Conditions: Intra-abdominal Infections
Keywords: Intra-abdominal infection LYS228 beta-lactam antibiotics creatinine clearance enterobacteriaceae
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate whether LYS228 can be developed for the treatment of complicated intra-abdominal infections.

It was planned that LYS228 exposure across patients with varying renal function would be evaluated during the study to confirm that LYS228 concentrations are predicted to be adequate to treat the patient population. It was planned that the PK exposure of the initial 8 patients would be analyzed.

PK analysis was not conducted as per protocol the first analysis required 8 patients.

Detailed description:

Arms:
arm 1: IV infusion every 6 hours for at least 5 days arm 2: IV infusion of standard of care antibiotics for at least 5 days

Interventions: intervention 1: LYS228 intervention 2: Standard of care therapy
Intervention descriptions: intervention 1: LYS228 IV infusion every 6 hours intervention 2: IV infusion of standard of care antibiotics

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LYS228
Clinical Trial Protocol CLYS228X2202
A randomized, controlled, evaluator-blinded, multi-center 
study to evaluate LYS228 pharmacokinetics, clinical 
response, safety, and tolerability in patients with 
complicated intra-abdominal infection
Document type:
Amended Protocol Version
EUDRACT number:
2017-003130-90
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
11-Jun-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section9.2of the protocol for SAE criteria and additional 
requirements.See also page 2 of the SOMfor further details on the method of reporting a 
SAE.
Complete SAE report
Submit SAE report to Novartis ChiefMedical Office & Patient Safety (CMO&PS) within 
24 hours after awareness of the SAE
Notify the Novartis Medical Lead
The fax number(s) and email address(es) are located in the SOM. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................7
List of figures......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................17
1 Introduction.......................................................................................................................20
1.1
Background............................................................................................................20
1.4
Study purpose........................................................................................................24
2 Objectives and endpoints...................................................................................................24
2.1
Primary objectives.................................................................................................24
2.2
Secondary objectives.............................................................................................24
3 Investigational plan...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale of study design.......................................................................................27
3.2.1
Study population...................................................................................27
3.2.2
Design...................................................................................................27
3.2.3
Clinical response endpoints...................................................................28
3.3 
Rationale for dose/regimen, route of administration and duration of treatment....28
3.3.1
Efficacious dose....................................................................................28
3.3.2
Treatment duration................................................................................29
3.3.3
Dose or regimen adjustment..................................................................30
3.4
Rationale for choice of comparator.......................................................................
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3.5
Purpose and timing of interim analyses/design adaptations..................................30
3.6
Risks and benefits..................................................................................................31
3.6.1
Hypersensitivity reaction......................................................................31
3.6.2
Hepatotoxicity.......................................................................................31
3.6.3
Nephrotoxicity.......................................................................................31
3.6.4 
Local Reaction......................................................................................31
3.6.5
Gastrointestinal discomfort...................................................................32
3.6.6
Clostridium difficile–associated diarrhea..............................................32
3.6.7
Seizure...................................................................................................32
3.6.8
Thrombocytopenia................................................................................32
3.7
Blood sample volumes...........................................................................................33
4 Population..........................................................................................................................33
4.1
Inclusion criteria....................................................................................................33
4.2
Exclusion criteria...................................................................................................35
5 Restrictions for Study Patients..........................................................................................38
5.1
Contraception requirements...................................................................................38
5.2
Prohibited treatment...............................................................................................38
5.3
Dietary restrictions and smoking...........................................................................38
5.4 
Other restrictions...................................................................................................38
6 Treatment...........................................................................................................................39
6.1
Study treatment......................................................................................................39
6.1.1
Investigational treatment and control drugs..........................................39
6.1.2 
Alternative and rescue antibiotic treatment...........................................40
6.2
Treatment arms......................................................................................................40
6.3 
Treatment assignment and randomization.............................................................40
6.4
Treatment blinding.................................................................................................40
6.5
Treating the patient................................................................................................41
6.6
Permitted dose adjustments and interruptions of study treatment.........................41
6.7
Emergency breaking of assigned treatment code..................................................42
6.8
Treatment exposure and compliance.....................................................................42
6.9
Recommended treatment of adverse events..........................................................42
6.10
Rescue antibiotic medication.................................................................................42
6.11 Concomitant treatment...........................................................................................42
7 Study completion and discontinuation..............................................................................42
7.1
Study completion and post-study treatment..........................................................42
7.2
Discontinuation of study treatment........................................................................43
7.3
Withdrawal of informed consent...........................................................................44


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7.4
Lost to follow-up...................................................................................................45
7.5
Study Stopping rules..............................................................................................45
7.6
Early study termination by the sponsor.................................................................45
8 Procedures and assessments..............................................................................................46
8.1
Assessment schedule.............................................................................................46
8.2
Informed consent procedures.................................................................................50
8.3
Patient screening....................................................................................................51
8.4
Patient demographics/other baseline characteristics.............................................51
8.5
Efficacy / Pharmacodynamics...............................................................................51
8.5.1
Clinical evaluation of cIAI infection.....................................................51
8.5.2
Microbiologic evaluation......................................................................52
8.6
Safety.....................................................................................................................52
8.6.1
Physical examination............................................................................52
8.6.2
Vital signs..............................................................................................52
8.6.3
Body height and body weight...............................................................53
8.6.4
Laboratory evaluations..........................................................................53
8.6.5
Electrocardiogram (ECG).....................................................................53
8.6.6
Pregnancy and assessments of fertility.................................................54
8.7
Pharmacokinetics...................................................................................................54
9 Safety monitoring..............................................................................................................56
9.1
Adverse events.......................................................................................................56
9.2
Serious adverse event reporting.............................................................................57
9.2.1
Definition of SAE.................................................................................57
9.2.2
SAE reporting........................................................................................58
9.3
Liver safety monitoring.........................................................................................59
9.4
Renal safety monitoring.........................................................................................60
9.5
Reporting of study treatment errors including misuse/abuse................................60
9.6
Pregnancy reporting...............................................................................................61
9.7
Early phase safety monitoring...............................................................................62
10 Data review and database management.............................................................................62
10.1 Site monitoring......................................................................................................62
10.2 Data collection.......................................................................................................63
10.3 Database management and quality control............................................................63
10.4 Data Monitoring Committee..................................................................................
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10.5 Adjudication Committee........................................................................................64
11 Data analysis......................................................................................................................64
11.1 Analysis sets..........................................................................................................64
11.2 Subject demographics and other baseline characteristics......................................65
11.3 Treatments.............................................................................................................65
11.4 Analysis of the primary variable(s).......................................................................65
11.4.1
Primary Variable(s)...............................................................................65
11.4.2
Statistical model, hypothesis, andmethod of analysis..........................66
11.4.3
Handling of missing values/censoring/discontinuations.......................67
11.4.4
Sensitivity analyses...............................................................................67
11.5 Analysis of secondary variables............................................................................67
11.5.1
Efficacy / Pharmacodynamics...............................................................67
11.5.2
Safety.....................................................................................................68
11.5.3
Pharmacokinetic -exposure relationships.............................................68
11.7 Sample size calculation..........................................................................................69
11.8 Power for analysis of key secondary variables......................................................69
12 Ethical considerations........................................................................................................70
12.1 Regulatory and ethical compliance........................................................................70
12.2 Responsibilities of the investigator and IRB/IEC..................................................70
12.3 Publication of study protocol and results...............................................................70
12.4 Quality Control and Quality Assurance.................................................................70
13 Protocol adherence............................................................................................................71
13.1 Protocol Amendments...........................................................................................71
14 References.........................................................................................................................72
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................74
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................
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List of tables
Table 6-1
Overview of study medication..............................................................39
Table 6-2
Blinding and unblinding plan................................................................41
Table 8-1
Assessment schedule.............................................................................46
Table 9-1
Guidance for capturing study treatment errors......................................61
Table 15-1 
Liver Event Definitions.........................................................................74
Table 15-2
Actions required for Liver Events.........................................................74
Table 15-3
Exclusion of underlying liver disease...................................................75
Table 16-1
Specific Renal Alert Criteria and Actions.............................................76
Table 16-2
Follow-up of renal events......................................................................77
List of figures
Figure 17-1
Patients
' Flowchart................................................................................78


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APACHE II
Acute Physiology and Chronic Health Evaluation II
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CDC
Centers for Disease Control and Prevention
CE
clinically evaluable
CFR
U.S. Code of Federal Regulations
CFU
colony forming units
cIAI
complicated intra-abdominal infection
CK
creatinine kinase
cm
centimeter(s)
CMO&PS 
Chief Medical Office & Patient Safety
CrCl
creatinine clearance
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CVVH
continuous veno-venous hemofiltration 
dL
deciliter(s)
ECG
electrocardiogram
eCrCl
estimated creatinine clearance
EDC
Electronic Data Capture
EEG
electroencephalogram
EOAT
End of Antibiotic Treatment/Therapy
EOS
End of Study
EOSD
End of Study Drug
ESBLs 
extended-spectrum β-lactamases
FDA
Food and Drug Administration


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GABA
gamma-aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
i.v.
intravenous
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB 
Institutional Review Board
IRT
Interactive Response Technology
KPC
Klebsiella pneumoniae carbapenemases 
kg
kilogram
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
MBL
metallo-β-lactamase 
ME
microbiologically evaluable
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
µg
microgram(s)
µL
microliters(s)
MIC
minimal inhibitory concentration 
micro-
microbiologic
mITT
modified intention-to-treat


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mL
milliliter(s)
MRSA
methicillin-resistant Staphylococcus aureus
MTD
maximum tolerated dose
NCDS
Novartis Clinical Data Standards
NDM-1
New Delhi metal-β-lactamase-1
ng
Nanogram(s)
OAT
organic anion transporter 
p.o.
oral
PBP
penicillin binding protein 
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PM
Pharmacy Manual
PTA
probability of target attainment 
qSOFA
quick sequential sepsis-related organ failure assessment
RBC
red blood cell(s)
RDC
Remote Data Capture
SAE
serious adverse event
SBL
serine-β-lactamase
sCR
serum creatinine
SD
standard deviation
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TD
Study Treatment Discontinuation
TOC
Test of Cure
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Pharmacokinetic definitions and symbols
%fT>MIC
Percentage of time that free drug concentration is above the MIC inplasma
AUCtau
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau at steady state [mass x 
time / volume]
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
Cmax
The observed maximum plasma (or serum orblood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
MIC90
The minimal inhibitory concentration (MIC) to inhibit the growth of 90% of 
organisms tested 
PTA
Probability of target attainment
T1/2
The terminal elimination half-life [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vss
The volume of distribution at steady state following intravenous 
administration [volume]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of patients fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested in 
the trial
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in 
the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
Investigational 
drug
The Study Drugwhose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Patient
An individual with the condition of interest
Patient Number
A unique number assigned to each patient upon signing the informed 
consent. This number is the definitive, unique identifier for the patient 
and should be used to identify the patient throughout the study for all 
data collected, sample labels, etc.
Personal data
Patient information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes patient 
identifier information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment assignment
Screen Failure
A patient who is screened but is not treated or randomized


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Source 
Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study Drug
Intravenous LYS228 in combination with intravenous vancomycin and 
intravenous or oral metronidazole, or standard of care intravenous 
antibiotic therapy for the treatment of cIAI, administered between 
randomization and End of Study DrugVisit.
Study treatment
See definition for Study Drug
Study treatment 
discontinuation
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
patient, corresponding to a specific treatment 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does 
not want to participate in the study any longer, anddoes not allow any 
further collection of personal data.


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Protocol No. CLYS228X2202
Protocol summary
Protocol number
CLYS228X2202
Full Title
A randomized, controlled, evaluator-blinded, multi-center study to evaluate 
LYS228 pharmacokinetics, clinical response, safety, and tolerability in patients 
with complicated intra-abdominal infection
Brief title
LYS228 pharmacokinetics, clinical response, safety and tolerabilityin patients 
with complicated intra-abdominal infection (cIAI)
Sponsor and 
Clinical Trial Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this non-confirmatory study is to evaluate the probability of 
LYS228 pharmacokinetic-pharmacodynamic (PK/PD) target attainment and 
clinical response in patients with cIAI in order to refine human efficacious dose 
selection for future confirmatory studies
Primary Objectives
To evaluate the plasma pharmacokinetics of LYS228 in patients with cIAI
To evaluate the clinical response to LYS228 incombination with 
vancomycin and metronidazole compared to standard of care antibiotics for 
treating patients with cIAI
Secondary 
Objectives
To evaluate the safety and tolerability of LYS228 in combination with 
vancomycin and metronidazole in patients with cIAI
To evaluate the microbiological response to LYS228 in combination with 
vancomycin and metronidazole compared to standard of care antibiotics for 
treating patients with cIAI
Study design
This 
is a 
randomized, comparator-controlled, evaluator-blinded, 
non-confirmatory study to evaluate the pharmacokinetics, clinical response, 
safety and tolerability of intravenous LYS228 in patients with cIAI. The study 
will enroll approximately 60 patients with cIAI who have not yet been treated for 
their current infection. Patients will be randomized to receive LYS228 in 
combination with vancomycin and metronidazole or standard of care antibiotic 
therapy for cIAI for no lessthan 5 days and up to 14 days.The study treatment 
will be administered on an open-label basis. Ablinded evaluator will perform 
safety and clinical response assessments.
The study cons
ists of a Screen
ing and Base
l
ine Per
iod (D-1 to D1), a Treatment 
Per
iod of var
iab
le durat
ion (D1 to D5, and poss
ib
ly up to D15) and a Fo
l
low-up 
per
iod of at 
least 14 days and an End of Study (EOS) v
is
it on Day 28.
Pat
ients who meet the e
l
ig
ib
i
l
ity cr
iter
ia at screen
ing w
i
l
l be random
ized to one of the 
2 treatment arms:(1) LYS228 
in comb
inat
ion w
ith vancomycin and metron
idazo
le
,or 
(2) standard of careant
ib
iot
ictherapy for the treatment of cIAI. B
lood cu
ltures w
i
l
l be 
obta
ined before adm
in
istrat
ion of Study Drugand preferab
ly before adm
in
istrat
ion of 
any ant
ib
iot
ic therapy. In add
it
ion, cu
ltures from the intra
-abdom
ina
l focus of infect
ion 
w
i
l
l be obta
ined dur
ing surgery,or at the t
ime of percutaneous dra
inage. The 
Screen
ing/Base
l
ine(D-1to 1) and first dos
ing v
is
its (D1) may occur on the same 
day. Study Drugwill be administered for no less than 5 days in an in-patient 
setting. Please refer to the full protocol for definitions of End of Study Drugvisit 
(EOSD) and End of Antibiotic Treatment visit (EOAT). The EOSvisit will be 
completed on Day 28 after randomization.


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Population
Approximately 60 patients will be randomized to LYS228 or a comparator 
(standard ofcare therapy) in 2:1 ratio and are expected to be included in the 
microbiologic modified intention to treat (micro-mITT) population.
Key Inclusion 
criteria
Male and female patients 18 to 65 years of ageinclusive and after an 
interim analysis of8 patients, inclusion of patients up to85 years of 
age with visual confirmation (presence of pus within the abdominal 
cavity) of an intra-abdominal infection associated with peritonitis 
including at least 1 of the following inclusionary diagnoses during
surgical intervention (e.g. laparotomy, laparoscopic surgery, or 
percutaneous draining of an abscess):
Cho
lecyst
it
is (
inc
lud
ing gangrenous cho
lecyst
it
is) w
ith rupture, 
perforat
ion, or progress
ion of the 
infect
ion beyond the ga
l
lb
ladder wa
l
l;
Diverticular disease with perforation or abscess;
Appendiceal perforation or periappendiceal abscess;
Acute gastric or duodenal perforation, only if operated 
on >24hours after perforation occurs;
Traumatic perforation of the intestine, only if operated 
on >12hours after perforation occurs;
Secondary peritonitis due to perforated viscus, postoperative or 
spread from other focus of infection (but not spontaneous 
[primary] bacterial peritonitis or peritonitis associated with 
cirrhosis and chronic ascites);
Intra-abdominal abscess (including of liver or spleen provided 
that there was extension beyond the organ with evidence of 
intraperitoneal involvement)
Provided all other inclusion criteria are met, patients can be enrolled 
before surgical intervention in certain conditions, as described in the 
full protocol.
Key Exclusion 
criteria
Any of the excluded diagnoses: abdominal wall abscess, small bowel 
obstruction, traumatic bowel perforation undergoing surgery within 12 
hours, perforation of gastroduodenal ulcer with surgery within 24 
hours, an intra-abdominal process that is not likely caused by 
infection. Please refer to the full protocol for the full list.
Pre-operat
ive treatment of any durat
ion w
ith non-Study Drugsystem
ic 
ant
ib
iot
ic therapy for per
iton
it
is or abscess 
is not a
l
lowed un
less certa
in
cr
iter
ia are met. P
lease refer to the fu
l
l protoco
l for the requ
ired cr
iter
ia.
Concomitant bacterial infection at time of enrollment requiring non-
Study Drugantibiotics and that may interfere with the evaluation of 
clinical response to the study antibiotic.
Known non-abdominal source of infection, including endocarditis, 
osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 
days prior to enrollment.
Patient hasan Acute Physiology and Chronic Health Evaluation II
(APACHE II)score > 30 or is considered, in the judgement of the 
investigator, unlikely to survive 4 weeks (e.g. rapidly progressive 
terminal illness, including septic shock).
Patients that meet sepsis criteria as defined by the quick sequential 
sepsis-related organ failure assessment(qSOFA)
Women of child-bearing potential unless they are using highly 
effective methods of contraception during dosing and for 7 days after 
stopping study treatment.


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Significant lab abnormalities, as described in the full protocol.
Study treatment
Patients will be randomized to one of the following two treatment arms in a 
ratio of 2:1.
Arm 1: LYS228 in addition tovancomycin and metronidazole (n=40). 
LYS228 dose for each patient will be based on the renal function as 
described in the full protocol.
Arm 2: Standard of care intravenous therapy for the treatment of cIAI 
(n=20)
Pharmacokinetic 
(PK) assessments
Cmax, Tmax, AUCTau,T1/2, %fT>MIC, CL and Vss will be assessed from the 
plasma concentration-time data
Efficacy/PD 
assessments
Clinical evaluation of cIAI infection
Microbiologic evaluation
Key safety 
assessments
Adverse event monitoring
Physical examination and vital signs
Monitoring of laboratory markers in blood and urine
Electrocardiogram (ECG)
Assessment of fertility and pregnancy
Other 
assessments
Blood cultures
Data analysis
Noncompartmental PK analysis will be performed on LYS228 plasma 
concentration-time profiles. Descriptive summary statistics of LYS228 
concentrations and PK parameters will be provided by visit/sampling time-
point.
Clinical Response
The proportion of patients who achieved clinical success or failure will be 
computed for each treatment arm and provided along with a 80% two-sided 
confidence interval based on the Clopper-Pearson method. The 80% 
confidence interval for the difference in clinical success between treatment 
arms will be computed according to the Wilson score method without continuity 
correction. Clinical success or failure will be evaluated at the EOSD, at the 
EOAT, and at 28 days post-randomization (EOS).
Bayesian methodswill be implemented based on the Beta-Binomial model to 
compare the clinical success rate in micro-mITT population at 28 dayspost-
randomization. Informative prior on LYS228 and control will be used. An80% 
posterior credible interval of the clinical success rate at Test of Cure (TOC)visit 
in the micro-mITT population will be provided for each treatment group as well 
as the treatment difference.
Key words
Intra-abdominal infection, LYS228, beta-lactam antibiotics, creatinine 
clearance, Enterobactericeae
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1
Introduction
1.1
Background
Intra-abdominal infections (IAIs) are common in clinical practice and comprise a variety of 
pathological conditions, ranging from uncomplicated appendicitis to fecal peritonitis. 
Intra-abdominal infections are considered complicated (cIAI) when they are associated with 
perforation or necrosis of the gastrointestinal tract, and extension beyond the hollow viscus of 
origin into the peritoneal space. The release of enteric bacteria into the peritoneal and 
retroperitoneal space is associated with systemic signs and symptoms of infection, and either 
abscess formation or peritonitis (Solomkin et al 2010).Enteric flora includes Gram-negative 
Enterobacteriaceae, as well as Gram-positive and anaerobic bacteria.
Patients with infections caused by multi drug resistant Enterobacteriaceaeare currently 
treated withcarbapenems (Hooten et al 2010, Golan 2015). Carbapenems are characterized by 
a broad spectrum of antibacterial activity,however many bacterial strains have acquired the 
ability to express carbapenemases of the serine- β-lactamase (SBL) and/or 
metallo-β-lactamase (MBL) classes (i.e. Klebsiella pneumoniacarbapenemase and NewDelhi 
metallo-β-lactamase-1), rendering carbapenems ineffective. Infections caused by these strains 
often require the administration of poorly-tolerated antibiotics such as colistin 
(Pogueetal2011, Navarro-San Francisco et al 2013).
The US CDC classifies carbapenem-resistant Enterobacteriaceaeas an “urgent threat” and 
Enterobacteriaceae that express extended-spectrum β-lactamases (ESBLs)as a “serious threat” 
(CDC 2013). Furthermore, the World Health Organization has issued a global priority list of 
antibiotic-resistant bacteria for drug development of new antibiotics. Enterobacteriaceae, 
which are a common cause of hospital and community-acquired infections, have been 
assigned a critical priority status (WHO 2017).
LYS228 is a novel monobactam antibiotic which kills bacteria by inhibiting cell wall 
synthesis through covalent modification of the active site serine of penicillin binding protein 3 
(PBP3). Monobactams represent a class of beta-lactam antibiotics which, unlike carbapenems, 
are intrinsically-stable to MBLs. PBP3 is a clinically validated antibacterial target, as it is 
targeted by aztreonam, a monobactam widely that is widely used inclinical settings 
(TunkelandScheld1990). Monobactams are efficacious for treating infections with 
susceptible strains, are generally well tolerated, are primarily eliminated through urine, and 
have a predictable pharmacokinetic profile.
LYS228 is stable to most SBLs and all known MBLs and is therefore expected to be effective 
against bacterial infections caused by clinical strains of Enterobacteriaceae expressing 
β-lactamaseswhich are susceptible to LYS228. MBL-expressing Enterobacteriaceaecan 
inactivate all classes of β-lactam drugs, except monocyclic β-lactams like the monobactams. 
MBLs are frequently co-expressed with SBLs. The prevalence of strains expressing the 
NewDelhi metallo-β-lactamase-1 (NDM-1) is as high as 12% in clinical isolates from 
patients with invasive infections in India (Biedenbach et al 2015, Rahmanetal2014); 
infections caused by strains expressing NDM-1 and other MBLs have been detected globally, 
including in Europe, the United States, China, and Japan (Kazmierczaketal2016). 


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Further,the prevalence of MBL-expressing Enterobacteriaceaeis increasing in environmental 
isolates and is expected to increase rapidly in the clinic as they are likely to be selected 
following the recent introduction of novel β-lactam antibiotics such as ceftazidime/avibactam 
that cover strains expressing SBLs but not MBLs.
In summary, LYS228 is a monobactam antibiotic potent against Enterobacteriaceaeand is 
stable in the presence of many serine-and all known metallo-β-lactamases. It is expected that 
LYS228 as monotherapy will be effective in treating patients with infections caused by 
LYS228-susceptible Enterobacteriaceae, including those expressing ESBLs and 
carbapenemases.
This study will evaluate the pharmacokinetics of LYS228,and theclinical response, safety, 
and tolerabilityof LYS228in combination with vancomycin and metronidazole in patients 
with complicated intra-abdominal infections (cIAI).
The most relevant data for the present study are summarized in the sections below. 
Fordetailed information about LYS228, please refer to the Investigator
's Brochure
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1.4
Study purpose
The purpose of this non-confirmatory study is to evaluate the probability of LYS228 
pharmacokinetic-pharmacodynamic (PK/PD) target attainment and clinical response in order 
to refinehuman efficacious dose selection for future confirmatory studies. 
2
Objectives and endpoints
2.1
Primary objectives
Primary objectives
Endpointsrelated to primary objectives
To evaluate the plasma pharmacokinetics 
of LYS228 in patients with cIAI
Plasma PK onDay 5
To evaluate the clinical response to 
LYS228 in combination with vancomycin 
and metronidazole compared to standard 
of care antibiotics for treating patients 
with cIAI
Clinical success at 28 days after 
randomization (End of Study) determined 
by signs, symptoms, and the need for 
additional antibiotics, unplanned surgical 
procedures, or drainage.
2.2
Secondary objectives
Secondary objectives
Endpoints related to secondary objectives
To evaluate the safety and tolerability of 
LYS228 in combination with vancomycin 
and metronidazole in patients with cIAI
Adverse events
Clinical laboratory tests
Vital signs
To evaluate the microbiological response 
to LYS228 in combination with 
Microbiologic success at 28 days after 
randomization (End of Study) determined 
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Secondary objectives
Endpoints related to secondary objectives
vancomycin and metronidazole compared 
to standard of care antibiotics for treating 
patients with cIAI
by culture from the intra-abdominal focus 
of infection when available or presumed 
eradication based on clinical success
3
Investigational plan
3.1
Study design
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This is a randomized, comparator-controlled, evaluator-blinded, non-confirmatory study to 
evaluate the pharmacokinetics, clinical response, safety and tolerability of intravenous 
LYS228 in patients with complicated intra-abdominal infection (cIAI). The study will enroll 
approximately 60 patients with cIAI who have not yet been treated for their current infection 
and will be randomized to receive LYS228 in combination with vancomycin and 
metronidazole or standard of care antibiotic therapy for cIAI for no less than 5 days and up to 
14 days. The study treatment will be administered to patients on an open-label basis. There 
will be no placebo-treated patients. A blinded evaluator at each site will perform safety and 
clinical response assessments.
The study consists of a Screening and Baseline Period (D-1 to D1), a Treatment Period of 
variable duration (D1 to D5, and possibly up to D15), a Follow-up period of at least 14 days 
and an EOSvisit on Day 28.A patients’ flowchart is provided in Section 17.
Screening and Baseline Period
Patients who meet the eligibility criteria at screening and are admitted to an inpatient unit will 
be randomized to one of the 2 treatment arms:(1) LYS228 in combination with vancomycin 
and metronidazole,or (2)standard of careantibiotictherapy for the treatment of cIAI. Blood 
cultures will be obtained before administration of Study Drugand preferably before 
administration of any antibiotic therapy. In addition, cultures from the intra-abdominal focus 
of infection will be obtained during surgery or at the time of percutaneous drainage. The 
Screening/Baseline(D-1to 1), and first dosing visits (D1) may occur on the same day. 
Patients can be screened and enrolled before or after surgery or percutaneous drainage of 
infection, as detailed in the inclusion criteria.
TreatmentPeriod
The first dose of Study Drugwill be administeredon D1after confirmation of eligibility, 
randomization and collection of blood cultures. 
“Study Drug”and “study treatment” include: Intravenous LYS228 in combination with 
intravenous vancomycin and intravenous or oral metronidazole (Arm 1), or standard of care 
intravenous antibiotic therapy for the treatment of cIAI(Arm 2), administered between 
randomization and End of Study Drug. Study Drugwill be administered for no less than 5 
days and it is expected to be administered in an in-patient setting. 
Change of treatment from Study Drugto alternative antibiotics is permissible in the following 
circumstances:
1. Change to oral antibiotics after completing 5 days of intravenous Study Drugif a 
patient is clinically improved and discharged,or 
2. Patient requires additional therapy or change to rescue therapy in the case of clinical 
failure, or adverse event thatmerits discontinuation of Study Drugas detailed in 
Section7.2. 
Alternative antibiotics must be effective against the relevant clinical isolates. The total 
antibiotic treatment duration, including Study Drugand any alternative antibiotic, will be no 
less than 5 days and up to 14 days, unless discussed with sponsor.


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During the treatment period all patients will complete a minimum of 5 visits (V101 –V105) 
and up to 15visits (V101-V115), depending on the duration of hospitalization. Allpatients 
that change treatment to an alternative antibiotic must have an EOSDvisit prior to antibiotic 
change. 
Follow-up Period
The follow-up period spans the period after completion of antibiotic treatment (EOAT visit) 
up to 28 days after randomization, at which time all patients will have an EOS visit. This visit 
is considered the Test of Cure (TOC) visit for evaluation of clinical response. A post-study 
safety phone call will be conducted 30 days after the last administration of study treatment.
3.2
Rationale of study design
3.2.1
Study population
The study includes patients with complicated intra-abdominal infections that extend beyond 
the hollow viscus and local viscera into the peritoneal or retroperitoneal space, leading to 
either abscess formation or peritonitis, and associated withsystemic symptoms of infection. 
Itincludes patients with a wide range of estimated creatinine clearances(>30 mL/min) to 
increase the understanding of LYS228 PK in cIAI patients with normal renal function, as well 
as mild and moderate renal dysfunction. It excludes patients that received previous effective 
antibiotic therapy for a continuous duration of more than 24 hours during the 72 hours prior to 
screening to prevent confounding of the clinical response endpoints. SeeSection4.1and 
Section4.2for thefullinclusion and exclusion criteria.
3.2.2
Design
All patients with cIAI require treatment with antibiotics to prevent additional morbidity and 
mortality. Standard of care treatment for cIAI includes antibiotics effective against enteric 
Gram-negative, Gram-positive, and anaerobic bacteria. LYS228 is expected to be effective 
only against enteric Gram-negative bacteria, therefore it will be administered in combination 
with vancomycin and metronidazole to provide adequate treatment of Gram-positive and 
anaerobic bacteria. The combination will be compared to standard of care broad spectrum 
intravenous therapy for treatment of cIAI. Best available oraltherapy is permitted only for 
documented infections caused by multiple-drug resistant bacteria where intravenous 
antibiotics are not effective.
The use of a control arm and evaluator-blinded design will mitigate potential bias in safety 
and clinical response assessments. For clinical response, bias may be introduced by the 
patients for some of the more subjective endpoints (symptoms), but many of the endpoints are 
much less likely to be subject to bias. These include fever and white blood cell counts. 
Patientblinding is not considered feasible or desirable given the need to adopt a double 
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Expected clinical response rates can be derived fromcontrolled studies of similar antibiotics
to treat patients with cIAI and from regulatory guidance. With these data, the clinical response 
of LYS228 can be assessed using historical data as controls. Use ofhistorical controls 
supports the 2:1 randomization ratio, which maximizes thenumber ofpatients to beenrolled 
in the LYS228 arm to assess clinical response.
3.2.3
Clinical response endpoints
The primary endpoint of clinical success, defined by improvement of clinical signs and 
symptoms of infection, has been validated in controlled studies of similar antibiotics to treat 
patients with cIAI. Bacterial cultures to document microbiologic eradication are not likely to 
be available for this infection, therefore presumed microbiologic success is derived from 
clinical success. The study uses clinical response endpoints that are consistent with the ones 
used by the historical controlsto minimize confounders in the evaluation of clinical response.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The probability of microbiologic target attainment to achieve efficacy can be derived from 
existing knowledge of PK drivers of efficacy from other β-lactam antibiotics with similar 
mechanisms of action, 
 
Initial LYS228 dose will beselectedbased on renal function as determined byestimated
creatinine clearance (eCrCL) calculated at screening based on data obtained from local 
laboratories and the study qualified formula (Cockcroft Gault equation) as described in the 
SOMand Pharmacy Manual(PM). During the treatment course, dose must be adjusted based 
on the eCrCL, asindicated based on changes in serum creatinine.See Table3-1for the dosing 
of LYS228.
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3.3.1
Efficacious dose
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3.3.2
Treatment duration
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The current standard of care for the treatment of cIAI is 5 to 14 days of antibiotic therapy. 
Theoptimal duration of antimicrobial therapy for the treatment of acute symptomatic episodes 
has not been systematically studied. Furthermore, because of the wide variation in underlying 
abnormalities and clinical presentations, a uniform recommendation for treatmentduration 
cannot be made. However, shorter courses of therapy appear to be sufficient, particularly 
among patients who demonstrate a positive response to treatment, show no signs of persistent 
leucocytosis or fever, and are able to resume oral diet. Patients who meet these criteria usually 
do not require more than 5 days of treatment.
All patients will receive intravenous LYS228 or standard of care therapy in an in-patient 
setting for a minimum of 5 days and up to 14 days. Extension of the treatment duration might 
be allowed with non-LYS228 antibiotics, and must be discussed with sponsor on a case by 
case basis.
A minimum of 5 days of therapy will allow analysis of safety, clinical response and LYS228 
PK, at a time-point where steady state and clinical successis expected in this population. 
Continuation of therapy up to 14 days allows patients with more refractory infections to 
receive a longer course of antibiotics and have a higher probability of clinical and 
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Practice guidelines, patient convenience, and risks associated with an indwelling intravenous 
catheter make the administration of an intravenous antibiotic for the up to 14 day treatment 
duration difficult and impractical. Allowing a change of treatment from Study Drugto 
alternative oral antibiotics, if a patient is clinically improved, will facilitate outpatient 
administration to complete the required course of therapy. Oral therapy in many cases mimics 
the standard of care.
3.3.3
Dose or regimen adjustment 
The sponsor may recommend an additional dose regimen for LYS228 based on the 
availability of new data. Longer infusion times result in increased fT%>MIC. 
Therefore,continuous infusion of LYS228 may be considered based on ongoing analysis of 
exposure, stability andsterility data,and/oranalysis of theongoing clinical studiesof LYS228. 
 
 
 
The investigator is expected to adjust the LYS228 dose, as required, based on individual 
patients
' renal function during the treatment periodor emerging new PK data. Please refer to 
the SOM for further details.
3.4
Rationale for choice of comparator
Using pre-specified local standard of care antibiotic therapy for cIAI, provides an adequate 
controlwith antibiotics that are used in clinical practice for the indication. The study 
implements a preferredstandard of care regimen, piperacillin/tazobactam, in order to limit 
confounding factors when comparing treatment groups. Considering that LYS228 activity is 
limited to Enterobacteriaceae, and piperacillin/tazobactam has broad spectrum activity, the 
study also implements preferred antibiotics to be used in combination with LYS228 to 
provide adequate treatment of gram-positive and anaerobic bacteria, which are relevant 
pathogens in cIAI. Modifications to the preferred comparatorare allowed in orderto optimize 
empiric antibiotic therapy based on host risk factors for bacterial drug resistance, local 
antibiograms, documented drug resistance, tolerability, or other relevant limitations to the 
preferred comparator.(See Section6.1.1)Modification to the preferred antibiotic to be used 
for treatment of gram-positive bacteria (e.g vancomycin) is also allowed in instances of 
documented bacterial drug resistance, tolerability, or other relevant limitations.
3.5
Purpose and timing of interim analyses/design adaptations
LYS228 exposure across patients with varying renal function will be evaluated during the 
study to confirm that LYS228 concentrations are predicted to be adequate to treat the patient 
population. The PK exposure of the initial 8 patients will be analyzed.  A second PK analysis 
with 20 patientswill be conducted. This will enable an emergingdata review of the required 
doses for patients in each renal function category and adjustment as necessary(see 
Section11.8
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3.6
Risks and benefits
Patients participating in the study. may benefit from receiving effective antibiotic therapy to 
treat cIAI. 
The risk to patients in this trial will be minimized by adherence to theeligibility criteria, close 
clinical monitoring, andfollowing study stopping rules.
 
 
 
3.6.1
Hypersensitivity reaction
Other β-lactam antibiotics have been associated with the development of hypersensitivity 
(Romanoetal2016). Rare cases of toxic epidermal necrolysis have been reported following 
administration of aztreonam and other β-lactam antibiotics (LeFrock et al 1987). These have 
usually been observed in patients undergoing bone marrow transplantation. 
 
 
Patients will be closely monitored for evidence of rash or 
other forms of hypersensitivity. Patients will be excluded from the study if they have a history 
of β-lactam allergy or hypersensitivity.
3.6.2
Hepatotoxicity
Markers of liver toxicity, including transaminases, will be monitored in the study.
3.6.3
Nephrotoxicity
 
 Nephrotoxicity is a known adverse effect of many β-lactam antibiotics 
(Lagacé-Wiens and Rubinstein 2012). Markers of renal toxicity, including serum creatinine, 
will be monitored and LYS228 dose will beadjusted based on the estimated creatinine 
clearance.
3.6.4
Local Reaction
Local reactions such as phlebitis or thrombophlebitis following intravenous administration of 
aztreonam occur at rates of 1.9% to 2.4% but may be higher depending on how they are 
assessed (Henry and Bendush 1985,Ray-Barrueletal 2014).In hospitalized patients, catheter-
related phlebitis rates can be as high as 42% of catheters andtherelative risk of phlebitis is 2.5 times 
higher with antibiotics(Maki and Ringer1991
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). LYS228 administration may result in similar 
local reactions.To reduce the risk of such reactions, catheter placement and management 
 
 
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should follow local standard of care. Such local reactions will be monitored as detailed in the 
SOM.
3.6.5
Gastrointestinal discomfort
Administration of β-lactam antibiotics is associated with the development of abdominal pain 
or discomfort, diarrhea, nausea, and vomiting (Lagace-Wiens and Rubinstein 2012). These 
symptoms generally occur in less than 2% of patients receiving aztreonam 
(Newmanetal1985). Patients will be monitored for gastrointestinal symptoms.
3.6.6
Clostridium difficile–associated diarrhea
C. difficile-associated diarrhea has been reported following treatment with nearly all 
antibiotics, including aztreonam (Lagace-Wiens and Rubinstein 2012). Such diarrhea may 
range in severity from mild abdominal discomfort to severe colitis that may result in death. 
Patients suspected of having symptoms due to C. difficile should be tested for the presence of 
C. difficile antigen followed by a confirmatory test for the C. difficile toxin in the stool. 
Patients testing positive should be treated with appropriate standard of care.
3.6.7
Seizure
Seizures are associated with β-lactam antibiotics (Sutter et al 2015). 
 
 
 
 Patients will be monitored for seizure 
activity.
3.6.8
Thrombocytopenia
 Cytopenias, including
thrombocytopenia, have been observed in patients receiving β-lactam antibiotics 
(LagaceWiens and Rubinstein 2012). Aztreonam administration demonstrated noadverse 
effectson platelet function in healthy subjects (Tartaglioneetal1986, Agnelli et al 1987).
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in Section 4.2(Exclusion Criteria).If there is any question that the 
patient will not reliably comply, they should not be entered or continue in the study.
Sexually active males must be informed of the requirement to wear a condom for the 
following reasons:

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Prevent pregnancy in a female partner
AND
Prevent potential delivery of investigational drug via seminal fluid to their partner as study 
treatment may involve unknown risks to the fetus if pregnancy were to occur
There may be unknown risks of LYS228 which may be serious.
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3.7
Blood sample volumes
Approximately250 mL of blood is planned to be collected over a period of approximately 28 
days, from each patient as part of the study.Additional samples may be required for safety 
monitoring.
Timings of blood sample collection are outlined in the Assessment schedule(Section 8.1).
A summary blood log is provided in the SOM. Instructions for all sample collection, 
processing, storage and shipment information is also available in the SOM and Central 
Laboratory Manual.
See Section 8.9regarding the potential use of residual samples. 
4
Population
Approximately 60 patients will be randomized to LYS228 or a comparator in 2:1 ratio and are 
expected to be included in themicrobiologic modified intention to treat(micro-mITT)
population, as defined in Section 11.1.
Patients that do not meet criteria for inclusion in the efficacy analysis sets may be replaced as 
needed.Additionally, patientswho discontinue the study for reasons other than safety may 
also be replaced.
The investigator or designee must ensure that all patients being considered for the study meet 
the following eligibility criteria. No additional criteria should be applied by the investigator, 
in order that the study population will be representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at screening. 
Arelevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
Additional patientsmay be enrolled in the event that the sponsor recommends changes or 
additional dosing regimens, or change in the infusion procedures based on emerging 
pharmacokinetics or safety data. 
4.1
Inclusion criteria
1. Written informed consent must be obtained by one of the following mechanismsbefore 
any study assessment can be performed:
a. A patient who has capacity to give informed consent,signs and dates the 
informed consent form;
b. A patient who has capacity to give informed consent,is physically unable to 
sign and date the informed consent form (e.g. due to inability to write), but 
gives consent and an impartial witness signsand datesthe consent form to 
indicate that consent was given.
c. A patient who lackscapacity to give informed consent,is enrolled after a
Legally Authorized Representative signs and dates the informed consent form, 
giving consent on the patient’s behalf using the principle of substituted 
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Note: band capplies only if permitted by local country regulations, and the 
governing ethicscommittee, which shall determine the qualifications of the Legally 
Authorized Representative.
2. Male and female patients 18 to 65 years inclusive, and after interim analysis of 8 patients
(see Section 3.5and Section 11.8) patients up to 85 years, inclusive, withvisual 
confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection 
associated with peritonitis including at least 1 of the following diagnoses during surgical 
intervention (e.g. laparotomy, laparoscopic surgery, or percutaneous draining of an 
abscess):
Cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or 
progression of the infection beyond the gallbladder wall;
Diverticulitis with perforation or abscess;
Appendicitis with appendiceal perforation or periappendiceal abscess;
Acute gastric or duodenal perforation, if operated on >24 hours after perforation;
Traumatic perforation of the intestine, if operated on >12 hours after perforation;
Secondary peritonitis or intra-abdominal abscess due to perforated viscus, or spread 
from other focus of infection 
And one of the following:
a. Patient has undergone surgery for the inclusionary infection and pus has been 
visualized within the peritoneal cavity, either directly (i.e. by laparotomy or 
laparoscopy), or by aspiration.
b. Surgical intervention is scheduled to take place within 24 hours of entryand all 
criteria below are met:
The patient has fever (>38ºC), hypothermia (with a core temperature <35 
ºC), leukocytosis (>12,000/µL), orchills.
The patient has abdominalpain, nausea, vomiting, tenderness to 
palpation, rebound tenderness,orguarding.
Radiologic imaging findings support inclusionary diagnosis
3. Patients receiving antibiotic treatment of any duration judged to be inadequate due to 
persistent signs and symptoms of infection and documented bacterial resistance to the 
antibiotic received provided they meet all of the following criteria:
a. The patient had a surgical intervention(e.g. laparotomy, laparoscopic surgery, 
or percutaneous draining of an abscess) that was completed within 24 hours 
prior to study entry or is scheduled to have such an intervention no more than 
24 hours after study entry
b. Findings of persistent infection were documented at the time of surgical 
intervention
c. Specimens for bacterial cultures and susceptibility testing from the intra-
abdominal focus of infection were taken during surgical intervention
d. No further non-study antibiotic therapy is administered after randomization
4. Patients must weigh at least 40 kg to participate in the study, and must have a body mass 
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5. Expectationthat, in the judgment of the Investigator, the patient will survive with effective 
antibiotic therapy and appropriate supportive care for the anticipated duration of the study.
6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations.
2. Any of the following:
Abdominal wall abscess
Small bowel obstruction
Traumatic bowel perforation undergoing surgery within 12 hours
Perforation of gastroduodenal ulcer with surgery within 24 hours
An intra-abdominal process that is not likely caused by infection
Simple cholecystitis
Gangrenous cholecystitis without rupture
Simple appendicitis
Acute suppurative cholangitis
Infected necrotizing pancreatitis
Pancreatic abscess
Qualifying cIAI managed by
 staged abdominal repair 
Source control ofinfection is not likely to be achieved
Perinephric abscess or peritonitis due to anindwelling peritoneal dialysis catheter
Qualifying cIAI diagnosis suspected to bedue to fungus, parasites (e.g. amoebic liver 
abscess), virus, or tuberculosis.
3. Received prior antibiotics within 72 hours before the initiation of study therapy, with the 
following exceptions:
The patient received less than 24 hours of total prior antibiotic therapy (based on the 
dosing interval)
Patients receiving ongoing antibacterial drug prophylaxis that will be discontinued at 
study screening and until study completion
Patients whoreceived antibacterial drugs for surgical prophylaxis and then developed 
cIAI
Patients who meet inclusion criteria number 4
4. Received long-acting antibiotic (≥24 hours dosing interval)intra-or post-operatively
5. Receivedany non-study antibioticmore than 6 hours post-procedure
6. Concomitant bacterial infection at time of enrollment requiring non-Study Drug
antibiotics and that may interfere with the evaluation of clinical response to the study 
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7. Non-abdominal bacterialinfectiondiagnosed within 7 days prior to enrollmentincluding 
endocarditis, osteomyelitis, abscess, meningitis, or pneumonia.
8. Patient has APACHE II score > 30 (Knaus et al 1985) or is considered, in the judgement 
of the investigator, unlikely to survive 4 weeks (e.g. rapidly progressive terminal illness, 
including septic shock)
9. Patients who require vasopressors or other agents for hemodynamic support, or admission 
to an intensive care unit due to critical illness
10.Patient cannot tolerateadministration of intravenous StudyDrug(≥1 L of fluid per day)
11.Patients that meet sepsis criteria as defined by the quick sequential sepsis-related organ 
failure assessment (qSOFA) (Singer et al 2016)
Respiratory rate ≥ 22breathsper minute AND
Altered mentation AND
Systolic BP ≤ 100 mmHg
Assessment can be repeated once after fluid resuscitation and treatment of fever
12.Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test
13.Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 7 days after stopping all study treatment.Highly effective 
contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug.In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). For femalepatientson the 
study the vasectomized male partner should be the sole partner for that patient  (see 
SOM regardingvasectomized partners)
Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug


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14.Sexually active males unwilling to use a condom during intercourse during treatment 
period and for 1 day (> 5* T1/2) after completion of treatment. A condom is required for 
all sexually active male participants, including vasectomized men, to prevent them from 
fathering a child ANDto prevent potential delivery of the drug via seminal fluid.
15.Patients withan estimatedcreatinine clearanceof< 30mL/min calculated based onthe
study qualified formula or who require renal replacement therapy [hemodialysis, 
peritoneal dialysis or continuous veno-venous hemofiltration (CVVH)]
16.Any of the following lab abnormalities at screening:
ALT, γ-GT, and / or AST ≥3 x the upper limit of normal (ULN)
Serum bilirubin ≥ 3 mg/dL
Hemoglobin levels ≤ 9 g/dL
Thrombocytopenia as defined by ≤ 100,000 platelets/µL
Neutropenia as defined by ≤ 1,000 polymorphonuclear leukocytes /µL
17.History or current diagnosis of ECG abnormalities indicating significantsafetyrisk for 
participationin the study,such as:
Concomitant clinically significant cardiac arrhythmias (e.g. sustained 
ventricular tachycardiaand clinically significant second or third degree AV 
block without a pacemaker)
History of familial long QT syndrome or known family history of Torsades de 
Pointes
18.History of seizures requiring current treatment with an anti-seizure medication.
19.History of adrenal diseasethat requires the use of steroids  (≥ 60 mg prednisone or 
equivalent).
20.History of hypersensitivity to, Study Drugor beta-lactam antibiotics (e.g.penicillins, 
cephalosporins,  carbapenems, or monobactams), metronidazole
21.History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), unless considered cured or in remission (not receiving therapy and no evidence 
of local recurrence or metastases that require therapy).
22.History of positive HIV(confirmatory testing) except patients receiving effective 
antiretroviral therapy and with documented virologic control (HIV RNA < 500 
copies/mL) and an absolute CD4 1 cell count of ≥350 cells/mm3within the preceding 6 
months
23.Patients with estimated glomerular filtration rate <30mL/min calculated based on study 
qualified formula or who require renal replacement therapy (hemodialysis, peritoneal 
dialysis, or continuous veno-venous hemofiltration
24.Taking medications prohibited by the protocol [as detailed in Section 5.2(Prohibited 
treatment)].
No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients.


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5
Restrictions for Study Patients
For the duration of the study, the patients should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement outlined 
in the Section 4.2(Exclusion Criteria).
Sexually active males should be reminded of the requirement to wear a condom for the 
following reasons:
Prevent pregnancy in a female partner
AND
Prevent delivery of investigational drug via seminal fluid to their partner as study treatment 
may involve unknown risks to the fetus if pregnancy were to occur
If there is any question that the patientwill not reliablycomply in the judgement of the 
investigator, the patient should not be entered or continue in the study.Male patients should 
be informed that if a female partner becomes pregnant while he is enrolled in the study, 
contact with the female partner will be attempted to request her consent to collect pregnancy 
outcome information.Please refer to Section 4.2 (Exclusion criteria) for details of 
contraception requirements for the study.
5.2
Prohibited treatment
The use of effective concomitant systemic antibiotics with activity against Gram-negative 
bacteria (oral, IV, or intramuscular) in addition to those designated in the two study groups is 
prohibited. 
Antibiotic therapy for documented clinical or microbiologic failures (rescue antibiotic 
therapy) or required to treat adverse events are permitted. Antifungals or antivirals are 
allowed to treat concomitant non-bacterial infections. 
 
 
No other clinically relevant drug-drug interactions are expected.
5.3
Dietary restrictions and smoking
There is no restriction on diet or on smoking status.
5.4
Other restrictions
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There are no other restrictions


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6
Treatment
6.1
Study treatment
LYS228 (Arm 1) will be provided by the sponsor
Standard of care intravenous antibiotic therapy (Arm2)and alternative antibiotics used in the 
event of change from Study Drug will be provided locally.
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for patientnumbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM and the PM.
6.1.1
Investigational treatment and control drugs
 
LYS228 will be packed and labeled under responsibility of Novartis and will be 
supplied to the Investigator sites as open label bulk supply. LYS228 preparation instructions 
will be provided in the PM. 
Antibiotics to be used in combination with LYS228 for treatment of Gram-positive and 
anaerobic bacteria (vancomycin and metronidazole) will be provided locally and prepared 
consistent with local practices.
The preferred standard of care antibiotic to be used as an active comparator for LYS228 is 
piperacillin / tazobactam, the active comparator will be provided locallyand prepared 
consistent with local practices.Every reasonable effort should be made to ensure that the 
preferred standard of care antibiotic is used (piperacillin/tazobactam). In instances such as 
documented drug resistance, poor tolerability, or drug shortages, the preferred standard of 
care control can be modified to meropenem(see Section 3.4).
Alternative antibiotics with Gram-positive activity only (daptomycinorlinezolid) are not 
considered prohibited medications, and may be used based on microbiologic susceptibility 
data.Alternative antibiotics used as rescue therapy or in the event of change from Study Drug 
will be provided locally.
Table 6-1
Overview of study medication
Study drug name
Formulation Unit dose
Packaging
PSourcing
LYS228
Open label patient specific 
kits 
Provided by 
Novartis
Vancomycin
Commercially available presentation
Locally
Metronidazole
Commercially available presentation
Locally
Piperacillin/Tazobactam
Commercially available presentation
Locally
Alternatively to 
Piperacillin/Tazobactam*:
Meropenem
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*Alternative standard of care antibiotic regimen (meropenem) may only be used if 
Piperacilling/Tazobactam treatment regimen cannot be used (e.g. in the case of resistance)
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6.1.2
Alternative and rescue antibiotic treatment
Alternativeoralantibiotics allowed after completion of intravenous Study Drugor rescue 
antibiotics used during the treatment period, as described in Section 3, will be provided 
locally by the sites.
6.2
Treatment arms
Patients will be randomized to one of the following two treatment arms in a ratio of 2:1.
Arm 1: LYS228 (n=40). LYS228 dose for each patient will be based on the renal function 
as described in Section 3.3.Vancomycin and metronidazole will be given in addition to
LYS228 to treatGram-positive and anaerobic spectra of bacteriabased on local standard 
of care procedures.
Arm 2: Standard of care intravenousantibioticfor the treatment of cIAI (n=20)with 
activity against Gram-negative, Gram-positive and anaerobic bacteria based on local 
standard of care procedures.
Adjustmentofthe non-LYS228 Study Drug components oftreatment arms may be permitted 
based on microbiologic data as detailed in the SOM 
6.3
Treatment assignment and randomization
The randomization numbers will be assigned using an Interactive response Technology (IRT). 
Please refer to the SOM for the process and timing of treatment assignment and 
randomization of patients.
6.4
Treatment blinding
This is an evaluator-blinded study. The physician performing the safety and clinical response 
assessments will remain blinded to study treatment throughout the study, except where 
indicated below.
Thiswill require the investigator site staff to apply certain restrictions to ensure the evaluator 
physician does not have access to study documents, and does not observe the drug 
administration because the Study Drugs are provided in an open-label fashion. 
Adouble-dummy design is not feasible,as explained in Section 3.3.Further details can be 
found in the SOM
With the exception of the blinded evaluator, all site staff (including study investigator and 
study nurse) will be unblinded to study treatment during treatment allocation andpatient
dosing.
The Sponsor staff will be unblinded in this study.


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Table 6-2
Blinding and unblinding plan
Role
Time or Event
Randomization 
list generated
Treatment 
allocation and 
administration
Safety 
emergency event 
(unblinding of a 
single patient)
Patients
B
UI
UI
Evaluator physician
B
B
UI
Unblinded site staff (see 
text for details)
B
UI
UI
Drug supply and 
randomization office
UI
UI
UI
Unblinded sponsor staff
B
UI
UI
Statistician/statistical 
programmer/data 
analysts
B
UI
UI
Independent committees 
used for assessing 
interim results
NA
NA
NA
B Remains blinded
NA Not applicable
UI Allowed to unblinded on individual patient level
6.5
Treating the patient
See the SOMand the PMfor further detailson LYS228 administration.All other antibiotics 
will be administered according to local practices.
Sponsor qualified medical personnel will be readily available toadvise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Dose adjustments are permitted during the study to adjust for changes in renal function. 
As described in Section 3.3
Corporate 
Confidential 
Information
and the SOM, the dose of LYS228 is selected according to 
estimated CrCl at screening. Patients with anestimated CrCl ≥ 90 ml/min will receive 
every 6 hours andpatients with anestimated CrCl < 90/mL/min will receive 
every 6 hours. During the treatment period, if changes in estimated CrCl occur,the
LYS228 dose must be adjusted accordinglywith the study formula as described in the PM.In 
case of notable adverse events, safety concerns,or emerging pharmacokinetic data, 
administration of an LYS228dose below the initial dose, or adjustments to theLYS228
infusion may be considered in consultation with the sponsoror by the sponsor. Other study 
treatment dose adjustments and/or interruptions are not permitted. 
These changes willbe recorded on the Dosage Administration Record CRF.


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6.7
Emergency breaking of assigned treatment code
Not applicable. The Study Drugs will be administered in an open-label fashion. The blinded 
evaluator designated by the investigator may have access to the treatment assignment if 
needed.
6.8
Treatment exposure and compliance
IV infusions will be administered at the study site. The site staff will instruct patients to take 
any medications administered in an out-patient settingas prescribed. LYS228 concentrations 
will be measured in all patients treated with LYS228, as detailed in Section8.5.
6.9
Recommended treatment of adverse events
Adverse events should be treated per local standard of care. 
 
 Medicationsused to treat AEs must be 
recorded on the Concomitant medications/Significant non-drug therapies CRF.
6.10
Rescue antibiotic medication
The use of rescue antibiotics is at the discretion of the investigator, and should be limited to 
instances of clinical failure as defined in Section 11.4.1including persistence or worsening of 
symptoms of cIAI. Symptoms of cIAI and clinical failures must be recorded in the CRF. Use 
of rescue medication must be recorded in the CRF.
6.11
Concomitant treatment
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies CRF. 
Administration of supportive intravenous fluids, enteric or parenteral nutrition, and therapies 
for local wound care will be captured only in the source documents.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medications. If in doubt, the investigator should contact Novartis before randomizing a patient 
or, if the patient is already enrolled, to determine if the patientshould continue participation in 
the study.
7
Study completion and discontinuation
7.1 
Study completion and post-study treatment
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Each patient will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.


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Study completion(end of trial)is defined as when the last patient completes their EOSvisit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All treated patients should have a safety follow-up call conducted 30 days after End of Study 
Drug. The information collected is kept as source documentation.All SAEs reported during 
this time period must be reported as described in Section 9.2and the SOM. Documentation of 
attempts to contact the patientshould be recorded in the source documentation.
7.2
Discontinuation of study treatment
Discontinuation of the study treatmentfor a patient occurs when study treatment is stopped 
earlier than the protocol planned duration.
Study treatment for an individual patient must be discontinued under the following 
circumstances:
Patient/guardian decision -patients may choose to discontinue study treatment for any 
reason at any time.
The investigator believes that continuation would negatively impact the safety of the 
patient or the risk/benefit ratio of trial participation. This might include patientsthat have 
bacterial isolates inbloodor cIAI focus of infection culturesat baseline that arenot 
susceptible to study treatment
Any protocol deviation that results in a significant risk to the patient’s safety.
Pregnancy [see Section 8.6(Safety)and Section 9.6(Pregnancy reporting)]
Study Drugtreatment for an individual patient must be placed on hold until a full review of 
the safety data occurs for any of the following events/findings:
Use of prohibited treatment as outlined in Section 5.2
Emergence of the following adverse events:
One AE of grade 3 or higher by Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0, (2017)criteria requiring intervention considered to be related 
to Study Drugor SAE believed to be related to Study Drug.
Creatinine increase to 2.0 x baseline considered to be related to Study Drug
≥ Grade 2 decrease in plateletcount (<70x10
9/L) considered to be related to Study 
Drug
Any evidence(clinical signs and symptoms) of seizure activity. NOTE: Patients can 
continue Study Drugif an alternative (notStudy Drug-related) cause is clear and 
likely.
≥ Grade 2 hypersensitivity reaction as defined by flushing or rash, temperature >38°C 
or therapeutic intervention required. Immediate interruptionof thestudy treatment
infusionis required in such cases. NOTE: Patients can continue Study Drugif an 
alternative cause (not Study Drug-related) is clear and likely.
Clinical or microbiologic failure as defined in Section 11.4.2.
If a liver or renal event occurs, follow guidelines outlined in Appendix 1andAppendix2
regarding discontinuation of study treatment


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Any medical condition, laboratory abnormalities, or adverse event that in the judgment of 
the investigator and the sponsor justify dosing discontinuation for the individual patient, 
taking into consideration the patient’s overall status.
Patients that miss one or more doses of Study Drug may continue in the study if the 
investigator feels that this is the appropriate course of therapy,unless the patient missed doses 
because of an adverse event related to administration of the Study Drug. If an alternative 
cause is identified,such patients may continue Study Drug.
If discontinuation of study treatment occurs,theinvestigator must determine the primary 
reason for the patient’s premature discontinuation of study treatment and record this 
information on the Dosage Administration CRF.
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
theirconsent (see Section 7.3, Withdraw of Informed Consent). If they fail to return for the 
EOS assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact thepatient/pre-designated contact as specified in Section7.4(Lost to follow-
up). This contact would preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:
new / concomitant treatments
adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.Please refer to the SOM and IRT Manual for details.
7.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs only when a patient:
Does not want to participate inthe study anymore and
Does not allowfurther collection of personal data
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent andrecord 
this information.Study treatment must be discontinued and no further assessments conducted, 
and the data that would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unlesssafety findings require 
communicating or follow-up.All efforts should be made to complete the assessments prior to 
study withdrawal. A final evaluation at the time of the patient’s study withdrawal should be 
made as detailed in the assessment table. 
Novartis/sponsorwill continue to keep and use collected study information (including any 
data resulting from the analysis of a patient’s samples until their time of withdrawal) 
according to applicable law.


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7.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
The investigators and the sponsor will continually review adverse events and laboratory 
findings during the study.
The study may be stopped(i.e. stop new enrollment and stop dosing for all patients)in case of 
safety concerns that are suspected to be related to Study Drug,including:
≥ 5 patients have a Study Drug-related Grade 2 increase in serum creatinine (≥ 1.5 x 
baseline)
≥3 patients have a Study Drug-related similar adverse event of Grade 3 or higher (per 
CTCAEscoring)
≥2 patients have a Study Drug-related seizures
The principal investigator or the sponsor consider that the number and/or severity and/or 
system organ class of adverse events justify discontinuation of drug administration
The sponsor unilaterally requests it
The severity of adverse events will be graded by the study site investigator (or his designee) 
based on clinical judgment using CTCAE v. 5.0. CTCAEgrades will be used in the source 
documents to quantify events that may lead to patient’s discontinuation. Safety reviews will 
be conducted jointly between medically qualified representatives of the sponsor and 
Investigators. Dosing can be reviewed provided the safety data supports this.
7.6
Early study termination by the sponsor
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Thestudy can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should thisbe necessary, patients must 
be seen as soon as possible and treated as a prematurely discontinued patient. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protectionof the patients’interests. The investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial.


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8
Procedures and assessments
8.1
Assessment schedule
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and concomitant medications recorded on the 
CRF.
Table 8-1
Assessment schedule
Study phase
Screening/
Baseline
Treatment
Follow
up
Visit Name
Screening/
Baseline
Minimum Study Drug 
treatment visits
Additional Study Drug treatment visits2,3,4
End of 
Study 
Drug 
(EOSD) 
visit2,3,4
End of 
Antibiotic
Treatment 
(EOAT) 
visit3,4,5
End of
Study 
(EOS)
visit
Visit Number1
V1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 
115 
116 
199
Days
-1 to 1
1 
2 
3 
4 
5 
6 
7 
8 
9
10 
11 
12 
13 
14
Flexible, 5 
up to 15
Flexible, 
6 up to 15
28
Informed consent
X
Inclusion / Exclusion 
criteria
S6
Medical history/current 
medical conditions
X
Demography
X
Clinical evaluation of IAI
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
X7
As Required7
X
As Required8
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Study phase
Screening/
Baseline
Treatment
Follow
up
Visit Name
Screening/
Baseline
Minimum Study Drug 
treatment visits
Additional Study Drug treatment visits2,3,4
End of 
Study 
Drug 
(EOSD) 
visit2,3,4
End of 
Antibiotic
Treatment 
(EOAT) 
visit3,4,5
End of
Study 
(EOS)
visit
Visit Number1
V1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 
115 
116 
199
Days
-1 to 1
1 
2 
3 
4 
5 
6 
7 
8 
9
10 
11 
12 
13 
14
Flexible, 5 
up to 15
Flexible, 
6 up to 15
28
Estimated creatinine 
clearance9
X
As Required
X
Physical Examination
S6
As Required (S)6
Pregnancy and 
assessments of fertility
X
X
Body Height
X
Body Weight
X
X
Body Temperature
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
Blood Pressure
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
Pulse rate
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
Urinalysis
X 
X10
X
X
X 
X
Hematology
X 
X10
X
X
X
X
X
X 
X
Blood chemistry
X 
X10
X
X
X
X
X
X 
X
ECG evaluation
X
X
X
Study Drug 
administration11
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Switch to alternative(oral)
antibiotic
As 
Required
Alternative(oral)antibiotic 
compliance
X
Rescue Antibiotic
As Required


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Study phase
Screening/
Baseline
Treatment
Follow
up
Visit Name
Screening/
Baseline
Minimum Study Drug 
treatment visits
Additional Study Drug treatment visits2,3,4
End of 
Study 
Drug 
(EOSD) 
visit2,3,4
End of 
Antibiotic
Treatment 
(EOAT) 
visit3,4,5
End of
Study 
(EOS)
visit
Visit Number1
V1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 
115 
116 
199
Days
-1 to 1
1 
2 
3 
4 
5 
6 
7 
8 
9
10 
11 
12 
13 
14
Flexible, 5 
up to 15
Flexible, 
6 up to 15
28
PK blood collection12
X13
X14
X14
X14
X2,15
X14
X14
X14
X14
X14
X
X
Adverse Events
As Required
Serious Adverse Events17
As Required
Concomitant therapies
As Required
Comments
As Required
Safety Follow up Call
S6,18
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1Visit structure given for internal programming purpose only
2Upon discontinuing Study Drug, patients must undergo an End of Study Drug visit. That day
's scheduled Study Drug treatment visit/assessments will be 
replaced by the End of Study Drug visit/assessments; with the exception that, if an End of Study Drug visit takes place on Day 5, PK blood collection 
must still be performed on Day 5
3After completing an End of Study Drug visit, patients who are switched to alternative antibiotics are only required to complete the End of Antibiotic 
Treatment and End of Study Visits. All other treatment visits and their relevant assessments are no longer required 
4After completing an End of Study Drug visit, patientwho discontinue antibiotic therapy (i.e. are not switched to alternative antibiotics) are only required 
to complete the End of Study Visit. All other visits and their relevant assessments are no longer required 
5End of Antibiotic Treatment visit only applies to patients who are switched to alternative antibiotics. This visit must take place after discontinuing 
alternative antibiotics.
6S= assessment will be recorded on source documentation only and will not be entered into the CRF
9 Calculated based on SCr analyzed by local lab.
10If Screening visit occurs within 24 hours of Day 1, the urinalysis, hematology, and blood chemistry assessments do not need to be performed on Day1
11Study Drug will be administered for a minimum of 5 days and up to 14 days. Study Drug no longer administered after a switch to alternative antibiotics
12PK samples only to be collected for patients randomized to receive LYS228.
13Samples to be collected at 1, 2, 4 hours after the start of any ONE Day 1 LYS228 infusion.
14One pre-dose sample to be collected before any ONE LYS228 dose on Days 2, 3, 4, 7, 9, 11, 13 and EOSD visit.
15Samples to be collectedPre-dose and at 1, 2, 3,4, and 6 hours after the start of any ONE Day 5 LYS228 infusion. 
17Serious Adverse Events (SAEs) must be reported according to the timeframe specified in the protocol
18
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Post study safety contact is via phone or email and will take place 30 days after End of Study Drug. Information collected will be kept as source 
documentation only; Exception: in the case of a reported SAE, follow instructions for SAE reporting outlined in the protocol and SOM
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8.2
Informed consent procedures
As described inSection 4.1written consent is preferred and may be the only method 
acceptable according to certain local laws and regulations. If verbal assent is obtained(where 
permissible),a patient’s representative must be present andwritten consent by the patient 
must be obtained as soon as the patientis capable of providingit. Informed consent/assent
must be witnessed, where required by law or regulationandusing anIRB/IEC-approved
document.
If applicable, in cases where the subject’s representative gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible 
given his/her understanding. If the patient is capable of doing so, he/she must indicate assent 
by personally signing and dating the written informed consent document or a separate assent 
form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patientsource documents.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the patientagrees to future research.
Theprocedures set out in the main consent form concerning the storage, maintenance of 
privacy, and release of the data or specimensfor the main study will also be adhered to for 
any future research. Any changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator
's Brochure (IB). This information will be included in the patient
informed consent and should be discussed with the patientduring the study as needed. Any 
new information regarding the safetyprofile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the patient.
Ensure patients are informed of the contraception requirements outlined in the Section4.2
(Exclusion criteria) and in Section 5.1
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(Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.


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Refer to the SOMfor a complete list of Informed Consent Forms included in this study.
8.3
Patient screening
It is permissible to re-screen a patient one time only if s/he fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis.In the case 
of the laboratory assessment at screening is outside of the range, the assessmentmay be 
repeated once prior to enrollment. If the repeated value remains outside of the specified ranges, 
the patient will be excluded from the study.
Information on what data should be collected for screening failures is outlined in the SOM.
8.4
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all patients.Relevant 
medical history/current medical conditions data will also be collected until signature of 
informed consent.Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.5
Efficacy / Pharmacodynamics
8.5.1
Clinical evaluation of cIAI infection
A blinded evaluator will conduct the clinical evaluation necessary to determine clinical 
response at the time-points defined in the Assessment schedule(Section 8.1). For further 
details on evaluator blinding, please refer tothe SOM.
The following data will be recorded in the CRFas part of the clinical evaluation of cIAI 
infection:
Underlying inclusionary diagnosis (Inclusion criterion 2)
Signs and symptoms of intra-abdominal infection: Onset, resolution or improvement, 
determined by CTCAE grading criteria. Signs and symptoms will be recorded daily during 
hospitalization and at the EOSD, EOAT, and EOSvisits.
Present at inclusion, or before surgical intervention if enrolled post-operatively: fever 
(defined as body temperature > 38ºC), hypothermia with a core body temperature 
<35ºC, elevated WBC count (>12,000/µL), chills, abdominal pain, nausea, vomiting, 
tenderness to palpation, rebound tenderness, and guarding
New signs and symptoms attributed to progression of cIAI. Progression of infection 
other than cIAI (e.g. sepsis) will be captured as an SAE as detailed in Section 9.2
Surgical intervention (e.g. laparotomy, laparoscopic surgery, or percutaneous draining of 
an abscess) 
Primary intervention for baseline (index) cIAI
Re-intervention for progression or relapse of cIAI if required 96 hours after the start 
of Study Drug.


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8.6
Safety
Safety assessments are specified below. Methods for assessment and recording are specified 
in the SOM, with the Assessment schedule(Section 8.1) detailing when each assessment is to 
be performed.
8.6.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and/or pelvic exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded in the CRF. Significant findings that are present prior to 
informed consent are included in the Medical History CRF. Significant findings observed 
after informed consent signature which meet the definition of an Adverse Event must be 
appropriately recorded on theAdverse Event CRF.
8.6.2 
Vital signs
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Vital signs include blood pressure (BP), body temperature, and pulse measurements. After the 
patienthas been sitting/supine position for 3 minutes, systolic and diastolic BP will be 
measured using an automated validated device, with an appropriately sized cuff. In case the 
cuff sizes available are not large enough for the patient’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used.


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8.6.3
Body height and body weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured.
Body mass index (BMI) will be calculated using the following formula:
BMI = Body weight (kg) / [Height (m)]2
8.6.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met.
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (e.g., 
neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
measured. Coagulation testing including prothrombin time (PT) also reported as INR and 
activated partial thromboplastin time (aPTT) will be measured.
Blood chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/carbon dioxide (CO2), calcium, 
cholesterol, chloride, creatinine, creatinine kinase (CK), GGT, glucose, lactic dehydrogenase 
(LDH), inorganic phosphorus, lipase, amylase, magnesium, potassium, total protein, AST, 
ALT, sodium, triglycerides, blood urea nitrogen (BUN) uric acid. If the total bilirubin 
concentration is increased above 1.5 times the upper limit of normal, direct and indirect 
reacting bilirubin shouldbe differentiated.
Urinalysis
A midstream urine sample (approximately 30 mL) will be obtainedfrom patients with no 
urinary catheters,in order to avoid contamination with epithelial cells and sediments, and 
allow proper assessments. A semi-quantitative “dipstick” evaluation for the following 
parameters will be performed: specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, 
leukocytes and blood. If the dipstick result is positive for protein, nitrite, leucocytes and/or 
blood, the sample will be sent for microscopic analysis of WBC, RBC and casts.
8.6.5
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
SOM.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTc.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.


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As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the 
ECG machine, the investigator must calculate QTcF at the Screening visit to assess eligibility. 
See the Site Operations Manual for additional details.
Clinically significant abnormalities must be reported in the AE CRF.
8.6.6
Pregnancy and assessments of fertility
Pregnancy
All pre-menopausal women who are not surgically sterile will have pregnancytesting.See the 
Assessment schedule(Section 8.1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements*.A positive urine 
pregnancy test requires immediate halt of study treatment until serum β-hCG is performed and 
found to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.  
Refer to Section 9.6for details on Reporting Pregnancy.
Assessments of Fertility
Refer to Section 4.2for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source, if available. Subsequent hormone level assessment to confirm the woman is not of 
child bearing potential must also be available as source documentation in the following cases:
surgical bilateral oophorectomy without a hysterectomy
reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
If a female patientcannot beconfirmed to be of non-childbearing potential, highly effective 
contraception methods should be used as describedin Section 4.2.
8.7
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected at the timepoints defined in the 
Assessmentschedule(Section 8.1). Follow instructions outlined in the Site Operations 
Manual regarding sample collection, numbering, processing and shipment. See Section8.9
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Information
for 
information regarding the potential use of residual samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol.
Pharmacokinetic (PK) samples will be obtained and evaluated in all LYS228 treated patients.
LYS228will be determined by avalidated LC-MS/MS method; 
 
Concentrations will be expressed in mass per volume units.


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Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled 
as such in the Bioanalytical Data Report.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters on the last day of LYS228 dosing will be 
determined using the actual recorded sampling times and non-compartmental method(s) with 
Phoenix WinNonlin (Version 6.4 or higher): Cmax, Tmax, AUCTau, , T1/2, %fT>MIC and 
CL, Vss from the plasma concentration-time data.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the 
terminal plasma elimination phase for the determination of T1/2 will include at least 3 data 
points after Cmax. If the adjusted R2
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value of theregression analysis of the terminal phase 
will be less than 0.75, no values will be reported for T1/2.


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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient
afterproviding written informed consentfor participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section9.5for 
an overview of the reporting requirements.
The occurrence of adverse events must be sought by non-directivequestioning of the patient
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patientduring or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
They induce clinical signs or symptoms,
They are considered clinically significant,
They require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patientand identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix1and Appendix2, respectively.
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. The severity grade: the Common Toxicity Criteria (CTC) AE grade 5.0CTCAE grading
will be provided separately. If CTCAE gradingdoes not exist for an adverse event, use:
1=mild,
2=moderate,
3=severe
4=life threatening* (see Section 9.2for definition of a serious adverse event (SAE))
*Note: There may be cases where a CTCAE with a grade of 4 (life -threatening) may not 
necessarily be an SAE (e.g. certain laboratory abnormalities in the absence ofmeeting 
other seriousness criteria).
CTC-AE grade 5 (death) is not used, but is collected as a seriousness criteria and also 
collected in other CRFs (e.g. Study Completion, Death/Survival).
2. its relationship to the study treatment:

Yes orNo


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3. its duration (start and end dates) or if the event isongoing an outcome of not recovered/not 
resolved must be reported.
4. whether it constitutes a serious adverse event (see Section 9.2for definition of SAE) and 
which seriousness criteria have been met
5. action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of 
the following:
no action taken (e.g. further observation only)
investigational treatment dosage increased/reduced
investigational treatment interrupted/withdrawn
concomitant medication or non-drug therapy given
hospitalization/prolonged hospitalization (see Section9.2for definition of SAE)
its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator
's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications.Once an adverse event is detected, it must be followed 
until its resolution or until it is judged to be permanent, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each patientto report any new adverse event (beyond the 
protocol observation period) that the patient,or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
Progression of signs and symptoms associated with baseline (index) cIAI will be reported as 
efficacy endpoints (detailed in Section 8.5) and not as adverse events. Progression of infection 
other than baseline cIAI (e.g.surgical wound infection) will be reported as AE.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection 
for patients that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:
is fatal or life-threatening
results in persistent or significant disability/incapacity
constitutes a congenital anomaly/birth defect


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requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study and has not worsened since the start of Study Drug
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
is medically significant, e.g. defined as an event that jeopardizes the patientor may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patientwas at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH-E2D Guideline 2004).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patientormight require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to ICH-E2D Guideline 2004).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to the local Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section9.2.2.
Progression of baseline to life threatening infection (e.g.sepsis, septic shock) will be reported 
as SAE.
9.2.2
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the patient has 
provided informed consent until the time the patient is deemed a Screen Failuremust be 
reported to Novartis.
Treated Patients
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last administration of study treatment 
must be reportedto Novartis within 24 hours of learning of its occurrence as described below.


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Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patientcontinued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a CMO& PSDepartment 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
Follow the detailed instructions outlined in the SOMregarding the submission process for 
reporting SAEs to Novartis. Note:SAEs must be reported to Novartis within 24 hours of the 
investigator learning of its occurrence/receiving follow-up information.
9.3
Liver safety monitoring
To ensure patients
' safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2 -Appendix 1.
Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation within48-72 hours.
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeat laboratory test results must be reported as appropriate via an electronic data transfer 
(ifapplicable), or entered on the appropriate unscheduled local laboratory CRF.
If the initial elevation is confirmed, close observation of the patientwill be initiated, 
including consideration of treatment halt if deemed appropriate.


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Discontinuation of the investigational drug (refer to Section 7.2(Discontinuation of study 
treatment), if appropriate
Hospitalization of the patientif appropriate
Causality assessment of the liver event
Thorough follow-up of the liver event should include
Repeating liver chemistry tests two or three times weekly. Testing should include ALT, 
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation into 
direct and indirect bilirubin is required. To rule out muscular origin of transaminase 
elevations, CPK should be measured along with liver chemistry tests. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the Study Drug
has been discontinued and the patientis asymptomatic. Retesting should be continued up 
to resolution.
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.
Exclusion of underlying liver disease, as specified in Table 15-3.
Imaging such as abdominal US, CT or MRI, as appropriate
Obtaining a history of exposure to environmental chemical agents.
Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the SOMfor additional details. 
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details
9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer.
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.


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All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF. Study treatment errors are only to be 
reported to Chief Medical Office and Patient Safety (CMO& PS) department if the treatment 
error is associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety 
(CMO& PS). As such, instances of misuse or abuse are also to be reported using the SAE 
form/CRF. Table 9-1summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose 
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1and Section 9.2, respectively.
9.6
Pregnancy reporting
 
 no guidelines on therapeutic recommendations in case of pregnancy are 
available. This study enrolls women who are considered to beof non-child-bearing potential 
or receiving highly effective methods of contraceptionthus pregnancy is not an expected 
outcome for any female study participant. However, in the case that a pregnancy in a female 
study participant should occur, please follow the below reporting guidelines.
To ensure patientsafety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours
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of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The Study Drugmust be discontinued, though the patientmay stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The patientmay continue all other protocol assessments.


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Pregnancy outcomes should be collected for the female partners ofany males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Suchevaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The monitor will 
visit the site to check the completeness of patientrecords, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and ensure that Study Drugis being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each patientin the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient(asigned copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be 
used for all primary and safety variables. Additional checks of the consistency of the source 
data with the CRFs are performed according to the study-specific monitoring plan. 
Noinformation in source documents about the identity of the patients will be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis.The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
Afterdatabase lock, the investigator will receive copies of the patientdata for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule(Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
CRO working on behalf of Novartisreview the data entered into the CRFs by investigational 
staff for completeness and accuracy and instruct the site personnel to make any required 
corrections or additions. Queries are sent to the investigational site using an electronic data 
query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to the 
data management team who will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all Study Drug(s) dispensed to the patientand all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.


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The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Anychanges to the database after that time can only be made afterwritten agreement by 
Novartis management.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all patientdata at the time the trial ends. Any data analysis
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The following are considered thedefinitions for the statistical analysis populations:
Safety (or modified intent-to-treat, mITT)population: All patients that received at least 
one dose of Study Drug.
Pharmacokinetics (PK) population: All patients in mITT that have at least one available 
valid (i.e. not flagged for exclusion) PK concentration measurement, and experienced no 
protocol deviations with relevant impact on PK data.
Microbiological modified intent-to-treat (micro-mITT) population: All patients in mITT 
who have a baseline bacterial pathogen known to cause cIAI.

Corporate Confidential Information
Clinically evaluable (CE) population: All patients in mITT with cIAI confirmed by 
operative or percutaneous drainage findings, with sufficient information to determine 
clinical outcome at the TOC visit (EOS), and have no other protocol deviation with 
relevant impact on clinical data. Patients who received < 5 days of Study Drugdue to 
clinical failure will NOT be excluded from the clinically evaluable population.


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Microbiologically evaluable (ME) population: All patients in micro-mITT who also have 
at least one clinically relevant pathogen susceptible to the study treatment isolated in the 
initial specimen collected from the intra-abdominal focus of infection.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment arm and patient. 
Summary statistics will be provided by treatment.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment  and patient.
11.3
Treatments
Data forstudy drug administration, rescue medication, and concomitant therapies will be 
listed by treatment  and patient.
11.4
Analysis of the primary variable(s)
The primary aim of this study is to evaluate the LYS228 pharmacokinetic exposures for 
Pharmacokinetic/Pharmacodynamic (PK/PD) target attainment assessment and to evaluate the 
clinical response rateof LYS228in combination with vancomycin and metronidazole in 
patients with complicated intra-abdominal infections (cIAI).
11.4.1
Primary Variable(s)
The primary PK variables are LYS228 plasma concentration and the following PK 
parameters:
AUCtau, Cmax, Tmax, CL, Vss, T1/2, %fT > MIC (=2 ug/mL) in plasma on Day 5.
The primary clinical response variable is clinical success at 28 days after randomization(EOS 
visit). Clinical response isdefined as follows:
Clinical success is defined as resolution,or substantial improvement (i.e. reduction of 
severity of all baseline signs and symptoms and worsening ofnone) of all or most baseline 
signs and symptoms of cIAI infection without the need for additional antibiotic therapy 
other than any oral antibiotics given to complete treatment at home following 
discontinuation of Study Drug and no drainage or surgical reintervention required 96 
hours after the start of Study Drug. Clinical success will be evaluated in the micro-mITT 
and CE populations.
Clinical failure is defined as lack of response to study therapy as documented by 
persistence or worsening of baseline symptoms and/or signs of cIAI infection, such that 
alternative or additional antibiotic therapy or surgical interventions are required. Failure 
also includes the following: death related to the cIAI at any time, persisting or recurrent 
infection within the abdomen documented by findings from percutaneous or operative 
reintervention 96 hours after the start of Study Drug, relapse, and use of additional 
antibiotics for baseline or new cIAI. Patients that require replacement or reinsertion of 
percutaneous draindue to mechanical failure (obstruction of catheters, misplaced 
catheters) will not be considered clinical failures.


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These primary variables will be assessed separately.
11.4.2
Statistical model, hypothesis, and method of analysis
Pharmacokinetics
Noncompartmental PK analysis will be performed ontheLYS228 plasma concentration-time 
profiles and the following PK parameters characterizing the disposition of LYS228 will be 
generated using WinNonlin Phoenix (Version 6.4 or higher, Pharsight, Mountain View, CA):
AUCtau, Cmax, Tmax, CL, Vss, T1/2, %fT>MIC. 
Additional PK parameters may be determined and compartmental PK modeling may be 
performed where appropriate.
LYS228 plasma concentration data will be listed by patient and visit/sampling time-point. 
Descriptive summary statistics will be provided by visit/sampling time-point. 
Descriptivesummary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum and maximum values. Graphical presentation 
will be used to display the trough concentrations versus the study visit days.  Concentrations 
below the lower level of quantification (LLOQ) of the assay will be treated as zero in 
summary statistics. A geometricmean will not be reported if the dataset includes zero values.
PK parameters will be calculated as described above and will be listed by patient, and will be 
summarized by dose and renal category. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum values. An exception to this is Tmax where median, minimum and maximum will 
be presented. 
Additionally, 95% confidence intervals will be computed for log-transformed primary PK 
parameters (AUCtau and Cmax). These intervals will be reported on the original exponential 
scale.
A population PK/PD analysis combining all data from this study and from other studies will 
be performed for target attainment analysis and will be reported separately.
Graphical presentation will be used to explore the relationship between the quartile exposure 
parameters and clinical response. Individual clinical response vs AUCtau, Cmax, 
and %fT>MIC will be explored, respectively.
Pharmacodynamics/clinical response
The proportion of patients who achieved clinical success or failurewill be computed for each 
treatment and provided along with an80% two-sided confidence interval based on the 
Clopper-Pearson method. The 80% confidence interval for the difference in clinical success 
between treatment s will be computed according to the Wilson score method without 
continuity correction.
Clinical success or failure will be evaluated at the end of Study Drugtherapy (EOSD), at the 
end of all antibiotic therapy (EOAT), and at 28 days post-randomization (EOS).
Bayesian methods will be implemented based on the Beta-Binomial model to compare the 
clinical success rate in micro-mITT population at 28 dayspost-randomization. Informative 


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prior on LYS228 and control will be used as follows: Meta-analytic-predictive (MAP) 
informative prior (Spiegelhalter et al 2004, Neuenschwander et al 2010 and 
Schmidlietal2014) for the clinical success rate in micro-mITT population on active control 
was obtained based on the evaluable historical data (FDA guidance, 2015): 
0.67*Beta(172,38)+0.23*Beta(9,3)+0.1*Beta(1, 1), where median=0.81, sd=0.144, 95% 
CI=[0.25, 0.93] and the quantified information is equivalent to an effective sample size of 7.
An80% posterior credible interval of the clinical success rate at EOS visit in the micro-mITT 
population will be provided for each treatment group as well as the treatment difference.
11.4.3
Handling of missing values/censoring/discontinuations
For PK analysis, all concentrations below the limit of quantification or missing data will be 
labeled as such in the concentration data listings. Concentrations below the lower limit of 
quantification (LLOQ) will be treated as zero in summary statistics and for the calculation of 
PK parameters.
Patients with missing or indeterminate outcome data will be classified as clinical failure in the 
micro-mITT population and will be excluded from the CE population.
11.4.4
Sensitivity analyses
Additional sensitivity analyses may be performed in which adjustments are made for factors 
that cannot be controlled at randomization.
Sensitivity analyses to explore the homogeneity of treatment effects across different centers, 
and to reflect the effect of the choice of thecontrol group treatment on the treatment effect of 
LYS228, may be done if the sample sizes are adequate to do so. For the former analysis,a 
fixed effects model with treatment, center and treatment-by-center interaction as fixed effects 
will be used. For the latter analysis, centers using the same standard of care will be pooled in 
one group, and the analysis will be conducted by using a fixed effects model with treatment, 
center group, and treatment-by-center group as fixed effects.
11.5
Analysis of secondary variables
11.5.1
Efficacy / Pharmacodynamics
The proportion of patients who achieved microbiological success will be computed for each 
treatment and provided along with an80% two-sided confidence interval based on the 
Clopper-Pearson method. The 80% confidenceinterval for the difference between treatment s 
will be computed according to the Wilson score method without continuity correction.

Corporate Confidential Information
Microbiological success is defined as documentedmicrobiological eradication of all 
baseline intra-abdominal pathogens following at least 5 days of Study Drug, orpresumed 
microbiological eradication is defined as a clinical success (see above). Microbiological 
success will be evaluated in micro-mITT and ME populations.


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Microbiological failure is defined as i) culture of the intended to treat baseline Gram-
negative pathogen from a specimen obtained from the site of abdominal infection 
following at least 5 days of Study Drug, or ii) presumed microbiological failure if no 
cultures obtained and there isclinical failure.
Microbiological success will be evaluated at the EOSD, at the EOAT, and at 28 days post-
randomization (EOS). 
Subgroup summaries will also be provided by bacterial genetic characterization and in a 
subset of patients with cIAI causedby drug resistance mechanisms including CRE.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, patient, and visit/time and if ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
ECG evaluations
All ECG data will be listed by treatment, patient and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratorydata will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment arm 
and visit/time.
Adverse events
All information obtained on adverse events willbe displayed by treatment arm and patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body system.
11.5.3
Pharmacokinetic -exposure relationships
Graphical presentation may be used to explore the relationship between the quartile exposure 
parametersAUCtau, Cmax, and %fT>MICand clinical response. The analysis results will be 
reported in a separate document.


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11.7
Sample size calculation
The sample size calculation takes into account the likely distribution of renal function and PK
variability in the study population 
In addition, with40 patients on LYS228 vs. 20 patients on active control will produce a two-
sided 80% frequentist CI for the differencein population proportions of (-0.13, 0.15) ifthe 
observedclinical success rates in the micro-mITT population for both treatment groups are 
80%. For the same sample sizes of 40 vs 20, the two-sided 80% posterior credible interval for 
the difference in clinical success rate is (-0.059, 0.062) ifthe observedclinical success rates in 
micro-mITT population for both treatment groups are 80%. 
11.8
Power for analysis of key secondary variables
Corporate Confidential Information
Not applicable.
Corporate Confidential Information
Corporate Confidential Information


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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment 
procedures (e.g. advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial willbe either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
12.4
Quality Control and Quality Assurance
Corporate Confidential Information
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.


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Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring orperforming 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patientincluded in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9(Safety Monitoring) must be followed and the Study Lead 
informed.


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References
References are available upon request.
Agnelli G, Guerciolini R, Grasselli S, et al (1987) Effects of the monobactam antibiotic 
aztreonam on platelet function and blood coagulation. Chemotherapy p. 9-14.
Biedenbach D, Bouchillon S, Hackel M, et al (2015) Dissemination of NDM metallo-β-
lactamase genes among clinical isolates of Enterobacteriaceaecollected during the SMART 
global surveillance study from 2008 to 2012. Antimicrob. Agents Chemother. p. 826-30.
CDC (2013) Antimicrobial resistance threats in the United States, 2013 (Internet). US 
Department of Health and Human Services,Centers for Disease Control and Prevention. 
Available at: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf(Accessed 4
August 2017).
CTCAE (2017) Common Terminology Criteria for Adverse Events v5.0(Internet). Available 
from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 4 June2018)
Golan Y (2015) Empiric therapy for hospital-acquired, Gram-negative complicated intra-
abdominal infection and complicated urinary tract infections: a systematic literature review of 
current and emerging treatment options. BMC Infect. Dis. p. 313.
Henry SA, Bendush CB (1985) Aztreonam: worldwide overview of the treatment of patients 
with gram-negative infections. Am. J. Med. p. 57-64.
Hooton TM, Bradley SF, Cardenas DD, et al (2010) Diagnosis, prevention, and treatment of 
catheter-associated urinary tract infection in adults: 2009 International Clinical Practice 
Guidelines from the Infectious Diseases Society of America. Clin. Infect. Dis. p. 625-63.
Hubschwerlen C (2007)β-Lactam Antibiotics, In Comprehensive Medicinal Chemistry II, 
edited by John B. Taylor and David J. Triggle, Elsevier, Oxford, Pages 479-518.
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002807.pdf  Accessed on: 02Dec2016.
Kazmierczak KM,Rabine S,Hackel M, et al (2016)Multiyear,multinational survey of the 
incidence and global distributionof metallo-β-lactamase producing Enterobacteriaceaeand 
Pseudomonas aeruginosa. Antimicrob. Agents Chemother. p. 1067-78.
Knaus WA, Draper EA, Wagner DP, et al (1985)"APACHE II: a severity of disease 
classification system". Critical Care Medicine13 (10): 818–29.
Lagacé-Wiens P, Rubinstein E (2012) Adverse reactions to β-lactam antimicrobials. Expert 
Opin Drug Saf p. 381-99.
LeFrock JL, Smith BR, Chandrasekar P, et al (1987) Efficacyand Safety of Aztreonam in the 
Treatment of Serious Gram-Negative Bacterial Infections. Arch Intern Med; 147:325-328.


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Maki DG, Ringer M (1991) Risk factors for infusion-related phlebitis with small peripheral 
venous catheters. A randomized controlled trial. Ann. Intern. Med. p. 845-54.
Navarro-San Francisco C, Mora-Rillo M,Romero-Gómez MP, et al (2013) Bacteraemia due 
to OXA-48-carbapenemase-producing Enterobacteriaceae: a major clinical challenge. Clin. 
Microbiol. Infect. p. E72-9.
Newman TJ, Dreslinski GR, Tadros SS (1985) Safety profile of aztreonam in clinical trials. 
Rev. Infect. Dis. p. S648-55.
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials p. 5-18.
Pogue JM, Lee J, Marchaim D, et al (2011) Incidence of and risk factors for colistin-
associated nephrotoxicity in a large academic health system. Clin. Infect. Dis. p. 879-84.
Rahman M, Shukla SK, Prasad KN, et al (2014) Prevalence and molecular characterisation of 
New Delhi metallo-β-lactamases NDM-1, NDM-5, NDM-6 and NDM-7 in multidrug-
resistant Enterobacteriaceaefrom India. Int. J. Antimicrob. Agents p. 30-7.
Ray-Barruel G, Polit DF, Murfield JE, et al (2014) Infusion phlebitis assessment measures: a 
systematic review. J Eval Clin Pract p. 191-202.
Romano A, Gaeta F, Arribas Poves MF, et al (2016) Cross-Reactivity among Beta-Lactams. 
Curr Allergy Asthma Rep p. 24.
Schmidli H, Gsteiger S, Roychoudhury S, et al (2014) Robust meta-analytic-predictive priors 
in clinical trials with historical control information. Biometrics p. 1023-32.
Singer M,DeutschmanCS, SeymourCW, et al (2016)The Third International Consensus 
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA315(8):801-10.
Solomkin JS, Mazuski JE, Bradley JS, et al (2010) Diagnosis and management of complicated 
intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society 
and the Infectious Diseases Society of America. Clin. Infect. Dis. p. 133-64.
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical trialsand 
Health-Care Evaluation.
Sutter R, Rüegg S, Tschudin-Sutter S (2015) Seizures as adverse events of antibiotic drugs: A 
systematic review. Neurology85:1332–41.
Tartaglione TA, Duma RJ, Qureshi GD (1986) In vitroand in vivostudies of the effect of 
aztreonam on platelet function and coagulation in normal volunteers. Antimicrob. Agents 
Chemother. p. 73-7.
Tunkel AR, Scheld WM (1990) Aztreonam. Infect Control Hosp Epidemiol p. 486-94.
WHO (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, 
and development of new antibiotics(Internet). World Health Organization. Available at: 
http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-
ET_NM_WHO.pdf?ua=1 (Accessed 4August 2017).


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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase 
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required forLiver Events
Criteria
Actions required
Potential Hy’s Law case
Discontinue the study treatment immediately
Hospitalize, if clinically appropriate
Establish causality
Complete CRFs per liver event guidance*
ALT or AST elevation with coagulopathy
ALT orAST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN
If confirmed, consider interruption or discontinuation 
of Study Drug
If elevation persists for more than 2 weeks, 
discontinue the Study Drug
Establish causality
Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 
× ULN (patient is asymptomatic)
Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation
Repeat liver chemistry tests within 48-72 hours
If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality
Complete CRFs per liver event guidance*
Any AE potentially indicative of liver 
toxicity
Consider study treatment interruption or 
discontinuation
Hospitalize if clinically appropriate
Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual


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Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV RNA, 
IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV 
infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy
Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency
Alpha-1-antitrypsin


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Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase 25 –49% 
compared to baseline
Consider causes and possible interventions
Follow up within 2-5 days
Serum creatinine increase > 50%
Consider causes and possible interventions
Repeat assessment within 24-48h if possible
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 
3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol
Consider causes and possible interventions
Assess serum albumin & serum protein
Repeat assessment to confirm
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset glucosuria on urine dipstick (unless 
related to concomitant treatment, diabetes)
Assess & document:
Blood glucose (fasting)
Serum creatinine
Urinealbumin-creatinine ratio
New hematuria on dipstick
Assess & document:
Urine sediment microscopy
Assess sCr and urine albumin-creatinine ratio
Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation
Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation byNovartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Protocol No. CLYS228X2202
Whenever a renal event is identified, a detailed patienthistory and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:
Blood pressure assessment (after 5 min rest, with an appropriate cuff size)
Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data load. 
Review and record possible contributing factors 
to the renal event (co-medications, other co-
morbid conditions) and additional diagnostic 
procedures (MRI etc) in the CRF.
Urine dipstick and sediment microscopy
Blood pressure and body weight
Serum creatinine, electrolytes (sodium, 
potassium, phosphate, calcium), bicarbonate 
and uric acid
Urine output
Monitor patientregularly (frequency at 
investigator’s discretion) until:
Event resolution: (sCr within 10% of baselineor 
protein-creatinine ratio within 50% of baseline)
or
Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level with 
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause
rather than tubular toxicity.


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Protocol No. CLYS228X2202
Corporate Confidential Information

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LYS228
CLYS228X2202
A randomized, controlled, evaluator-blinded, multi-center 
study to evaluate LYS228 pharmacokinetics, clinical 
response, safety, and tolerability in patients with 
complicated intra-abdominal infection
Statistical Analysis Plan (SAP)
Document type: 
SAP Documentation –NIBR
Document status:
Final
Release date:
22-Jan-2018
Number of pages:
19
Corporate Confidential Information
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Corporate Confidential Information


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Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................4
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study objectives.......................................................................................................6
1.3.1
Primary objectives...................................................................................6
1.3.2
Secondary objectives...............................................................................6
1.4
Study design and treatment......................................................................................6
2 First interpretable results (FIR)...........................................................................................8
4 Statistical methods: Analysis sets........................................................................................8
5 Statistical methods for Pharmacokinetic (PK) parameters................................................11
5.1
Primary objective...................................................................................................11
5.2
Variables................................................................................................................11
5.3
Descriptive analyses..............................................................................................12
5.3.1
Handling of missing values/censoring/discontinuations.......................12
5.4
Graphical presentation...........................................................................................12
6 Statistical methods for Pharmacodynamic (PD) parameters/clinical response.................12
6.1
Primary objective...................................................................................................12
6.1.1
Variables...............................................................................................13
6.1.2
Descriptive analyses..............................................................................13
6.1.3
Statistical model, assumptions and hypotheses.....................................13
6.2
Secondary objectives.............................................................................................16
6.2.1
Variables...............................................................................................16
6.2.2
Descriptive analyses..............................................................................16
6.2.3
Statistical model, assumptions and hypotheses.....................................17
6.2.4
Pharmacokinetic / pharmacodynamics/clinical response 
interactions............................................................................................17
7 Statistical methods for safety and tolerability data............................................................17
7.1
Variables................................................................................................................17
7.2
Descriptive analyses..............................................................................................17
73
Graphical presentation
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19
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9 Reference list.....................................................................................................................19
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................9


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1
Introduction 
1.1
Scopeof document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLYS228X2202”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v01dated 02-Nov-2017.


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1.3
Study objectives
1.3.1
Primary objectives
Primary objectives
Endpoints related to primary objectives
To evaluate the plasma pharmacokinetics of 
LYS228 in patients with complicated 
intra-abdominal infection (cIAI)
Plasma PK on Day 5
To evaluate the clinical response to LYS228 in 
combination with vancomycin and 
metronidazole compared to standard of care 
antibiotics for treating patients with cIAI
Clinical success at 28 days after 
randomization (End of Study) determined by 
signs, symptoms, and the need for additional 
antibiotics, unplanned surgical procedures, 
or drainage
1.3.2
Secondary objectives
Secondary objectives
Endpoints related to secondary objectives
To evaluate the safety and tolerability of 
LYS228 in combination with vancomycin and 
metronidazole in patients with cIAI
Adverse events
Clinical laboratory tests
Vital signs
To evaluate the microbiological response to 
LYS228 in combination with vancomycin and 
metronidazole compared to standard of care 
antibiotics for treating patients with cIAI
Microbiologic success at 28 days after 
randomization (End of Study) determined by 
culture from the intra-abdominal focus of 
infection when available or presumed 
eradication based on clinical success
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1.4
Study design and treatment


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This is a randomized, comparator-controlled, evaluator-blinded, non-confirmatory study to 
evaluate the pharmacokinetics, clinical response, safety and tolerability of intravenous 
LYS228 in patients with complicated intra-abdominal infection (cIAI). The study will enrol 
approximately 60 patients with cIAI who have not yet been treated for their current infection 
and will be randomized to receive LYS228 in combination with vancomycin and 
metronidazole or standard of care antibiotic therapy for cIAI for no less than 5 days and up to 
14 days. The study treatment will be administered in an open-label basis. There will be no 
placebo-treated patients. A blinded evaluator at each site will perform safety and clinical 
response assessments.
The study consists of a Screening and Baseline Period (D-1 to D1), a Treatment Period of 
variable duration (D1 to D5, and possibly up to D15), a Follow-up period of at least 14 days 
and an EOS visit on Day 28. A patients’ flowchart is provided in Section 17of the protocol.
Patients will be randomized to one of the following two treatment arms in a ratio of 2:1.
Arm 1: LYS228 in combination with vancomycin and metronidazole (n=40). LYS228 
dose for each patient will be based on the renal function as described in Section 3.3 of the 
protocol.
Arm 2: Standard of care intravenous antibiotic therapy for the treatment of cIAI (n=20)
Adjustment of the non-LYS228 Study Drug components of treatment arms may be permitted 
based on microbiologic data as detailed in the SOM.
Change of treatment from Study Drug to alternative antibiotics is permissible in the following 
circumstances:
1. Change to oral antibiotics after completing 5 days of intravenous Study Drug if a 
patient is clinically improved and discharged, or
2. Patient requires additional therapy or change to rescue therapy in the case of clinical 
failure, or adverse event that merits discontinuation of Study Drug as detailed in 
Section 7.2 of the protocol.
Alternative antibiotics must be effective against the relevant clinical isolates. The total 
antibiotic treatment duration, including Study Drug and any alternative antibiotic, will be no 
less than 5 days and up to 14 days, unless discussed with sponsor.
During the treatment period all patients will complete a minimum of 5 visits (V101 –V105) 
and up to 15 visits (V101-V116), depending on the duration ofhospitalization. All patients 


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that change treatment to an alternative antibiotic must have an EOSD visit prior to antibiotic 
change.
The follow-up period spans the period after completion of antibiotic treatment (EOAT visit) 
up to 28 days after randomization, at which time all patients will have an EOS visit. This visit 
is considered the Test of Cure (TOC) visit for evaluation of clinical response. A post-study 
safety phone call will be conducted 30 days after the last administration of study treatment.
2
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for this trial.
4
Statistical methods: Analysis sets
For patientsfor which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
The following are considered the definitions for the statistical analysis populations:
Safety (or modified intent-to-treat, mITT) population: All patients that received at least one 
dose of Study Drug, and experienced no protocol deviations with relevant impact on 
clinical data.
Pharmacokinetics (PK) population: All patients in mITTthat have at least one available 
valid (i.e. not flagged for exclusion) PK concentration measurement, and experienced no 
protocol deviations with relevant impact on PK data.
Microbiological modified intent-to-treat (micro-mITT) population: All patients inmITT 
who have a baseline bacterial pathogen known to cause cIAI.

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Clinically evaluable (CE) population: All patients in mITT with cIAI confirmed by 
operative or percutaneous drainage findings, with sufficient information to determine 
clinical outcome at the TOC visit (EOS)(i.e. data relating to the same signs and symptoms 


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recorded at both screening/baseline and  the TOC visit), and have no other protocol 
deviation with relevant impact on clinical data. Patients who received < 5 days of Study 
Drug due to clinical failure will NOT be excluded from the clinically evaluable population.
Microbiologically evaluable (ME) population: All patients in micro-mITT who also have at 
least one clinically relevant pathogen (Enterobacteriaeceae) suspected to be susceptible to 
the study treatment isolated in the initial specimen collected from the intra-abdominal 
focus of infection, and experienced no protocol deviations with relevant impact on clinical 
data.
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Patients are excluded from all (safety, mITT)analysis in case of 
these PDs:
Exclude patientcompletely 
from all (safety, mITT)
poulations
None
Patientsare excluded from PK analysis in case of these PDs:
Exclude patientfrom PK 
population
TRT01
Study treatment deviations
Yes
Patients are excluded from micro-mITT analysis in case of these 
PDs:
Exclude patient from 
micro-mITT population
None
Patients are excluded from CE analysis in case of these PDs:
Exclude patient from CE 
population
INCL03
Deviation from inclusion criterion 3 (Expectation 
that, in the judgment of the Investigator, the 
patient will survive with effective antibiotic 
therapy and appropriate supportive care for the 
anticipated duration of the study.)
Yes
EXCL02
Deviation from exclusion criterion 2 (Any 
excluded diagnoses)
Yes
EXCL03
Deviation from exclusion criterion 3 (Received 
more than 24 hours of total prior antibiotic 
therapy (based on dosing interval) in the 72 
hours prior to the planned dosing of Study 
Drug)
Yes
EXCL04
Deviation from exclusion criterion 4 (Received 
long-acting antibiotic (≥24 hours dosing interval) 
intra-or post-operatively.)
Yes
EXCL05
Deviation from exclusion criterion 5 (Received 
any non-study antibiotic more than 6 hours 
post-procedure.)
Yes


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Category
Deviation code
Text description of deviation
Data exclusion
EXCL06
Deviation from exclusion criterion 6 
(Concomitant bacterial infection at time of 
enrollment requiring non-Study Drug antibiotics 
and that may interfere with the evaluation of 
clinical response to the study antibiotic.)
Yes
EXCL07
Deviation from exclusion criterion 7 (Known 
non-abdominal source of infection, including 
endocarditis, osteomyelitis, abscess, 
meningitis, or pneumonia diagnosed within 7 
days prior to enrollment.)
Yes
EXCL08
Deviation from exclusion criterion 8 (Patient has 
APACHE II score > 30 or is considered, in the 
judgment of the investigator, unlikely to survive 
4 weeks.)
Yes
EXCL09
Deviation from exclusion criterion 9 (Patients 
that meet sepsis criteria as defined by the quick 
sequential sepsis-related organ failure 
assessment (qSOFA).)
Yes
WITH01
Withdrawal criteria met but subject not 
discontinued
Yes
COMD01
Use of prohibited medication during the study
Yes
TRT02
Patients who received <80% of study drug 
doses (includes comparator SOC as well as 
LYS228 +vancomycin + metronidazole)
Yes
TRT03
Patients who missed two consecutive doses
Yes
Patients are excluded from ME analysis in case of these PDs:
Exclude patient from ME 
population
INCL03
Deviation from inclusion criterion 3 (Expectation 
that, in the judgment of the Investigator, the 
patient will survive with effective antibiotic 
therapy and appropriate supportive care for the
anticipated duration of the study.)
Yes
EXCL02
Deviation from exclusion criterion 2 (Any 
excluded diagnoses)
Yes
EXCL03
Deviation from exclusion criterion 3 (Received 
more than 24 hours of total prior antibiotic 
therapy (based on dosing interval) in the72 
hours prior to the planned dosing of Study 
Drug)
Yes
EXCL04
Deviation from exclusion criterion 4 (Received 
long-acting antibiotic (≥24 hours dosing interval) 
intra-or post-operatively.)
Yes
EXCL05
Deviation from exclusion criterion 5 (Received 
any non-study antibiotic more than 6 hours 
post-procedure.)
Yes


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Category
Deviation code
Text description of deviation
Data exclusion
EXCL06
Deviation from exclusion criterion 6 
(Concomitant bacterial infection at time of 
enrollment requiring non-Study Drug antibiotics 
and that may interfere with the evaluation of 
clinical response to the study antibiotic.)
Yes
EXCL07
Deviation from exclusion criterion 7 (Known 
non-abdominal source of infection, including 
endocarditis, osteomyelitis, abscess, 
meningitis, or pneumonia diagnosed within 7 
days prior to enrollment.)
Yes
EXCL08
Deviation from exclusion criterion 8 (Patient has 
APACHE II score > 30 or is considered, in the 
judgment of the investigator, unlikely to survive 
4 weeks.)
Yes
EXCL09
Deviation from exclusion criterion 9 (Patients 
that meet sepsis criteria as defined by the quick 
sequential sepsis-related organ failure 
assessment (qSOFA).)
Yes
WITH01
Withdrawal criteria met but subject not 
discontinued
Yes
COMD01
Use of prohibited medication during the study
Yes
If updates to this table are needed,anamendment tothe SAP needs tobe implemented priorto
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Primary objective
To evaluate the plasma pharmacokinetics of LYS228 in patients with complicated 
intra-abdominal infection (cIAI).
5.2
Variables
The primary PK variables are LYS228 plasma concentration and the following PK 
parameters:
AUCtau, Cmax, Tmax, CL, Vss, T1/2, %fT>MIC in plasma on Day 5.
Noncompartmental PK analysis will be performed on the LYS228 plasma concentration-time 
profiles and the PK parameters listed above characterizing the disposition of LYS228 will be 
generated using WinNonlin Phoenix (Version 6.4 or higher, Pharsight, Mountain View, CA). 
Additional PK parameters may be determined and compartmental PK modeling may be 
performed where appropriate.


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5.3
Descriptive analyses
LYS228 plasma concentration data will be listed by patient and visit/sampling time-point. 
Descriptive summary statistics will be provided by visit/sampling time-point. Descriptive 
summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum values.
PK parameters will be calculated as described above and will be listed by patient, and will be 
summarized by dose and renal category. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum values. An exception to this is Tmax where median, minimum and maximum will 
be presented.
Additionally, 95% confidence intervals will be computed forlog-transformed primary PK 
parameters (AUCtau and Cmax). These intervals will be reported on the original exponential 
scale.
A population PK/PD analysis combining all data from this study and from other studies will 
be performed for target attainment analysis and will be reported separately.
5.3.1
Handling of missing values/censoring/discontinuations
All concentrations below the limit of quantification or missing data will be labeledas such in 
the concentration data listings. All drug concentrations below the lower limit of quantification 
(LLOQ) will be treated as zero in summary statistics and for the calculation of PK parameters.
A geometric mean will not be reported if the datasetincludes zero values.
5.4
Graphical presentation
Arithmetic mean (SD) plasma concentration data will be plotted across time, with separate 
line types for dose.
Graphical presentation will be used to display the trough concentrations versus the study visit 
days.
Overlaying individual plasma concentration-time profiles will be generated.
Individual plasma concentration-time profiles will be generated.
Graphical presentation will be used to explore the relationship between the quartile exposure 
parameters and clinical response. Individual clinical response vs AUCtau, Cmax, 
and %fT>MIC will be explored, respectively.
6
Statistical methods for Pharmacodynamic (PD) 
parameters/clinical response
6.1
Primary objective
To evaluate the clinical response to LYS228 in combinationwith vancomycin and 
metronidazole compared to standard of care antibiotics for treating patients with cIAI.


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6.1.1
Variables
The primary clinical response variable is clinical success at 28 days after randomization. 
Clinical success and clinical failure are defined as follows:
Clinical successis defined as resolution, or substantial improvement (i.e. reduction of 
severity of all baseline signs and symptoms and worsening of none) of all or most(i.e. 
>50%)baseline signs and symptoms of cIAI infection without the need for additional 
antibiotic therapy other than any oral antibiotics given to complete treatment at home 
following discontinuation of Study Drug and no drainage or surgical reintervention 
required 96 hours after the start of Study Drug. 
Clinical failureis defined as lack of response to study therapy as documented by 
persistence or worsening of baseline symptoms and/or signs of cIAI infection, such that 
alternative or additional antibiotic therapy or surgical interventions are required  
 
These primary variables will be assessed separatelyin the micro-mITT, CE and ME 
populations.
Each sign will be assessed as “new”, “improved”, “unchanged” or “worsened”.
Each symptom will be assigned a CTCAE grade. If the CTCAE grade increases, the symptom 
is worsening. If the CTCAE grade decreases, the symptom is improving.Clinical success or 
failure will be evaluated at the end of Study Drug therapy (EOSD), at the end of all antibiotic 
therapy (EOAT), and at 28 days post-randomization (EOS).
6.1.2
Descriptive analyses
The primary clinical response variables will be summarized with descriptive statistics by 
treatment arm.
6.1.3
Statistical model, assumptions and hypotheses
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Clinical success or failure will be evaluated at the end of Study Drug therapy (EOSD), at the 
end of all antibiotic therapy (EOAT), and at 28 days post-randomization (EOS).
The proportion of patients who achieved clinical success or failure will be computed for each 
treatment arm and provided along with an 80% two-sided confidence interval based on the 
Clopper-Pearson method. The 80% confidence interval for the difference in clinical success 
between treatment arms will be computed according to the Wilson score method without 
continuity correction.


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Bayesian methods will be implemented based on the Beta-Binomial model to compare the 
clinical success rate in micro-mITT population at 28 days post-randomization. Informative 
prior on LYS228 and control will be used as follows: Meta-analytic-predictive (MAP) 
informative prior (Spiegelhalter et al 2004, Neuenschwander et al 2010 and Schmidli et al 
2014) for the clinical success rate in micro-mITT population on active control was obtained 
based 
on 
the 
evaluable 
historical 
data 
(FDA 
guidance, 
2015): 
0.67*Beta(172,38)+0.23*Beta(9,3)+0.1*Beta(1,1), 
where 
median=0.81,
sd=0.144, 
95%CI=[0.25, 0.93] and the quantified information is equivalent to an effective sample size 
of 7.


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Denote by p
Tand pC the event probabilities for the LYS228 treatment arm and the active 
control arm, respectively.
For pT:
Prior: pT~ [0.67 x Beta(172, 38)] + [0.23 x Beta(9, 3)] + [0.1 x Beta(1, 1)]
Observed: yTevents in n
Tpatients (binomial distribution with event probability p
T)
Posterior: pT| yT~ [w1x Beta(172 + yT, 38 + n
T–yT)]
                                + [w2x Beta(9 + yT, 3 + n
T–yT)]
                                + [w3x Beta(1 + yT, 1 + n
T–yT)]
where
= 
0.67
0.67 + 0.23 + 0.1
= 
0.23
0.67 + 0.23 + 0.1
= 
0.1
0.67 + 0.23 + 0.1
and
= (172+38)
(172)(38)
(172+
)(38+
−
)
(172+38+
)
= (9+3)
(9)(3)
(9+
)(3+
−
)
(9+3+
)
= (1+1)
(1)(1)
(1+
)(1+
−
)
(1+1+
)
For pC:
Prior: pC~ [0.67 x Beta(172, 38)] + [0.23 x Beta(9, 3)] + [0.1 x Beta(1, 1)]
Observed: yCevents in n
Cpatients (binomial distribution with event probability p
C)
Posterior: pC| yC~ [w1x Beta(172 + yC, 38 + n
C-y
C)]
                                + [w2x Beta(9 + yC, 3 + n
C-y
C)]
                                + [w3x Beta(1 + yC, 1 + n
C-y
C)]
where
= 
0.67
0.67 + 0.23 + 0.1
= 
0.23
0.67 + 0.23 + 0.1
= 
0.1
0.67 + 0.23 + 0.1
and
= (172+38)
(172)(38)
(172+
)(38+
−
)
(172+38+
)


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=
(9+3)
(9)(3)
(9+
)(3+
−
)
(9+3+
)
=
(1+1)
(1)(1)
(1+
)(1+
−
)
(1+1+
)
An 80% posterior credible interval of the clinical success rate at TOC visit in the micro-mITT 
population will be provided for each treatment armas well as the treatment difference.
6.1.3.1 Graphical presentation of results
All posterior distributions will be summarized graphically.
6.1.3.2 Sensitivity analyses
Additional sensitivity analyses may be performed in which adjustments are made for factors
that cannotbe controlled at randomization, such as delays in surgical intervention, presence of 
bacterial resistance at baseline, age, total duration of therapy.Any sensitivity analyseswill be 
conducted by Novartis.
6.2
Secondary objectives
To evaluate the microbiological response to LYS228 in combination with vancomycin and 
metronidazole compared to standard of care antibiotics for treating patients with cIAI.
6.2.1
Variables
The secondary clinical response variable is microbiological outcome. Microbiological success 
and microbiological failure are defined as follows:
Microbiological success is defined as documented microbiological eradication of all
baseline intra-abdominal pathogens following at least 5 days of Study Drug, or presumed
microbiological eradication is definedas a clinical success (see section 6.1.1 above). 
Microbiological failure is defined as i) culture of the intended to treat baseline Gram
negative(Enterobacteriaceae) pathogen from a specimen obtained from the site of 
abdominal infectionfollowing at least 5 days of Study Drug, or ii) presumed 
microbiological failure if nocultures obtained and there is clinical failure.
Microbiological outcomewill be consideredindeterminatewhen no post-baseline specimen 
culture results are obtained for patients with indeterminate clinical response.
Microbiological outcomewill be evaluated at the EOSD, at the EOAT, and at 28 days 
postrandomization(EOS)in the micro-mITTand ME populations.
6.2.2
Descriptive analyses
The secondary clinical response variables will be summarized with descriptive statistics by 
treatment arm.
Subgroup summaries will also be provided by bacterial genetic characterizationincluding 
beta-lactamase identification (i.e ESBLs, KPCs, MBLs)and in asubset of patients with cIAI 
caused by drug resistance mechanisms including CRE.


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The distribution of bacterial isolates and bacterial response by treatment arm will be provided.
6.2.3
Statistical model, assumptions and hypotheses
Microbiological success will be evaluated at the EOSD, at the EOAT, andat 28 days post
randomization(EOS).
The proportion of patients who achieved microbiological success will be computed for each 
treatment arm and provided along with an 80% two-sided confidence interval based on the 
Clopper-Pearson method. The 80% confidence interval for the difference between treatment 
arms will be computed according to the Wilson score method without continuity correction.
6.2.4
Pharmacokinetic / pharmacodynamics/clinical response interactions
Graphical presentation will be used toexplore the relationship between the quartile exposure 
parameters and clinical response. Individual clinical response vs AUCtau, Cmax, 
and %fT>MIC will be explored, respectively.
The analysis results will be reported in a separate document.
7
Statistical methods for safety and tolerability data
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as patientdemographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background (underlying inclusion diagnosis, type of surgical intervention) and 
demographic variables will be listed by treatment arm and patient. Summary statisticswill be 
provided bytreatment arm.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed bytreatment arm and patient.
Treatment
Data for Study Drug administration,rescue medication, alternative antibiotics and 
concomitant therapies will be listed by treatment arm and patient.
Vital signs
All vital signs data will be listed by treatmentarm, patient, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment arm and visit/time.


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ECG evaluations
All ECG data will be listed by treatmentarm, patientand visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment arm and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatmentarm, patient, and visit/time and if normal ranges 
are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a patientwith any abnormal values. Summary statistics will be provided by 
treatment arm and visit/time.
The number of patients with treatment-emergent CTCAE grade 2 or higher in clinical 
laboratory evaluations will be summarized by CTCAE grade and treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment arm and patient.
The number and percentage of patientswith adverse events will be tabulated by body system 
and preferred term with a breakdown by treatmentarmand also by body sytem, preferred 
term and maximum severity with a breakdown by treatment arm. A patientwith multiple 
adverse events within a body system is only counted once towards the total of this body 
systemand treatmentarm.Tabulations will also be provided for special interest adverse 
events (e.g. hypersensitivity reaction, hepatotoxicity, nephrotoxicity, local infusion reactions, 
gastrointestinal 
discomfort, 
Clostridium 
difficile-associated 
diarrhea, 
seizure, 
thrombocytopenia).
Summaries will be provided for all treatment adverse events and also for treatment adverse 
events suspected to be related to study drug.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and on treatment emergent serious adverse events and SAE suspected to be 
related to study treatment will beprovided by system organ class and preferred term on the 
safety set (mITT) population.These tables will be produced by Novartis.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurredwith the same SOC and PT:
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE
's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT. 


Novartis
For business use only
Page 19
SAP
CLYS228X2202
7.3
Graphical presentation
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
Fever curves will be created as overlaying individual profiles of the highest temperature 
entered in the clinical evaluation page.
9
Reference list
Corporate Confidential Information
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials p. 5-18.
Schmidli H, Gsteiger S, Roychoudhury S, et al (2014) Robust meta-analytic-predictive priors 
in clinical trials with historical control information. Biometrics p. 1023-32.
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical trials and 
Health-Care Evaluation.