
X 
X 
Pregnancy test d 
X 
 
 
 
X 
 
 
 
X 
Clinical lab assessments e 
X 
 
 
X 
X 
 
 
 
Xy 
Urinalysis 
X 
 
 
Xq 
X 
 
 
 
Xy 
Procalcitonin (central lab) 
X 
 
 
 
X 
 
 
 
X 
Ventilator device status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray/thoracic CT scan 
X 
 
X 
Xr 
X 
 
 
 
Xr 
Nasal swab for culture 
X 
 
 
 
 
 
 
 
 
Collection/culture of respiratory 
microbiological specimens f 
X 
 
Xs 
Xt 
 
 
 
Xt 
Collection/culture of additional 
microbiological specimens g 
 
 
 
X 
X 
 
 
 
X 
Clinical assessment of 
signs/symptoms of pneumonia  
X 
X 
X 
X 
X 
 
 
 
X 
Other S. aureus infection assessment  
X 
X 
X 
X 
X 
 
 
 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
Blood collection for ADA and  
anti-S. aureus toxin antibodies 
X 
 
 
Xu 
X 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
X 
X 
X 
Survival and discharge disposition 
 
 
 
 
X 
X 
X 
X 
X 


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Study Period 
Random-
ization 
Treatment 
Monitoring Period 
Follow-Up Period 
ET 
Study Day 
Day 1  
Pre-dose 
Day 1 
Day 2/3j 
(BAL PK 
Sub-study) 
Days 2 
to 21k 
Day 22 
(+2 days)  
Day 28 
(+2 days)l  
Days 40 
to 89m 
Day 90 
(±7 days) 
Safety Visitn 
Unschedo 
Study Procedures 
Study drug administration h 
 
X 
 
 
 
 
 
 
 
BAL for PK (Optional) 
 
 
X 
 
 
 
 
 
 
Blood collection for PK sampling and 
anti-S. aureus toxin antibodies 
 
Xv 
Xw 
Xx 
Xx 
 
Xx 
X 
X 
Track days on ventilator from 
randomization 
 
X 
X 
X 
X 
 
X 
X 
X 
Track days in ICU (or other 
observation area)  
 
X 
X 
X 
X 
 
X 
X 
X 
Concomitant medications i 
X 
X 
X 
X 
X 
 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
 
X 
X 
X 
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; CT = computed tomography; ECG = electrocardiogram; eCRF = electronic Case Report Form; ELF = epithelial lining 
fluid; ET = Early Termination; ETA = endotracheal aspirate; ICF = Informed Consent Form; ICU = intensive care unit; IV = intravenous; MRSA = methicillin-resistant S. aureus; 
MSSA = methicillin-susceptible S. aureus; PK = pharmacokinetic; S. aureus = Staphylococcus aureus; Unsched = unscheduled. 
 
a. 
Review and record medical history and antibiotic/medication history 
b. 
A limited physical examination will be performed at the Randomization Visit, daily during the Monitoring Period (if the subject is hospitalized), on Day 22 (if the subject is 
hospitalized), at the time of hospital discharge (if discharge occurs between Day 40 and Day 90), at the Safety Visit (Day 90) if the visit occurs onsite, and at ET (if 
applicable). The limited physical examination will include, at a minimum, a pulmonary examination (including auscultation). 
c. 
Vital sign measurements will include temperature, systolic and diastolic blood pressure, pulse, respiratory rate, and oxygenation status. Blood pressure and pulse will be 
assessed via an automated device. Manual techniques are only to be used if an automated device is not available. Oxygenation status will be determined via measurement of 
arterial blood gas, provided the subject has an arterial line placed. If no arterial line is present, pulse oximetry may be used. 
d. 
Pregnancy test. Female subjects of childbearing potential must have a documented negative pregnancy test at the Day 1 Pre-Dose (Randomization) Visit. A pregnancy test 
will also be performed on Day 22 or ET (if applicable). Additional pregnancy testing may occur throughout the duration of the study, per applicable country requirements. 
e. 
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1 day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, and twice weekly during 
Week 2 (Days 8 through 14) and/or Week 3 (Days 15 through 21) of the Monitoring Period while the subject remains hospitalized. 
f. 
An adequate respiratory sample to determine the microbiological etiology of the pneumonia should be collected within 36 hours of randomization, although all attempts 
should be made to obtain the specimen as close as possible to when the diagnosis of pneumonia was made.  Note:  Any time a BAL/non-bronchoscopic BAL or protected 
specimen brush (PSB) is performed to collect a respiratory microbiological sample, then a PK sample also should be will be collected to determine ASN-1 and ASN-2 levels 
to derive blood to ELF ratio, and to measure S. aureus toxins. 
g. 
If, as part of routine standard of care, additional non-respiratory microbiological specimens are collected for culture during the study, results will be documented within the 
eCRF; follow laboratory manual for which pathogens should be sent to central lab if isolates are available. 


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100 
h. 
Study drug will be administered in a double-blind manner. Subjects will receive ASN100 or matching placebo via 2 IV infusions over a duration of approximately 50 to 60 
minutes per infusion. Both ASN100 and placebo will be administered as 2 separate infusions (either sequentially or simultaneously). The last infusion will be completed 
within 5 hours from initiation of drug preparation in the pharmacy. 
i. 
All prior medications received by the subject within 14 days prior to study drug administration and any concomitant medications used throughout the duration of the study 
will be recorded in the source documents and on the appropriate eCRF. 
j. 
Procedures are to be performed 48 hours (±36 hours) post-dose on approximately Day 2 or Day 3, depending on time of study drug administration, for those subjects 
participating in the BAL fluid PK sub study only or if BAL fluid is collected as part of a standard of care procedure for any subject at any other time post-randomization for 
any other reason. 
k. 
Procedures are to be performed daily (unless otherwise indicated) from Day 2 to Day 21 while the subject is hospitalized. For subjects participating in the BAL fluid PK sub 
study, procedures noted for the Day 2 visit only need to be performed 1 time. 
l. 
A follow-up visit will occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the subject is no longer hospitalized. 
m. For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they receive study treatment, a follow-up safety visit will be performed on the day 
of discharge. 
n. 
If the subject is unable to return to the site, this visit may be conducted by telephone, with procedures performed as appropriate (i.e., concomitant medications and adverse 
events collected). 
o. 
An ET visit will be conducted for subjects who are withdrawn from the study prior to Day 22. 
p. 
At the Day 1 Pre-Dose (Randomization) Visit, subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to be eligible for this sub-study. 
q. 
Urinalysis to be obtained on Day 6 (±1 day) of the Monitoring Period only 
r. 
Any chest X-ray or thoracic CT scan performed during the monitoring period as part of standard of care will be documented in EDC  
s. 
All respiratory specimens collected as part of standard of care are to be documented in EDC and any isolates stored for transport to the central laboratory.  Additionally, if a 
subject’s clinical symptoms of pneumonia improve such that no further antibiotic therapy is required, or if the pneumonia persists requiring a change in antibiotic therapy, 
then all attempts will be made to collect an adequate respiratory specimen. 
t. 
When possible, an adequate respiratory specimen should be obtained from subjects who remain ventilated and non-ventilated subjects who are able to produce sputum. 
u. 
Obtain sample for ADA (to be obtained only upon discharge from the ICU, if discharge occurs prior to Day 22). 
v. 
Blood samples for PK analysis will be collected immediately following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 24 hours (±6 hours) 
post dose. 
w. Obtain a blood sample for PK measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection or if BAL fluid is collected as part of a 
standard-of-care procedure from any subject enrolled in the sub-study at any time post-randomization). 
x. 
A PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be 
collected on the day of discharge (if discharge occurs between Day 40 and Day 90). 
y. 
To be obtained if clinically indicated. 

Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Determine the Safety and Efficacy of a Single Dose of ASN100 for 
the Prevention of Staphylococcus aureus Pneumonia in Heavily 
Colonized, Mechanically Ventilated Subjects  
 
Investigational Product: ASN100 
Protocol Number: ASN100-201 
IND Number: 128766 
EudraCT Number: 2016-002146-23 
 
Sponsor: 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA  
02451-1472 
 Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 
 
Version Number: 4.0 
Date: 02 May 2017 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Arsanis, Inc. except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Arsanis, Inc. You are allowed to 
disclose the contents of this document only to your Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed/notified that the 
protocol content is confidential and proprietary to Arsanis, Inc. and that it may not be further 
disclosed to third parties. 




Arsanis, Inc. 
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3
INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Arsanis, Inc. (Arsanis) to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study procedures. I will 
let them know that this information is confidential and proprietary to Arsanis and that it may not 
be further disclosed to third parties. I understand that the study may be terminated or enrollment 
suspended at any time by Arsanis, with or without cause, or by me if it becomes necessary to 
protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with the United States Food and Drug 
Administration (FDA) Regulations, Institutional Review Board/Ethic Committee Regulations and 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  


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SYNOPSIS 
TITLE:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Determine the 
Safety and Efficacy of a Single Dose of ASN100 for the Prevention of Staphylococcus aureus
Pneumonia in Heavily Colonized, Mechanically Ventilated Subjects 
PROTOCOL NUMBER:  ASN100-201 
INVESTIGATIONAL PRODUCT:  ASN100 
PHASE:  2 
INDICATION:  The prevention of Staphylococcus aureus (S. aureus) pneumonia in 
mechanically ventilated subjects who are heavily colonized with S. aureus. 
STUDY DEFINITION:  For the purposes of this study, heavy colonization of S. aureus will be 
defined as a quantitative threshold of ≥105 CFU/mL or 3+ to 4+ by semi-quantitative culture from 
an endotracheal aspirate. 
OBJECTIVES: 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of a single 
dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus. 
The secondary objectives of this study are: 
• To compare the duration of mechanical ventilation post-treatment in subjects treated with 
ASN100 versus placebo;  
• To compare the length of stay in the intensive care unit (ICU) post-treatment for subjects 
treated with ASN100 versus placebo;  
• To determine the serum pharmacokinetics (PK) (i.e., maximum serum concentration [Cmax], 
time to maximum serum concentration [Tmax], area under the serum concentration-time curve 
[AUC], and terminal elimination half-life [t1/2]) of ASN-1 and ASN-2 in mechanically 
ventilated subjects heavily colonized with S. aureus; and 
• To compare 28-day all-cause mortality in subjects treated with ASN100 versus placebo. 
The exploratory objectives are: 
• To compare the incidence of hospital-acquired bacterial pneumonia (HABP) occurring 
>48 hours post-extubation up to but not including Day 22 in extubated subjects treated with 
ASN100 versus placebo; 
• To compare the incidence of ventilator-associated bacterial pneumonia (VABP) up to but not 
including Day 22 in subjects treated with ASN100 versus placebo; 


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• To determine the immunogenicity of a single dose of ASN100; 
• To compare the incidence of other S. aureus-associated infections which occur after dosing up 
to but not including Day 22 in subjects treated with ASN100 versus placebo; and 
• To assess ASN-1 and ASN-2 levels in bronchoalveolar lavage (BAL) fluid and calculate a 
blood to epithelial lining fluid (ELF) ratio in those subjects participating in the BAL fluid PK 
sub-study. 
POPULATION: 
Inclusion Criteria 
Subjects must meet all of the following criteria at the Screening and Randomization Visits in order 
to be eligible for randomization into the study: 
1. Subject, legally authorized representative, or council of independent physicians (CIP) (if 
applicable) has provided written informed consent; 
2. Subject is ≥18 years of age at the time of enrollment; 
3. Subject is currently hospitalized and is mechanically ventilated endotracheally
(i.e., orotracheal or nasotracheal) and, in the Investigator’s opinion, will require ongoing 
ventilator support for at least 48 hours; 
NOTE: Subjects with a tracheostomy at the time of enrollment are not eligible. After 
enrollment, conversion to tracheostomy is permitted per standard of care. 
4. Female subjects must not be pregnant or lactating. Female subjects of childbearing potential 
must have a documented negative pregnancy test at the Screening Visit. Female subjects may 
be enrolled on the basis of a negative urine pregnancy test, pending the result of a negative 
serum pregnancy test prior to randomization; and 
5. Female subjects of childbearing potential and non-surgically sterile male subjects who are 
sexually active must agree to use an approved highly effective form of contraception from the 
time of informed consent until 165 days post-dose. Approved forms of contraception include 
hormonal intrauterine devices, hormonal contraceptives (oral birth control pill, depo, patch, or 
injectable) together with supplementary double barrier methods such as condoms or 
diaphragms with spermicidal gel or foam. 
NOTE: The following categories define women who are NOT considered to be of childbearing 
potential: 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy, 
o Documented bilateral salpingectomy, or 
o Documented bilateral oophorectomy, or 
• Postmenopausal female, defined as having amenorrhea for at least 12 months without an 
alternative medical cause.  


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Exclusion Criteria 
Subjects who meet any of the following criteria at the Screening and/or Randomization Visit will 
be excluded from participation in the study: 
1. Subject has received intravenous (IV) immunoglobulin therapy within 4 months prior to the 
Screening Visit; 
2. Subject has a chest X-ray or thoracic computed tomography (CT) scan that is definitive for a 
diagnosis of pneumonia; 
3. Subject demonstrates both of the following: 
a. Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
positive end-expiratory pressure; AND 
NOTE: Changes made in ventilator support due to day-to-day maintenance other than 
those changes made to improve oxygenation will not exclude a subject from participation 
in the study. 
b. New onset of purulent suctioned respiratory secretions; 
4. Subject has a known and documented ETA culture showing heavy colonization with a 
Gram-negative organism at enrollment or at any time during the Screening period; 
NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
5. Subject has been diagnosed with neutropenia (absolute neutrophil count <500/mm3); 
6. Subject has a severe non-pulmonary source of infection which, in the Investigator’s opinion, 
would interfere with the conduct of the study or jeopardize the subject’s safety; 
7. Subject is currently on either continuous veno-venous hemodialysis or extracorporeal 
membrane oxygenation; 
8. Subject has been previously exposed to ASN100 or ASN-1 or ASN-2, individually; 
9. Subject has a known hypersensitivity to ASN100 or any of its excipients; 
10. Subject has received any investigational product within 30 days prior to the Screening Visit 
(or 5 half-lives of the investigational product, whichever is longer); 
11. Subject has, in the opinion of the Investigator, a high probability of death within 72 hours of 
enrollment;  
12. Subject is, in the opinion of the Investigator, not able or willing to comply with the protocol; 
13. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
subject, the potential activity of the study drug, or the quality of the data; or 
14. Subjects with a known history or current (suspected) diagnosis of cytokine release syndrome
associated with the administration of peptides, proteins, and/or antibodies.20 
NOTE: Subjects with a prior history of sepsis are not excluded. 
 


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Randomization Criteria 
At the Randomization Visit, subjects must meet all of the following requirements to be 
randomized into the study: 
1. Subject continues to meet all of the inclusion criteria and none of the exclusion criteria 
required at the Screening Visit; 
NOTE: Subjects who undergo tracheostomy after enrollment are still eligible for 
randomization, provided they remain mechanically ventilated (see criterion 3 below). 
2. Subject is heavily colonized with S. aureus as determined by either quantitative or 
semi-quantitative culture of an endotracheal aspirate (ETA);  
NOTE: The results of the qualifying ETA culture must allow randomization to occur within 
48 hours (or up to 60 hours with Medical Monitor approval) from the time the ETA sample 
was collected. Subjects with ETA culture results obtained after 60 hours showing heavy 
colonization of S. aureus may not be randomized and will be discontinued from the study. 
3. Subject remains mechanically ventilated and, in the Investigator’s opinion, will require 
ongoing ventilator support for at least 48 hours; and 
4. Subject has, in the opinion of the Investigator, a probability of survival beyond 72 hours 
post-randomization. 
STUDY DESIGN AND DURATION: 
This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus. Subjects will be screened for eligibility; once an Informed Consent Form is signed
(or, in countries where it is applicable, a decision is made by the CIP), and all entry criteria are 
met, a subject is considered to be enrolled in the study. All enrolled subjects will undergo an 
observational stage evaluating endotracheal colonization. Subjects who are randomized will 
undergo a treatment, monitoring, and follow-up period. 
Approximately 2250 eligible subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be screened daily (while mechanically ventilated) for up to 8 days to 
identify those subjects who are heavily colonized with S. aureus.  
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 
14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the 
Investigator and providing the subject remains mechanically ventilated.  
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or 
semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of 
methicillin-susceptible S. aureus and methicillin-resistant S. aureus (e.g., CHROMagarTM Staph 
aureus) for more rapid and specific detection of S. aureus. If the site is not able to obtain 
chromogenic media for S. aureus, appropriate chromogenic media may be supplied by the 
Sponsor.  


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Semi-quantitative cultures using chromogenic media are preferred for determination of eligibility 
for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to 
randomize the subject within 48 hours (or up to 60 hours with Medical Monitor approval) from 
the time the ETA sample was collected. 
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization
and meets all of the inclusion and none of the exclusion criteria, they are eligible for 
randomization. If they are not randomized on this occasion according to the protocol, they are no 
longer eligible for continued ETA sampling and randomization, and will be discontinued from the 
study; however, if subjects are extubated and subsequently re-intubated/mechanically ventilated, 
they are eligible for re-screening as a new subject enrollment. Subjects who were previously 
randomized are not eligible to be re-consented and re-screened. 
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into the study; however, 
randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
Nasal swab specimens (one from each nostril) will be obtained at the Randomization Visit and 
will be cultured by the central microbiology laboratory. Results from the nasal swab specimen 
cultures will be used to assess correlation with results of the qualifying ETA culture. 
Upon determination of eligibility, approximately 354 subjects will be randomized in a 1:1 ratio to 
1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate IV infusions of 
ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
To ensure balance among the treatment groups, randomization for this study will be stratified by 
receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the time of randomization 
that are potentially active against S. aureus pneumonia, including, but not limited to, nafcillin, 
oxacillin, vancomycin, linezolid, telavancin, ceftaroline, ceftobiprole, and teicoplanin. 
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg of 
ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-2) or 
matching placebos, per their assigned randomization scheme.  
Randomized subjects will be monitored daily for the signs and symptoms of pneumonia and other 
S. aureus-associated infections while hospitalized up to Day 21. 
All randomized subjects will undergo a study visit on Day 22 (+2 days). A follow-up visit will 
occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the 
subject is no longer hospitalized.  
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they 
receive study treatment, a follow-up safety visit will be performed on the day of discharge. 
All randomized subjects will return for a Safety Visit on Day 90 (±7 days) (if the subject is unable 
to return to the site, this visit may be conducted by telephone). Subjects who discontinue the study 


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prior to Day 22 will undergo an Early Termination Visit. The end of the study will occur upon 
completion of the last Day 90 visit by the last subject. 
Safety assessments for this study will include adverse event monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), chest X-rays and/or 
thoracic CT scans, and the determination of the presence of ASN-1 and ASN-2 anti-drug 
antibodies (ADAs). Additional safety assessments may be performed throughout the duration of 
the study if clinically indicated. 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), on the day 
of diagnosis of pneumonia (if applicable), and on Day 22 or Early Termination (if applicable). 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. Blood 
samples for PK analysis will be collected immediately following the completion of the second 
infusion (+15 minutes) and at 6 hours (± 4 hours) and 24 hours (±6 hours) post-dose following the 
second infusion. In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 
7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will 
be collected on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 
(if hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable). 
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25 to 
35 subjects who volunteer will participate in this sub-study and will have BAL fluid collected 
48 hours (±36 hours) post-dose (on approximately Day 2 or Day 3, depending on time of study 
drug administration) to determine ASN-1 and ASN-2 levels and blood to ELF ratio. Subjects 
participating in the BAL fluid PK sub-study will have a blood sample collected for PK 
measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection 
or if BAL fluid is collected as part of a standard of care procedure from any subject enrolled in 
the sub-study at any time post-randomization). 
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined and no 
genetic information will be extracted from these samples. Samples will be destroyed following 
the completion of all S. aureus anti-toxin antibody analyses. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
ASN100 is a combination product with 2 separate human monoclonal antibody (mAb) 
components of the immunoglobulin G1 isotype. The specific mAbs are formulated separately and 
called ASN-1 and ASN-2. Each component is supplied as a sterile, colorless, clear liquid solution 
formulated ready for injection. 
ASN-1 is a broadly cross-reactive anti-toxin mAb that targets alpha hemolysin and 
3 F-components (gamma hemolysin B, leukocidin F, and leukocidin D) involved in forming 4 of 
the 5 bi-component leukocidins of S. aureus. 
ASN-2 is directed against the fifth bi-component toxin of S. aureus, leukocidin GH. 
ASN-1 and ASN-2 will be supplied in separate 10 mL vials as a sterile solution for infusion with 
an extractable volume of 10 mL and a nominal mAb concentration of 20 mg/mL. Each vial will 


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contain 200 mg of ASN-1 or 200 mg of ASN-2. Matched vials of ASN-1 placebo and 
ASN-2 placebo will also be provided. 
ASN100 will be administered as separate infusions of 1800 mg ASN-1 and 1800 mg ASN-2
(9 vials of each to be pooled aseptically according to the Pharmacy Manual into separate infusion 
bags) delivered either sequentially within a 3-hour window from the time of initiation of the first 
infusion to the completion of the second infusion, or simultaneously. 
Placebo will be administered as separate infusions of 9 vials of ASN-1 placebo and 9 vials of 
ASN-2 placebo (vials to be pooled aseptically according to the Pharmacy Manual into separate 
infusion bags) delivered either sequentially within a 3-hour window from the time of initiation of 
the first infusion to the completion of the second infusion, or simultaneously. 
ANALYSIS POPULATIONS: 
Intent-to-Treat (ITT) Population 
The ITT Population includes all subjects who are randomized to receive study drug.  
Modified Intent-to-Treat (MITT) Population 
The MITT Population includes all subjects in the ITT Population who receive study drug who are 
heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an 
ETA. 
Per Protocol (PP) Population 
The PP Population includes all subjects in the MITT Population who also meet the following 
criteria: 
• Do not have any major protocol violations that would affect assessment of efficacy, and 
• Complete an adequate number of Monitoring Period assessments through and including 
Day 22. 
Pharmacokinetic (PK) Population 
The PK Population includes all subjects in the MITT Population with at least 1 serum PK sample 
collected post-dose. 
Safety Population 
The Safety Population includes all subjects who receive any amount of study drug and have at 
least 1 post-treatment safety assessment. 
EFFICACY VARIABLES:  
The primary efficacy endpoint is the proportion of subjects in the MITT Population who develop 
S. aureus pneumonia up to but not including Day 22. 
The secondary efficacy endpoints include: 
• Duration of mechanical ventilation during the first 21 days post-randomization for subjects in 
the MITT, ITT, and PP Populations; 


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• Length of ICU stay during the first 21 days post-randomization for subjects in the MITT, ITT,
and PP Populations;  
• The Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single dose of 
ASN100 in the PK Population; and 
• 28-day all-cause mortality in the MITT, ITT, and PP Populations. 
Exploratory efficacy endpoints include: 
• Proportion of subjects in the MITT and PP Populations with a diagnosis of HABP at >48 hours 
post-extubation up to but not including Day 22 in extubated subjects; 
• Proportion of subjects in the MITT and PP Populations with development of VABP up to but 
not including Day 22; 
• Incidence of all bacterial pneumonias in the MITT, ITT, and PP Populations; 
• Incidence of other non-S. aureus pneumonias up to but not including Day 22 in the MITT, 
ITT, and PP Populations; and  
• Incidence of other S. aureus infections acquired following study drug administration up to but 
not including Day 22 in the MITT, ITT, and PP Populations. 
MICROBIOLOGICAL AND CLINICAL ASSESSMENTS: 
ETA specimens will be collected for culture during Screening/Enrollment to determine the degree 
of S. aureus colonization. Additional respiratory specimens may be collected for culture 
throughout the Monitoring Period or Early Termination (if applicable) if clinically indicated 
according to standard of care. 
If, as part of routine standard of care, additional respiratory and/or other microbiological 
specimens are collected for culture during the study, results will be documented within the 
electronic Case Report Form. As fully described within the study laboratory manual, bacterial 
isolates recovered from these specimens that are deemed pathogens by the Investigator (if retained 
and available at the study site local microbiology laboratory) will be sent to a central microbiology 
laboratory for confirmation of pathogen identification (all isolates) and susceptibility testing 
(S. aureus isolates only). 
During the Monitoring Period, a diagnosis of S. aureus pneumonia will be determined if subjects 
have S. aureus identified from an adequate respiratory specimen and clinical signs and symptoms 
of pneumonia. For a diagnosis of S. aureus pneumonia, clinical signs and symptoms must occur 
±2 days from the time of collection of an adequate respiratory specimen culture that is positive for 
S. aureus.  
• For intubated subjects, a respiratory specimen obtained by BAL, non-bronchoscopic BAL, or 
protected specimen brush will be considered an adequate respiratory specimen; or 
• For extubated subjects, an adequate expectorated/induced sputum specimen is defined as 
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• For both intubated and extubated subjects, adequate respiratory specimens will undergo either 
semi-quantitative or quantitative culture in accordance with the local laboratory’s standard 
procedure. 
Subjects will be assessed daily throughout the Monitoring Period for the following clinical signs 
and symptoms: 
Clinical Signs and Symptoms 
Mechanically Ventilated Subjects 
Non-Mechanically Ventilated Subjects 
• 
Cough, 
• 
Rales, 
• 
Dullness on percussion,* 
• 
Bronchial breath sounds, 
• 
Egophony,* 
• 
Need for suctioning, 
• 
Need for ventilator support, and 
• 
Fever ≥38°C (≥100.4°F). 
• 
Cough, 
• 
Rales, 
• 
Dullness on 
percussion,* 
• 
Bronchial breath 
sounds, 
• 
Egophony,* 
• 
Dyspnea, 
• 
Tachypnea, 
• 
Respiratory rate, 
• 
Hypoxemia, and 
• 
Fever ≥38°C 
(≥100.4°F). 
*If routinely performed. 
A diagnosis of pneumonia (HABP or VABP) will be determined as defined below: 
Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia 
Indication 
Definition 
HABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed by the 
Investigator);  
• 
At least ONE of the following: 
o 
Has been hospitalized for >48 hours, or 
o 
Developed clinical signs and symptoms within 7 days following hospital discharge; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the requirement for 
mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
VABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed by the 
Investigator);  
• 
Subject has received mechanical ventilation via an endotracheal or nasotracheal tube for ≥48 hours; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the requirement for 
mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
HABP = hospital-acquired bacterial pneumonia; PEEP = positive end-expiratory pressure; VABP = ventilator-associated bacterial pneumonia; 
WBC = white blood cell. 
 
 


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PHARMACOKINETIC VARIABLES: 
The primary PK endpoints are the Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum
following a single IV dose of ASN100 in the PK Population. 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. At the 
completion of the second infusion, blood samples for PK analysis will be collected immediately 
following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 
24 hours (±6 hours) post-dose. 
In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 
14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected 
on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 (if 
hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable).
Subjects participating in the BAL fluid PK sub-study will have a blood sample collected for PK 
measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection 
or if BAL fluid is collected as part of a standard of care procedure from any subject enrolled in 
the sub-study at any time post-randomization). 
In order to maintain the study blind, all subjects, including those randomized to receive placebo, 
will have PK samples obtained at the above time points. 
The levels of ASN-1 and ASN-2 will be measured in BAL fluid in a PK sub-study (to include 
approximately 25 to 35 subjects who volunteer) which will allow the calculation of a blood to ELF 
ratio. Subjects participating in this sub-study will have BAL fluid collected 48 hours (±36 hours) 
post-dose (on approximately Day 2 or Day 3, depending on time of study drug administration) to 
determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid is collected as part of a 
standard of care procedure from any subject enrolled in the sub-study at any other time 
post-randomization for any other reason, if possible, a sample for PK analysis will also be 
obtained.  
SAFETY VARIABLES: 
Safety variables for this study will include adverse event monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead ECGs, chest X-rays and/or thoracic CT scans, and 
the determination of the presence of ASN-1 and ASN-2 (i.e., ASN100) ADAs.  
STATISTICAL ANALYSES: 
Continuous variables will be summarized by using the number of non-missing observations, 
arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive 
statistics. Categorical variables will be summarized by using the frequency count and the 
percentage of subjects in each category as descriptive statistics.  
All statistical tests will be performed at the 0.05 significance level using 2-sided tests, except 
where otherwise noted. 
The primary efficacy endpoint is whether the subject has developed S. aureus pneumonia up to 
but not including Day 22. The summary measure for efficacy is the proportion of subjects in the 
MITT Population who develop S. aureus pneumonia up to but not including Day 22. Analysis for 


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the primary endpoint will compare the proportion of subjects who develop S. aureus pneumonia
in the ASN100 arm versus the placebo arm in the MITT Population. The statistical test for 
comparing 2 event rates is based on a 2-sided test with a false positive rate of 5%.  
Analyses of the primary efficacy endpoint will also be performed separately for the ITT and 
PP Populations. 
Duration of mechanical ventilation and length of hospital ICU stay during the first 21 days 
post-randomization will be compared between treatment groups using a Wilcoxon rank sum test.
Other efficacy endpoints will be summarized by treatment group. 
All subjects in the Safety Population will be included in the safety analyses and analyzed based 
on the actual treatment received. 
One interim analysis will be conducted during the study, when approximately 125 subjects have 
reached Day 22. The interim analysis is for futility assessment of the study, and for a potential 
study sample size adjustment based on an overall blinded efficacy evaluation pooled across the 
treatment arms. Based on this assessment, the sample size may be increased. The interim analysis 
of futility assessment will be reviewed by an independent Data Review Committee (DRC).  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.
Treatment-emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred term. A TEAE is defined as an adverse event with a start date and time on or after the 
first dose of study treatment. Listings will be provided for serious adverse events and adverse 
events leading to drug discontinuation. In addition, all adverse events will be listed. 
Safety laboratory data and vital signs will be presented by each scheduled time point and for 
change from baseline to each time point. The results of all laboratory tests, physical examination 
findings, vital signs, and ADAs will be presented in data listings. 
Descriptive statistics will be provided for all PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population. Subject PK profiles will be determined using 
parameters such as Cmax, Tmax, AUC, and t1/2 for each of ASN-1 and ASN-2 in serum. Epithelial 
lining fluid PK will also be analyzed and an ELF/serum PK ratio will be calculated. 
SAMPLE SIZE DETERMINATION: 
The estimated incidence of progression to S. aureus pneumonia in mechanically ventilated 
subjects with heavy colonization is approximately 25% within 22 days of randomization.  
Assuming a 2-sided significance level of 0.05 and a desired power of 80% to detect a significant 
difference between S. aureus pneumonia incidence rates of 25% in the placebo group and 12.5% 
in the ASN100 treatment group (50% reduction), 152 evaluable subjects are required in each 
treatment group. A sample size of 304 subjects (152 subjects per treatment group) will yield 
80% power to detect a 50% reduction in the incidence of S. aureus pneumonia with ASN100 
treatment when assuming a 25% incidence rate of S. aureus pneumonia in placebo-treated 
subjects. Assuming a 14% non-evaluable rate, approximately 354 subjects (177 subjects per 
treatment group) will be randomized. Assuming the screen failure rate is about 84%, 
approximately 2250 subjects will be screened. 


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SITES:  Approximately 70 global sites. 
SPONSOR: 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA  
02451-1472 
Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................. 16 
LIST OF TABLES ........................................................................................................................ 20 
LIST OF FIGURES ...................................................................................................................... 21 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 22 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 24 
1.1 
Background ................................................................................................................. 24 
1.2 
Rationale ..................................................................................................................... 25 
1.3 
Risk/Benefit ................................................................................................................ 26 
2 
STUDY OBJECTIVES ..................................................................................................... 28 
2.1 
Primary Objective ....................................................................................................... 28 
2.2 
Secondary Objectives .................................................................................................. 28 
2.3 
Exploratory Objectives ............................................................................................... 28 
3 
STUDY DESCRIPTION .................................................................................................. 29 
3.1 
Definition of Heavy Colonization ............................................................................... 29 
3.2 
Summary of Study Design .......................................................................................... 29 
3.3 
Study Indication .......................................................................................................... 32 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 33 
4.1 
Inclusion Criteria ........................................................................................................ 33 
4.2 
Exclusion Criteria ....................................................................................................... 33 
4.3 
Randomization Criteria ............................................................................................... 34 
4.4 
Withdrawal Criteria .................................................................................................... 35 
5 
STUDY TREATMENTS .................................................................................................. 37 
5.1 
Treatment Groups ....................................................................................................... 37 
5.2 
Stratification ................................................................................................................ 37 
5.3 
Rationale for Dosing ................................................................................................... 37 
5.4 
Randomization and Blinding ...................................................................................... 38 
5.5 
Breaking the Blind ...................................................................................................... 38 


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5.6 
Drug Supplies.............................................................................................................. 38 
5.6.1  Formulation and Packaging .................................................................................. 38 
5.6.2  Study Drug Preparation and Dispensing ............................................................... 39 
5.6.3  Study Drug Administration ................................................................................... 39 
5.6.4  Treatment Compliance .......................................................................................... 40 
5.6.5  Storage and Accountability ................................................................................... 40 
5.7 
Prior and Concomitant Medications and/or Procedures ............................................. 40 
5.7.1  Excluded Medications and/or Procedures ............................................................. 40 
5.7.2  Documentation of Prior and Concomitant Medication Use .................................. 40 
6 
STUDY PROCEDURES .................................................................................................. 41 
6.1 
Informed Consent........................................................................................................ 41 
6.2 
Screening/Enrollment (Up to Day -14) ....................................................................... 41 
6.3 
Randomization Visit (Day 1 Pre-Dose) ...................................................................... 42 
6.4 
Treatment Period (Day 1) ........................................................................................... 43 
6.5 
Monitoring Period ....................................................................................................... 43 
6.5.1  Day 2/Day 3 – Bronchoalveolar Lavage Fluid Pharmacokinetic Sub-Study ....... 43 
6.5.2  Day 2 to Day 21 .................................................................................................... 44 
6.5.3  Day 22 ................................................................................................................... 45 
6.6 
Follow-Up Period........................................................................................................ 46 
6.6.1  Day 28 (+2 Days) Follow-Up ............................................................................... 46 
6.6.2  Day 40 to Day 89 (Follow-Up Safety Visit) ......................................................... 46 
6.6.3  Safety Visit (Day 90 [±7 Days]) ........................................................................... 46 
6.7 
Early Termination Visit and Withdrawal Procedures ................................................. 47 
7 
EFFICACY ASSESSMENTS .......................................................................................... 48 
7.1 
Primary Efficacy Endpoint ......................................................................................... 48 
7.2 
Secondary Efficacy Endpoints .................................................................................... 48 
7.3 
Exploratory Efficacy Endpoints .................................................................................. 48 
7.4 
Microbiological and Clinical Assessments ................................................................. 49 
7.4.1  Microbiological Assessment ................................................................................. 49 
7.4.2  Assessment of Clinical Signs and Symptoms ....................................................... 49 
8 
PHARMACOKINETIC ASSESSMENTS ....................................................................... 51 
8.1 
Pharmacokinetic Endpoint .......................................................................................... 51 


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8.2 
Pharmacokinetic Assessments .................................................................................... 51 
8.2.1  Serum Pharmacokinetic Sampling ........................................................................ 51 
8.2.2  Bronchoalveolar Lavage Fluid Pharmacokinetic Sampling ................................. 52 
8.2.3  Analysis of Anti-Staphylococcus aureus Toxin Antibody Titers ......................... 52 
9 
SAFETY ASSESSMENTS ............................................................................................... 53 
9.1 
Adverse Events ........................................................................................................... 53 
9.1.1  Adverse (Drug) Reaction ...................................................................................... 54 
9.1.2  Unexpected Adverse Drug Reaction ..................................................................... 54 
9.1.3  Assessment of Adverse Events by the Investigator .............................................. 54 
9.2 
Serious Adverse Events .............................................................................................. 55 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators .............................. 56 
9.4 
Pregnancy Reporting ................................................................................................... 57 
9.5 
Expedited Reporting ................................................................................................... 57 
9.6 
Clinical Laboratory Evaluations ................................................................................. 57 
9.7 
Radiographs and Imaging ........................................................................................... 58 
9.8 
Vital Signs ................................................................................................................... 58 
9.9 
Electrocardiograms ..................................................................................................... 59 
9.10 
Physical Examinations ................................................................................................ 59 
9.11 
Immunogenicity .......................................................................................................... 59 
10 
STATISTICS .................................................................................................................... 60 
10.1 
Analysis Populations ................................................................................................... 60 
10.2 
Statistical Methods ...................................................................................................... 60 
10.2.1  Disposition ............................................................................................................ 60 
10.2.2  Demographic and Baseline Characteristics .......................................................... 60 
10.2.3  Analysis of Efficacy .............................................................................................. 61 
10.2.4  Analysis of Safety ................................................................................................. 61 
10.2.5  Analysis of Pharmacokinetics ............................................................................... 61 
10.2.6  Sample Size Determination ................................................................................... 61 
10.2.7  Interim Analysis .................................................................................................... 62 
11 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 63 
11.1 
Data Management ....................................................................................................... 63 
11.1.1  Data Handling ....................................................................................................... 63 


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11.1.2  Computer Systems ................................................................................................ 63 
11.1.3  Data Entry ............................................................................................................. 63 
11.1.4  Medical Information Coding ................................................................................. 63 
11.1.5  Data Validation ..................................................................................................... 63 
11.2 
Record Keeping .......................................................................................................... 63 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 64 
12.1 
Ethical Conduct of the Study ...................................................................................... 64 
12.2 
Institutional Review Board/Independent Ethics Committee ....................................... 64 
12.3 
Informed Consent........................................................................................................ 64 
12.4 
Study Monitoring Requirements ................................................................................. 65 
12.5 
Protocol Deviations ..................................................................................................... 65 
12.6 
Disclosure of Data ....................................................................................................... 66 
12.7 
Retention of Records ................................................................................................... 66 
12.8 
Publication Policy ....................................................................................................... 66 
12.9 
Financial Disclosure .................................................................................................... 66 
12.10  Insurance and Indemnity ............................................................................................. 66 
12.11  Legal Aspects .............................................................................................................. 67 
13 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 68 
13.1 
Protocol Amendments ................................................................................................. 68 
13.2 
Address List ................................................................................................................ 68 
13.2.1  Sponsor ................................................................................................................. 68 
13.2.2  Global Contract Research Organization ............................................................... 68 
13.2.3  Drug Safety ........................................................................................................... 68 
13.2.4  Biological Specimens ............................................................................................ 69 
13.2.5  Study Drug Packaging, Labeling, and Distribution .............................................. 69 
14 
REFERENCES ................................................................................................................. 70 
APPENDIX A:  SCHEDULE OF PROCEDURES ...................................................................... 72 
APPENDIX B:  CLINICAL LABORATORY ANALYTES ....................................................... 76 


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LIST OF TABLES 
Table 1. 
Clinical Signs and Symptoms ..................................................................................... 49 
Table 2. 
Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia .... 50 
 
 


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LIST OF FIGURES  
Figure 1.  Study Schematic.......................................................................................................... 29 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ALT 
Alanine aminotransferase 
ASN-1 
Broadly cross-reactive anti-toxin monoclonal antibody that targets 
alpha hemolysin (Hla) and 3 F-components (HlgB, LukF, LukD) 
involved in forming 4 of the 5 bi-component leukocidins of 
Staphylococcus aureus 
ASN-2 
Anti-toxin monoclonal antibody that targets the fifth bi-component 
toxin of Staphylococcus aureus, LukGH 
ASN100 
A combination of 2 fully human monoclonal antibodies (ASN-1 and 
ASN-2) 
AST 
Aspartate aminotransferase 
AUC 
Area under the serum concentration-time curve 
BAL 
Bronchoalveolar lavage 
CFR 
Code of Federal Regulations 
CFU 
Colony forming units 
CIP 
Council of independent physicians 
Cmax 
Maximum serum concentration 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CT 
Computed tomography 
CTA 
Clinical trial authorization 
DRC 
Data Review Committee 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ELF 
Epithelial lining fluid 
ET 
Early Termination 
ETA 
Endotracheal aspirate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HABP 
Hospital-acquired bacterial pneumonia 
Hla 
Alpha hemolysin 
HlgAB 
Gamma hemolysin AB 
HlgB 
Gamma hemolysin B 
HlgCB 
Gamma hemolysin CB 
ICF 
Informed Consent Form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous  
LAR 
Legally authorized representative 
LukD 
Leukocidin D 
LukED 
Leukocidin ED 
LukF 
Leukocidin F 
LukGH 
Leukocidin GH 
LukSF 
Leukocidin SF or Panton-Valentine Leukocidin 
mAb 
Monoclonal antibody 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat 
MRSA 
Methicillin-resistant Staphylococcus aureus 
MSSA 
Methicillin-susceptible Staphylococcus aureus 
NIMP 
Non-investigational medical product 
PCT 
Procalcitonin  
PD 
Pharmacodynamic  
PK 
Pharmacokinetic  
PMN 
Polymorphonuclear cell 
PP 
Per Protocol 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PVL 
Panton-Valentine Leukocidin or leukocidin SF 
RBC 
Red blood cell 
S. aureus 
Staphylococcus aureus 
SAE 
Serious adverse event  
t1/2 
Terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum serum concentration 
VABP 
Ventilator-associated bacterial pneumonia 
WBC 
White blood cell 


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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Staphylococcus aureus (S. aureus) is a human pathogenic bacterium that causes severe infections, 
including pneumonia and sepsis. Hospital-acquired bacterial pneumonia (HABP) caused by 
S. aureus, including ventilator-associated bacterial pneumonia (VABP) in mechanically ventilated 
patients, is a significant public health threat despite efforts to optimize antibiotic treatment. 
The primary exotoxins of S. aureus are alpha hemolysin (Hla), which damages lung epithelial 
cells, facilitating pneumonia and systemic bacterial invasion, and a group of exotoxins known as 
bi-component, pore-forming leukocidins.1,2 Staphylococcus aureus isolates are capable of 
producing up to 5 potent leukocidins: 2 gamma hemolysins (gamma hemolysin AB [HlgAB] and 
gamma hemolysin CB [HlgCB]), the Panton-Valentine Leukocidin (PVL or leukocidin SF 
[LukSF]), leukocidin ED (LukED), and leukocidin GH (LukGH). Alpha hemolysin, the gamma 
hemolysins, and LukGH genes are present in all clinical isolates; however, LukSF and LukED are 
found in approximately 5% to 10% and approximately 60% of strains, respectively. The most 
prevalent community-acquired methicillin-resistant S. aureus (MRSA) strain in the United States 
is the USA300 pulsotype, which possesses genes for all 5 of these potent leukocidins. 
Alpha hemolysin and the bi-component leukocidins bind to various cell surface receptors and this 
leads to cell type specific cytotoxicity. The combined effect of these exotoxins in staphylococcal 
pathogenesis is multifold:  
• Hla destroys the epithelial barrier by direct cytolysis;  
• Leukocidins target phagocytic cells for lysis, reducing the capacity of immune cells to 
eliminate S. aureus; and 
• All cytotoxins induce inflammatory responses that lead to further tissue damage. Inflammatory 
signals further enhance the susceptibility of human polymorphonuclear cells (PMNs) to lysis 
by LukGH rendering this toxin dominant among the S. aureus leukocidins in vitro.3 
Counteracting these functions of staphylococcal toxins by means of monoclonal antibodies (mAbs) 
may contribute to or induce the prevention and/or treatment of S. aureus pneumonia. 
ASN100 is a combination of 2 fully human mAbs (ASN-1 and ASN-2, both of the 
immunoglobulin G1 [IgG1] subclass) that target these exotoxins of S. aureus. ASN-1 is a broadly 
cross-reactive anti-toxin mAb that targets Hla and 3 F-components (gamma hemolysin B [HlgB], 
leukocidin F [LukF], and leukocidin D [LukD]) involved in forming 4 of the 5 bi-component 
leukocidins of S. aureus, while ASN-2 is directed against the fifth bi-component toxin of S. aureus, 
LukGH.4,5,6  
The 2 antibodies (i.e., ASN-1 and ASN-2) are dosed in a 1:1 ratio and operate as follows: 
• ASN-1 binds to and neutralizes Hla and 4 bi-component S. aureus cytotoxins (leukocidins): 
HlgAB, HlgCB, LukED, and LukSF (also known as PVL); and 
• ASN-2 binds to and neutralizes the fifth S. aureus leukocidin, LukGH. 
While ASN-1 and ASN-2 each provide partial protection of human phagocytic cells against a 
combination of staphylococcal exotoxins, the 2 mAbs act in synergy to prevent lysis of human 
phagocytic cells in the presence of Hla and all 5 bi-component leukocidins. By neutralizing Hla 


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and inactivating HlgAB, HlgCB, LukED, and LukSF, ASN-1 prevents the lysis of granulocytes 
(PMNs) caused by these leukocidins. ASN-1 demonstrated superior efficacy compared to 
Hla-neutralizing mAbs against S. aureus pneumonia in a rabbit in vivo model.7 By neutralizing 
LukGH, ASN-2 protects PMNs, monocytes, and macrophages from lysis. 
ASN100 (i.e., ASN-1 and ASN-2) has demonstrated potency and efficacy against a wide range of 
S. aureus strains in in vitro studies and in vivo models of S. aureus pneumonia.4,5 Collectively, 
these studies support the synergy of ASN-1 and ASN-2 and the need for both mAbs in ASN100 to 
protect patients in the clinical setting against the full range of S. aureus strains 
(methicillin-susceptible S. aureus [MSSA] and MRSA).  
1.2 
Rationale 
Published studies have demonstrated that microbiologic screening of mechanically ventilated 
patients to determine those who are heavily colonized with S. aureus increases the probability of 
correctly predicting those patients who will eventually develop S. aureus pneumonia.8,9 
Approximately one-third of heavily colonized mechanically ventilated patients progressed to 
S. aureus pneumonia and these same studies demonstrated that patients still develop S. aureus 
pneumonia despite treatment with potentially effective anti-staphylococcal antibiotics. Secondary 
analyses of these studies have shown that antibiotic treatment is ineffective in reducing S. aureus 
colonization in the lower airways and preventing ventilator-associated tracheobronchitis or VABP, 
and S. aureus seems to be in competition for colonization with the normal respiratory flora.10 
Staphylococcus aureus, particularly MRSA, is frequently identified as the causative pathogen of 
pneumonia and the incidence of healthcare-related MRSA pneumonia among hospitalized patients 
is increasing.11,12,13 According to the American Thoracic Society and the Infectious Diseases 
Society of America, MRSA is associated with >50% of intensive care unit (ICU) infections in the 
United States.14  
Despite the availability of microbiologically appropriate antibiotics, mortality in patients with 
S. aureus pneumonia remains high.15 No specific prevention strategies have proven effective 
against S. aureus pneumonia in mechanically ventilated patients. While general pneumonia 
prevention measures demonstrate efficacy in many cases, not all ICU types benefit from these 
efforts.17 Although reported pneumonia rates have decreased over time, the remaining S. aureus 
cases are unlikely to be prevented by non-specific measures.17,18  
Data from retrospective observational studies indicate that mechanically ventilated patients who 
have moderate to heavy colonization with S. aureus as determined by culture of endotracheal 
aspirate (ETA) specimens (i.e., ≥3+ by semi-quantitative culture) have a higher risk of developing 
pneumonia.8,19 As noted above, many of these patients still ultimately develop S. aureus 
pneumonia despite treatment with potentially effective antibiotics.  
The USA300 pulsotype is the most prevalent community-acquired MRSA strain in the 
United States and is known to possess all 5 leukocidins produced by S. aureus. When Hla and the 
bi-component leukocidins bind to various cell surface receptors, cell type specific cytotoxicity 
results. In addition, Hla expression level of colonizing S. aureus MSSA strains have been observed 
as a biomarker for progression to VABP in ventilated patients.19  
Monoclonal antibodies may counteract these toxin activities and thereby offer benefit in the 
prevention of S. aureus pneumonia. Together, the components of ASN100 (i.e., ASN-1 and 


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ASN-2) have demonstrated potency and efficacy against a wide range of S. aureus strains in 
in vitro studies and in vivo models of S. aureus pneumonia, positioning ASN100 to be a needed 
therapy for the prevention of S. aureus pneumonia. The design of this Phase 2 prevention study 
with ASN100 is based on an assumption of a 50% reduction in the incidence of S. aureus 
pneumonia in these subjects, irrespective of the concomitant use of potentially effective 
antibiotics. 
A series of pharmacokinetic (PK) and pharmacodynamic (PD) experiments was conducted using 
the rabbit S. aureus pneumonia model and measured PK in both healthy rabbits and rabbits with 
pneumonia caused by several S. aureus strains. The range of effective doses for preventing 
S. aureus pneumonia in animal models was 2.5 to 10 mg/kg of each component of ASN100. 
The 20 mg/kg dose (10 mg ASN-1 and 10 mg ASN-2) translated into a 1600 mg dose for an 80 kg 
subject. 
ASN100 was well tolerated up to 8000 mg (i.e., 4000 mg ASN-1 and 4000 mg ASN-2) in a single 
ascending dose study conducted in healthy human volunteers. There were no reported related 
serious adverse events (SAEs) and 2 related treatment-emergent adverse events (TEAEs) of 
headache and fatigue were reported in this study. These data and data obtained from the nonclinical 
program determined that ASN100 3600 mg (i.e., 1800 mg ASN-1 and 1800 mg ASN-2) will be an 
appropriate dose to assess safety and efficacy in this first study in mechanically ventilated subjects 
who are heavily colonized with S. aureus. 
The significant unmet need, the lack of existing therapies to prevent S. aureus pneumonia in 
high-risk patients, and the demonstrated in vitro potency and in vivo efficacy of ASN100 provide 
sufficient rationale for this Phase 2 study in the prevention of S. aureus pneumonia in high-risk, 
mechanically ventilated subjects. 
1.3 
Risk/Benefit 
In mechanically ventilated subjects heavily colonized with S. aureus, ASN100 may prevent 
S. aureus pneumonia, a condition associated with significant morbidity and mortality and 
representing a significant unmet clinical need. 
The ASN100 drug components ASN-1 and ASN-2 are fully human mAbs belonging to the IgG1 
immunoglobulin subclass glycoproteins. They share a high degree of sequence homology with 
endogenous IgGs of the same subclass (approximately 90% to 95%) and are manufactured using 
standard mammalian cell expression and purification technologies (including 4 orthogonal viral 
clearance steps); therefore, they are expected to carry mammalian glycosylation pattern and to 
continue to be well tolerated in humans. 
The target toxins recognized by ASN-1 and ASN-2 are bacterial, non-human, and are not 
expressed in human tissues. Lack of off-target reactivity is supported by the results of human tissue 
cross-reactivity studies involving a panel of 33 tissue types that demonstrated no cross-reactivity 
with human tissues. The antibody function of ASN100 is based solely on neutralization; 
complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) 
mechanisms in the mode of action are irrelevant. ASN-1 and ASN-2 cannot bind to toxins already 
bound to human tissues and therefore unwanted ADCC reactions toward human cells and tissues 
is unlikely. 
A single ascending dose study conducted with ASN100 in doses up to 8000 mg 
(i.e., 4000 mg ASN-1 and 4000 mg ASN-2) demonstrated that ASN100 was well tolerated with 


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no reported related SAEs and 2 reported possibly related adverse events of headache and fatigue. 
No dose-limiting toxicity was observed up to the highest dose tested. 
The potential immunogenicity of the antibodies and resulting immune complex formation 
following the production of anti-drug immunoglobulin M and IgG antibodies by the host immune 
system cannot be excluded; however, the risk for this outcome is considered to be low. 
ASN100 belongs to the class of mAbs targeting foreign (bacterial), non-human antigens and is 
expected to yield a low risk of adverse events resulting from immunogenicity due to the 
single-dose administration used in this study. 
Subjects participating in this study will be closely monitored following study drug administration 
via means of adverse event monitoring, clinical laboratory assessments, vital sign measurements, 
physical examinations, 12-lead electrocardiograms (ECGs), chest X-rays and/or thoracic 
computed tomography (CT) scans, and the determination of the presence of ASN-1 and/or ASN-2 
anti-drug antibodies (ADAs). Additional safety assessments may be performed throughout the 
duration of this study if clinically indicated. Concomitant antibiotics are permitted per standard of 
care throughout the duration of this study. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety, tolerability, and efficacy of a single 
dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To compare the duration of mechanical ventilation post-treatment in subjects treated with 
ASN100 versus placebo;  
• To compare the length of stay in the ICU post-treatment for subjects treated with ASN100 
versus placebo;  
• To determine the serum PK (i.e., maximum serum concentration [Cmax], time to maximum 
serum concentration [Tmax], area under the serum concentration-time curve [AUC], and 
terminal elimination half-life [t1/2]) of ASN-1 and ASN-2 in mechanically ventilated subjects 
heavily colonized with S. aureus; and 
• To compare 28-day all-cause mortality in subjects treated with ASN100 versus placebo. 
2.3 
Exploratory Objectives 
The exploratory objectives are: 
• To compare the incidence of HABP occurring >48 hours post-extubation up to but not 
including Day 22 in extubated subjects treated with ASN100 versus placebo; 
• To compare the incidence of VABP up to but not including Day 22 in subjects treated with 
ASN100 versus placebo; 
• To determine the immunogenicity of a single dose of ASN100; 
• To compare the incidence of other S. aureus-associated infections which occur after dosing up 
to but not including Day 22 in subjects treated with ASN100 versus placebo; and 
• To assess ASN-1 and ASN-2 levels in bronchoalveolar lavage (BAL) fluid and calculate a 
blood to epithelial lining fluid (ELF) ratio in those subjects participating in the BAL fluid PK 
sub-study. 
 


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3 
STUDY DESCRIPTION 
3.1 
Definition of Heavy Colonization 
For the purposes of this study, heavy colonization of S. aureus will be defined as a quantitative 
threshold of ≥105 CFU/mL or 3+ to 4+ by semi-quantitative culture from an endotracheal aspirate. 
3.2 
Summary of Study Design 
This is a double-blind, randomized, single-dose, placebo-controlled study of ASN100 for the 
prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized 
with S. aureus.  
This will be a global study conducted at approximately 70 sites. Subjects will be screened for 
eligibility; once an Informed Consent Form (ICF) is signed (or, in countries where it is applicable, 
a decision is made by the council of independent physicians (CIP) [see Section 12.3]), and all entry 
criteria are met, a subject is considered to be enrolled in the study. All enrolled subjects will 
undergo an observational stage evaluating endotracheal colonization. Subjects who are 
randomized will undergo a treatment, monitoring, and follow-up period. 
A schematic of the study is presented in Figure 1. 
Figure 1. Study Schematic 
 
1. 
Subjects do not need to be colonized to be enrolled. 
2. 
For the purposes of this study, heavy colonization of S. aureus will be defined as a quantitative threshold of ≥105 CFU/mL or 3+ to 4+ by 
semi-quantitative culture. 
3. 
Once a subject has an ETA culture result signifying heavy growth of S. aureus, they must be randomized within 48 hours (or up to 60 hours 
with Medical Monitor approval) of sample collection or be discontinued from the study. 
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; ETA = endotracheal aspirate; ICF = Informed Consent Form; 
I/E = inclusion/exclusion; PK = pharmacokinetic; S. aureus = Staphylococcus aureus. 
Approximately 2250 eligible subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be screened daily (while mechanically ventilated) for up to 8 days to identify 
those subjects who are heavily colonized with S. aureus (see Section 3.1). 
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 14 days. 


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Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator 
and providing the subject remains mechanically ventilated.  
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or 
semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of MSSA 
and MRSA (e.g., CHROMagarTM Staph aureus) for more rapid and specific detection of S. aureus. 
If the site is not able to obtain chromogenic media for S. aureus, appropriate chromogenic media 
may be supplied by the Sponsor.  
Semi-quantitative cultures using chromogenic media are preferred for determination of eligibility 
for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to 
randomize the subject within 48 hours (or up to 60 hours with Medical Monitor approval) from 
the time the ETA sample was collected. 
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for randomization. 
If they are not randomized on this occasion according to the protocol, they are no longer eligible 
for continued ETA sampling and randomization, and will be discontinued from the study; however, 
if subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible 
for re-screening as a new subject enrollment. Subjects who were previously randomized are not 
eligible to be re-consented and re-screened. 
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into the study; however, 
randomization should not be delayed while waiting for Gram-negative results if heavy colonization 
with S. aureus has been confirmed. 
Nasal swab specimens (one from each nostril) will be obtained at the Randomization Visit and will 
be cultured by the central microbiology laboratory. Results from the nasal swab specimen cultures 
will be used to assess correlation with results of the qualifying ETA culture. 
Upon determination of eligibility, approximately 354 subjects will be randomized in a 1:1 ratio to 
1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate intravenous (IV) 
infusions of ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
To ensure balance among the treatment groups, randomization for this study will be stratified by 
receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the time of randomization 
that are potentially active against S. aureus pneumonia (see Section 5.2). 
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg of 
ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-2) or 
matching placebos, per their assigned randomization scheme.  
If, as part of routine standard of care, additional respiratory and/or other microbiological specimens 
are collected for culture during the study, results will be documented within the electronic Case 
Report Form (eCRF). As fully described within the study laboratory manual, bacterial isolates 


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recovered from these specimens that are deemed pathogens by the Investigator (if retained and 
available at the study site local microbiology laboratory) will be sent to a central microbiology 
laboratory for confirmation of pathogen identification (all isolates) and susceptibility testing 
(S. aureus isolates only). 
Randomized subjects will be monitored daily for the signs and symptoms of pneumonia 
(see Section 7.4.2 and Table 1) and other S. aureus-associated infections while hospitalized up to 
Day 21.  
All randomized subjects will undergo a study visit on Day 22 (+2 days). A follow-up visit will 
occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the 
subject is no longer hospitalized.  
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they 
receive study treatment, a follow-up safety visit will be performed on the day of discharge. 
All randomized subjects will return for a Safety Visit on Day 90 (±7 days) (if the subject is unable 
to return to the site, this visit may be conducted by telephone). Subjects who discontinue the study 
prior to Day 22 will undergo an Early Termination Visit. The end of the study will occur upon 
completion of the last Day 90 visit by the last subject. 
Safety assessments for this study will include adverse event monitoring, clinical laboratory 
assessments (including chemistry, hematology, coagulation, and urinalysis), physical 
examinations, vital sign measurements, 12-lead ECGs, chest X-rays and/or thoracic CT scans, and 
the determination of the presence of ASN-1 and ASN-2 ADAs. Additional safety assessments may 
be performed throughout the duration of the study if clinically indicated. 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), on the day 
of diagnosis of pneumonia (if applicable), and on Day 22 or Early Termination (if applicable). 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. Blood 
samples for PK analysis will be collected immediately following the completion of the second 
infusion (+15 minutes) and at 6 hours (± 4 hours) and 24 hours (±6 hours) post-dose following the 
second infusion. In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 
7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will 
be collected on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 
(if hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable).  
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25 to 
35 subjects who volunteer will participate in this sub-study and will have BAL fluid collected 
48 hours (±36 hours) post-dose (on approximately Day 2 or Day 3, depending on time of study 
drug administration) to determine ASN-1 and ASN-2 levels and blood to ELF ratio. Subjects 
participating in the BAL fluid PK sub-study will have a blood sample collected for PK 
measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection 
or if BAL fluid is collected as part of a standard of care procedure from any subject enrolled in the 
sub-study at any time post-randomization). 
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined and no 


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genetic information will be extracted from these samples. Samples will be destroyed following the 
completion of all S. aureus anti-toxin antibody analyses. 
3.3 
Study Indication 
The prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily 
colonized with S. aureus. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria at the Screening and Randomization Visits in order 
to be eligible for randomization into the study: 
1. Subject, legally authorized representative (LAR), or CIP (if applicable) has provided written 
informed consent; 
2. Subject is ≥18 years of age at the time of enrollment; 
3. Subject is currently hospitalized and is mechanically ventilated endotracheally 
(i.e., orotracheal or nasotracheal) and, in the Investigator’s opinion, will require ongoing 
ventilator support for at least 48 hours; 
NOTE: Subjects with a tracheostomy at the time of enrollment are not eligible. After 
enrollment, conversion to tracheostomy is permitted per standard of care. 
4. Female subjects must not be pregnant or lactating. Female subjects of childbearing potential 
must have a documented negative pregnancy test at the Screening Visit. Female subjects may 
be enrolled on the basis of a negative urine pregnancy test, pending the result of a negative 
serum pregnancy test prior to randomization; and 
5. Female subjects of childbearing potential and non-surgically sterile male subjects who are 
sexually active must agree to use an approved highly effective form of contraception from the 
time of informed consent until 165 days post-dose. Approved forms of contraception include 
hormonal intrauterine devices, hormonal contraceptives (oral birth control pill, depo, patch, or 
injectable) together with supplementary double barrier methods such as condoms or 
diaphragms with spermicidal gel or foam. 
NOTE: The following categories define women who are NOT considered to be of childbearing 
potential: 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy, 
o Documented bilateral salpingectomy, or 
o Documented bilateral oophorectomy, or 
• Postmenopausal female, defined as having amenorrhea for at least 12 months without an 
alternative medical cause. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria at the Screening and/or Randomization Visit will 
be excluded from participation in the study: 
1. Subject has received IV immunoglobulin therapy within 4 months prior to the Screening Visit; 
2. Subject has a chest X-ray or thoracic CT scan that is definitive for a diagnosis of pneumonia; 


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3. Subject demonstrates both of the following: 
a. Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
positive end-expiratory pressure; AND 
NOTE: Changes made in ventilator support due to day-to-day maintenance other than those 
changes made to improve oxygenation will not exclude a subject from participation in the 
study. 
b. New onset of purulent suctioned respiratory secretions; 
4. Subject has a known and documented ETA culture showing heavy colonization with a 
Gram-negative organism at enrollment or at any time during the Screening period; 
NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
5. Subject has been diagnosed with neutropenia (absolute neutrophil count <500/mm3); 
6. Subject has a severe non-pulmonary source of infection which, in the Investigator’s opinion, 
would interfere with the conduct of the study or jeopardize the subject’s safety; 
7. Subject is currently on either continuous veno-venous hemodialysis or extracorporeal 
membrane oxygenation; 
8. Subject has been previously exposed to ASN100 or ASN-1 or ASN-2, individually; 
9. Subject has a known hypersensitivity to ASN100 or any of its excipients; 
10. Subject has received any investigational product within 30 days prior to the Screening Visit 
(or 5 half-lives of the investigational product, whichever is longer); 
11. Subject has, in the opinion of the Investigator, a high probability of death within 72 hours of 
enrollment;  
12. Subject is, in the opinion of the Investigator, not able or willing to comply with the protocol; 
13. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
subject, the potential activity of the study drug, or the quality of the data; or 
14. Subjects with a known history or current (suspected) diagnosis of cytokine release syndrome 
associated with the administration of peptides, proteins, and/or antibodies.20 
NOTE: Subjects with a prior history of sepsis are not excluded. 
4.3 
Randomization Criteria 
Following the Screening Visit, eligible subjects who meet all of the inclusion criteria and none of 
the exclusion criteria will be screened daily (while mechanically ventilated) for up to 8 days via 
quantitative or semi-quantitative culture of an ETA to identify those subjects who are heavily 
colonized with S. aureus (see Section 3.1).  
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 14 days. 
Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator 
and providing the subject remains mechanically ventilated.  


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Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for randomization. 
If they are not randomized on this occasion according to the protocol, they are no longer eligible 
for continued ETA sampling and randomization, and will be discontinued from the study; however, 
if subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible 
for re-screening as a new subject enrollment. Subjects who were previously randomized are not 
eligible to be re-consented and re-screened. 
At the time of randomization, if a subject’s screening ETA culture also shows heavy colonization 
of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and 
Gram-negative organisms), the subject will not be randomized into the study. 
NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy 
colonization with S. aureus has been confirmed. 
At the Randomization Visit, subjects must meet all of the following requirements to be randomized 
into the study: 
1. Subject continues to meet all of the inclusion criteria and none of the exclusion criteria required 
at the Screening Visit; 
NOTE: Subjects who undergo tracheostomy after enrollment are still eligible for 
randomization, provided they remain mechanically ventilated (see criterion 3 below). 
2. Subject is heavily colonized with S. aureus as determined by either quantitative or 
semi-quantitative culture of an ETA (see Section 3.1);  
NOTE: The results of the qualifying ETA culture must allow randomization to occur within 
48 hours (or up to 60 hours with Medical Monitor approval) from the time the ETA sample 
was collected. Subjects with ETA culture results obtained after 60 hours showing heavy 
colonization of S. aureus may not be randomized and will be discontinued from the study. 
3. Subject remains mechanically ventilated and, in the Investigator’s opinion, will require 
ongoing ventilator support for at least 48 hours; and 
4. Subject has, in the opinion of the Investigator, a probability of survival beyond 72 hours 
post-randomization. 
4.4 
Withdrawal Criteria 
Participation of a subject in this clinical study may be discontinued for any of the following 
reasons: 
• The subject or LAR withdraws consent from the study for any reason; 
• The subject or LAR requests discontinuation from the study for any reason; 
• Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol; 
• Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the subject; 
• Pregnancy; 


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• Requirement of prohibited concomitant medication; 
• Subject failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by the Sponsor or the regulatory authority. 
If a subject withdraws prematurely from the study due to the above criteria (except in the case of 
withdrawal of consent) or any other reason, study staff should make every effort to complete the 
full panel of assessments scheduled for the Early Termination Visit. The reason for subject 
withdrawal must be documented in the eCRF. 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
Randomized subjects who are withdrawn will not be replaced.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Following Screening/Enrollment and upon determination that a subject is heavily colonized with 
S. aureus as determined by a positive quantitative or semi-quantitative culture of an ETA (see 
Section 3.1), eligible subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups: 
• ASN100 administered either sequentially or simultaneously as 2 separate IV infusions of 
ASN-1 and ASN-2, or 
• Placebo administered either sequentially or simultaneously as 2 separate IV infusions. 
Whether ASN-1, ASN-2, or placebo are administered sequentially or simultaneously will be 
determined by operational considerations of IV access at the time of dosing. If 2 IV lines are 
available for simultaneous administration this is preferable; however, if IV access or other 
considerations support sequential administration, this is allowed provided that both infusions are 
completed within 3 hours.  
Following randomization on Day 1, subjects will receive either a single IV dose of 3600 mg of 
ASN100 (comprised of separate infusions each of 1800 mg ASN-1 and 1800 mg ASN-2) or 
matching placebos, per their assigned randomization scheme.  
5.2 
Stratification 
To ensure balance among the treatment groups, randomization for this study will be stratified by 
receipt or non-receipt of concomitant anti-staphylococcal antibiotics at the time of randomization 
that are potentially active against S. aureus pneumonia, including, but not limited to, nafcillin, 
oxacillin, vancomycin, linezolid, telavancin, ceftaroline, ceftobiprole, and teicoplanin. 
5.3 
Rationale for Dosing 
A series of PK and PD experiments was conducted using the rabbit S. aureus pneumonia model 
and measured PK in both healthy rabbits and rabbits with pneumonia caused by several S. aureus 
strains. The range of effective doses for preventing S. aureus pneumonia in animal models was 
2.5 to 10 mg/kg of each component of ASN100. The 20 mg/kg dose (10 mg ASN-1 and 
10 mg ASN-2) translated into a 1600 mg dose for an 80 kg subject. 
ASN100 was well tolerated up to 8000 mg (i.e., 4000 mg ASN-1 and 4000 mg ASN-2) in a 
single-ascending dose study conducted in healthy human volunteers. There were no reported 
related SAEs and 2 related TEAEs of headache and fatigue were reported in this study. These data 
and data obtained from the nonclinical program determined that ASN100 3600 mg (i.e., 1800 mg 
ASN-1 and 1800 mg ASN-2) will be an appropriate dose to assess safety and efficacy in this first 
study in mechanically ventilated subjects who are heavily colonized with S. aureus.  
This study did not identify a maximum tolerated dose. Based on these observations from the single 
ascending dose study, as well as data obtained from the nonclinical program conducted to date, it 
is reasonable to select a dose of ASN100 of 3600 mg (i.e., 1800 mg ASN-1 and 1800 mg ASN-2) 
as an appropriate dose to assess safety and efficacy in this first study in mechanically ventilated 
subjects who are heavily colonized with S. aureus. 


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5.4 
Randomization and Blinding 
Randomization will occur at the Randomization Visit following determination of the subject’s 
eligibility. Subjects will be randomized via a centralized Interactive Response Technology (IRT) 
system in a 1:1 ratio to receive a single dose (2 infusions) of either ASN100 or matching placebo. 
The study follows a double-blind, placebo-controlled design. All study personnel, including 
investigators, site personnel, site pharmacist, Sponsor and contract research organization (CRO) 
staff involved in the conduct of the study (e.g., clinical research associate [CRA]/monitor), and 
subjects will be blinded to treatment assignment. ASN100 and placebo will be identical in 
appearance to preserve blinding. 
5.5 
Breaking the Blind 
Randomization data will be kept strictly confidential until the time of unblinding and will not be 
accessible by subjects, Investigators, or anyone performing assessments and having access to study 
data until unblinding occurs. Individual subject unblinding will only occur in the case of subject 
emergencies, with complete unblinding at the conclusion of the study. 
Emergency breaking of the assigned treatment code should only be undertaken when it is essential 
that knowledge of the treatment assignment is necessary to treat the subject’s emergency safely 
and effectively. Emergency treatment code breaks will be performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject’s identifying information and confirm the necessity to break the treatment code 
for the subject. The Investigator will then receive details of the investigational drug treatment for 
the specified subject and a fax or email confirming this information. The system will automatically 
inform the Sponsor and Medpace study personnel that the code has been broken. 
5.6 
Drug Supplies 
5.6.1 
Formulation and Packaging 
ASN100 is a combination product with 2 separate human mAb components of the IgG1 isotype. 
The specific mAbs are formulated separately and called ASN-1 and ASN-2.  
ASN-1 is a broadly cross-reactive anti-toxin mAb that targets Hla and 3 F-components (HlgB, 
LukF, and LukD) involved in forming 4 of the 5 bi-component leukocidins of S. aureus. 
ASN-2 is directed against the fifth bi-component toxin of S. aureus, LukGH. 
Each component is supplied as a sterile, colorless, clear liquid solution formulated ready for 
injection. 
ASN-1 and ASN-2 will be supplied in separate 10 mL vials as a sterile solution for infusion with 
an extractable volume of 10 mL and a nominal mAb concentration of 20 mg/mL. Each vial will 
contain 200 mg of ASN-1 or 200 mg of ASN-2. Matched vials of ASN-1 placebo and ASN-2 
placebo will also be provided. 
Additional details regarding formulation and packaging will be provided in the Pharmacy Manual 
and the Investigator’s Brochure. 


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5.6.2 
Study Drug Preparation and Dispensing 
Blinded study drug and reference preparations will be delivered to the study site. The site 
pharmacist will prepare the study drug for administration by extracting all volume from each set 
of 9 vials and inserting into an empty IV bag for each set, using aseptic technique according to the 
Pharmacy Manual. These will be delivered to the study site research staff in 2 blinded, ready-to-use 
infusion bags. 
Additional details regarding study drug preparation and dispensing will be provided in the 
Pharmacy Manual. 
5.6.3 
Study Drug Administration 
Subjects will receive ASN100 or matching placebo via 2 IV infusions over a duration of 
approximately 50 to 60 minutes per infusion.  
Both ASN100 and placebo will be administered as 2 separate infusions (either sequentially or 
simultaneously). The last infusion will be completed within 5 hours from initiation of drug 
preparation in the pharmacy. 
Infusions delivered simultaneously must be administered via distinct IV lines (either peripheral or 
central lines; in the instance that a multi-port central line is used, infusions will be delivered 
through separate ports) such that the infusions do not mix before entering the blood stream.  
In the occasion that the 2 infusion bags cannot be hung simultaneously, the blinded IV bags will 
indicate which bag should be infused first and which bag should be infused second. If administered 
sequentially, no more than a 3-hour window should elapse from the time of initiation of the first 
infusion to the completion of the second infusion.  
ASN100 will be administered as separate infusions of 1800 mg ASN-1 and 1800 mg ASN-2 
(9 vials of each to be pooled aseptically according to the Pharmacy Manual into separate infusion 
bags) delivered either sequentially within a 3-hour window from the time of initiation of the first 
infusion to the completion of the second infusion, or simultaneously. 
Placebo will be administered as separate infusions of 9 vials of ASN-1 placebo and 9 vials of 
ASN-2 placebo (vials to be pooled aseptically according to the Pharmacy Manual into separate 
infusion bags) delivered either sequentially within a 3-hour window from the time of initiation of 
the first infusion to the completion of the second infusion, or simultaneously. 
The infusion catheter and tubing will be flushed with sterile saline for injection immediately before 
and following completion of the infusion. 
Either infusion may be discontinued if deemed medically necessary at any time. 
If the first infusion is stopped at any point due to the concern of an adverse event, the second 
infusion will not be administered. 
Refer to the Pharmacy Manual for additional details regarding study drug administration. 


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5.6.4 
Treatment Compliance 
Study drug will be administered at the clinical site by blinded study personnel. The date and time 
of administration, including start and completion times of each infusion, will be accurately logged 
in the source documentation. Due to the single dose design of this study, treatment compliance is 
anticipated to be high. 
5.6.5 
Storage and Accountability 
Study drug (ASN-1, ASN-2, and matching placebos) will be stored at 2°C to 8°C, will be protected 
from light, and will be kept in a secure area with access limited to authorized personnel. The 
primary packaging (vials) is to be kept within the secondary packaging (carton box). 
Investigational site personnel (e.g., study pharmacist) will perform an ongoing inventory of study 
drug products. At the end of the study, a full reconciliation of drug inventory will be performed 
and the results of the inventory will be recorded in the drug accountability log. Any unused vials 
should be returned for destruction.  
Additional details regarding study drug storage and accountability will be provided in the 
Pharmacy Manual. 
5.7 
Prior and Concomitant Medications and/or Procedures 
5.7.1 
Excluded Medications and/or Procedures 
The use of any investigational product within 30 days prior to the Screening Visit (or 5 half-lives 
of the investigational product, whichever is longer) is prohibited. Any immunoglobulin preparation 
for any medical indication is prohibited through follow-up Day 90 of the study. 
Prior use of ASN100, ASN-1, or ASN-2 is prohibited. 
5.7.2 
Documentation of Prior and Concomitant Medication Use 
All prior medications received by the subject within 14 days prior to study drug administration and 
any concomitant medications used throughout the duration of the study will be recorded in the 
source documents and on the appropriate eCRF. The medication name, route of administration, 
dose, frequency, indication, and duration of treatment (start and stop dates) will be recorded. 
 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Written informed consent will be obtained from all subjects prior to any study-specific procedures 
being performed. A separate consent will be obtained from those subjects who participate in the 
BAL fluid PK sub-study. 
See Section 12.3 for additional details regarding informed consent. 
6.2 
Screening/Enrollment (Up to Day -14) 
Screening/Enrollment may be performed up to 14 days prior to randomization. Subjects who meet 
all of the inclusion criteria and none of the exclusion criteria will be screened daily (while 
mechanically ventilated) for up to 8 days to identify those subjects who are heavily colonized with 
S. aureus (see Section 3.1).  
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 
provided the subject remains mechanically ventilated, for a total Screening Period of up to 14 days. 
Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator 
and providing the subject remains mechanically ventilated.  
Once an enrolled subject has an ETA culture reported positive for heavy S. aureus colonization 
and meets all of the inclusion and none of the exclusion criteria, they are eligible for randomization. 
If they are not randomized on this occasion according to the protocol, they are no longer eligible 
for continued ETA sampling and randomization, and will be discontinued from the study; however, 
if subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible 
for re-screening as a new subject enrollment. Subjects who were previously randomized are not 
eligible to be re-consented and re-screened. 
The following procedures will be performed during Screening/Enrollment: 
• Obtain informed consent; 
• Review inclusion and exclusion criteria; 
• Record medical history;  
• Record demographics; 
• Record antibiotic and other medication history; 
• Obtain height and body weight measurements; 
• Perform complete physical examination; 
• Obtain vital sign measurements, including oxygenation status; 
• Perform pregnancy test for female subjects of childbearing potential only. Female subjects may 
be enrolled on the basis of a negative urine pregnancy test, pending the result of a negative 
serum pregnancy test prior to randomization; 
• Assess ventilator device status; 
• Perform chest X-ray or thoracic CT scan. A chest X-ray or thoracic CT scan obtained as part 
of standard of care within 24 hours prior to the initial Screening Visit is sufficient provided 


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there are no changes in the subject’s clinical status (e.g., no change in ventilation status, 
secretions, or signs/symptoms that may be suggestive of pneumonia) within the 24 hours 
following imaging; 
• Obtain ETA for culture;  
• Assess for other S. aureus-associated infections; and 
• Perform adverse event assessment (adverse events that occur between the time the subject signs 
the ICF and the Randomization Visit will only be recorded if related to a study-specific 
procedure). 
6.3 
Randomization Visit (Day 1 Pre-Dose) 
The Randomization Visit will occur pre-dose on Day 1. At the time of randomization, if a subject’s 
screening ETA culture also shows heavy colonization of a Gram-negative organism (i.e., heavy 
co-colonization of both Gram-positive and Gram-negative organisms), the subject will not be 
randomized into the study; however, randomization should not be delayed while waiting for 
Gram-negative results if heavy colonization with S. aureus has been confirmed. 
The following procedures will be performed at the Randomization Visit: 
• Review inclusion, exclusion, and randomization criteria; 
• Review and record medical history (if changes occurred since the Screening Visit); 
• Review and record antibiotic and other medication history (if changes occurred since the 
Screening Visit); 
• Perform limited physical examination (to include, at a minimum, a pulmonary examination 
[including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform clinical laboratory assessments, including chemistry, hematology, coagulation, and 
urinalysis; 
• Obtain a blood sample for procalcitonin testing; 
• Assess ventilator device status; 
• Perform chest X-ray or thoracic CT scan. A chest X-ray or thoracic CT scan obtained within 
24 hours of the Randomization Visit is sufficient, provided there are no changes in the subject’s 
clinical status (e.g., no change in ventilation status, secretions, or signs/symptoms that may be 
suggestive of pneumonia) since the time of imaging; 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain nasal swab specimens for culture (one from each nostril); 
• Randomize to study treatment; 
• Obtain a blood sample for ADA and assessment of pre-existing anti-S. aureus toxin antibodies; 
• Perform 12-lead ECG; 


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• Record concomitant medications; and 
• Perform adverse event assessment. 
6.4 
Treatment Period (Day 1) 
The following procedures will be performed on Day 1 following administration of study drug: 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status; 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Administer study drug; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin antibodies 
(to be collected immediately following the completion of the second infusion [+15 minutes] 
and at 6 hours [±4 hours] and 24 hours [±6 hours] post-dose); 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.5 
Monitoring Period 
6.5.1 
Day 2/Day 3 – Bronchoalveolar Lavage Fluid Pharmacokinetic Sub-Study 
The following procedures will be performed 48 hours (±36 hours) post-dose (Day 2 or Day 3 
depending on the time of study drug administration) for those subjects participating in the 
BAL fluid PK sub-study only or if BAL fluid is collected as part of a standard of care procedure 
for any subject at any other time post-randomization for any other reason: 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status; 
• Perform chest X-ray or thoracic CT scan; 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain BAL fluid to determine ASN-1 and ASN-2 concentrations (48 hours [±36 hours] 
post-dose) for those subjects participating in the BAL fluid PK sub-study (if BAL fluid is 
collected as part of a standard of care procedure from any subject enrolled in the sub-study at 
any other time post-randomization for any other reason, if possible, a sample for PK analysis 
will also be obtained);  


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• Obtain a blood sample for PK measurement ±1 hour relative to BAL fluid collection (including 
scheduled BAL fluid collection or if BAL fluid is collected as part of a standard of care 
procedure from any subject enrolled in the sub-study at any time post-randomization); 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.5.2 
Day 2 to Day 21 
The following procedures will be performed daily (unless otherwise indicated) from Day 2 to 
Day 21 while the subject is hospitalized. For subjects participating in the BAL fluid PK sub-study, 
procedures noted for the Day 2 visit only need to be performed 1 time: 
• Perform limited physical examination (to include, at a minimum, a pulmonary examination 
[including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform clinical laboratory assessments, including chemistry, hematology, coagulation, and 
urinalysis. Blood samples for chemistry, hematology, and coagulation will be obtained on 
Days 2 (+1 day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, and twice weekly during 
Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through Day 21) of the Monitoring 
Period while the subject remains hospitalized. Urine for urinalysis will be obtained on Day 6 
(±1 day) of the Monitoring Period only; 
• Obtain a blood sample for procalcitonin testing (on day of diagnosis of pneumonia only, if 
applicable); 
• Assess ventilator device status (if applicable); 
• Perform chest X-ray or thoracic CT scan (required during the Monitoring Period for those 
subjects presenting with signs and symptoms of a respiratory infection such as dyspnea, 
tachypnea, fever, or cough); 
• Obtain adequate respiratory specimen for culture (if clinically indicated); 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain a blood sample for ADAs (to be obtained only upon discharge from the ICU, if 
discharge occurs prior to Day 22); 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin antibodies 
(Days 4 [±1 day], 7 [±1 day], and 14 [±2 days] only); 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  


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• Record concomitant medications; and 
• Perform adverse event assessment. 
6.5.3 
Day 22 
The following procedures will occur on Day 22 (+2 days): 
• Perform limited physical examination (if subject is hospitalized) (to include, at a minimum, a 
pulmonary examination [including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform pregnancy test for female subjects of childbearing potential only (additional 
pregnancy testing may occur throughout the duration of the study, per applicable country 
requirements); 
• Perform clinical laboratory assessments including chemistry, hematology, coagulation, and 
urinalysis; 
• Obtain a blood sample for procalcitonin testing; 
• Assess ventilator device status (if applicable); 
• Perform chest X-ray or thoracic CT scan (required during the Monitoring Period for those 
subjects presenting with signs and symptoms of a respiratory infection such as dyspnea, 
tachypnea, fever, or cough); 
• Obtain adequate respiratory specimen for culture (if clinically indicated); 
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin antibodies; 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  
• Record concomitant medications; and 
• Perform adverse event assessment. 


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6.6 
Follow-Up Period 
6.6.1 
Day 28 (+2 Days) Follow-Up 
The following procedures will occur during a follow-up telephone call or visit, if the subject 
remains hospitalized, on Day 28 (+2 days): 
• Assess ventilator device status (if applicable); and 
• Assess for survival and discharge disposition. 
6.6.2 
Day 40 to Day 89 (Follow-Up Safety Visit) 
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they 
receive study treatment, a follow-up safety visit will be performed on the day of discharge.  
The following procedures will occur on the day of hospital discharge for subjects who are 
discharged between Day 40 and Day 90: 
• Perform limited physical examination (to include, at a minimum, a pulmonary examination 
[including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status (if applicable); 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin antibodies; 
• Track days on ventilator from randomization (if applicable); 
• Track days in ICU (or other observation area) from randomization; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.6.3 
Safety Visit (Day 90 [±7 Days]) 
The following procedures will be performed at the Safety Visit on Day 90 (±7 days). If the subject 
is unable to return to the site, this visit may be conducted by telephone, with procedures performed 
as appropriate (i.e., concomitant medications and adverse events collected): 
• Perform limited physical examination (to include, at a minimum, a pulmonary examination 
[including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Assess ventilator device status (if applicable); 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 


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• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin antibodies; 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization; 
• Record concomitant medications; and 
• Perform adverse event assessment. 
6.7 
Early Termination Visit and Withdrawal Procedures 
For subjects who are withdrawn from the study prior to Day 22, the following procedures will be 
performed at an Early Termination Visit: 
• Perform limited physical examination (to include, at a minimum, a pulmonary examination 
[including auscultation]); 
• Obtain vital sign measurements, including oxygenation status; 
• Perform pregnancy test for female subjects of childbearing potential only; 
• Perform clinical laboratory assessments including chemistry, hematology, coagulation, and 
urinalysis (if clinically indicated); 
• Obtain a blood sample for procalcitonin testing; 
• Assess ventilator device status (if applicable); 
• Obtain adequate respiratory specimen for culture (if clinically indicated);  
• Assess for clinical signs/symptoms of pneumonia (Section 7.4.2; Table 1); 
• Assess for other S. aureus-associated infections; 
• Obtain a blood sample for ADAs; 
• Perform 12-lead ECG; 
• Assess for survival and discharge disposition; 
• Obtain a blood sample for PK measurement and assessment of anti-S. aureus toxin antibodies; 
• Track days on ventilator from randomization; 
• Track days in ICU (or other observation area) from randomization;  
• Record concomitant medications; and 
• Perform adverse event assessment. 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects in the MITT Population who develop 
S. aureus pneumonia as defined in Section 7.4 up to but not including Day 22. 
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• Duration of mechanical ventilation during the first 21 days post-randomization for subjects in 
the MITT, Intent-to-Treat (ITT), and Per Protocol (PP) Populations; 
• Length of ICU stay during the first 21 days post-randomization for subjects in the MITT, ITT, 
and PP Populations;  
• The Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single dose of 
ASN100 in the PK Population; and 
• 28-day all-cause mortality in the MITT, ITT, and PP Populations. 
7.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
• Proportion of subjects in the MITT and PP Populations with a diagnosis of HABP at >48 hours 
post-extubation up to but not including Day 22 in extubated subjects; 
• Proportion of subjects in the MITT and PP Populations with development of VABP up to but 
not including Day 22; 
• Incidence of all bacterial pneumonias in the MITT, ITT, and PP Populations; 
• Incidence of other non-S. aureus pneumonias up to but not including Day 22 in the MITT, ITT, 
and PP Populations; and  
• Incidence of other S. aureus infections acquired following study drug administration up to but 
not including Day 22 in the MITT, ITT, and PP Populations. 


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7.4 
Microbiological and Clinical Assessments 
7.4.1 
Microbiological Assessment 
ETA specimens will be collected for culture during Screening/Enrollment to determine the degree 
of S. aureus colonization. Additional respiratory specimens may be collected for culture 
throughout the Monitoring Period or Early Termination (if applicable) if clinically indicated 
according to standard of care. 
If, as part of routine standard of care, additional respiratory and/or other microbiological specimens 
are collected for culture during the study, results will be documented within the eCRF. As fully 
described within the study lab manual, bacterial isolates recovered from these specimens that are 
deemed pathogens by the Investigator (if retained and available at the study site local microbiology 
laboratory) will be sent to a central microbiology laboratory for confirmation of pathogen 
identification (all isolates) and susceptibility testing (S. aureus isolates only). 
During the Monitoring Period, a diagnosis of S. aureus pneumonia will be determined if subjects 
have S. aureus identified from an adequate respiratory specimen (Section 7.4.1) and clinical signs 
and symptoms of pneumonia. For a diagnosis of S. aureus pneumonia, clinical signs and symptoms 
must occur ±2 days from the time of collection of an adequate respiratory specimen culture that is 
positive for S. aureus (Section 7.4.2).  
• For intubated subjects, a respiratory specimen obtained by BAL, non-bronchoscopic BAL, or 
protected specimen brush will be considered an adequate respiratory specimen; or 
• For extubated subjects, an adequate expectorated/induced sputum specimen is defined as 
<10 squamous epithelial cells and >25 PMNs/100× field; and 
• For both intubated and extubated subjects, adequate respiratory specimens will undergo either 
semi-quantitative or quantitative culture in accordance with the local laboratory’s standard 
procedure. 
7.4.2 
Assessment of Clinical Signs and Symptoms 
Subjects will be assessed daily throughout the Monitoring Period for the following clinical signs 
and symptoms presented in Table 1. 
Table 1. 
Clinical Signs and Symptoms 
Mechanically Ventilated Subjects 
Non-Mechanically Ventilated Subjects 
• 
Cough, 
• 
Rales, 
• 
Dullness on percussion,* 
• 
Bronchial breath sounds, 
• 
Egophony,* 
• 
Need for suctioning, 
• 
Need for ventilator support, and 
• 
Fever ≥38°C (≥100.4°F). 
• 
Cough, 
• 
Rales, 
• 
Dullness on 
percussion,* 
• 
Bronchial breath 
sounds, 
• 
Egophony,* 
• 
Dyspnea, 
• 
Tachypnea, 
• 
Respiratory rate, 
• 
Hypoxemia, and 
• 
Fever ≥38°C 
(≥100.4°F). 
*If routinely performed. 


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A diagnosis of pneumonia (HABP or VABP) will be determined as defined in Table 2. 
Table 2. 
Definition of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia 
Indication 
Definition 
HABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed by 
the Investigator); 
• 
At least ONE of the following: 
o 
Has been hospitalized for >48 hours, or 
o 
Developed clinical signs and symptoms within 7 days following hospital discharge; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the 
requirement for mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
VABP 
• 
A chest X-ray showing new or progressive infiltrates suggestive of pneumonia (as assessed by 
the Investigator);  
• 
Subject has received mechanical ventilation via an endotracheal or nasotracheal tube for 
≥48 hours; 
• 
At least ONE of the following: 
o 
New onset or worsening pulmonary signs/symptoms such as cough, dyspnea, tachypnea 
(e.g., respiratory rate >25 breaths per minute), expectorated sputum production, or the 
requirement for mechanical ventilation (if subject is not already ventilated); 
o 
Need for acute changes in ventilator support to enhance oxygenation or to the amount of 
PEEP; or 
o 
New onset of suctioned respiratory secretions; AND 
• 
At least ONE of the following clinical signs/symptoms: 
o 
Temperature >38°C or <35°C, 
o 
WBC count ≥10,000 cell/mm3 or ≤4500 cell/mm3, or 
o 
>15% immature neutrophils (bands) on peripheral blood smear. 
HABP = hospital-acquired bacterial pneumonia; PEEP = positive end-expiratory pressure; VABP = ventilator-associated 
bacterial pneumonia; WBC = white blood cell. 


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8 
PHARMACOKINETIC ASSESSMENTS 
8.1 
Pharmacokinetic Endpoint 
The primary PK endpoints are the Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum 
following a single IV dose of ASN100 in the PK Population. 
The levels of ASN-1 and ASN-2 will be measured in BAL fluid in a PK sub-study which will 
allow the calculation of a blood to ELF ratio.  
8.2 
Pharmacokinetic Assessments 
Samples for PK analysis will be obtained to determine the PK of ASN-1 and ASN-2 in serum and 
BAL fluid (for subjects participating in the BAL fluid PK sub-study only). Instructions for the 
collection, handling, and storage of biological samples will be provided in a separate Laboratory 
Manual.  
In order to maintain the study blind, all subjects, including those randomized to receive placebo, 
will have PK samples obtained at the specified time points. The actual date and time of each sample 
will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded Sponsor or CRO personnel until the study has been unblinded. 
8.2.1 
Serum Pharmacokinetic Sampling 
Blood samples will be obtained for the measurement of ASN-1 and ASN-2 in serum. At the 
completion of the second infusion, blood samples for PK analysis will be collected immediately 
following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 
24 hours (±6 hours) post-dose. 
In addition, a PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 
14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected 
on the day of discharge (if discharge occurs between Day 40 and Day 90), on Day 90 (if 
hospitalized or if the subject is able to return to the clinic), or Early Termination (if applicable). 
The following serum PK parameters will be assessed: 
• Maximum serum concentration (Cmax), 
• Time to maximum serum concentration (Tmax), 
• Area under the serum concentration-time curve (AUC), and 
• Terminal elimination half-life (t1/2). 
Subjects participating in the BAL fluid PK sub-study will have a blood sample collected for 
PK measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid 
collection or if BAL fluid is collected as part of a standard of care procedure from any subject 
enrolled in the sub-study at any time post-randomization). 


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8.2.2 
Bronchoalveolar Lavage Fluid Pharmacokinetic Sampling 
Select sites will be invited to participate in a BAL fluid PK sub-study. Approximately 25 to 
35 subjects who volunteer will participate in this sub-study and will have BAL fluid collected 
48 hours (±36 hours) post-dose (on approximately Day 2 or Day 3, depending on time of study 
drug administration) to determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid 
is collected as part of a standard of care procedure from any subject enrolled in the sub-study at 
any other time post-randomization for any other reason, if possible, a sample for PK analysis will 
also be obtained.  
8.2.3 
Analysis of Anti-Staphylococcus aureus Toxin Antibody Titers 
Blood samples obtained for ADA and PK analysis purposes will also be used to assess the amount 
of pre-existing anti-S. aureus toxin antibodies and the toxin neutralizing titer of the serum sample 
prior to and after randomization. Only antigen-specific antibody titers will be determined and no 
genetic information will be extracted from these samples. Samples will be destroyed following the 
completion of all S. aureus anti-toxin antibody analyses. 


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9 
SAFETY ASSESSMENTS 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events that occur between the time the subject signs the ICF and the Randomization Visit 
will only be recorded if related to a study-specific procedure. Beginning with randomization all 
adverse events, which include clinical laboratory test and physical examination variables, will be 
monitored and documented until study participation is complete. Subjects should be instructed to 
report any adverse event that they experience to the Investigator. Site personnel will ensure each 
adverse event is recorded on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at the time of randomization should not be reported as an 
adverse event unless the medical condition or signs or symptoms present at baseline change in 
severity or seriousness at any time during the study. In this case, it should be reported as an adverse 
event. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at the time of randomization and significantly worsen 
during the study should be reported as adverse events. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Any abnormal test that is determined to be an error does not 
require reporting as an adverse event. 
Lack of efficacy (i.e., development of pneumonia as defined in Section 7.4) will be captured as an 
efficacy measure and in general will not be considered an adverse event; however, new onset of 
specific pulmonary symptoms that do not meet the study-specific definition of pneumonia or 
worsening of baseline signs and symptoms should be captured as adverse events. Events that meet 
the criteria for an SAE (Section 9.2) should follow the procedures for SAE reporting as detailed in 
Section 9.3. 


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9.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product mean that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
9.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
The reference safety information for ASN100 is included in the current version of the 
Investigator’s Brochure. The reference safety information will be reviewed yearly and the 
periodicity of the review will be harmonized with the reporting period of the Development Safety 
Update Report. 
9.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 


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The following factors should also be considered: 
• The temporal sequence from study drug administration: 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event; 
• Underlying, concomitant, intercurrent diseases: 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have; 
• Concomitant drugs: 
o The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question; 
• Known response pattern for this class of study drug: 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect; 
• Exposure to physical and/or mental stresses: 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event; and 
• The pharmacology and PK of the study drug: 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
o NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in the view 
of either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 


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situational reasons (i.e., no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the 
development of drug dependency. 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
Serious adverse events related to a study-specific procedure that occur between the Screening Visit 
and the Randomization Visit, and all SAEs occurring from the time of randomization until the 
Day 90 Safety Visit, must be reported to Medpace Clinical Safety within 24 hours of the 
knowledge of the occurrence (this refers to any adverse event that meets any of the aforementioned 
serious criteria). All SAEs that the Investigator considers related to study drug occurring after the 
Day 90 Safety Visit must be reported to the Sponsor. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form.  
If the event meets serious criteria and it is not possible to access the EDC system, send an email 
to Medpace Safety at Medpace-safetynotification@medpace.com or call the Medpace SAE hotline 
(phone number listed below), and fax the completed paper SAE form to Medpace (fax number 
listed below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available.  
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, Dial 3 or +1-513-579-9911, Dial 3 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
Email: medpace-safetynotification@medpace.com 
Medpace SAE hotline – Europe: 
Telephone: +49-89-89-55-718-44 
Facsimile: +49-89-89-55-718-104 
Email: medpace-safetynotification@medpace.com 


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Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
9.4 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant from the time of 
randomization until the Day 90 Safety Visit, the Investigator should report the pregnancy to 
Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero form to the Investigator for completion.  
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
9.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the FDA, applicable competent 
authorities in all the Member States concerned, and to the Central Ethics Committee, and in any 
case no later than 7 days after knowledge by the Sponsor of such a case, and that relevant follow-up 
information will subsequently be communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable 
competent authorities concerned, and to the Central Ethics Committee concerned as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all Investigators as required.  
Expedited reporting of suspected unexpected serious adverse reactions related to 
non-investigational medical products (NIMPs) used in this study (and any other NIMPs) will not 
be necessary. Listings of cases related to NIMPs will be included in the Development Safety 
Update Report. 
9.6 
Clinical Laboratory Evaluations 
Standard clinical laboratory profiles for safety assessments (including chemistry, hematology, 
coagulation, and urinalysis) will be collected and evaluated at the Randomization Visit 
(Day 1 pre-dose).  
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1 day), 
4 (±1 day), and 6 (±1 day) of the Monitoring Period, or Early Termination (if applicable and if 


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clinically indicated). During Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through 
Day 21) of the Monitoring Period, clinical laboratory assessments of chemistry, hematology, and 
coagulation will be performed twice a week while the subject remains hospitalized.  
Urine for urinalysis will be obtained at the Randomization Visit (Day 1 pre-dose), on Day 6 
(±1 day) of the Monitoring Period, or Early Termination (if applicable and if clinically indicated). 
Procalcitonin testing will be performed at the Randomization Visit (Day 1 pre-dose), on the day 
of diagnosis of pneumonia (if applicable), and on Day 22 or Early Termination (if applicable). 
Study required laboratory samples will be sent to the central laboratory for analysis. Subject care 
should be directed by local laboratory testing. 
See Appendix B for a list of clinical laboratory analytes to be assessed. 
9.7 
Radiographs and Imaging 
A chest X-ray or thoracic CT scan is required on 4 occasions during the study as defined below 
for (1) initial Screening Visit, (2) Randomization Visit, (3) Post-BAL sampling for those subjects 
participating in the optional BAL sub-study, and (4) Monitoring Period (Day 2 through Day 22) 
for those subjects presenting with signs/symptoms suggestive of a respiratory infection. 
• Initial Screening Visit: A chest X-ray or thoracic CT scan will be obtained at the initial 
Screening Visit to ensure that the subject does not have pneumonia. A chest X-ray or thoracic 
CT scan obtained as part of standard of care within 24 hours of the initial Screening Visit is 
sufficient provided there are no changes in the subject’s clinical status (e.g., no change in 
ventilation status, secretions, or signs/symptoms that may be suggestive of pneumonia) within 
the 24 hours since the imaging procedure. 
• Randomization Visit: A chest X-ray or thoracic CT scan will be obtained at the Randomization 
Visit to ensure that the subject does not have pneumonia. A chest X-ray or thoracic CT scan 
obtained as part of standard of care within 24 hours of the Randomization Visit is sufficient 
provided there are no changes in the subject’s clinical status (e.g., no change in ventilation 
status, secretions, or signs/symptoms that may be suggestive of pneumonia) since the time of 
imaging. 
• BAL sub-study: A chest X-ray or thoracic CT scan will be obtained on Day 2/Day 3 post-BAL 
sampling for all subjects participating in the optional BAL fluid PK sub-study. 
• Monitoring Period (Day 2 through Day 22): A chest X-ray or thoracic CT scan is required 
during the Monitoring Period for those subjects presenting with signs and symptoms of a 
respiratory infection such as dyspnea, tachypnea, fever, or cough. 
Imaging should be conducted per institutional guidelines and assessed by the Investigator. 
The results of radiographs or imaging obtained at the Screening Visit and any subsequent visits 
should be documented on the appropriate eCRF. Radiograph or imaging reports and/or films will 
be collected for future analysis and will be captured within the EDC system. 
9.8 
Vital Signs 
Vital sign measurements will be obtained at the Screening Visit, the Randomization Visit (Day 1 
pre-dose), on Day 1 following administration of study drug, daily during the Monitoring Period (if 
subject is hospitalized), on Day 22, on the day of hospital discharge (for subjects who are 


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discharged between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs onsite), or 
Early Termination (if applicable). 
Vital sign measurements will include temperature, systolic and diastolic blood pressure, pulse, 
respiratory rate, and oxygenation status (as measured by pulse oximetry or arterial blood gas). 
Vital sign measurements will be recorded on the appropriate eCRF. 
Blood pressure and pulse will be assessed via an automated device. Manual techniques are only to 
be used if an automated device is not available. 
Oxygenation status will be determined at the Screening and Randomization Visits via 
measurement of arterial blood gas, provided the subject has an arterial line placed. If no arterial 
line is present, pulse oximetry may be used. Oxygenation status may be determined at subsequent 
visits by either measurement of arterial blood gas or pulse oximetry, if no arterial line is present. 
9.9 
Electrocardiograms 
A 12-lead ECG will be performed for all eligible subjects at the Randomization Visit 
(Day 1 pre-dose), on Day 22, on the day of hospital discharge (for subjects who are discharged 
between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs onsite), or 
Early Termination (if applicable). 
9.10 
Physical Examinations 
A complete physical examination will be performed at the Screening Visit and as deemed 
necessary by the Investigator and will include, at a minimum, a pulmonary examination (including 
auscultation) and assessments of the skin, abdomen, cardiovascular, gastrointestinal, and 
neurological systems. Body weight and height will also be measured.  
A limited physical examination will be performed at the Randomization Visit, daily during the 
Monitoring Period, on Day 22, on the day of hospital discharge (for subjects who are discharged 
between Day 40 and Day 90), at the Day 90 Safety Visit (if the visit occurs onsite), or 
Early Termination (if applicable). The limited physical examination will include, at a minimum, a 
pulmonary examination (including auscultation). 
9.11 
Immunogenicity 
Samples to evaluate ADA response including neutralizing antibodies to ASN-1 and ASN-2 will 
be collected from all subjects at the Randomization Visit (Day 1 pre-dose), upon discharge from 
the ICU (if discharge occurs prior to Day 22), on Day 22, on the day of hospital discharge (for 
subjects who are discharged between Day 40 and Day 90), and at the Day 90 Safety Visit (if the 
visit occurs onsite).  
Subjects who discontinue early or are withdrawn from the study should also have samples 
collected as part of their Early Termination Visit. These samples will be sent to the central 
laboratory for analysis. 
Samples will be screened for antibodies binding to ASN-1 and ASN-2 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to ASN-1 or ASN-2 and/or to further characterize the immunogenicity of ASN-1 and 
ASN-2. 
The impact of ADAs on safety, efficacy, and PK will be addressed in the Statistical Analysis Plan.  


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10 
STATISTICS 
10.1 
Analysis Populations 
Intent-to-Treat (ITT) Population 
The ITT Population includes all subjects who are randomized to receive study drug.  
Modified Intent-to-Treat (MITT) Population 
The MITT Population includes all subjects in the ITT Population who receive study drug who are 
heavily colonized with S. aureus as determined by quantitative or semi-quantitative culture of an 
ETA. 
Per Protocol (PP) Population 
The PP Population includes all subjects in the MITT Population who also meet the following 
criteria: 
• Do not have any major protocol violations that would affect assessment of efficacy, and 
• Complete an adequate number of Monitoring Period assessments through and including 
Day 22. 
Pharmacokinetic (PK) Population 
The PK Population includes all subjects in the MITT Population with at least 1 serum PK sample 
collected post-dose. 
Safety Population 
The Safety Population includes all subjects who receive any amount of study drug and have at 
least 1 post-treatment safety assessment. 
10.2 
Statistical Methods 
All statistical analyses will be provided in the Statistical Analysis Plan. Continuous variables will 
be summarized by using the number of non-missing observations, arithmetic mean, standard 
deviation, median, minimum, and maximum values as descriptive statistics. Categorical variables 
will be summarized by using the frequency count and the percentage of subjects in each category 
as descriptive statistics.  
All statistical tests will be performed at the 0.05 significance level using 2-sided tests, except where 
otherwise noted. All confidence intervals will have a confidence level of 95%. 
10.2.1 
Disposition 
The number of subjects randomized, treated, completed, and discontinued early from the study 
and the reasons for discontinuation will be summarized descriptively. In addition, reasons leading 
to study discontinuation will be summarized for each treatment group. The number and percentage 
of subjects for the randomized subjects included in each analysis population will also be presented. 
10.2.2 
Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment group for demographics (e.g., age, gender, race, 
and ethnicity) and for baseline characteristics. 


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10.2.3 
Analysis of Efficacy 
The primary efficacy endpoint is whether the subject has developed S. aureus pneumonia up to 
but not including Day 22. The summary measure for efficacy is the proportion of subjects in the 
MITT Population who develop S. aureus pneumonia up to but not including Day 22. Analysis for 
the primary endpoint will compare the proportion of subjects who develop S. aureus pneumonia 
in the ASN100 arm versus the placebo arm in the MITT Population. The statistical test for 
comparing 2 event rates is based on a 2-sided test with a false positive rate of 5%.  
Analyses of the primary efficacy endpoint will also be performed separately for the ITT and 
PP Populations. 
Duration of mechanical ventilation and length of hospital ICU stay during the first 21 days 
post-randomization will be compared between treatment groups using a Wilcoxon rank sum test. 
Other efficacy endpoints will be summarized by treatment group.  
10.2.4 
Analysis of Safety 
All subjects in the Safety Population will be included in the safety analyses and analyzed based on 
the actual treatment received.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events will be summarized by system organ class and preferred term. 
A TEAE is defined as an adverse event with a start date and time on or after the first dose of study 
treatment. Listings will be provided for SAEs and adverse events leading to drug discontinuation. 
In addition, all adverse events will be listed.  
Safety laboratory data and vital signs will be presented by each scheduled time point and for 
change from baseline to each time point. The results of all laboratory tests, physical examination 
findings, vital signs, and ADAs will be presented in data listings.  
10.2.5 
Analysis of Pharmacokinetics 
Descriptive statistics will be provided for all PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population. Subject PK profiles will be determined using 
parameters such as Cmax, Tmax, AUC, and t1/2 for each of ASN-1 and ASN-2 in serum. Epithelial 
lining fluid PK will also be analyzed and an ELF/serum PK ratio will be calculated.  
A description of the PK parameter analysis will be included in the Statistical Analysis Plan. 
10.2.6 
Sample Size Determination 
The estimated incidence of progression to S. aureus pneumonia in mechanically ventilated subjects 
with heavy colonization is approximately 25% within 22 days of randomization.  
Assuming a 2-sided significance level of 0.05 and a desired power of 80% to detect a significant 
difference between S. aureus pneumonia incidence rates of 25% in the placebo group and 12.5% 
in the ASN100 treatment group (50% reduction), 152 evaluable subjects are required in each 
treatment group. A sample size of 304 subjects (152 subjects per treatment group) will yield 
80% power to detect a 50% reduction in the incidence of S. aureus pneumonia with ASN100 
treatment when assuming a 25% incidence rate of S. aureus pneumonia in placebo-treated subjects. 
Assuming a 14% non-evaluable rate, approximately 354 subjects (177 subjects per treatment 


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group) will be randomized. Assuming the screen failure rate is about 84%, approximately 
2250 subjects will be screened. 
10.2.7 
Interim Analysis 
One interim analysis will be conducted during the study, when approximately 125 subjects have 
reached Day 22. The interim analysis is for futility assessment of the study, and for a potential 
study sample size adjustment based on an overall blinded efficacy evaluation pooled across the 
treatment arms. Based on this assessment, the sample size may be increased. The interim analysis 
of futility assessment will be reviewed by an independent Data Review Committee (DRC).  


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel with a 
role designated for data entry must log into the system using their secure user name and password 
in order to enter, review, or correct study data. These procedures must comply with Title 21 of the 
Code of Federal Regulations (21 CFR Part 11) and other appropriate international regulations. All 
passwords will be strictly confidential. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• MedDRA for adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
12.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
12.2 
Institutional Review Board/Independent Ethics Committee 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of subjects. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements (if 
applicable), written information given to the subjects, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB/IEC by the Investigator. 
Federal regulations and ICH require that approval be obtained from an IRB/IEC prior to 
participation of subjects in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for subject recruitment, and any other written 
information regarding this study to be provided to a subject or subject’s legal guardian must be 
approved by the IRB/IEC. Where applicable, the requirements of the CIP, as well as the 
decision-making process regarding inclusion of subjects into the study, must be approved by the 
IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor. 
It is the responsibility of the Sponsor or CRO to obtain the approval of the responsible ethics 
committees according to the national regulations.  
The study will only start at the respective sites once the respective committee’s written approval 
has been given. 
12.3 
Informed Consent 
The ICF, the ICF for the BAL fluid PK sub-study, and any changes to the ICFs made during the 
course of the study must be agreed to by the Sponsor or designee and the IRB/IEC prior to use and 
must be in compliance with all ICH GCP, local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each subject or the subject’s legal representative (if applicable) before any 
study-specific activity is performed and should document in the source documentation that consent 
was obtained prior to enrollment in the study. In the case that the subject is not fully conscious, a 
shortened version of informed consent will be signed by the subject and a complete version of 
informed consent will be signed, dependent on the country-specific requirements, by the subject’s 
legal representative or close person (e.g., husband/wife, child, or sibling), or by the CIP (if 
applicable), by an impartial witness, and by the Investigator prior to any study-specific procedure 


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being performed. A subject who is not fully conscious will be required to sign the complete version 
of informed consent once fully conscious. The original signed copy of the ICF must be maintained 
by the Investigator and is subject to inspection by a representative of the Sponsor, their 
representatives, auditors, the IRB/IEC, and/or regulatory agencies. A copy of the signed ICF will 
be given to the subject. 
In countries only where it is applicable, for subjects who are unable to read and sign either version 
of the ICF (i.e., shortened or complete version), decisions regarding the subject’s enrollment will 
be made by the CIP. The decision of the CIP to include the subject in the study must be documented 
in the minutes of the CIP meeting, signed by the members of the CIP, and the decision must be 
entered in the medical records of the subject. The minutes of the CIP meeting should contain the 
names of all physicians included in the composition of the CIP, the subject’s diagnosis, the 
subject’s condition at the time the decision was made, the interpretation of clinical, laboratory, 
instrumental, and other data, and the decision of the CIP. The documents supporting the CIP 
decision must be maintained by the Investigator. 
12.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki (Seoul 2008), and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
12.5 
Protocol Deviations 
Deviations from the protocol are not permitted. If a protocol deviation occurs, the CRA will ensure 
the deviation is appropriately documented. Substantial deviations will be compiled into a listing 
for inclusion in the final clinical study report and minor deviations will be recorded in the source 
documents at the site. Investigators must comply with all applicable IRB/IEC and local 
requirements in the reporting of protocol deviations.  


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12.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable national or regional health authorities, and the IRB/IEC as appropriate. 
Subjects or their legal representatives may request their medical information be given to their 
personal physician or other appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
12.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., CRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
12.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. However, the Investigator will be afforded the right to 
publish their individual results after the end of the trial if no agreement on the publication can be 
achieved within 2 years of database lock. 
12.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR §54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out subject liability 
insurance for all subjects who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 


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12.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e., initiation of study centers) when the CTA and favorable Ethics 
opinion have been received from those bodies governing those study centers.  


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for subject safety. In this 
case, the situation must be documented and reported to the IRB/IEC within 5 working days. 
13.2 
Address List 
13.2.1 
Sponsor 
Arsanis, Inc. 
890 Winter Street, Suite 230 
Waltham, MA 02451-1472 
Telephone: +1-781-819-5704 
Facsimile: +1-781-957-1267 
13.2.2 
Global Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-513-579-9911 
Facsimile: +1-513-579-0444 
13.2.3 
Drug Safety 
Medpace Clinical Safety 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: +1-800-730-5779, Dial 3 or +1-513-579-9911, Dial 3 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
Email: Medpace-safetynotification@medpace.com 


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13.2.4 
Biological Specimens 
Clinical and Microbiology Laboratory 
ACM Global 
160 Elmgrove Park 
Rochester, NY 14624 
Telephone: +1-585-429-2374 or +1-866-405-0400 
Pharmacokinetic and Immunogenicity Laboratory 
Eurofins | ADME BIOANALYSES 
75 A, Avenue de Pascalet 
30310 Vergèze, France 
Telephone: +33-(0)4-66-73-17-73 
Facsimile: +33-(0)4-66-73-17-74 
13.2.5 
Study Drug Packaging, Labeling, and Distribution 
ABF Pharmaceutical Services GmbH 
Gastgebgasse 5-13 
1230 Vienna, Austria 
Telephone: +43-1-890-12-00-30 
Facsimile: +43-1-890-12-00-11 
 
 


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14 
REFERENCES 
1. Berube BJ, Bubeck Wardenburg J. Staphylococcus aureus α-toxin: nearly a century of intrigue. 
Toxins (Basel). 2013;5(6):1140-66. 
2. Reyes-Robles T, Torres VJ. Staphylococcus aureus pore-forming toxins. Curr Top Microbiol 
Immunol. 2016. Epub ahead of publication. DOI: 10.1007/82_2016_16. 
3. Janesch P, Rouha H, Weber S, et al. Selective Sensitization of Human Neutrophils to LukGH 
Mediated Cytotoxicity by Staphylococcus aureus and IL-8. J Infect 2017. Epub ahead of 
publication. 
4. Rouha H, Badarau A, Visram ZC, et al. Five birds, one stone: neutralization of 
alpha-hemolysin and 4 bi-component leukocidins of Staphylococcus aureus with a single 
human monoclonal antibody. MAbs. 2015;7(1):243-54. 
5. Badarau A, Rouha H, Malafa S, et al. Context matters: The importance of dimerization-induced 
conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of 
neutralizing antibodies. MAbs. 2016;8(7):1347-60. 
6. Badarau A, Rouha H, Malafa S, et al. Structure-function analysis of heterodimer formation, 
oligomerization, and receptor binding of the Staphylococcus aureus bi-component toxin 
LukGH. J Biol Chem. 2015;290(1):142-56. 
7. Diep BA, Le VT, Visram ZC, et al. Improved Protection in a Rabbit Model of 
Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia 
upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin. Antimicrob Agents 
Chemother. 2016; 60(10):6333-40. 
8. Craven DE, Lei Y, Ruthazer R, Sarwar A, Hudcova J. Incidence and outcomes of 
ventilator-associated tracheobronchitis and pneumonia. Am J Med. 2013;126(6):542-9. 
9. Arsanis, Inc. Data on file. 
10. Stulik L, Hudcova J, Craven DE, Nagy G, Nagy E. Low Efficacy of Antibiotics against 
Staphylococcus aureus Airway Colonization in Ventilated Patients. Clin Infect Dis. 2017. 
Epub ahead of publication. 
11. Smith SB, Ruhnke GW, Weiss CH, Waterer GW, Wunderink RG. Trends in pathogens among 
patients hospitalized for pneumonia from 1993 to 2011. JAMA Intern Med. 
2014;174(11):1837-9. 
12. Lewis SS, Walker VJ, Lee MS, et al. Epidemiology of methicillin-resistant 
Staphylococcus aureus pneumonia in community hospitals. Infect Control Hosp Epidemiol. 
2014;35(12):1452-7. 
13. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator 
associated bacterial pneumonia. Clin Infect Dis. 2010;51(S1):S81-7. 
14. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and 
ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases 
Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. 


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15. Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable mortality of 
ventilator-associated pneumonia from randomized prevention studies. Crit Care Med. 
2011;39(12):2736-42. 
16. Croce MA, Brasel KJ, Coimbra R, et al. National Trauma Institute prospective evaluation of 
the ventilator bundle in trauma patients: does it really work? J Trauma Actue Care Surg. 
2013;74(2):354-60. 
17. Blot S, Lisboa T, Angles R, Rello J. Prevention of VAP: is zero rate possible? Clin Chest Med. 
2011;32(3):591-9. 
18. Klompas M, Kleinman K, Khan Y, et al. Rapid and reproducible surveillance for 
ventilator-associated pneumonia. Clin Infect Dis. 2012;54(3):370-7. 
19. Stulik L, Malafa S, Hudcova J, et al. α-Hemolysin activity of methicillin-susceptible 
Staphylococcus aureus predicts ventilator-associated pneumonia. Am J Respir Crit Care Med. 
2014;190(10):1139-48. 
20. Doessegger L and Banholzer ML. clinical development methodology for infusion-related 
reactions with monoclonal antibodies. Clin Transl Immunology. 2015;4(7):e39. 
 


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APPENDIX A:  SCHEDULE OF PROCEDURES 
Study Period 
Screening/ 
Enrollment 
Randomization 
Treatment 
Monitoring Period 
 
Follow-Up Period 
ET 
Study Day 
 
Up to 
Day -14a 
Day 1 pre-dose 
Day 1 
Day 2/3b
(BAL PK 
sub-study) 
Day 2 to 
Day 21c 
Day 22 
(+2 days)  
Day 28 
(+2 days)d  
Day 40 
to 
Day 89e 
 
 
Day 90 
(±7 days)
Safety 
Visitf 
Unschedg 
Study Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion/ 
randomization criteria 
Xh,i 
Xj 
 
 
 
 
 
 
 
 
Medical history 
Xh 
Xk 
 
 
 
 
 
 
 
 
Demographics 
Xh 
 
 
 
 
 
 
 
 
 
Antibiotic/medication historyl 
X 
X 
 
 
 
 
 
 
 
 
Height/weight 
Xh 
 
 
 
 
 
 
 
 
 
Physical examinationm 
Xh 
X 
 
 
X 
X 
 
X 
X 
X 
Vital signsn 
Xh 
X 
X 
X 
X 
X 
 
X 
X 
X 
Pregnancy testo 
Xh 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory 
assessments (chemistry, 
hematology, and coagulation)  
  
X 
 
 
Xp 
X 
 
 
 
Xq 
Urinalysis 
 
X 
 
 
Xr 
X 
 
 
 
Xq 
Procalcitonin (analysis 
performed at central lab) 
 
X 
 
 
Xs 
X 
 
 
 
X 
Ventilator device status 
X 
X 
X 
X 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
Chest X-ray/thoracic CT scan 
Xu 
Xv 
 
X 
Xw 
Xw 
 
 
 
 
Nasal swab specimens for 
culture 
 
X 
 
 
 
 
 
 
 
 
ETA for culturex 
X 
 
 
 
 
 
 
 
 
 
Collection/culture of 
additional microbiological 
specimensy 
 
 
 
 
X 
X 
 
 
 
X 
Clinical assessment of 
signs/symptoms of pneumonia  
 
X 
X 
X 
X 
X 
 
 
 
X 
Other S. aureus infection 
assessment  
X 
X 
X 
X 
X 
X 
 
 
 
X 
Footnotes begin on the next page. 


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APPENDIX A:  SCHEDULE OF PROCEDURES (Continued) 
Study Period 
Screening/ 
Enrollment 
Randomization 
Treatment 
Monitoring Period 
 
Follow-Up Period 
ET 
Study Day 
Up to 
Day -14a 
Day 1 pre-dose 
Day 1 
Day 2/3b
(BAL PK 
sub-study) 
Day 2 to 
Day 21c 
Day 22 
(+2 days) 
Day 28 
(+2 days)d  
Day 40 
to 
Day 89e 
 
 
Day 90 
(±7 days)
Safety 
Visitf 
Unschedg 
Study Procedures 
Randomization 
 
X
 
 
 
 
 
 
 
 
Blood collection for ADA and 
anti-S. aureus toxin antibodies 
 
X 
 
 
Xz 
X 
 
X 
X 
X 
12-lead ECG 
 
X
 
 
 
X
 
X 
X
X 
Assess survival and discharge 
disposition 
 
 
 
 
 
X 
X 
X 
X 
X 
Study drug administrationaa 
 
 
X 
 
 
 
 
 
 
 
BAL for PKbb 
 
 
 
X 
 
 
 
 
 
 
Blood collection for PK 
sampling and anti-S. aureus 
toxin antibodies 
 
 
Xcc 
Xdd 
Xee 
Xee 
 
Xee 
X 
X 
Track days on ventilator from 
randomization 
 
 
X 
X 
X 
X 
 
X 
X 
X 
Track days in ICU (or other 
observation area)  
 
 
X 
X 
X 
X 
 
X 
X 
X 
Concomitant medicationsl 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Adverse event assessment 
Xff 
X 
X 
X 
X 
X 
 
X 
X 
X 
a. 
Eligible subjects will be screened daily (while mechanically ventilated) for up to 8 days to identify those subjects who are heavily colonized with S. aureus (see Section 3.1). 
Screening for heavy S. aureus colonization by ETA culture will continue on Day 11 and Day 14 provided the subject remains mechanically ventilated, for a total Screening 
Period of up to 14 days. Additional ETA screening may occur on Days 9, 10, 12, and 13 at the discretion of the Investigator and providing the subject remains mechanically 
ventilated.  
b. 
Procedures are to be performed 48 hours (±36 hours) post-dose on approximately Day 2 or Day 3, depending on time of study drug administration, for those subjects participating 
in the BAL fluid PK sub-study only or if BAL fluid is collected as part of a standard of care procedure for any subject at any other time post-randomization for any other reason. 
c. 
Procedures are to be performed daily (unless otherwise indicated) from Day 2 to Day 21 while the subject is hospitalized. For subjects participating in the BAL fluid PK 
sub-study, procedures noted for the Day 2 visit only need to be performed 1 time. 
d. 
A follow-up visit will occur on Day 28 (+2 days) to assess mortality. This visit may be conducted via telephone if the subject is no longer hospitalized. 
e. 
For subjects who remain hospitalized between Day 40 and Day 90 at the institution where they receive study treatment, a follow-up safety visit will be performed on the day of 
discharge. 
f. 
If the subject is unable to return to the site, this visit may be conducted by telephone, with procedures performed as appropriate (i.e., concomitant medications and adverse 
events collected). 
g. 
An ET visit will be conducted for subjects who are withdrawn from the study prior to Day 22. 


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h. 
To be performed at the initial Screening Visit only. 
i. 
At the Screening Visit, subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to be eligible to return for the Randomization Visit. 
j. 
At the Randomization Visit, subjects must continue to meet all of the inclusion criteria and none of the exclusion criteria. Subjects must also meet all randomization criteria to 
be eligible to be randomized into the study. 
k. 
Review and record medical history (if changes occurred since the Screening Visit). 
l. 
All prior medications received by the subject within 14 days prior to study drug administration and any concomitant medications used throughout the duration of the study will 
be recorded in the source documents and on the appropriate eCRF. 
m. A complete physical examination will be performed at the Screening Visit and as deemed necessary by the Investigator and will include, at a minimum, a pulmonary examination 
(including auscultation) and assessments of the skin, abdomen, cardiovascular, gastrointestinal, and neurological systems. A limited physical examination will be performed at 
the Randomization Visit, daily during the Monitoring Period (if the subject is hospitalized), on Day 22 (if the subject is hospitalized), at the time of hospital discharge (if 
discharge occurs between Day 40 and Day 90), at the Safety Visit (Day 90) if the visit occurs onsite, and at ET (if applicable). The limited physical examination will include, 
at a minimum, a pulmonary examination (including auscultation). 
n. 
Vital sign measurements will include temperature, systolic and diastolic blood pressure, pulse, respiratory rate, and oxygenation status. Blood pressure and pulse will be assessed 
via an automated device. Manual techniques are only to be used if an automated device is not available. Oxygenation status will be determined via measurement of arterial 
blood gas, provided the subject has an arterial line placed. If no arterial line is present, pulse oximetry may be used. 
o. 
Female subjects of childbearing potential must have a documented negative pregnancy test at the Screening Visit. Female subjects may be enrolled on the basis of a negative 
urine pregnancy test, pending the result of a negative serum pregnancy test prior to randomization. A pregnancy test will also be performed on Day 22 or ET (if applicable). 
Additional pregnancy testing may occur throughout the duration of the study, per applicable country requirements. 
p. 
Blood samples for chemistry, hematology, and coagulation will be obtained on Days 2 (+1 day), 4 (±1 day), and 6 (±1 day) of the Monitoring Period, and twice weekly during 
Week 2 (Day 8 through Day 14) and/or Week 3 (Day 15 through Day 21) of the Monitoring Period while the subject remains hospitalized. 
q. 
To be obtained if clinically indicated. 
r. 
Urinalysis to be obtained on Day 6 (±1 day) of the Monitoring Period only. 
s. 
Procalcitonin testing to occur on the day of diagnosis of pneumonia, if applicable. 
t. 
If applicable. 
u. 
A chest X-ray or thoracic CT scan is to be obtained 1 time at the initial Screening Visit. A chest X-ray or thoracic CT scan obtained as part of standard of care within 24 hours 
prior to the initial Screening Visit is sufficient provided there are no changes in the subject’s clinical status (e.g., no change in ventilation status, secretions, or signs/symptoms 
that may be suggestive of pneumonia) within the 24 hours following imaging. 
v. 
A chest X-ray or thoracic CT scan obtained within 24 hours of the Randomization Visit is sufficient, provided there are no changes in the subject’s clinical status (e.g., no 
change in ventilation status, secretions, or signs/symptoms that may be suggestive of pneumonia) since the time of imaging. 
w. A chest X-ray or thoracic CT scan is required during the Monitoring Period for those subjects presenting with signs and symptoms of a respiratory infection such as dyspnea, 
tachypnea, fever, or cough. 
x. 
ETA specimens collected during Screening/Enrollment will be cultured by quantitative or semi-quantitative methods as required by the protocol. Sites are encouraged to perform 
semi-quantitative cultures using a chromogenic media that tests for both the presence of MSSA and MRSA (e.g., CHROMagarTM Staph aureus) for more rapid and specific 
detection of S. aureus. If the site is not able to obtain chromogenic media for S. aureus, appropriate chromogenic media may be supplied by the Sponsor. Semi-quantitative 
cultures using chromogenic media are preferred for determination of eligibility for randomization; however, any quantitative or semi-quantitative culture performed that indicates 
that a subject is heavily colonized with S. aureus is permitted if the culture results are available to randomize the subject within 48 hours (or up to 60 hours with Medical Monitor 
approval) from the time the ETA sample was collected. If subjects are extubated and subsequently re-intubated/mechanically ventilated, they are eligible for re-screening as a 
new subject enrollment. Subjects who were previously randomized are not eligible to be re-consented and re-screened. Subjects with a screening ETA culture that also shows 
heavy colonization of a Gram-negative organism (i.e., heavy co-colonization of both Gram-positive and Gram-negative organisms), will not be randomized into the study; 
however, randomization should not be delayed while waiting for Gram-negative results if heavy colonization with S. aureus has been confirmed. 
y. 
Adequate respiratory specimen or other microbiological specimens to be obtained if clinically indicated. If, as part of routine standard of care, additional respiratory and/or other 
microbiological specimens are collected for culture during the study, results will be documented within the eCRF. 
z. 
Obtain sample for ADA (to be obtained only upon discharge from the ICU, if discharge occurs prior to Day 22). 


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aa. Study drug will be administered in a double-blind manner. Subjects will receive ASN100 or matching placebo via 2 IV infusions over a duration of approximately 50 to 
60 minutes per infusion. Both ASN100 and placebo will be administered as 2 separate infusions (either sequentially or simultaneously). The last infusion will be completed 
within 5 hours from initiation of drug preparation in the pharmacy. 
bb. Obtain BAL fluid 48 hours (±36 hours) post-dose to determine ASN-1 and ASN-2 levels and blood to ELF ratio. If BAL fluid is collected as part of a standard of care procedure 
from any subject enrolled in the sub-study at any other time post-randomization for any other reason, if possible, a sample for PK analysis will also be obtained. 
cc. Blood samples for PK analysis will be collected immediately following the completion of the second infusion (+15 minutes) and at 6 hours (±4 hours) and 24 hours (±6 hours) 
post-dose. 
dd. Obtain a blood sample for PK measurement ±1 hour relative to BAL fluid collection (including scheduled BAL fluid collection or if BAL fluid is collected as part of a standard 
of care procedure from any subject enrolled in the sub-study at any time post-randomization). 
ee. A PK sample will be obtained from all subjects on Days 4 (±1 day), 7 (±1 day), 14 (±2 days), and 22 (+2 days) of the Monitoring Period. Additional PK samples will be collected 
on the day of discharge (if discharge occurs between Day 40 and Day 90). 
ff. 
Adverse events that occur between the time the subject signs the ICF and the Randomization Visit will only be recorded if related to a study-specific procedure. 
ADA = anti-drug antibody; BAL = bronchoalveolar lavage; CT = computed tomography; ECG = electrocardiogram; eCRF = electronic Case Report Form; ELF = epithelial lining 
fluid; ET = Early Termination; ETA = endotracheal aspirate; ICF = Informed Consent Form; ICU = intensive care unit; IV = intravenous; MRSA = methicillin-resistant S. aureus; 
MSSA = methicillin-susceptible S. aureus; PK = pharmacokinetic; S. aureus = Staphylococcus aureus; Unsched = unscheduled.


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Confidential & Proprietary 
 
Version 4.0, 02 May 2017 
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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Direct bilirubin 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Hematology  
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with 
differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
RBC indices: mean corpuscular volume 
(MCV), mean corpuscular hemoglobin 
(MCH), %Reticulocytes 
Coagulation  
Prothrombin time (PT) 
Partial thromboplastin time (PTT) 
Urinalysis  
pH 
Blood 
Ketones 
Specific Gravity 
Leukocyte esterase 
Bilirubin  
Glucose 
Nitrite 
Protein 
 
Other Screening Tests as Needed (for female subjects of childbearing potential only) 
Urine and/or serum pregnancy test 
Other Tests 
Procalcitonin (PCT)