Clinical trial NCT02655419
Conditions: Complicated Intra-Abdominal Infections, cIAIs
Keywords: cIAIs in hospitalized adults
Sponsor: Pfizer
Start date: 2016-05-19; Completion date: 2017-10-26
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Determine the PK and safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of hospitalized adults with cIAI

Detailed description:
A Phase IIa prospective, open-label, multicenter study to determine the pharmacokinetics (PK) and safety and tolerability of aztreonam-avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults.

Arms: arm 1: Aztreonam-avibactam + metronidazole
Interventions: intervention 1: ATM-AVI intervention 2: Metronidazole
Intervention descriptions: intervention 1: Cohort 1:

(Creatinine clearance \> 50 mL/min)6500mg ATM/1777mg AVI on day 1 followed by total daily dose of 6000mg ATM/1640mg AVI

Cohorts 2 and 3:

(Creatinine clearance \> 50 mL/min) As above, or: 6500 mg ATM/2167 mg on Day 1 followed by a total daily dose of 6000 mg ATM/2000 m AVI

(Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1162 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/820 mg AVI, or:

4250 mg ATM/1417 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/1000 mg AVI intervention 2: Metronidazole 500mg infused over 1 hour every 8 hours

Protocol documents:
Prot_000.pdf: 
Revised Clinical Study Protocol 
Drug Substance
ATM-AVI
Pfizer Study Code
C3601001
AstraZeneca Study Code
D4910C00009
Edition Number
Final 3.0
Date
29March 2017
A Phase IIaprospective, open-label, multicenter study to determine the 
pharmacokinetics (PK) and safety and tolerability of aztreonam-
avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal 
Infections (cIAIs) in hospitalized adults
Sponsor:Pfizer Inc., 235 East 42ndStreet, New York, NY 10017, USA (as of Amendment 3) 
Prior Sponsor:AstraZeneca AB, 151 85 Södertälje, Sweden
Clinical Trials Centre Cologne (CTCC)
Medical Faculty,
University of Cologne
 MD
CTCC study representative
 Germany
Phone: 
Date 
The following Amendment(s) and Administrative Changes are included in this revised protocol:
Amendment No.
Date of Amendment
Local Amendment 
No:
Date of Local Amendment
1
31 March 2016
2
05August2016
3
29March 2017
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to the sponsorand opportunity to object.
PPD
The clinical study protocol is publicly registered and the results are disclosed and/or published 
in compliance with the sponsorand COMBACTE-CARE publication policies and in 
PPD
PPD
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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compliance with prevailing laws and regulations.COMBACTE-CARE is a consortium of 19
academic and 3 pharmaceutical partners focussing on carbapenem resistance in Europe.
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Revised Clinical Study Protocol
Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
4(99)
Study design
This is a prospective, open-label, single-arm, dose-confirming multicenter study to determine 
the pharmacokinetics (PK), safety and tolerability of aztreonam-avibactam (ATM-AVI) in the 
treatment of hospitalized patientswith a complicated intra-abdominal infection (cIAI). Forty 
adult patients with a diagnosis of cIAIand the need for a surgical intervention will be 
enrolled. The surgical intervention may take place within 24 hours before or after
administration of the first dose of study drug. After obtaining written informed consent and 
confirming eligibility, patients will be assigned the following treatment:
From the study start, onlypatients with normal renal function or mild renal impairment (i.e. 
creatinine clearance >50 mL/min)will be eligible(Cohort 1). The proposed administration of 
ATM-AVI for these patients is a loading dose (500 mg ATM plus 137 mg AVI by intravenous 
infusion over a 30 minute period), immediately followed by a maintenance infusionof 1500 
mg ATM plus 410 mg AVI over a 3 hour period (to be administered every 6hours). The 
targeted total dose on Day 1 will be 6500 mg ATM and 1777 mg AVI. FromDay 2onwards,
this will be 6000 mg ATM / 1640 mg AVI. For anaerobic coverage, patients will also receive 
500 mg metronidazole infused over 1 hour every 8 hours (q8h), starting after the first ATM-
AVI maintenance infusion.
The PK, safety and tolerability of the dosing regimen described above will be assessed in 
Cohort 1. Recruitment into this initial cohort of patients will continue until 10 patients with 
creatinine clearance(CrCl)>50mL/minhave completed all scheduled safety and PK 
assessments. Upon completion, an early patient review regarding safety and PK data will be 
made.Patient safety laboratory data will be monitored on ongoing basis and a summary output 
will be available for the 10 patients. There will be a pause in enrolment to complete the 
ongoing safety reviewand provide confirmation thatthe study can proceed beyond Cohort1, 
based on the available safety data. Patients with moderate renal impairment (creatinine 
clearanceof 31 to50 mL/min)must not be included prior to the completion of the 10 patient 
earlysafety and PK review and subsequent confirmation of an appropriate dosing regimen.
Following review of safety and PK data from Cohort 1, the Scientific Advisory Committee 
(SAC) will make recommendations to either;
Discontinue the study
Initiate Cohort 2-continue dosingwith no dose change(compared toCohort 1)or 
escalate to ahigher AVI dose. 
o The SAC will also have an opportunity to recommendrecruitment of patients 
with moderate renal impairment, and select an appropriate dose regimen, 
taking into account the dose to be used in Cohort 2.
In the event that a higher AVI dosewill be administered in Cohort 2, all patients with normal 
renal function or mild renal impairment (CrCl > 50 mL/min) will receive a loading dose (500 
mg ATM plus 167mg AVI by intravenous [IV] infusion over a 30 minute period), 
immediately followed by a dose of 1500 mg ATM plus 500mg AVI by IV infusion over a 3 
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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hour period every 6hours (maintenance infusion). Patients will also receive 500 mg 
metronidazole infused over 1 hour every 8 hours (q8h), starting after the first ATM-AVI 
maintenance infusion.
In the eventa higher AVI dose will be administeredin Cohort 2, asecond safety and PK 
review will occur once at least10 patients in Cohort 2 have completed all safety and PK 
assessments.There will be anotherpause in enrolment at this time to complete the second 
safety and PK review and provide confirmation that the study can proceed, based on the 
available safety data.The SAC will make recommendations for the continuation of thestudy, 
i.e., to continue treating patients in Cohort 3 at the higher AVI dose, or to de-escalate the AVI 
dose in Cohort 3 according to the dose regimen used for Cohort 1.
For all cohorts,intravenous study therapy (ATM-AVI plus metronidazole)will be continued 
for a period of time (5 to 14 full days, where a full day is defined as a 24-hour period) deemed 
appropriate by the investigator based on the patient’s clinical response. After at least 5 full 
days of IV study therapy and at the discretion of the investigator, all study therapies may be 
discontinued if the patient has shown significant clinical improvement. 
All patients will undergo sparse pharmacokinetic sampling on Day 1 of treatment. On Day 4
(± 1 day if required), the first twenty five (25) patients will undergo intensive pharmacokinetic 
sampling, whereas the following fifteen (15) patients will undergo sparse sampling.
Study periods are defined in the following table.
Study periods
Eligibility/Screening 
Visit 1 (Eligibility/Screening)
Day 0
Treatment perioda
Visit 2 (baseline assessments and 
Day 1 of study therapy)
Day 1
Visits 3 to 15 (Days 2 to 14)
Ongoing study therapy
Visit 16 (End of Treatment with 
study therapy)
Within 24 hours after the completion of the last infusion 
of the intravenous study therapy
Follow-up period 
Visit 17 (Test of Cure)
Day 25 visit (allowed visit window: Day 22 -28)
Visit 18 (Late Follow-up)
Day 35 visit (allowed visit window: Day 32 -38)
a: Treatment period is defined as a minimum of 5 full days toa maximum of 14 full days, where a full day is 
defined as a 24-hour period. Treatment period starts with administration of the first dose of intravenousstudy 
therapy which marks the beginning of Study Day 1. Visit 2 includes the baseline assessments and Day 1.
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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Objectives
Primary Objectives:
Outcome Measure:
To determine the pharmacokinetics (PK) of 
ATM-AVI in this patient population
Concentrations of ATM and AVI in plasma; 
concentration-time profile of ATM and AVI
The derived PK parameters Cmax, t
max, AUC(0-6), 
AUC(0-last), t
last, t
1/2, V
ss, V
zand CL for the patients 
undergoing intensive sampling on Day 4
To assess the safety of ATM-AVI in this 
patient population
Safety and tolerability as assessed by adverse events, 
physical examination, vital signs, ECGs, and 
laboratory assessments
Secondary Objectives:
To assess the treatment outcome per patient at 
the test of cure (TOC) visit
Proportion of patients with clinical cure at the TOC 
visit
To assessthe relationship between exposure 
and clinical curefor ATM-AVI
Correlation of derived PKparametersfor ATM-AVI 
and clinical cureat TOC
Exploratory Objective:
To develop and evaluate pharmacokinetic / 
pharmacodynamic (PK/PD) models (Nonlinear 
Mixed Effect Model analysis [NONMEM], 
simulation) and to characterize population PK
Estimates of model parameters and their precision, 
goodness-of-fit, individual and mean predictions
Target subject population
Forty adult patients (18 to 90 years of age, inclusive) with a diagnosis of complicated intra-
abdominal infection and the need for a surgical intervention will be enrolled.
Duration of treatment
Intravenous study therapy (ATM-AVI) plus metronidazole will be continued for a period of 
time (5 to 14 full days, where a full day is defined as a 24-hour period) deemed appropriate by 
the investigator based on the patient’s clinical response. After at least 5 full days of IV study 
therapy and at the discretion of the investigator, all study therapies may be discontinued if the 
patient has shown significant clinical improvement. Thus, the total expected duration of the 
study for a patient is 32 to 39 days, depending on the exact timing of Visit 1 and Visit 18 (see 
above).
Investigational medicinal product(IMP), dosage and mode of administration
IMP
Dosage form and strength
Avibactam
Avibactam lyophilisate for concentrate for solution for infusion 600 
mg
Aztreonam
Aztreonam powder for solution for infusion 2 g or 1 g
Metronidazole
Metronidazole 500 mg / 100 ml solution for infusion
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Drug Substance ATM-AVI
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Edition Number Final 3.0
Date 29 March 2017
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The Investigational Medicinal Products (IMPs) ATM and AVI will be supplied in vials. The 
IMP ATM-AVI will be prepared using standard aseptic intravenous infusion preparation using 
saline. The IMP Metronidazole will be supplied in infusion bags. All IMPs will be 
administered by intravenous infusion. 
Patients in Cohort 1 with creatinine clearance >50 mL/min will receive a loading dose (500 
mg ATM plus 137 mg AVI by intravenous infusion over a 30 minute period), immediately 
followed by maintenance infusions of 1500 mg ATM plus 410 mg AVI over a 3 hour period 
every 6 hours. The targeted total dose on Day 1 will be 6500 mg ATM and 1777 mg AVI. For 
the following (full) days, this will be 6000 mg ATM / 1640 mg AVI. 
In the event that a higher AVI dose will be administeredin Cohort 2, patients with normal 
renal function or mild renal impairment (CrCl > 50 mL/min) will receive a loading dose (500 
mg ATM plus 167 mg AVI by intravenous [IV] infusion over a 30 minute period), 
immediately followed by a dose of 1500 mg ATM plus 500mg AVI by IV infusion over a 3 
hour period every 6hours (maintenance infusion).
Patients in Cohort 2 with moderate renal impairment (CrCl31 -50 mL/min)will receive
either;
A loading dose consistent with Cohort 1 (500 mg ATM plus 137 mg AVI by 
intravenous infusion over a 30 minute period), immediately followed by an extended 
loading infusion of 1500 mg ATM plus 410 mg AVI over a 3 hour period. The 
subsequent maintenance infusions (starting 3 hours after stop of the second loading 
infusion) will be 750 mg ATM plus 205 mg AVI overa 3 hour period (to be 
administered every 6 hours). The targeted total dose on Day 1 will be 4250 mg 
ATM:500 mg (loading dose) + 1500 mg (extended loading infusion) + 3x 750 mg = 
2250 mg (maintenance infusion)and 1162 mg AVI: 137 mg (loading dose) + 410 mg 
(extended loading infusion) + 3x 205 mg (maintenance infusion). From Day 2 
onwards, the targeted total daily dose will be 3000 mg ATM(4x 750 mg maintenance 
infusion)/ 820 mg AVI(4x 205 mg maintenance infusion).
Or
Aloading dose consistent with a higher AVI dose in Cohort 2 (500 mg ATM plus 167 
mg AVI by intravenous infusion over a 30 minute period), immediately followed by an
extended loadinginfusion of 1500 mg ATM plus 500mg AVI over a 3 hour period. 
The subsequent maintenance infusions (starting 3 hours after stop of the second 
loading infusion) will be 750 mg ATM plus 250 mg AVI over a 3 hour period (to be 
administered every 6 hours). The targeted total dose on Day 1 will be 4250 mg ATM: 
500 mg (loading dose) + 1500 mg (extended loading infusion)+ 3x 750 mg = 2250 mg 
(maintenance infusion)and 1417 mg AVI: 167 mg (loading dose) + 500 mg (extended 
loading infusion) + 3x 250mg (maintenance infusion). From Day 2 onwards, the 
targeted total daily dose will be 3000 mg ATM (4x 750 mg maintenance infusion)/ 
1000 mg AVI(4x 250mg maintenance infusion).
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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Overview: Proposed ATM-AVI dosing regimens 
Loading dose
Extended loading 
infusion
Maintenance infusion 
Patients in Cohort 1 
with normal renal 
function or mild renal 
impairment (CrCl > 50 
mL/min)
500mg ATM plus 
137 mg AVI by 
intravenous infusion 
over a 30 minute 
period
Not applicable
1500 mg ATM plus 410 
mg AVI over a 3 hour 
period (to be 
administered every 6 
hours)
Patients in Cohort 2 & 3 
with normal renal 
function or mild renal 
impairment (CrCl >50 
mL/min)
500 mg ATM plus 
137 mg AVI by 
intravenous infusion 
over a 30 minute 
period
Not applicable
1500 mg ATM plus 410 
mg AVI over a 3 hour 
period (to be 
administered every 6 
hours)
Or
500 mg ATM plus 
167 mg AVI by 
intravenous infusion 
over a 30 minute 
period)
Not applicable
1500 mg ATM plus 500 
mg AVI over a 3 hour 
period (to be 
administered every 6 
hours)
Patients in Cohort 2 & 3 
with moderate renal 
impairment (CrCl 31 -
50 mL/min)
500 mg ATM plus 
137 mg AVI by 
intravenous infusion 
over a 30 minute 
period
Extended loading 
infusion of 1500 mg 
ATM plus 410 mg 
AVI over a 3 hour 
period
750 mg ATM plus 205 
mg AVI over a 3 hour 
period (to be 
administered every 6 
hours)
Or
500 mg ATM plus 
167 mg AVI by 
intravenous infusion 
over a 30 minute 
period
Extended loading 
infusion of 1500 mg 
ATM plus 500 mg 
AVI over a 3 hour 
period
750 mg ATM plus 250 
mg AVI over a 3 hour 
period (to be 
administered every 6 
hours)
In the case that renal functionrecovers or deteriorates (i.e., local or central lab results show
CrCl increases from 31 –50 mL/min at baseline to >50 mL/min, or decreases from >50 
mL/min at baseline to31 –50 mL/min) during the treatment period, the dose of ATM-AVI 
shouldbe adjusted by the investigator to meet the applicable dose regimen,based onthe latest 
CrCl value.
In addition, anaerobic coverage for cIAI will be providedfor all patientsby administration of 
500 mg metronidazole, infused over 1 hour. Metronidazole will be administered every 8 
hours, starting after the first ATM-AVI maintenance infusion and maintained until end of 
study therapy.
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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Statistical analyses
Up to 40 patients will be enrolled into the study in total. Although the study is not powered to 
perform statistical tests, assessment of safety, and complete PK assessments from atleast 30 
patients with cIAI, is considered sufficient to adequately confirm the PK and safety profile of 
ATM-AVI in a population with a representative burden of disease. It is expected that 10 
patients in Cohort 1 (and 10 patients in Cohort 2 if the higher AVI dose is used)having 
completed all safety assessments are sufficient for an initial review of key safety criteria of 
ATM-AVI,in order to progress with the continued treatment of patients.A comprehensive 
Statistical Analysis Plan (SAP) will be prepared prior to first patientincluded.
Definitions of analysis sets
The modified intent to treat (MITT) population will include all enrolled patients who receive 
any amount of study drug.
The microbiologically modified intent-to treat (mMITT) population is asubset of the MITT 
population and includes all enrolled patients who have a diagnosis of cIAI and have an intra-
abdominal pathogen at baseline (regardless of susceptibility to the study drug).
The pharmacokinetic (PK) population includes all patients who have at least 1 plasma 
concentration data assessment available for ATM-AVI, no fundamental violations of the 
inclusion and exclusion criteria and no important protocol violations affecting assessment of 
PK as defined in the finalised Statistical Analysis Plan. The reason for exclusion will be listed 
for all subjects in question.
There are two efficacy analysis sets: the MITT and mMITT population. The safety analysis set 
is the MITT population. The PK analysis set is the PK population.
Outcome measures for analyses
The primary outcome measures will be:
ATM and AVI concentrations in plasma (samples to be collected for 6 hours after 
the start of an ATM-AVI 3 hour infusion).They will be analyzed in the PK 
analysis set.
Derived PK parameters C
max, t
max, AUC
(0-6), AUC
(0-last), t
last, t
1/2, V
ss, V
zand CL for 
the patients undergoing intensive sampling on day 4. They will be analyzed in the 
PK analysis set.
Safety and tolerability as assessed by adverse events, physical examination, vital 
signs, ECGs, and laboratoryassessments. They will be analyzed in the safety 
analysis set.
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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The secondary outcome measures will be:
Proportion of patients with clinical cure at the TOC visit. This will be analyzed in
the MITT and mMITT populations.
Correlation of derived PK parameters for ATM-AVI and clinical cure at TOC. This 
will be analyzed in the mMITTpopulation.
Methods for statistical analyses
The following characteristics will be summarised in the safety population: demographics (age, 
sex, and race), medical and surgical history, description of cIAI, baseline assessments of 
clinical signs and symptoms, microbiological assessment of primary infection site or blood, 
study therapy administration and baseline pathogens. Minimum inhibitory concentration 
frequencies for each infecting species isolated from either the abdominal site or blood at 
baseline will be reported. Pathogens isolated from cultures obtained post-baseline will be 
listed. 
No confirmatory interim analysis is planned. However, safety and PK of the ATM-AVI 
dosing regimen will be assessed in an early reviewof the first 10 patients having completed 
all PK and safety assessmentsin Cohort 1, including a careful evaluation of patient liver 
transaminases. The assessment will be both a per patient assessment throughout the study 
period and per a cohort review. It will input to a decision on whether
(a)
the study can continue and, if so
(b)
the remainder of the study will continue (Cohort 2) with the same dose regimen for 
patients with normal renal function or mild renal impairment (CrCl >50 mL/min), 
or:
(c)
Cohort 2 will commence at the higher AVI dose regimen(see above) for patients 
with normal renal function or mild renal impairment (CrCl > 50 mL/min) and
patients with moderate renal impairment (creatinine clearance 31-50 mL/min) 
should be included and administered areduced dose to reflect the agreed dose 
regimen in Cohort 2.
In the event that the AVI dose is escalated in Cohort 2, a second safety and PK review of 10 
patientsin Cohort 2 having completedall safety and PK assessments (including Day 35) will 
input into the decision on whether
a)the remainder of the study will continue (Cohort 3) at the same (higher AVI 
dose)regimen,or:
b)the remainder of the study will continue (Cohort 3) with the lower AVI dose 
regimenfor patients with CrCl > 50 mL/min and for patients with CrCl 31-50 
mL/min, respectively (as described in section7.2)
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
11(99)
Analysis of the primary variables
Descriptive statistical analyses will be performed. Number of observations, arithmetic mean, 
standard deviation (SD), median, first quartile, third quartile, minimum, and maximum will be 
given for quantitative variables. If reasonable, geometric mean and coefficient of variation 
will also be given. Absolute and relative frequencies are given for qualitative variables. If 
variables are measured over time, each time point will be summarized. Summaries of the 
number and frequency of AEs will be presented. 95% confidence intervals will be given 
where reasonable.
Adverse events occurring from the first dose of study therapy up to the Late Follow-up visit 
will be summarized by preferred term, system organ class, relationship to study therapy and 
severity. Summaries and listings of death, Adverse Events (AEs), Serious Adverse Events, 
other significant AEs, and AEs that led to discontinuation or withdrawal will be presented.
Analysis of the secondary variables
The number and percentage of patients with clinical cure (shown with 80% and 95% 
confidence intervals) will be tabulated for the MITT and mMITT analysis set. Key patient 
subgroups (e.g. the group of patients with extended-spectrum β-lactamase phenotype 
pathogens) will be summarised in the same way, and illustrated graphically as a forest plot.
The proportion of clinical cure at the Test of Cure visit will be determined excluding any 
patients with concomitant antibiotics not administered for failure (mMITT).Refer to section 
7.7for rules relating to concomitant antibiotics (mMITT).
Evaluation of the pharmacokinetics of ATM and AVI
The actual sampling times will be used in all final plasma PK parameter calculations. 
Pharmacokinetic parameters will be derived for the first 25 patients (undergoing intensive PK 
sampling on Day 4) using non-compartmental methods.
The final datamay be pooled with data from other studies to conduct population PK analysis. 
Using these parameter estimates (mean PK parameters including inter-individual variance 
estimates), Monte-Carlo simulations will be undertaken and potential PK/PD relationships 
will be explored. A detailed population PK/PD analysis plan will be prepared prior to any 
such analysis/es, the results of which will be reported separately.
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
12(99)
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................................3
TABLE OF CONTENTS.......................................................................................................12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................................17
1.
INTRODUCTION.................................................................................................20
1.1
Background and rationale for conducting this study.............................................20
1.2
Rationale for study design, doses and control groups............................................22
1.3
Benefit/risk and ethical assessment........................................................................27
1.4
Study Design..........................................................................................................29
2.
STUDY OBJECTIVES..........................................................................................35
2.1
Primary objective...................................................................................................35
2.2
Secondary objectives.............................................................................................35
2.3
Safety objectives....................................................................................................35
2.4
Exploratory objectives...........................................................................................35
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................36
3.1
Inclusion criteria....................................................................................................36
3.2
Exclusion criteria...................................................................................................39
3.3
Patient enrolment...................................................................................................43
3.4
Procedures for handling incorrectly enrolled subjects...........................................43
3.5
Methods for assigning treatment groups................................................................44
3.6 
Methods for ensuring blinding: Not applicable.....................................................44
3.7 
Methods for unblinding: Not applicable................................................................44
3.8
Restrictions for patients during the study..............................................................44
3.9
Discontinuation of Investigational Medicinal Product (IMP)...............................45
3.9.1
Procedures for discontinuation of a patient from IMP...........................................46
3.10
Withdrawal from study..........................................................................................46
3.11
Discontinuation of the study..................................................................................47
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................47
4.1
Study visits and procedures....................................................................................49
4.1.1
Visit 1: eligibility/screening procedures (Day 0)...................................................49
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Drug Substance ATM-AVI
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Date 29 March 2017
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4.1.2
Visit 2: eligibility/baseline procedures and Day 1 of treatment.............................51
4.1.3
Visits 3 to 15 (Days 2 to 14): ongoing treatment period........................................52
4.1.4 
Visit 16: end of IV therapy (EOT) procedures......................................................53
4.1.5
Visit 17 test of cure (TOC) procedures (Day 25 +/-3 days).................................54
4.1.6
Visit 18: late follow-up (LFU) procedures (Day 35 +/-3 days)............................55
5.
STUDY ASSESSMENTS.....................................................................................56
5.1
Clinical and microbiological assessments.............................................................56
5.1.1
Efficacy assessment: Clinical response..................................................................56
5.1.2
Microbiological assessments.................................................................................57
5.2
Safety assessments.................................................................................................59
5.2.1
Laboratory safety assessments...............................................................................60
5.2.2
Physical examination.............................................................................................61
5.2.3
ECG........................................................................................................................62
5.2.4
Vital signs..............................................................................................................62
5.2.4.1
Blood pressure and heart rate.................................................................................62
5.2.4.2
Body temperature...................................................................................................62
5.2.4.3
Respiratory rate......................................................................................................63
5.2.5 
Safety and PK Assessments by the Scientific Advisory Committee.....................63
5.2.5.1
Early safety assessment –Cohort 1 review............................................................63
5.2.5.2
Second safety assessment –Cohort 2 review........................................................63
5.2.5.3
Criteria for immediate progression........................................................................64
5.2.5.4 Criteria for stop and review...................................................................................64
5.2.5.5
Criteria for non-progression...................................................................................65
5.3
Pharmacokinetics...................................................................................................66
5.3.1
Collection of samples.............................................................................................66
5.3.2 
Determination of drug concentration in plasma.....................................................67
5.3.3
Early patient review and second safety and PK assessment–evaluation of 
the pharmacokinetics of ATM and AVI................................................................68
5.3.4 
Storage and destruction of pharmacokinetic samples............................................68
5.4
Pharmacodynamics................................................................................................68
5.5
Pharmacogenetics: not applicable..........................................................................68
5.6
Biological sampling procedures.............................................................................68
5.6.1
Storage, re-use and destruction of biological samples...........................................69
5.6.2
Labelling and shipment of biological samples.......................................................70
5.6.3
Chain of custody of biological samples.................................................................70
5.6.4
Withdrawal of Informed Consent for donated biological samples........................71
6.
SAFETY REPORTING ANDMEDICAL MANAGEMENT..............................71
6.1
Definition of adverse event....................................................................................71
6.2
Definition of serious adverse event........................................................................72
6.3 
Recording of adverse events..................................................................................72
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6.3.1
Time period for collection of adverse events.........................................................72
6.3.2
Follow-up of unresolved adverse events................................................................72
6.3.3
Variables................................................................................................................73
6.3.4
Causality collection................................................................................................74
6.3.5 
Adverse events based on signsand symptoms.......................................................74
6.3.6
Adverse events based on examinations and tests...................................................75
6.3.7
Hy’s Law................................................................................................................75
6.3.8 
Exceptions from standard adverse event collection...............................................76
6.3.8.1
Lack of effect.........................................................................................................76
6.3.8.2
Disease progression...............................................................................................76
6.4
Reporting of serious adverse events.......................................................................76
6.4.1
Other significant adverse events............................................................................77
6.5
Overdose................................................................................................................77
6.6
Pregnancy...............................................................................................................78
6.6.1
Maternal exposure..................................................................................................78
6.6.2
Paternal exposure...................................................................................................79
6.7
Medical management and monitoring during the study........................................79
6.7.1 
Coagulation and concomitant use of anticoagulants..............................................79
6.7.2
Renal function........................................................................................................79
6.7.3
Monitoring of liver-related laboratory parameters.................................................79
6.8
Management of IMP related toxicities...................................................................80
6.9
Study governance and oversight............................................................................80
6.9.1
Scientific Advisory Committee..............................................................................80
6.10
Medical emergencies, management and SAE contacts..........................................81
7.
INVESTIGATIONAL MEDICINAL PRODUCT AND OTHER 
TREATMENTS.....................................................................................................82
7.1
Identity of investigational medicinal products (IMPs)..........................................82
7.2 
Dose and treatment regimens.................................................................................82
7.3
Labelling................................................................................................................84
7.4
Storage...................................................................................................................84
7.5
Compliance............................................................................................................84
7.6
Accountability........................................................................................................84
7.7 
Concomitant and other treatments.........................................................................86
7.8
Post study access to study treatment......................................................................88
8.
STATISTICAL ANALYSES................................................................................88
8.1 
Statistical considerations........................................................................................88
8.2
Sample size estimate..............................................................................................88
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8.3
Definitions of analysis sets....................................................................................88
8.3.1
Efficacy analysis set...............................................................................................89
8.3.2
Safety analysis set..................................................................................................
89
8.3.3
PK analysis set.......................................................................................................89
8.4
Outcome measures for analyses.............................................................................89
8.5
Methods for statistical analyses.............................................................................89
8.5.1
Analysis of the primary variables..........................................................................
90
8.5.2
Analysis of the secondary variables.......................................................................90
8.5.3
Exploratory analysis...............................................................................................90
8.5.4 
Evaluation of pharmacokinetics and of pharmacokinetic -
pharmacodynamic relationships.............................................................................90
8.5.4.1
Evaluation of the pharmacokinetics of ATM and AVI..........................................91
8.5.4.2
Population pharmacokinetic/pharmacodynamic analyses.....................................91
9.
STUDY AND DATA MANAGEMENT...............................................................91
9.1
Pre-study activities.................................................................................................91
9.2
Training of study site personnel.............................................................................91
9.3
Monitoring of the study.........................................................................................92
9.3.1
Source data.............................................................................................................93
9.3.2
Study agreements...................................................................................................93
9.3.3
Archiving of study documents...............................................................................93
9.4
Study timetable and end of study...........................................................................93
9.4.1
Clinical Study Report.............................................................................................94
9.5
Data management...................................................................................................94
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................94
10.1
Ethical conduct of the study...................................................................................94
10.2
Patient data protection............................................................................................94
10.3
Ethics and regulatory review..................................................................................95
10.4
Informed consent...................................................................................................95
10.5 
Changes to the protocol and informed consent form.............................................96
10.6 
Audits and inspections...........................................................................................96
11.
LIST OF REFERENCES.......................................................................................97
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LIST OF TABLES
Table 1 Study Plan detailing the procedures.......................................................................48
Table 2: Definitions of clinical response at the EOT, TOC, LFU visits..............................57
Table 3: Laboratory Safety Variables..................................................................................61
Table 4: Pharmacokinetic ATM-AVI Sample Collection Time Points...............................66
Table 5: Volume of blood to be drawn from each patient...................................................69
Table 6: Contacts for medical emergencies and SAE reporting..........................................81
LIST OF FIGURES
Figure 1 Study Flow.............................................................................................................33
Figure 2 Study Outline.........................................................................................................34
Figure 3 Sampling regimen on Day 1...................................................................................67
Figure 4 Sampling regimen on Day 4 –intensive sampling................................................67
Figure 5 Sampling regimen on Day 4 –sparse sampling.....................................................67
LIST OF APPENDICES
Appendix A Signatures
Appendix B Additional Safety Information 
Appendix C International Airline Transportation Association 6.2 Guidance document
Appendix D Actions required in cases of combined increase of Alanine or Aspartate 
Aminotransferase and Total Bilirubin –Hy’s Law 
Appendix E
Calculation of Estimated Creatinine Clearance
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or special 
term
Explanation
ADR
Adverse Drug Reaction
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATM
Aztreonam
AUC(0-6)
Area under the plasma concentration vs. time curve from time point zero up 
to 6 hours
AUC(0-last)
Area under the plasma concentration vs. time curve from time point zero up 
to the last measured concentration above LOQ
AVI
Avibactam
β-hCG
β-human chorionic gonadotropin
bpm
beats per minute 
cIAI
Complicated Intra-Abdominal Infection(see definition in section 3)
CK
Creatine kinase
CL
Clearance
CLSI
Clinical and Laboratory Standards Institute
Cmax
Maximum plasma concentration
COMBACTE-CARE
Aconsortium which consistsof 19academic and 3 pharmaceutical partners,
focussing on carbapenem resistance in Europe
CrCl
Creatinine Clearance
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Threshold concentration
CTCC
Clinical Trial CentreCologne, Medical Faculty University of Cologne
CTCAE
Common Terminology Criteria for Adverse Event
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Abbreviation or special 
term
Explanation
CTX-M
A type of Class A β-lactamase(CTX = cefotaximase)
DDI
Drug-Drug Interaction
DNA
Deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOT
End of treatment (with intravenous therapy)
ESBL
Extended spectrum β-lactamases
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone 
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IMI
Innovative Medicines Initiative
International 
Coordinating
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the investigatorcoordinating the investigators and/or activities 
internationally. 
IMP
Investigational Medicinal Product 
INR
International Normalized Ratio
IRB
Institutional Review Board
IV
Intravenous
KPC
Klebsiella pneumoniaecarbapenemase
LFU
Late Follow-up
LOQ
Limit of quantification
LSLV
Last Subject Last Visit
LH
Luteinizing hormone 
MBL
Metallo-β-lactamases
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Abbreviation or special 
term
Explanation
MDR
Multiple-Drug Resistant
MedDRA
Medical Dictionary for Regulatory Activities
MIC
Minimum Inhibitory Concentration
MITT
Modified intent-to-treat
mMITT
Microbiologically modified intent-to-treat
MRI
Moderate renal impairment
NDM
New Delhi Metallo-β-lactamase
NONMEM
Nonlinear Mixed Effect Model analysis
OXA
A type of Class D β-lactamase(OXA = oxacillin)
PET
Positron Emission Tomography
PHL
Potential Hy’s Law case
PK/PD
Pharmacokinetic/Pharmacodynamic
PI
Principal Investigator 
q6h
Every 6 hours
q8h
Every 8 hours
SAC
Scientific Advisory Committee
SAE
Serious adverse event 
SmPC
Summary of Product Characteristics
STAR
Staged Abdominal Repair
t
1/2
Plasma elimination half-life
t
last
Time of last measured concentration above LOQ
t
max
Time of observed maximum concentration
TOC
Test of Cure
ULN
Upper Limit of Normal
VIM
A type of Class B β-lactamase(VIM Verona Integron encoded)
Vss
Apparent volume of distribution at steady state after IV administration 
Vz
Volume of distribution during terminal phase after IV administration
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
The incidence of multiple-drug resistant (MDR) bacteria is increasing worldwide. This has 
become a significant public health threat as there are fewer, or even sometimes no, effective 
antimicrobial agents available for infections caused by MDR bacteria(Lucasti et al. 2013; 
Magiorakos et al. 2012). In particular, ongoing surveillance studies have demonstrated an 
increasing frequency of antibiotic resistance among Gram-negative pathogens. New 
antibioticsor combinations of existing antibiotics with resistance enzyme inhibitors are 
urgently needed to provide treatment options for patients with infectionsknown or suspected 
to be caused by MDR Gram-negative pathogens (IMI 2015).
One of the most common resistance mechanisms in Gram-negative pathogens isthe 
production of extended-spectrum β-lactamases (ESBL) (Lucasti et al. 2013).Infections due to 
ESBL-producing organisms present a major therapeutic dilemmaespecially as isolates are 
also increasingly expressingresistance to other first line agents such as fluoroquinolones or 
aminoglycosides, leaving few available options for therapy.ESBL are found in a significant 
percentage of Enterobacteriaceae (including E. coli, Klebsiella pneumoniae, Enterobacter, 
Citrobacter, Proteus, Morganella morganii, Serratia marcescens, and Shigella dysenteriae). 
They can also be found in Pseudomonas aeruginosaalthough they do not contribute 
significantly to resistance in this organism.
Carbapenems are the preferred treatment option for serious infections due to such MDR 
Gram-negative pathogens but carbapenemases have steadily accumulated in the 
Enterobacteriaceaewith the epidemiology of carbapenem resistant Enterobacteriaceae(CRE) 
characterized by large heterogeneity in genotypes (with >20 reported resistance gene families, 
such as NDM, KPC, VIM, OXA48 (Nordmann et al. 2013). The expression of metallo-β-
lactamases (MBLs)such as VIM and NDM 1, in addition to other resistance mechanisms,is 
of increasing concern as the treatment options are extremely limited. 
A particular threat is posed by a family of MBLs known as NDM (New Delhi metallo-β-
lactamases).NDM-1-producing pathogens have already been reported in a number of 
countries outside of the regions where the first producing strains were identified in 2009 
(India, Pakistan, Sweden, UK), including Australia, Singapore, Taiwan, and the United States. 
The recent emergence of NDM-1 has caused particular concern in the international infection 
community, as the genetic element encoding NDM-1 is able to rapidly spread amongst 
bacteria in both community and hospital settings.
The spread of resistance due to the ESBL CTX-M may provide a useful model for the spread 
of NDM-1 as the blaNDM-1gene is found on the same promiscuous ST131 clone as CTX-M. In 
particular, organisms that produce NDM-1 have spread geographically and are now seen in 
community-acquired infections, similar to the spread of CTX-M, which has reached endemic 
levels in much of Asia, Europe, and South America. These pathogens have become endemic 
in the Indian subcontinent, where they have been detected in the environment (Walsh et al. 
2011).
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Arepresentative example of a serious Gram-negative infectionincludescomplicated intra-
abdominal infection (cIAI; see definition in section3). Most commonly, Enterobacteriaceae
are isolated in cIAI.For therapy, the current Guidelines of the Infectious Diseases Society of 
America (Solomkin et al. 2010) recommend surgical intervention along with broad spectrum 
single agent (β lactam/β lactamase inhibitor, carbapenem) or combination antibioticregimens 
(metronidazole plus cephalosporin or aztreonam or fluoroquinolone).Specific regimens are 
recommended for higher risk patients with severe orpostoperative nosocomial intra-
abdominal infections where resistant pathogens such as Enterococcusspp.or Pseudomonas
aeruginosamay occur.
The combination product aztreonam and avibactam (ATM-AVI) is being developed for 
intravenous (IV) treatment of serious infections caused by Gram-negative pathogens 
producing metallo-β-lactamases (MBL) in addition toother β-lactamases. Commonly, such 
organisms termedmultiple-drug resistant (MDR)show non-susceptibility to at least 3 classes 
of antibiotics.
ATM, with more than 25 years of use worldwide, is an established injectable antibiotic 
indicated for the treatment of various infections caused by susceptible Gram-negative bacteria.
It has a unique monocyclic β-lactam nucleus that makes it structurally different from other 
β-lactam antibiotics (including penicillins and cephalosporins), as well as several chemical 
side groups that interfere with degradation by MBLs. In this way, activity against MBL (Class 
B) producing pathogens is possible, although potential inactivation by Class A, C, or D β-
lactamases remains problematic.
AVI (formerly AVE1330 or NXL104) is a novel, non β-lactam, β-lactamase inhibitor of a 
broad spectrum of enzymes, including Ambler Class A ESBLs, Class A KPC, and Class C 
(AmpC) enzymes, and some Class D enzymes, notably OXA-48, a problematic 
carbapenemase in the European Union (EU) and Middle East. AVI’s β-lactamase inhibition 
occurs through formation of a covalent bond between AVI and enzyme. Alone, AVI hasno 
meaningful antibacterial activity; rather, its beneficial effect in combination with ATM occurs 
by rendering inactive those enzymes that inactivate ATM.
Together, ATM and AVI have the potential to address the unmet need for safe and effective 
agents tocombat MBLs and other problematic β-lactamases, such as ESBLs and KPCs, which 
may be co-expressed with MBLs and contribute toaMDRphenotype.
The combination product referred to as ATM-AVI in this Clinical Study Protocol(CSP)is 
being developed for the treatment of serious infections caused by susceptible Gram negative
bacteria for which there are limited or no treatment options. These include infections caused 
by MBL-producingpathogens that can also co-produceESBLs, KPC and/orAmpC β-
lactamases.Relevant to the clinical development of the study therapy is the fact that ATM-
AVI has shown excellent activity in pre-clinical studies against a broad range of Gram 
negative pathogens, including several of the most problematic MDR pathogens as listed above 
(see Investigator’s Brochure for further details).
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Mostintra-abdominal infections are polymicrobial andcaused by organisms residing inthe 
gastrointestinal tract, including aerobes and facultative and obligate anaerobes. In this study, 
metronidazole will beadded to ATM-AVI to provide coverage for anaerobic organismssuch 
as the Bacteroides fragilisgroup. The spectrum of activity of ATM-AVI when combined with 
metronidazole is well suited to treatment of pathogens commonly responsible for cIAIs.
To date, 92 healthy volunteershave been dosed with the investigational medicinal product 
(i.e., ATM-AVI, placebo or ATM/AVI separately), in a single Phase I study. Additional 
details can be found in section 1.2and in the ATM-AVI Investigator’s Brochure (IB).
The objective of this Phase IIa, patient PK study is to investigate the PK, tolerability and 
safety of ATM-AVI in patients with a serious bacterial infection (cIAI) and to provide dose 
confirmation. The PK/PD data generated will contribute to a robust package of data, supported 
by prior experience with ATM and AVI administered separately, and validated by qualitative 
data for the combination from a proposed randomized Phase III clinical trialin patients with 
infections suspected to becaused by these specific but rare pathogens.
This ATM-AVI Phase IIa trial is part of the work package 2 (WP2a)in the Innovative 
Medicines Initiative (IMI) supported COMBACTE-CARE project.IMI is a joint undertaking 
between the European Union and the pharmaceutical industry association EFPIA (see 
http://www.imi.europa.eu).COMBACTE-CARE is a consortium of 19 academic and 3 
pharmaceutical partners focussing on carbapenem resistance in Europe. The trial is registered 
in the EudraCT database with the number 2015-002726-39.
1.2
Rationale for study design, doses and control groups
Study design and control group
This ATM-AVI study is aPhase IIa prospective, open-label, multicenter studyto determine 
the PK, safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of 
hospitalized patientssuffering fromcomplicated intra-abdominal infections(cIAI).
The non-comparative, single arm study design is sufficient to enable an intensive patient PK 
analysis and a within patient cohort safety evaluation. As a single arm study there is no 
requirement for blinding or randomization. Given the risk to patients and severity of disease, a 
placebo controlled trial would not be ethically appropriate.The duration of study drug therapy 
(5 to 14 full days, where a full day is defined as a 24-hour period) takes into account the 
current FDA recommendations for the development of drugs for treatment of cIAI (FDA 
2015).
A multicenter design was chosen for thistrial. This approach accounts for the selected patient 
population. In order to be able to include the required number of 40 patients within a 
reasonable timeframe, parallel recruitment in several study sites is indispensable. Thus, the 
study is expected to start in the first quarter 2016 and to end by the fourthquarter 2017.
The chosen design as described below takes into account the current regulatory guidelines, i.e. 
the European Medicines Agency (EMA) “Guideline on the evaluation of medicinal products 
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indicated for treatment of bacterial infections” (EMA 2011) and the U.S. Food and Drug 
Administration (FDA) Guidance for Industry “Complicated Intra-Abdominal Infections: 
Developing Drugs for Treatment” (FDA 2015).
Dose selection (ATM-AVI)
The intention for ATM-AVIis that it will be active against clinically isolated Gram negative 
bacteria for which there are limited or no treatment options. The ATM-AVI doses for this 
PhaseIIa trial have been selected based on pre-clinical and clinical data on ATM-AVI, using 
PK data for aztreonam, avibactam and ATM-AVI and includingcovariate information 
collected in healthy volunteersandas presented in the Investigator’s Brochure. Furthermore, 
PK and safety data together with PK/PD modelling results obtained during development of the 
new ceftazidime-avibactam (CAZ-AVI) combination productZavicefta have been taken into 
account(European Commission: Product information Zavicefta 2016). 
At the time of dose selection for the start of this study partial PK data for both ATM and AVI 
wereavailable from a Phase I study with 28 healthy volunteers receiving ATM-AVI 
(D4910C00001; dosing cohorts A, B1, B2, and B3as displayed in the Investigator’s 
Brochure) and were used in development of a population PKmodel. For AVI dose finding, 
additionaldata obtained during development of the new ceftazidime/avibactamcombination 
(i.e. four Phase I studies and one Phase II study in patients with cIAI)were utilised in the 
population PK model. The population PK model was used in Monte Carlo simulations to
select a dosing regimen which achieveda joint probability of target attainment (PTA) for 
ATM andAVI of approx. >90%; based on PK/PD targets of free (unbound) concentrations of 
ATM ≥60% T>MIC(time concentration exceeds minimum inhibitory concentration) andfree 
concentrations of AVI ≥50% T>CT(time concentration exceeds threshold concentration; 
calculated for a CTof 2.5 mg/L). The chosen dose is to ensure (based on current knowledge) 
that the study drugscan achieve the requiredlevel of activityin patients with cIAI while 
taking also safety aspects into account. 
Dose selection (ATM-AVI) for patients with normal renal function or mild renal impairment 
(CrCl >50 mL/min)
For patients with serious bacterial infections where there are limited or no treatment options, it 
is recommended for β-lactams to rapidly achieve target attainment and steady state 
concentrations and prolonging time over MIC with extended infusion time and shorter 
intervals. The rationale for selected dose regimenis based upon an empirical approach taken 
to modify the transaminase elevation observed in the Phase I healthy volunteerstudy(see 
section1.3and IB), but also with objective of obtaining optimal exposure to maintain 
probability of target attainment(PTA). 
Theempirical approach taken during the Phase Ihealthy volunteer studywas toyield lower 
maximum plasma concentrations (Cmax), with the same exposure (AUC) over the dosing 
interval to modify observed transaminase elevations. Based on representative population PK 
modeling, target attainment simulationswere conductedduring the Phase I study to support 
dose adjustments. The modeling data shows that extension of the infusion time up to a 3 hour 
intravenous [IV] infusion every 6 hours (i.e., extended infusion) results in adequate target 
attainment for the joint ATM-AVI PK/PD target. The modeling data also show that inclusion 
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of a loading dose results in more patients achieving the predicted target attainmentduring the 
initial dosing interval and duration of treatment.
Thus, for both components of the study therapy, the final dosing regimen evaluated –and 
demonstrated to be well tolerated in both normal aged and elderly human volunteer cohorts in 
the Phase I study –was a dosing regimen ofa loading dose (500 mg ATM plus 137 mg AVI 
by IV infusion)over a 30 minute periodimmediately followed by a first maintenance dose of 
1500 mg ATM plus 410 mg AVI by IV infusion for 2.5 hours, which was followed by 
maintenance infusions of 1500 mg ATM plus 410 mg AVIovera 3 hour period every 6hours. 
This dosing regimen was simplified with a minor adjustment to be more clinically acceptable. 
Thus, the dose regimen that will be evaluated in Cohort 1is a loading dose of 500 mg ATM 
plus 137 mg AVI by IV infusion over a 30 minute period, immediately followed by a 
maintenance infusion of 1500 mg ATM plus 410 mg AVI overa 3 hour period every 6hours. 
The targeted total dose on Day 1 will be 6500 mg ATM / 1777 mg AVI. From Day 2 onwards, 
this will be 6000 mg ATM / 1640 mg AVI. This minor adjustment to the first 3 hour 
maintenance infusion, from 2.5 hours to 3 hours, does not make any significant difference to 
the exposure of either component and does not impact PTA predictions. 
The population PK model has recently been updated, and for ATM now includesall the data 
from the Phase I study (65 healthy volunteersfrom Cohorts A, B1-5 and C1-2of study 
D4910C00001) and AVI data from the CAZ-AVI Phase I, II and III program(1836 subjects 
of which 1491 were patients with complicated urinary tract infections orcIAI). The additional 
data has allowed variability of avibactam in the patient population to be more robustly 
predicted and the probability oftarget attainment for ATM and AVI has been calculated to be 
slightly lower than previously estimatedbased on the same PK/PD targets mentioned above. 
The data suggests that whilst the current ATM dose is expected to beadequate, the AVI dose 
could be further optimised.
Therefore, with the aim to optimise the dose going forward, while assessing the benefit/risk at 
this dose, it is proposed that a second cohort of patients (Cohort 2) will receive a higher dose 
of AVI. The proposed dose regimen is a loading dose of 500mg ATM plus 167mg of AVI 
over a 30 minute infusion, followed by maintenance dosesof 1500 mg ATM plus 500 mg AVI 
over a 3 hour period every 6 hours. The targeted daily dose on Day 1 will be 6500 mg ATM/ 
2167mg AVI and from Day 2 onwards, this will be 6000 mg ATM / 2000 mg AVI.
A decision to proceed to the higher AVI dose in Cohort 2 will be taken following a favourable 
outcome of the early safety and PK assessment of the first 10 patients in Cohort 1having 
completedall PK and safety assessments. 
In the event that the higher AVI dose is administered in Cohort 2, afurtherreview of the 
safety and PK data of the first 10 patients in Cohort 2 will be conducted (see section 5.2.5.2) 
and a decision taken as to the continuation of treatment in the remaining patients(Cohort 3) 
either at the higher AVI dose from Cohort 2 orreturn to the dose from Cohort 1.
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Dose selection for patients with moderate renal impairment (CrCl 31to 50 mL/min)
As both ATM and AVI are eliminated primarily as unchanged substances by the kidney, a 
population PK/PD model wasdeveloped to support an appropriate dose for patients with 
moderate renal impairment.Included in the population PK model is data from a renal 
impairment study of avibactam which was conducted as part of the CAZ-AVI development 
programme and also two published studies of aztreonam[El Guinaidy et al. 1989; Mihindu et 
al. 1983].The updated population PKmodel described above was used in simulations to 
derive a dose whose predicted exposure is comparable to the exposure in patients with normal 
renal function, whilst still maintaining >90% PTA against the PK/PD targets. The simulations 
predict that this is achieved by halving the dose in patients with moderate renal impairment 
(compared to patients with normal renal function). 
Thus, if the maintenance dose for patients with normal renal function is 1500mg ATM plus 
500mg AVI infused over 3 hours every 6 hours, the maintenance dose for patients with 
moderate renal impairment would be ATM 750 mg/AVI 250 mg infusedover 3 hours, every 6 
hours. Alternatively, if the dose for patients with normal renal impairment is 1500mg ATM 
plus 410mg AVI, the maintenance dose for patients with moderate renal impairment would be 
ATM 750 mg/AVI 205 mg.
In both scenarios, the loadingdose and anextended loadinginfusion for patients with 
moderate renal impairment will be the same as the loading dose and maintenance dosesin 
patients with normal renal function. It is anticipated that the exposure (AUC) following the 
extended loadingdose in patients with moderate renal impairment will be greater than the 
predicted exposure at steady state in patients with normal renal function by 1.34 for ATM and 
1.67-fold for AVI; however, this exposure is transient and will facilitate rapid and effective 
treatment in these critically ill patients. 
In summary doses for patients with moderate renal impairment are as follows:
If the maintenance dose selected for patients with normal renal functionis 1500mg 
ATM plus 500mg AVI: 500mg ATM plus 167mg AVI as a 30 minute infusion, 
immediately followed by anextended loading infusionof 1500mg ATM plus 500mg 
AVI given over a3 hour period. The maintenance infusions (starting 3 hours after stop 
of the extendedloading infusion) will be 750 mg ATM plus 250 mg AVI over a 3 hour 
period (to be administered every 6 hours).
If the maintenance dose selected for patients with normal renal function is 1500mg 
ATM plus 410mg AVI:  500mg ATM plus 137mg AVI as a 30 minute infusion, 
immediately followed by anextended loadinginfusionof 1500mg ATM plus 410mg 
AVI given as a 3 hour infusion. The maintenance infusions (starting 3 hours after stop 
of the extendedloading infusion) will be 750 mg ATM plus 205 mg AVI over a 3 hour 
period (to be administered every 6 hours). 
Dose selection for metronidazole
Metronidazole will be co-administered with ATM-AVIfor the entire duration of study drug 
therapy (5to 14 full days) to provide coverage for anaerobic pathogens. The dose to be 
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administered (500 mg metronidazole every 8 hours) waschosen based on the current 
Guidelines of the Infectious Diseases Society of America for management of cIAI (Solomkin 
et al. 2010)and is also in line with nationally approved SmPCs in Europe [Baxter Healthcare 
Ltd]which donot indicate a need for dose adjustments in patients with moderate renal 
impairment.
Pharmacokinetic sampling regimen
As this is the first ATM-AVI study in patients, a mixture ofintensive and sparse sampling will 
be employed to define the PK in thepatient population, whilst minimising the PK sampling 
burden. The intensive PK sampling in the first 25 patients (15 samples per patient) is similar 
toa schedule used in the completed Phase I study D4910C00001. All remaining patients will 
have reduced/sparse PK sampling (7 samples per patient) based on the population PK model 
developed in Phase I. Sampling will take place on days 1 and 4 of treatment to assess drug 
exposure following single and multiple doses of ATM-AVI.
PK and safety analyses
To further assess the safety and PK profile of ATM-AVI in the target population (cIAI 
patients), this trial will carefully obtain and evaluate comprehensive PK and safety data, 
including interimreview of patient safety (in particular hepatic safety) and PK (see sections
1.3,1.4, 5.2.5and 5.3.3). There will be an assessment of the PK-PD relationship regarding 
clinical cure response on study completion. 
Cohort 1:An early safety and PK review of 10 patientswith CrCl>50mL/min (and having 
completed all PK and safety assessments; see section 5.2.5)will input into the decision on 
whether
a)
the study will continue and, if so:
b)
the remainder of the study will continue (Cohort 2) with the same dose regimen as
Cohort 1for patients with normal renal function or mild renal impairment (CrCl 
>50 mL/min), or:
c)
Cohort 2 will commence at the higherAVIdose regimen for patients with normal 
renal function or mild renal impairment (see above) and
(d)
patients with moderate renal impairment (CrCl 31to 50 mL/minshould be included 
and administered a reduced dose consistent with the agreed dose in Cohort 2(see 
above).
In the event that the AVI dose is escalated in Cohort 2, a second safety and PK review of 10 
patients having completed all PK andsafety assessments will input into the decision on 
whether
a)The remainder of the study (Cohort 3) will continue at the same (higher AVI 
dose)regimen, or:
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b)The remainder of the study (Cohort 3) will continue with the lower AVI dose 
regimen for patients with CrCl > 50 mL/min and for patients with CrCl 31-50 
mL/min, respectively (as describedabove)
c)Thedose regimen selected is confirmed for the development of ATM-AVI.
The overall objective of this trial including 40 patients is to confirm a suitable dose for the 
development of ATM-AVI and to provide for additional PK, PK/PD and safety/ tolerability 
data in patients with a representative burden of infection.
1.3
Benefit/risk and ethical assessment
Patients enrolled into this clinical study will have cIAIs that are of sufficient severity to 
require hospitalization and treatment with IV antibiotics and surgical intervention (including 
open laparotomy, percutaneous drainage of an abscess and laparoscopic surgery). The 
potential benefit to patients participating in this study is that they will receive effective 
antibiotic therapy for their infection. Avibactam has been shown to prevent hydrolysis of 
aztreonamin vitro by avibactam susceptible β-lactamases and has been shown to be effective 
in combination with ceftazidime in clinical studies in patients with cIAI. The potential benefit 
of the study, in general, is the identification of a novel antibiotic combination product that is 
an effective treatment for a representative serious bacterial infection, in the face of the 
changing pattern and increasing frequency of antibiotic resistance (see section 1.1). 
It is however possible that ATM-AVI will not prove to be a sufficiently effective treatment for 
cIAI. This risk is mitigated in that the study patients are closely monitored and will be 
managed with appropriate therapies as determined by the investigator who is providing 
treatment,based on the clinical response of the patient.
The risk considerations for this study should encompass the known and potential risks for the 
development product ATM-AVI and its component drugs aztreonam and avibactam, as well 
as the risks associated with furtherstudy-related procedures and with the treatments that will 
be co-administered according to this protocol, i.e. the marketed metronidazole. As the risks for 
marketed products are widely available in their respective prescribing information, such risks 
will not be discussed in this section.Information on contraindications, special warnings and 
precautions and interactions with other medicinal products and other forms of interaction for 
metronidazole are available in the metronidazole SmPC and investigators are recommended to 
refer to this for further prescribing information.
General study-related risks encompass venepunctureand/or placement of indwelling catheters 
for blood sampling, whichmay cause pain and occasionally results in thrombosis or 
thrombophlebitis and/or peripheral nerve damage (numbness).The total volumeof blood to be 
drawn from each patientis expected to range –depending on clinical response –from 106 to 
200mL;21 to 45 mL thereof will be used for PK analysis (see Table 5). The results of safety 
lab sampling (clinical chemistry, hematology) will be made available to the investigators. 
Similarly, the results of microbiological blood cultures obtained for study purposes will be 
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made available to the investigators without delayand may yield clinicallyimportant additional 
information.
Discomfort may be caused by any further study procedure such as study-relatedexaminations,
microbiological sampling, and recording of ECGs etc.These procedures however are not 
considered as risks for the patients that would affect the benefit-risk assessment.
ATM-AVI is not approved for marketing in any country. The risks for ATM-AVI have not 
been fully elucidated; however it is assumed that known or potential risks for ATM-AVI 
should include those identified in the clinical study experience with ATM-AVI, ATM alone, 
and AVI alone. 
ATM solution for injection (Azactam™) was first approved by the US Food and Drug 
Administration (FDA) in 1986 and subsequently approved in Europeand is indicated for intra-
abdominal infections. The most frequent adverse drug reactions forATM comprise 
gastrointestinal disorders (diarrhoea, nausea, vomiting: commonaccording to CIOMS 
Working Group III standard categories; see IB). Further relevant ADRs are Clostridium 
difficilecolitis, anaphylactic reactions and ventricular extrasystoles (uncommon). For further 
information regarding the risks attributable to ATM see IB and SmPC (ER Squibb & Sons 
Limited 2014). 
Human experience with AVI includes studies of all phases in which AVI was administered 
either as a single agent or in combination with other antibiotics (ceftazidime or ceftaroline). 
As part of the ceftazidime-avibactam development program and in a Phase I study for the 
ATM-AVI development, the safety and PK of AVI have been investigated in more than 10 
clinical pharmacology studies after IV administration of avibactam alone or in combination 
with ceftazidime or ATM. Ceftazidime-avibactam was approved by the FDA on 25 February 
2015 (Trademark: Avycaz)and by the European Commission on 28 June 2016 (Trademark: 
Zavicefta).
In a single Phase I study in healthy Japanese volunteers, noteworthy elevations in liver 
transaminases in a single volunteerwho received AVI alone wasreported as another 
significant adverse event (see IB). As a result, drug-induced liver injury, while not considered 
an expected adverse reaction, is now considered an important potential risk. As such, 
appropriate pharmacovigilance and risk mitigation measures have been outlined for the 
clinical study programme, with details for this study given in sections 3.9, 5.2.5, 6.3.7, 6.7.3
and Appendix D. This finding, however, does not alter the benefit-risk profile for ATM-AVI.
Human experience with the ATM-AVI combination consists of a single Phase I First-Time-In-
Man (FTiM) study (D4910C00001), in 92healthy volunteers, of which 8 received single
doses of ATM-AVI, 58 received multiple doses of ATM-AVI and the remainder received 
placebo. Data from this Phase I FTiM studysuggest that the following ADRs are expected for 
the ATM-AVI combination: headache (very common), abnormal liver function test 
(common), diarrhoea (common)and infusion/cannula site pain or reaction (common). Clinical 
data with ATM-AVI remains limited at this time but provided no evidencethat the benefit-
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risk profile of the combination is different from that of the individual combination 
components. 
Elevations in liver transaminases(in particular alanine aminotransferase (ALT)have been 
seen in a number of healthy volunteers in the Phase IFTiM study,all of which have rapidly 
resolved after cessation of therapy.Modifications taken over the course of the Phase I study to 
reduce the concentrations of both aztreonam and avibactam and extend the infusion times 
have significantly reduced the extent of transaminase elevation to facilitate the clinical utility 
of ATM-AVI. The clinical utility will be further examined in this Phase IIa, patient PK study, 
with an early evaluation of at least 10 patients in both Cohorts 1 and 2, initially to confirm the 
doses for patients with normal renal functionand mild renal impairment,and with ongoing 
and final analysesto reconfirm tolerated doses totake forward into developmentof ATM-
AVI.
Data from Phase I studies did not show evidence of a drug-drug interaction (DDI) between 
ATM and AVI. Based on current knowledge, also the potential for DDIs between ATM-AVI 
and other drugs is low. Both ATM and AVI:
show linear (approximately dose proportional) pharmacokinetics, undergo limited 
metabolism and are eliminated primarily as unchanged substances by the kidney. 
showed no significant inhibition or induction of cytochrome P450 (CYP) enzymes in 
vitro and/or in vivo.
have low binding to human plasma proteins(ATM: approx. 43% [Crandon and 
Nicolau 2013; Vinks et al. 2007]; AVI: 5.7% to 8.2% [FDA prescribing info: 
AVYCAZTM2015])
Furthermore, data from Phase I studies suggest that there is no clinically relevant influence of 
sex or age on the pharmacokinetics of AVI (Tarral et al. 2015). Additional risk information for 
ATM, AVI and ATM-AVI is located in the IB.
In summary, the known and potential risks of receiving ATM-AVI are expected to be similar 
to those seen with ATM. Thus far, no unique riskshave been identified for the avibactam 
component or the combination of aztreonam and avibactam. 
The potential risks and discomforts to the individual subject are well balanced by providing 
best practice medical monitoring and clinical care for each patient and by the group-ethical 
relevance of the study. Under theconditions of the study as described in the present protocol, 
the investigators and the sponsor consider the benefit/risk relation to be positive (i.e. 
medically and ethically justified). 
1.4
Study Design 
This is a prospective, open-label, dose-confirming multicenterPhase IIa study to determine 
the PK, safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of 
hospitalized patientswith a complicated intra-abdominal infection (cIAI). Forty adult patients 
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with a diagnosis of cIAIand the need for a surgical intervention will be enrolled.The surgical 
intervention may take place within 24 hours before or afteradministration of the first dose of 
study drug. After obtaining written informed consent and confirming eligibility, patients will 
be assigned the following treatment:
Three potential cohorts are planned. From the study start, only patients with normal renal 
function or mild renal impairment (i.e. CrCl >50 mL/min; see Appendix E)will be eligible. 
The proposed administration of ATM-AVI for Cohort 1patientsis a loading dose (500 mg 
ATM plus 137 mg AVI by intravenous [IV] infusion over a 30 minute period), immediately 
followed by a dose of 1500 mg ATM plus 410 mg AVI by IV infusion over a 3 hour period 
every 6hours (maintenance infusion). The targeted total dose on Day 1 will be 6500 mg ATM 
and 1777 mg AVI. FromDay 2onwards,this will be 6000 mg ATM / 1640 mg AVI. Patients 
will also receive 500 mg metronidazole infused over 1 hour every 8 hours (q8h), starting after 
the first ATM-AVI maintenance infusion.Cohort 1 will contain a minimum of 10 and a 
maximum of 20patients.
Cohort 2 may useanincreased AVI dose. For patients with CrCl >50 mL/min, this would be 
an ATM-AVIloading dose (500 mg ATM plus 167mg AVI by intravenous [IV] infusion over 
a 30 minute period), immediately followed by a dose of 1500 mg ATM plus 500mg AVI by 
IV infusion over a 3 hour period every 6hours (maintenance infusion). Thus, the targeted total 
dose on Day 1 will be 6500 mg ATM and 2167mg AVI. FromDay 2onwards,this will be 
6000 mg ATM / 2000mg AVI. Patients will also receive 500 mg metronidazole infused over 
1 hour every 8 hours (q8h), starting after the first ATM-AVI maintenance infusion.In the 
event that Cohort 2 uses a higher AVI dose,Cohort 3 willbe a safetyexpansion cohort at one 
of the two dose regimens detailed above (to bring total number of enrolledpatients up to a 
maximum of 40).In the event that Cohort 2 uses the same AVI dose as Cohort 1, the study 
will continue up to a maximum of 40 patients with that same dosing regimen.
The PK, safetyand tolerability of the dosing regimen described above will be assessed in a 
first cohort of at least10 patients; i.e. recruitment into this initial cohort of patients will 
continue until 10 patients with CrCl >50mL/minhave completed all scheduled safety and PK 
assessments. After completion of all safety and PK assessments in 10 patients, an early patient 
review regarding safety and PK data will be made(see sections 5.2.5and 5.3.3).Patient safety 
laboratory data will be monitored on an ongoing basis and a summary output will be available 
for the 10 patients. Once 10 patients have completed all safety and PK assessments, there will 
be a pause in enrolment to complete the ongoing safety review and provide confirmation that 
the study can proceed beyond the first 10 patients, based on the available safety data.
At this time, the scientific advisory committee (SAC) will make recommendations to either 
discontinue the study, continue dosing Cohort 2 with no dose change, or to escalate to the 
higher AVI dose in Cohort 2. 
In the event that a higher AVI dose will be administered in Cohort 2, a second safety and PK 
review will occur once at least10 patients inCohort 2 have completed all safety and PK 
assessments. Patient safety laboratory data will be monitored on an ongoing basis and a 
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summary output will be available for the 10 patients. There will be a second pause in 
enrolment at this time to complete the second safety and PK review.
The SAC will make recommendations for the continuation of the study i.e., to continue 
treating patients in Cohort 3 (expansion) at the higher AVI dose, or to de-escalate the AVI 
dose.
Patients with moderate renal impairment (CrClof 31to 50 mL/min)must not be included 
prior to the completion of the earlysafety and PK review and subsequent confirmation of the
dosing regimen for these patients (see also section 1.2). Based on available population PK/PD 
modelling, the proposed administration of ATM-AVI for patients with moderate renal 
impairment will be a dose consistent with the dose selected for Cohort 2: 
In the event that the AVI dose in Cohort 2 is increased, a loading dose (500 mg 
ATM plus 167 mg AVI by intravenous infusion over a 30 minute period), 
immediately followed by an extended loading infusion of 1500 mg ATM plus 
500mg AVI over a 3 hour period. The maintenance infusions (starting 3 hours 
after stop of the extendedloading infusion) will be 750mg ATM plus 250 mg 
AVI over a 3 hour period, to be administered every 6 hours. The targeted total 
dose on Day 1 will be 4250 mg ATM: 500 mg (loading dose) + 1500 mg 
(extended loading infusion) + 3x 750 mg = 2250 mg (maintenance infusion)and 
1417 mg AVI: 167 mg (loading dose) + 500 mg (extended loading infusion) + 
3x 250 mg (maintenance infusion). From Day 2 onwards, this will be 3000 mg 
ATM (4x 750 mg maintenance infusion)/ 1000 mg AVI(4x 250 mg 
maintenance infusion). 
Or
In the event that Cohort 2 continues at the lower AVI dose, a loading dose (500 
mg ATM plus 137 mg AVI by intravenous infusion over a 30 minute period), 
immediately followed by an extended loading infusion of 1500 mg ATM plus 
410 mg AVI over a 3 hour period. The maintenance infusions (starting 3 hours 
after stop of the extendedloading infusion) will be 750mg ATM plus 205 mg 
AVI over a 3 hour period, to be administered every 6 hours. The targeted total 
dose on Day 1 will be 4250 mg ATM: 500 mg (loading dose) + 1500 mg 
(extended loading infusion) + 3x 750 mg = 2250 mg (maintenance infusion) and 
1162 mg AVI: 137 mg (loading dose) + 410 mg (extended loading infusion) + 
3x 205 mg (maintenance infusion). From Day 2 onwards, this will be 3000 mg 
ATM(4x 750 mg maintenance infusion)/ 820 mgAVI(4x 205 mg maintenance 
infusion). 
For anaerobic coverage, patients will also receive 500 mg metronidazole infused over 1 hour 
every 8 hours (q8h), starting after the firstATM-AVI maintenance infusion. 
Where possible, the SAC will use available information from population modelling and 
simulation methods as part of the safety and PK assessmentto evaluatethe relationships 
between emerging safety and PK data and confirm the dose regimensto be used. 
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Patients with a creatinine clearance of 31 –50 mL/min will be eligible if the results ofthe 
early PK and safety review (along with respective PK modellingincluding confirmation of the 
PK model used)
support inclusion of such patients and 
confirmtheproposed dosing regimen forthese patients
In all Cohorts, intravenous study therapy (ATM-AVI) plus metronidazole will be continued 
for a period of time (5 to 14 full days, where a full day is defined as a 24-hour period) deemed 
appropriate by the investigator based on the patient’s clinical response. After at least 5 full 
days of IV study therapy and at the discretion of the investigator, all study therapies may be 
discontinued if the patient has shown significant clinical improvement. Clinical improvement 
will be assessed by the investigator based upon fever and other signs and symptoms that 
demonstrate clear evidence of local and systemic improvement. The white blood cell count 
should be <12500/μL. The patient should be afebrile [<37.8°C] for at least 24hours, without 
the influence of antipyretic drugs,if possible. If analgesic medication is required for pain, the 
use of analgesics without antipyretic properties is preferred. 
It is anticipated that each patient willcomplete the study, including the Late Follow-up (LFU) 
visit. In the event the patient is discharged from the hospital before the End of Treatment 
(EOT), Test of Cure (TOC), or LFU visit, they will return to the study centrefor their 
scheduled assessment(see section 4.1).If treatment with antibiotics is required beyond 14 
days, the designated COMBACTE-CARE national coordinator or other designated study 
personnel should be contacted(see section 6.10). 
All patients will undergo sparse pharmacokinetic sampling on Day 1 of treatment. On Day 4, 
the first twenty five (25) patients will undergo intensive pharmacokinetic sampling, whereas 
the following fifteen (15) patients will undergo sparse sampling.
A flow-chart of the overall study design is shownin Figure 1.The study outline (visit 
schedule) is displayed in Figure 2.The detailed study plan and timing of procedures is 
presented in Table 1. For details on dosesand treatment regimes, see section 7.2.
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Figure 2
Study Outline
Visit 16
End of 
Therapy 
24h post 
infusion
Visit 3-15
Days 2-14
On 
treatment
Visit 1
Day 0
Eligibility / 
screening
Visit 2
Day 1
Baseline
and Day 1 
of study 
therapy
Visit 17
Days 25 3
Test of cure
Visit 18
Days 353
Late follow-
up
ATM-AVI 
Loading dose
+ q6h, 3hr infusion)
+ metronidazole
Min 5d, Max 14 d
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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To determine the pharmacokinetics (PK) of 
ATM-AVI in this patient population
Concentrations of ATM and AVI in plasma; 
concentration-time profile of ATM and AVI
The derived PK parameters Cmax, t
max, AUC
(0-6), 
AUC(0-last), t
last, t
1/2, V
ss, V
zand CL for the patients 
undergoing intensive sampling on day 4
To assess the safety of ATM-AVI in this 
patient population
Safety and tolerability as assessed by adverse events, 
physical examination, vital signs, ECGs, and 
laboratory assessments
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To assess the treatment outcome per patient at 
the test of cure (TOC) visit
Proportion of patients with clinical cure at the TOC 
visit
To assessthe relationship between exposure 
and clinical curefor ATM-AVI
Correlation of derived PKparametersfor ATM-AVI 
and clinical cureat TOC
2.3
Safety objectives
Safety Objective:
Outcome Measure:
See section 2.1(primary objective)
2.4
Exploratory objectives 
Exploratory Objective:
Outcome Measure:
Todevelop and evaluate pharmacokinetic / 
pharmacodynamic (PK/PD) models (Nonlinear 
Mixed Effect Model analysis [NONMEM], 
simulation) and to characterize population PK
Estimates of model parameters and their precision, 
goodness-of-fit, individual and mean predictions
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3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
The target subject population is 40 patients with a diagnosis of complicated intra-abdominal 
infection (cIAI). Apresumed diagnosis of cIAI is necessary for enrolment. The diagnosis of 
cIAI will be based on the patient’s clinical syndrome and will be supported by intra-operative 
findings, including intra-operative cultures. Operative intervention must be required and 
includes open laparotomy, laparoscopic surgery, and percutaneous drainage of an abscess. All 
patients will undergo a preliminary evaluation for eligibility within the 24-hour period prior to 
initiation of IV study therapy. 
Clinically indicated antibiotic treatment must not be delayed because patient is being 
considered for clinical trial participation.
According tocurrent scientific guidelines (“Guidelines by the Surgical Infection Society and 
the Infectious Diseases Society of America” [Solomkin et al. 2010])and regulatory guidelines
(FDA guideline on cIAI drug development as of February 2015 [FDA 2015]),cIAI is defined 
as follows:
Intra-abdominal infections comprise a wide variety of clinical presentations and differing 
sources of infection. cIAIs extend beyond the hollow viscus of origin (e.g. a singularly 
infected organ) into the peritoneal space and are associated with either abscess formation or 
peritonitis.Different bacterial pathogens are responsible for cIAIs, including Gram-negative 
aerobic bacteria, Gram-positive bacteria, and anaerobic bacteria, and there are also mixed 
infections. Uncomplicated intra-abdominal infections and complicated intra-abdominal 
infections may be difficult to distinguish, but in general cIAIs extend beyondlocal viscera into 
peritoneal or retroperitoneal spaces and are associated with systemic signs and symptoms of 
illness.Complicated intra-abdominalinfections require operative intervention or percutaneous 
drainage in conjunction with broad-spectrum antibacterial therapy. 
The exact clinical diagnoses and brief descriptions that define the population of patients with 
cIAI eligible for this study are given in section 3.1. Each patient should meet all of the 
inclusion criteria and none of the exclusion criteria for this study. The inclusion and exclusion 
criteria will be assessed by a siteinvestigator before enrolment of the patient to the study. 
Under no circumstances can there be exceptions to thisrule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteriawhich will be assessed 
by a siteinvestigator:
1. 
Provision of informed consent prior to any study specific procedures. If a patient is 
unable to provide informed consent at Screening, he/she may be entered into the 
study by his/her guardian or legal representative if in accordance with national and 
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local regulationsand as approved by the institutional specific guidelines. Those 
patients who are entered by the consent of a legally acceptablerepresentative should 
provide their own written informed consent for continuing to participate in the study 
as soon as possible on recovery, as applicable in accordance with national and local 
regulations.
2.
Male or female from 18 to 90 years of age inclusive
3.
Female patients are authorized to participate in this clinical study if at least one of 
the following criteria are met:
a)
Surgical sterilization, including hysterectomy and/or bilateral oophorectomy and/or 
bilateral salpingectomy, but excluding bilateral tubal occlusion;
b)
Age ≥50 and post-menopausal as defined by amenorrhea for 12 months or more 
following cessation of all exogenous hormonal treatments;
c)
Age <50 and post-menopausal as defined by luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) levels in the post-menopausal range PLUS amenorrhea 
for 12 months or more following cessation of all exogenous hormonal treatments 
(Note: if desired, LH and FSH may be checked at study entry to determine if 
women <50 and amenorrheic for 12 months are post-menopausal, but the patient 
must meet criterion “d” until LH and FSH confirm menopausal status);
d)
Both of the following conditions are met:

Patient has a negative serum pregnancy test (serum β-human chorionic 
gonadotropin [β-hCG]) within 1 day prior to enrolment (if the results of 
the serum β-hCG cannot be obtained prior to dosing of the investigational 
medicinal product[IMP], a patient may be enrolled on the basis of a 
negative urine pregnancy test, though serum β-hCG must still be obtained 
after enrolment). If either test is positive, the patient must be excluded. 
Since urine and serum tests may miss a pregnancy in the first days after 
conception, relevant menstrual history and sexual history, including 
methods of contraception, should be considered.

Patient agrees not to attempt pregnancy while receiving study drugs and 
for a period of 7 days after last dose of IV study therapy and agrees tothe 
use of the following acceptable methods of contraception: prior to and 
during the study(including 7 days after the last dose of IV study therapy)
use of an intrauterine device (with copper banded coil), levonorgestrel 
intrauterine system (e.g., Mirena®), regular medroxyprogesterone 
injections (e.g. Depo-Provera®), or sexual intercourse with only 
vasectomized partners (and verbal confirmation of azoospermia), or 
complete sexual abstinence for the recommended period. The woman 
should be stable on her chosen method of birth control for a minimum of 
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3 months at the time of signing informed consent forward to initiation of 
the IMP.See additional restrictions in section 3.8.
4.
Diagnosis of cIAI as defined in section 3as
EITHER:
Intra-operative/postoperative enrolment with visual confirmation (presence of pus 
within the abdominal cavity) of an intra-abdominal infection associated with 
peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage 
of an abscess, or laparoscopic surgery. Specimens from the surgical intervention 
must be sent for culture. Patients who undergo a surgical procedure with complete 
fascial closure are appropriate for the trial. The skin incision may be left open for 
purposes of wound management as long as complete fascial closure is 
accomplished. The patient has at least 1 of the following diagnosed during the 
surgical intervention:
(a)
Cholecystitis with gangrenous rupture or perforation or progression of the infection 
beyond the gallbladder wall
(b)
Diverticular disease with perforation or abscess
(c)
Appendiceal perforation or peri-appendiceal abscess
(d)
Acute gastric or duodenal perforations, only if operated on >24hours after 
diagnosis
(e)
Traumatic perforation of the intestines, only if operated on >12hours after 
diagnosis
(f)
Secondary peritonitis (but not spontaneous bacterial peritonitis associated with 
cirrhosis and chronic ascites)
(g)
Intra-abdominal abscess (including of liver or spleen provided that there is
extension beyond the organ with evidence of intraperitoneal involvement)
OR
Preoperative enrollment where the following clinical criteria are met with 
confirmation of infection by surgical intervention within 24 hours of entry
:
(h)
Requirement for surgical intervention, defined per protocol as open laparotomy, 
percutaneous drainage of an abscess, or laparoscopic surgery
(i)
Evidence of systemic inflammatory response, with at least one of the following:
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Fever (defined as body temperature >38°C) or hypothermia with a core body 
temperature <35°C
Elevated white blood cells (>12000 cells/µL)
Systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg, or a 
systolic blood pressure decrease of >40 mmHg
Increased heart rate ( >90 bpm) and respiratory rate (>20breaths/min)
Hypoxemia (defined as oxygen saturation < 95% by pulse oximetry)
Altered mental status.
(j)
Physical findings consistent with intra-abdominal infection, such as:
Abdominal pain and/or tenderness, with or without rebound
Localized or diffuse abdominal wall rigidity
Abdominal mass.
(k)
Supportive radiologic imaging findings of intra-abdominal infection such as 
perforated intraperitoneal abscess detected on computed tomography scan, magnetic 
resonance image, or ultrasound.
(l)
Specimens from the surgical intervention will be sent for culture for isolation of 
both aerobic and anaerobic bacteria.
5.
If applicable:Patientswho failed prior antibacterial treatment for theircurrent cIAI 
can be enrolled but must: 
Have a known or suspectedpathogen causing cIAI resistantto the prior therapy 
while assuming the organism is sensitive to ATM-AVI.
Require surgical intervention. 
Such patients can be enrolled before the results of the culture are known(see also 
exclusion criterion 10).
6.
Patient must have had or will have a surgical intervention within 24 hours (before or 
after) the administration of the first dose of study drug. As a prerequisite for 
inclusion, a specimen from an abdominal source must be obtained for culture during 
surgical intervention. Surgical intervention includes open laparotomy, percutaneous 
drainage of an abscess, or laparoscopic surgery. Isolates taken from surgical wound 
exudates mustnot be used.
3.2
Exclusion criteria
Patients should not enter the study if any of the followingexclusion criteria are fulfilledwhich 
will be assessed by a siteinvestigator:
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1.
Involvement in the planning and/or conduct of the study (applies to both sponsor
staff and/or staff at the study site)
2.
Patient has been previously enrolled in this study, previously treated with ATM-
AVI or previously participated in an investigation study containing AVI
3.
Patient has participated or intends to participatein any other clinical study that 
involves the administration of an investigational medication at the time of 
presentation, during the course of the study, or during the 30 days prior to study 
start
4.
Patient has a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any 
serious reaction to aztreonam, carbapenem, monobactam or other β-lactam 
antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of 
the respective (investigational) medicinal products to be administered during the 
study
5. 
Patient has a diagnosis of abdominal wall abscess; small bowel obstruction or 
ischemic bowel disease without perforation; traumatic bowel perforation with 
surgery within 12 hoursof diagnosis; perforation of gastroduodenal ulcer with 
surgery within 24 hours of diagnosis (these are considered situations of peritoneal 
soiling before infection hasbecome established); another intra-abdominal process in 
which the primary etiology is not likely to be infectious
6.
Patient has a simple cholecystitis, gangrenous cholecystitis without rupture, simple 
appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, 
pancreatic abscess or ischaemic/necrotic intestine without perforation
7.
Patient has a cIAI managed by staged abdominal repair (STAR), open abdomen 
technique or any situation where infection source control is not likely to be 
achievedor in whom the abdomen is left open, or those unlikely to solely respond 
to antimicrobial therapy
8. 
At screening, if it is known the patient has an infection due to a pathogenthat is 
unlikely to respond to ATM-AVI plus metronidazole treatment
9. 
Patient has arapidly progressive (expected to die in <30 days) or terminal illness, 
including acute hepatic failure, respiratory failure or septic shock with a high risk of 
mortality due to other causes than cIAI
10.
Patient has received systemic antibacterial agents within the 72-hour period prior to 
study entry, unless either of the following pertains:
(a) Patient has a new infection (not considered a treatment failure) and the 
following is met:
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
Patient received no more than 24 hours of total prior antibiotic therapy 
within the 72hour periodprior to study entry
(b) Patient is considered to have failed the previous treatment regimen (see 
Inclusion criterion no 5)
In this case, preoperative treatment of any duration with non-study systemic 
antimicrobial therapy for peritonitis or abscess is permitted provided that all of the 
following are met:

The treatment regimen has been administered for at least 72 hours and is 
judged to have been inadequate.

The patient has an operative intervention completed within 24 hours prior 
tostudy entryoran operative intervention is intended no more than 24 
hours afterstudy entry

Findings of infection were documented at surgery.

Specimens for bacterial cultures and susceptibility testing are taken at 
operativeintervention. 

Non-study antibacterials are discontinued at the time of study enrolment
11.
Patient has a concurrent infection that may interfere with the evaluation of clinical 
cure for the study therapy
12.
Patient needs effective concomitant systemic antibacterials (oral, IV, or 
intramuscular) or antifungals in addition to ATM-AVI and metronidazole, except 
vancomycin, linezolid, or daptomycin if started for suspected or documented 
methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus spp. (see 
section 7.7)
13.
Patient has creatinine clearance ≤30 ml/min as calculated by Cockcroft-Gault 
formula(Cockcroft and Gault 1976; see Appendix E)or requirement for peritoneal 
dialysis, hemodialysis orhemofiltration, or oliguria (<20 mL/h urine output over 24 
hours).
14. 
Patient has had acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis 
(any Child-Pugh class), acute hepatic failure, or acute decompensation of chronic 
hepatic failure
15.
Presence of hepatic disease as indicated by aspartate aminotransferase (AST) or 
alanine transaminase (ALT)>3 × upper limitof normal (ULN) at Screening. 
Patients with AST and/or ALT >3 × ULN and <5 × ULN are eligible if these 
elevations are acute, not accompanied by a total bilirubin ≥2xULNand documented 
by the investigatoras being directly related to the infectious process being treated
16.
Patient has a totalbilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly 
related to the acute infection or due to known Gilbert’s disease
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17.
Alkaline phosphatase (ALP) >3× ULN. Patients with values >3 × ULN and <5x
ULN are eligible if this value is acute and directly related to the infectious process 
being treated. 
18. 
Patients with an immunocompromising illness, including known human 
immunodeficiency virus (HIV) with<200/µLCD4+ positivity or acquired 
immunodeficiency syndrome (AIDS), organ (including bone marrow) transplant 
recipients, and uncontrolled hematological malignancy. Immunosuppressive 
therapy, including use of high-dose corticosteroid therapy (e.g. >40 mg prednisone 
or equivalent per day for greater than 2 weeks)
19.
KnownactiveClostridium difficileassociated diarrhoea
20.
Any other condition that, in the opinion of the investigator, may confound the 
results of the studyor pose additional risks in administering the study therapy to the 
patients
21. 
Patient with a do not resuscitate order (i.e., those patients in whom life sustaining 
measures [cardio-pulmonary resuscitation and / or mechanical ventilation] would 
not be undertaken when medically indicated)
22. 
Patient has an absolute neutrophil count <1000/µL
23.
Patient has a hematocrit <25% or hemoglobin <8 gm/dL. 
24.
Patient has a platelet count <75,000/µL. Patients with a platelet count as low as 
50,000/µLare permitted if the reduction is historically stable
25.
Patient is currently receiving treatment with probenecid.
26. 
Patient is pregnant or breastfeeding or if of child bearing potential, not using a 
medically accepted, effective method of birth control as listed in the Inclusion 
criteria. Any patient whose menstrual or sexual history suggests the possibility of 
early pregnancy must be excluded.A serum β-hCG pregnancy test must be 
performedfor women of childbearing potential at the screening visit. If the results 
of a serum β-hCG pregnancy test cannot be obtained prior to dosing of the 
investigational medicinal product, a patient maybe enrolled on the basis of negative 
urine pregnancy test though serum β-hCG must still be obtained. If either test is 
positive, the patient will beexcluded.
27.
Patient is unlikely to comply with protocol, e.g., uncooperative attitude, inability
 to 
return for LFU visits and unlikelihood of completing the study
28.
Patient is currently receiving anti-convulsant therapy to prevent recurrence of a past 
history of seizures. Past history of seizures or epilepsy (excluding febrile seizures of 
childhood). 
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29.
Patient has a prior liver, pancreas or small-bowel transplant.
Procedures for withdrawal of incorrectly enrolled subjects:see section 3.4.
3.3
Patient enrolment 
All investigators should keep a record, the patient screening log, of patients who entered pre-
study screening.
The investigators will:
1.
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. If a patient is unable to provide informed consent at 
Screening, he/she may beentered into the studyby his/her guardianor legal 
representative if in accordance with national and local regulations. Those patients
who are entered by the consent of a legally acceptable representative should provide 
their own informed consent for continuing to participate in the study as soon as 
possible on recovery, as applicable in accordance with national and local 
regulations.
2.
Assign the potential patient a unique enrolment number, beginning with ‘E#’.
(EXXXX-YYY)” where XXXX reflects the center number and YYY will be 
allocated sequentially to enrolled patients at each center. Example: “E0001-001” 
represents patient number one at centernumber one.
3. 
Confirm patient eligibility (according to inclusion and exclusion criteria)
As this is an open-label study withPK and safetyas primary objectives, there will be no 
randomization (see section 1.2). The enrolment number is assigned to each subject as a unique 
identifier. Upon completing the enrolment information in the eCRF, a notification will be sent 
out to the sponsorand Clinical Trial Center Cologne (CTCC). 
If a subject withdraws from participation in the study, then his/her enrolment number cannot 
be reused. Withdrawn or discontinued patients will not be replaced.
3.4
Procedures for handling incorrectly enrolled subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. 
Where a subject does not meet all the eligibility criteria but is enrolledin error, or incorrectly 
started on study treatment, the investigator should contact the country specific national study 
coordinator or the sponsor’s Medical Monitoras outlined in section 6.10. Adiscussion should 
occur between thesponsor’s Medical Monitorand the investigator regarding whether to 
continue or discontinue the patient from study treatment. The study physician mustultimately
ensure all decisions are appropriately documented.Contact details of the respective national 
coordinators and the sponsor’smedical contacts are also provided in appropriate site 
documents.
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3.5
Methods for assigning treatment groups
All patients being enrolled and fulfilling all eligibility criteria will receive an intravenous 
treatment with ATM-AVI and metronidazole. There will be no randomization (see section 
1.2).
In a first cohort of 10 patients, with CrCl>50 mL/min, having completed allsafetyandPK 
assessments, an early patient review regarding safety and PK data will be undertaken. There 
will be a pause in enrolment to complete the ongoing safety review and provide confirmation 
that the study can proceed beyond the first 10 patient cohort, based on the available safety 
data. For the first cohort,only subjects with normal renal function or mild renal impairment 
(CrCl>50 mL/min;to be determined as described in Appendix E) will be eligible. 
After completion of the earlysafety and PK review,recruitment of patients with moderate 
renal impairment (CrCl 31to 50 mL/min) maybe allowed with a separate dosing regimen. In 
Cohort 2, and in a potential Cohort 3, anincreased AVI dose may be administered. For details 
on the dosing regimens and on the criteria for assigning patients to treatments inCohorts 2 
and 3,see sections 1.4Study design and 7.2Dose and treatment regimens.
In some patients, the creatinine clearance estimated from serum creatinine can change quickly, 
especially early in the course of treatment for the infection.Renal function should be closely 
monitored throughout the treatment period i.e., daily, and the dose of ATM-AVI adjusted
according to the CrCl value calculated by the Cockcroft-Gault formula (Appendix E), using 
serum creatinine measurement by the local laboratory. Local laboratory test results will be 
entered into the eCRF.
In the case that renal functionrecovers or deteriorates in Cohort 2 or 3 patients during the 
treatment period (i.e., local or central lab results show CrCl increases from 31 –50 mL/min at 
baseline to >50 mL/min, or decreases from >50 mL/min at baseline to 31 –50 mL/min), the 
dose of ATM-AVI should be adjusted by the investigator to meet the applicable dose regimen, 
based on the latest CrCl value.
All patients will undergo sparse pharmacokinetic sampling on Day 1 of treatment. On Day 4, 
the first twenty five (25) patients will undergo intensive pharmacokinetic sampling, whereas 
the following fifteen (15) patients will undergo sparse sampling.
3.6
Methods for ensuring blinding: Not applicable
3.7
Methods for unblinding: Not applicable
3.8
Restrictions for patients during the study

Patients must abstain from donating blood/plasma from the time of informed 
consent and for at least 3 weeks after the last dose of the investigational medicinal 
product (i.e. until late follow-up visit). 

Hormonal contraceptives potentially subject to drug-drug interaction, such as oral 
contraceptives, patches and intra-vaginal devices, are not acceptable methods of 
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contraception during this study based on the potential ofantibiotics to alter gut 
flora, hormone absorption and hormone effectiveness. The effect of ATM-AVI on 
the efficacy of such contraceptives has not yet been established. If a female study 
participant was previously using hormonal contraceptives such as pills, patches and 
intra-vaginal devices, she should follow her health care provider’sspecific 
recommendations for effective use of these methods after completing the study 
drugs. Such recommendations may address the need for a second method of 
contraception until the hormonal method becomes fully effective. 
During the study, barrier methods (such as male condom or diaphragm with 
spermicide) can be used only if another method of acceptable contraception is also 
used. Acceptable methods are listed in section 3.1.
3.9
Discontinuation of Investigational Medicinal Product(IMP)
Patients may be prematurely discontinued from IMP (i.e., prior to cure) in the following 
situations:

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

Occurrence ofan adverse event or any other condition posing a risk to a patient or 
jeopardizing a safe continuation of the study treatment for the respective patient (as 
judged by the investigator and/or the national coordinators, and/or the CTCCon 
behalf of COMBACTE-CARE andthesponsor).

Severe noncompliance to study protocol, as judged by the investigator and/or 
CTCC or the sponsor.

Positive pregnancy test at any time during the study.

Treatment failure.

In the opinion of the investigator, it is not in the best interest of the patient to 
continue the IV study therapy or at the request ofnational coordinators, and/or the 
CTCC on behalf of COMBACTE-CARE and thesponsor, that the patient stops 
participation.

Prior to availability of the results of the early patient safety and PK review:
If CrCl falls to ≤ 50 mL/min, the IV study therapy should be stopped and the patient 
followed up to the end of the study. Recruitment into this initial cohort of patients 
will continue until 10 patients with CrCl > 50 mL/min have completed all PK and 
safety assessments as scheduled. 
After availability of the results of the early patient safety and PK review:
Provided the results confirm the eligibility of patients with CrCl of 31 –50 mL/min, 
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the following discontinuation criterion applies: If CrCl falls to ≤ 30 mL/min,the IV 
study therapy should be stopped and the patient followed up to the end of the study.

In the absence of any alternative explanationfor an increase in the following 
abnormalities, individual patients should be withdrawn if the following criteria are 
met:
ALT or AST >8 × ULN
ALT or AST >5× ULN for more than 2 weeks
ALT or AST >3 × ULN and either total bilirubin >2 × ULN or evidence of 
coagulopathy. Evidence of coagulopathy should be discussed with the study
physician where possible.
ALT or AST >3 × ULN and with appearance of symptoms suggestive of new 
or progressive liver disease. Symptoms suggestive of new or progressive liver 
disease should be discussed with the studyphysician where possible.
Patients with initial baseline transaminases >3xULN and<5xULN, documented 
as being directly related to infection being treated, progressing to:

ALT or AST ≥ 5×ULN and evidence of coagulopathy 

ALT or AST ≥ 5×ULN with symptoms suggestive of new or progressive 
liver disease 
For monitoring of liver-related laboratory parameters, see section 6.7.3. For early safety 
review, see section 5.2.5.For (potential) Hy’s Law cases, see section 6.3.7and Appendix D.
3.9.1
Procedures for discontinuation of a patient from IMP
A patient who decides to discontinue IMP will always be asked about the reason(s) and the 
presence of any AEs. If possible, the patient will be seen and assessed by an investigator at the 
time of discontinuation from the IMP. For patients who discontinue IMP, their scheduled 
follow-up visits, data collection and study procedures / assessments should be performed 
according to study plan until study closure. 
The patient should be scheduled for the EOT visit within 24 hours after IV study therapy 
discontinuation. Liver CRF modules should be completed for patients discontinued after 
meeting hepatic/liver criteria. Adverse events and SAEs will be followed up as described in 
sections 6.3and 6.4. For handling of unused IMP see section 7.6. 
3.10
Withdrawal from study
Patients are at any time free to withdraw from the study (i.e. IMP andassessments), without 
prejudice to further treatment (withdrawal of consent). Such patients will always be asked 
about the reason(s) and the presence of any AEs. If possible, the patient will be seen and 
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assessed by an investigator at the time of withdrawal and at the LFU visit. Adverse events and 
SAEs will be followed up as described in sections 6.3and 6.4. For handling of unused IMP 
see section 7.6.
Any withdrawal should be notified immediately to the CTCCand the sponsor. To this end, 
study center personnel should fill out the end of study form in the study database. Ifa patient 
withdraws from participation in the study, then his/her enrolment code cannot be reused.
Withdrawal of consent for the use of donated biological samples is discussedin Section 5.6.4.
3.11
Discontinuation of the study
Criteria for discontinuation of the study before (or following) the early safety review are 
described in sections 5.2.5.4and 5.2.5.5. Furthermore, the entire study may be stopped by the 
Sponsor at any time ifconcerns for safety arise within this study or in any other study with 
ATM-AVI. In particular, the study may be stopped, if (in the judgment of the Sponsor)trial 
patients are placed at undue risk because of clinically significant findings that:

meet individual stopping criteria or are otherwise considered significant 
(see also section 3.9)

are assessed as causally related to study therapy

are not considered to be compatiblewith continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented. In terminating the study, the Sponsor will ensure that adequate 
consideration is given to the protection of the patients’ interests. 
The study may be terminated at individual centers at any time by the Sponsor if the study 
procedures are not being performed according to GCP,if concerns for safety arise or if 
recruitment is slow. 
For end-of-study definition and timetable seesection 9.4.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Study periods are defined inFigure 2. Details of the study plan and timing of procedures are 
provided inTable 1. 
Every effort should be made to collect all the data, blood samples, and cultures and to 
complete all assessments required for each visit as detailed in the Study Plan detailing the 
proceduresand discussed by visit in the following sections.
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4.1
Study visits and procedures 
Prior to any study specific procedures, patients (or their legally acceptable representative if 
applicable) must provide written informed consent. Enrolment/screening procedures will be 
performed according to the Study Plan detailing the procedures. At screening, patients are
assessed to ensure that they meet eligibility criteria. Patients who do not meet all of these 
criteria must not be enrolled in the study.
All subjects will be asked to provide consent to supply blood, urine and microbiological 
samples as required for the eligibility assessment and further study procedures. This consent is 
included in the patient informed consent form (ICF).
4.1.1
Visit 1: eligibility/screening procedures (Day 0)
Procedures for Visit 1 will vary depending on the timing of surgery relative to the visit.At 
Eligibility/Screening (Day0), each potential patient (or his/her legally acceptable 
representative) will providewritteninformed consent prior to starting any study-specific 
procedures. Visit 1 (eligibility/screening) may occur up to 24 hours pre-or postoperatively.
Each patient will undergo screening assessment procedures within24hours prior to the first 
dose of IV study therapy. Local laboratory test results will be used to qualify patients for 
inclusion. To this end, the following assessments need to be performed in the local laband 
entered in the eCRF: serum creatinine (includingcalculation of CrCl), serum pregnancy test 
(orurine pregnancy test for preliminary enrolment if serum test result is not available at 
screening; see section3.1d)), AST, ALT, ALP, total bilirubin, and hematologyas listed in 
section 3.1and 3.2. GGTand INR will be determined in the local lab at screening as baseline 
safety assessment.
Provided all lab values tobe determinedin the local lab (see above) have been determinedfor 
routine clinical management of the patientwithin 24 hours prior to the first dose of IV study 
therapy, additional sampling for analysesin the local labat screening is not required, and the 
values already obtained should be entered in the eCRF.
In addition, safety lab samples mustbe sent to the central reference laboratoryfor testing(see 
section 5.2.1).
Screening assessments will consist of:
1. 
Obtaining informed consent.
2.
Reviewing of the inclusion and exclusion criteria with the patient or a legally 
acceptable representative.
3.
Collecting demographics.
4.
Collecting smoking and alcohol history
5.
Collecting medical and surgical history.
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6.
Reviewing prior and current medications (including prior antibiotic therapy).
7.
Performing complete physical examination as defined in Section5.2.2
8. 
Assessing infection-related(e.g. abdominal) signsand symptoms.
9.
Measuringvital signs including supine blood pressure, heart rate, body temperature 
and height/weight prior to dosing as defined in Section 5.2.4. 
10.
Collecting AEs.
11.
Obtaining blood cultures.
12. 
Obtain clinically relevant culturesand send any pathogen isolated to the central lab. 
Clinically relevant isolates may originate from both intra-abdominal and other sites. 
13.
Obtaining blood and urine samples for safety analysis (central reference laboratory)
14.
Obtaining blood samples for eligibility andbaseline safety assessmentsat the local 
lab: serum creatinine (including calculation of CrCl), serum pregnancy test (orurine 
pregnancy testfor preliminary enrolment if serum test result is not available at 
screening; see section 3.1d)), AST, ALT, ALP, GGT, INR, total bilirubin, and 
hematology.
15. 
Estimating creatinine clearance using the serum creatinine results from the local 
laboratory.In case a local lab result is not available, the creatinine result of the 
safety lab must be used (to be sent to central lab). See Appendix E for calculation.
16.
Obtaining blood sample for serum β-hCG for women of childbearing potential
(central reference laboratory)
17.
Recording radiologicalexaminations (only if done as part of the diagnosis of the 
disease under study). Radiological examinations include -but are not limited to -
white blood cell scans, PET scans, plain abdominal radiographs, computed 
tomography scans, ultrasound, and/or magnetic resonance image scans with or 
without contrast
Patients who have Visit 1 postoperatively should have the following additional assessments:
18.
Focused physicaland wound examinations postoperatively.
19. 
Must have obtained a specimen for culture from the site of abdominal infection as 
described in section 5.1.2during a surgical procedure.
20.
Collecting description of operative procedures (as available).
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4.1.2
Visit 2: eligibility/baseline procedures and Day 1 of treatment
Procedures for visit 2 will vary depending on the timing of the visits 1 and 2 relative to 
surgery. Visit 2 may occur pre-or postoperatively. 
Local laboratory test results obtained at Visit 1 will be used to qualify patients for inclusion
(see section 4.1.1).At Visit 2, blood and urine samples for safety analysis (and further 
assessments as listed in points 12to 15 of this section) are only required if Visit 1 and Visit 2 
are separated by surgery or are more than 12 hours apart.Ifsafety lab samplesare required, 
theyshould be collected prior to dosing (exception: if visit 2 occurs pre-operatively, study 
drug may be administered before collecting abdominal cultures; see below 7). The samples 
mustbe sent to the central reference laboratory for testing. 
The following assessments should be performed for all patientsat Visit 2:
1. 
Reviewing of the inclusion and exclusion criteria with the patientor alegally 
acceptable representative.
2.
Reviewing prior and concomitant medications.
3. 
Measuring vital signs including supine bloodpressure, heart rate and body 
temperature as defined in Section 5.2.4.
4.
Performing a standard 12-lead electrocardiogram (ECG) prior to dosing. The patient 
should be resting in a supine position for at least 10 minutes prior to the evaluation 
(see section 5.2.3).
5.
Collecting new AEs and reviewing ongoing AEs.
6.
If a previous blood culture result was positive, repeat samples must be collected at 
least every 3 days until clearance of bacteremia has been documented. Blood 
cultures may also be obtained as clinically indicated.
7.
Obtaining culture from site of abdominal infection (if not already collected at 
Visit1 [Note: if Visit 2 occurs pre-operatively, study drug may be administered 
before collecting abdominal cultures;however,they must be collected during the 
surgery]).
8.
Obtain isolates from any body sites where infection is suspected. Any isolated 
pathogen must be sent to the central lab. Clinically relevant isolates may originate 
from both intra-abdominal and other sites.
9.
Collecting description of operative procedures (as available and if not obtained at 
Visit 1).
10. 
Administering IV study therapy. Note:all other baseline assessments should be 
completedbefore the patient receivesthe first dose of IV therapy. The only 
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exception to this is that patients may receive study therapy before obtaining 
abdominal cultures if Visit 2 occurs pre-operatively.
11.
Obtaining blood samples for PK analysis (see section 5.3.1for details)
In addition, the following assessments mustbe performed only if Visit 1 and Visit 2 are 
separated by surgery or occur >12 hours apart:
12. 
Assessing infection-related signs and symptoms plus abdominal and wound 
examinations postoperatively.If Visit 2 occurs preoperatively, this assessment 
needs to be done after surgery.
13.
Obtaining blood and urine samples for safety analysis (central reference laboratory).
14. 
Estimating creatinine clearance using the serum creatinine results from the local 
laboratory.In case a local lab result is not available, use the creatinine clearance 
result of the Safety lab (samples sent to central lab). Check applicable dose 
according to CrCl result(see section 7.2). See Appendix E for calculation.
4.1.3
Visits 3 to 15 (Days 2 to 14):ongoing treatment period
The total durationof combined treatment with IV study therapy will be a minimum of 5 and a 
maximum of 14 full days(one day = 24 hours). Those patients who require continuation ofIV 
study therapy after 5 days (i.e. after the loading dose and 20 maintenance IV doses) will 
continue to receive their IV study therapy by study center personnel in the hospital. Following 
discharge from the hospital,the patientsareto return to the study center for their scheduled 
visits. Thefollowing assessment procedures will be performed during treatment with IV study 
therapy:
1. 
Reviewing concomitant medications (daily).
2.
Assessing infection-related signs and symptoms plus abdominal and wound 
examinations postoperatively (daily).
3.
Measuring vital signs (daily) including supine blood pressure, heart rate and body 
temperature as defined in section 5.2.4.
4.
On Day 3 only -two ECG measurements: one measurement at the end of an 
ATM/AVI infusion period and one measurement prior to starting the next ATM-
AVI infusion(see section 5.2.3).
5.
Collecting new AEs and reviewing ongoing AEs (daily). Should a patient 
experience significant diarrhea during or after IV study therapy, the investigator 
should obtain a stool sample for Clostridium difficiletoxin testing.
6.
Obtaining culture from site of abdominal infection and any other body site where 
infection is suspected (as clinically indicated).
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7.
If a previous blood culture result was positive, repeat samplesmust be collected at 
least every 3 days until clearance of bacteremia has been documented. Blood 
cultures may also be obtained as clinically indicated.
8.
Obtaining blood and urine samples for safety analysis and calculation of CrCl (only 
day 4, 7, 10and 13; i.e. every 3 days until EOT; send samples to central reference 
laboratory).Samples collected on day 4, 7, 10 and 13 can be collected ±1 day.
9.
During treatment, daily assessment of AST, ALT, ALP, GGT, total bilirubin and 
creatinine clearance in local lab.On treatment days where clinical chemistry 
samples are taken for routine clinical management of the patient, these samples 
should be used to assess AST, ALT, ALP, GGT, total bilirubinand CrCl, in order to 
avoid additional sampling for study purposes.Enter valuesin the eCRF.Review of 
calculated CrCl and, where necessary, adjustment of ATM-AVI dose (Cohort 2 and 
3 only; see section 7.2). Review of AST, ALT, ALP, GGT andtotal bilirubin value 
and, where necessary, initiation of additional measures as listed insections 6.7.3
and 3.9. 
10.
On Day 4 only -obtaining blood samples for PK analysis (see section 5.3.1for 
details). To provide greater flexibility, PK samples can becollected on Day 4 ± 1 
day. 
11.
Collecting description of operative procedures (any post-baseline procedures as 
available and if not obtained at prior visits).
12.
Administering IV study therapy (daily for a minimum of 5full days to a maximum 
of 14full days, where a full day is defined as a 24-hour period).
4.1.4 
Visit 16:end of IV therapy (EOT) procedures
The following procedures will be performed within 24 hours after the completion of the last 
infusion of IV study therapy:
1. 
Reviewing concomitant medications.
2.
Performing complete physical examination as defined in Section5.2.2
3.
Assessing infection-related signs and symptoms plus abdominal and wound 
examinations postoperatively.
4. 
Measuring vital signs including supine blood pressure, heart rate and body 
temperature as defined in Section 5.2.4.
5.
Performing a standard 12-lead electrocardiogram (ECG). The patient should be 
resting in a supine position for at least 10 minutes prior to the evaluation (see 
section 5.2.3).
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6.
Collecting new AEs and reviewing ongoing AEs (daily). Should a patient 
experience significant diarrhea after IV study therapy, the investigator should obtain 
a stool sample for Clostridium difficiletoxin testing.
7. 
Obtaining culture from site of abdominal infection and any other body site where 
infection is suspected (as clinically indicated).
8.
If a previous blood culture result was positive, repeat samples must be collected at 
least every 3 days until clearance of bacteremia has been documented. Blood 
cultures may also be obtained as clinically indicated
9.
Obtaining blood and urine samples for safety analysis (central reference laboratory).
10. 
Assessingcreatinine clearance using the creatinine clearance results from the safety 
analysis (samples sent to central lab). 
11.
Collecting description of operative procedures (any post-baseline procedures as 
available and if not obtained at prior visits).
12. 
Determining clinical response assessment (see section 5.1.1for details)
13.
Mortality assessment by the investigator in case of death (including causality 
attribution and reason of death)
4.1.5
Visit 17 test of cure (TOC) procedures (Day 25 +/-3 days)
If it is not possible to perform the TOC on study Day 25 (e.g., the patient is on holiday), then 
the allowed visit window is Day 22 to 28.
TOC visit assessment procedures include:
1. 
Reviewing concomitant medications.
2.
Performing complete physical examination as defined in Section5.2.2
3.
Assessing infection-related signs and symptoms plus abdominal and wound 
examinations postoperatively.
4. 
Measuring vital signs including supine blood pressure, heart rate and body 
temperature as defined in Section 5.2.4.
5.
Collecting new AEs and reviewing ongoing AEs (daily). Should a patient 
experience significant diarrhea after IV study therapy, the investigator should obtain 
a stool sample for Clostridium difficiletoxin testing.
6.
Obtaining culture from site of abdominal infection and any other body site where 
infection is suspected (as clinically indicated).
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7.
If a previous blood culture result was positive, repeat samples must be collected at 
least every 3 days until clearance of bacteremia has been documented. Blood 
cultures may also be obtained asclinically indicated.
8.
Obtaining blood and urine samples for safety analysis (central reference laboratory).
9. 
Assessingcreatinine clearance using the creatinine clearance resultsfrom the safety 
analysis (sent to central lab). 
10.
Collecting description of operative procedures (any post-baseline procedures as 
available and if not obtained at prior visits).
11. 
Determining clinical response assessment (see section 5.1.1for details)
12.
Mortality assessment by the investigator in case of death (including causality 
attribution and reason of death)
4.1.6
Visit 18: late follow-up (LFU) procedures (Day 35 +/-3 days)
If it is not possible to perform the LFU on study Day 35 (e.g., the patient is on holiday), then 
the allowed visit window is Day 32 to 38.
LFU visit assessment procedures include:
1. 
Reviewing concomitant medications.
2.
Performing complete physical examination as defined in Section5.2.2
3.
Assessing infection-related signs and symptoms plus abdominal and wound 
examinations postoperatively.
4. 
Measuring vital signs including supine blood pressure, heart rate and body 
temperature as defined in Section 5.2.4.
5.
Collecting new AEs and reviewing ongoing AEs (daily). Should a patient 
experience significant diarrhea after IV study therapy, the investigator should obtain 
a stool sample for Clostridium difficiletoxin testing.
6.
Obtaining culture from site of abdominal infection and any other body site where 
infection is suspected (as clinically indicated)
7.
If a previous blood culture result was positive, repeat samples must be collected at 
least every 3 days until clearance of bacteremia has been documented. Blood 
cultures may also be obtained as clinically indicated.
8. 
Obtaining blood and urine samples for safety analysis (central reference laboratory).
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9. 
Assessingcreatinine clearance using the creatinine clearance results from the safety 
analysis(sent to central lab). 
10.
Obtaining blood sample for serum β-hCG for women of childbearing potential 
(central reference laboratory).
11.
Collecting description of operative procedures (any post-baseline procedures as 
available and if not obtained at prior visits).
12.
Determining clinical response assessment (see section 5.1.1for details).
13.
Mortality assessment by the investigator in case of death (including causality 
attribution and reason of death)
5.
STUDY ASSESSMENTS 
The web based Electronic Data Capture (EDC)and Clinical Data Management System 
TrialMaster (OmniComm Systems, Inc.) will be used for data collection and query handling. 
The investigator will ensure that data are recorded on the electronic Case Report Forms 
(eCRF) as specified in the study protocoland in accordance with the instructions provided.
The central laboratory will provide ongoing safety laboratory data, including liver function 
test data, to the CTCC and the sponsorand the scientific advisory committee, to inform per 
patient decisions and for the earlypatient safety and PK review.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign thecompleted eCRF. A copy of the completed eCRFwill be archived at 
the study site at the end of the trial.
5.1
Clinical and microbiologicalassessments
5.1.1
Efficacy assessment:Clinical response
The investigator will determine the treatment outcome (clinical response) at the EOT, TOC 
and LFU visitas either cure, failure or indeterminate in the MITT populationsaccording to the 
definitions given in Table 2. In case of failure, the reason for failure will be indicated 
according to the clinical response definitions shown in Table 2.
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Table 2: 
Definitions of clinical response at the EOT, TOC, LFU visits
Clinical 
Response
Definition
Cure
Complete resolution or significant improvement of signs andsymptoms of the index 
infection (cIAI) such that no further antimicrobial therapy, drainage, or surgical 
intervention is necessary and does not meet any of the failure criteria listed below.
Failure
Patients who meet any 1 of the following criteria will be considered a treatment failure:
Death related to intra-abdominal infection
Patient who received treatment with additional antibiotics for ongoing symptoms 
of cIAI (including patients prematurely discontinued from study therapy due to an 
adverse event who require additional antibiotics for cIAI)
Patient previously met criteria for failure (i.e. prior to respective visit)
Persisting or recurrent infection within the abdomen documented by the findings at 
re‑intervention either percutaneously or operatively(exception: the re-intervention 
was already planned at initial surgery to check proper infection/focus control, 
occurs within 96 hours after enrolment, does not show deterioration and includes 
fascial closure)
Post-surgical wound infections defined as an open wound with signs of local 
infection such as purulent exudates, erythema, or warmth that requires additional 
antibiotics and/or non-routine wound care
Indeterminate
Study data are not available for evaluation of efficacy for any reason, including:
Patient lost to follow-up or assessment not undertaken such that a determination of clinical 
response cannot be made
Abbreviations: cIAI, complicated intra-abdominal infection; EOT, End of Treatment (with study therapy); LFU, 
Late follow-up; TOC, Test of Cure.
5.1.2
Microbiological assessments
All microbiological assessments will be initiated at the local laboratory for specimen 
collection, shipment of isolates, and analysis of isolates according to the sections below and as 
outlined in more detail in the microbiological (study site)manual.Details regarding the 
microbiological analyses in the Central Laboratory are described in the Laboratory Manual.
The data obtainedat the Central Laboratory will be used for further study-related assessments 
(see below).
Specimen collection:
An adequate intra-abdominal culture specimen (such as tissue or aspirate suitable for isolation 
of both aerobic and anaerobic bacteria) should be obtained from all patients at surgery and 
sent to the local laboratory for culture, identification, and in vitro susceptibility testing. The 
specimens should be processed according to recognized methods that culture for both aerobic 
and anaerobic organisms (Murray et al 2007) following the standard operating procedures of 
the clinical microbiology laboratory at each study center. Furthermore, throughout the study, 
specimensfrom relevant infection sitesshould be obtained and cultured at the local lab as 
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clinically indicated.Clinically relevant isolates may originate from both intra-abdominal and 
other sites(e.g.,additional specimens should be collected in case of second surgery or 
bacteraemia).
Blood culture specimens will be taken at eligibility/screening (visit 1). Thereafter, blood 
culture specimens will be taken as clinically indicated (e.g. repeated sampling if prior blood 
cultures were positive). Two sets of blood cultures should be collected (i.e., 4 bottles) from 2 
different sites for aerobic and anaerobic incubation. One set of blood cultures must be 
obtained through a venepuncture.Each bottle should be inoculated with 10 mL of blood for a 
total of 40 mL per collection. Details concerning the collection of blood cultures are provided 
in the laboratory manual.
Pure cultures of all pathogenic isolates must be sent to the central reference laboratory for 
confirmation of identificationand susceptibility testing. Duplicate copies of the isolates
should be kept by the local laboratory at –20°C or colder (preferably at –70°C) until the end of 
the study or when contacted by the central reference laboratory that they may be destroyed. 
All microbiological sampling and pathogens isolated in the local lab during the study (i.e. in 
the blood at baseline or thereafter, intra-abdominal cultures at surgery, and clinically relevant 
cultures throughout the study from any site) will be recorded and entered in the eCRF, along 
with disc susceptibility testing results.
If treatment is discontinued early because the patientis failing therapy and the patient requires 
a second surgery, an appropriate specimen for culture should be obtained, ideally after 
stopping the initial treatment but before the new treatment is administered. The eCRF should 
indicate whether or not a sample was obtained.
Analysis of isolates
The local laboratory must identify all aerobic bacterial pathogens to the genus and species 
level using confirmatory (not presumptive)identification methods from blood, intra-
abdominal or other specimens. Antimicrobial susceptibility should be determined for each 
aerobic pathogen isolated according to local practices. In addition, a disk diffusion test for 
ATM-AVI must be performed on each aerobic isolate using CLSI methods [CLSI document 
M2].Reporting of susceptibility results on ATM-AVI to the principal investigator will be 
detailed in the study site manual. The local laboratory can perform any additional testing on 
further agents as they normally do to provide susceptibility results of isolated aerobic 
microorganisms.
All anaerobic bacterial pathogens must be identified to at least the genus level. If the local 
laboratory cultures and performs susceptibility testing on anaerobic organisms, it should 
follow CLSI methodologies by either broth microdilution (Bacteroides fragilisgroup) or agar 
dilution with minimum inhibitory concentration (MIC) testing only on metronidazole. 
However, all anaerobic isolates mustbe sent to the central reference laboratory for 
confirmation of identification and susceptibility testing.
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Handling of microbiological dataand shipment of isolates
The investigator should record information on all specimens according to the microbiological 
investigator’s manual supplied by the central reference laboratory. All specimenscollected at 
baseline or post baseline should be entered in the eCRF with regards to a) day, time and site of 
sampling b) local identification for each pathogen andc)disc susceptibility / MIC to the study 
therapy for each pathogen.
An isolate ID number will be allocated to all isolates obtained at the local lab, using the 
reference number allocated to the transportation kit provided by the central lab. Samples of all 
microbiological isolates must be shipped to the central reference laboratory for confirmation 
of microbiological assessments.The central reference laboratory will supply the local 
laboratory with all media containing transport vials and instructions for shipment of isolates to 
the central reference laboratory. The central labwill also supply susceptibility testing discs for 
ATM-AVI and monitor /verify resistant isolates reported by the local lab. 
The central reference laboratory will confirm pathogen identifications and susceptibility test 
results on all clinical isolates reported and shipped by the local laboratory. Thus, the central 
laboratory is responsible for thedefinitive identification for each microbiological organism 
and determination of MICs for ATM-AVI and comparator antibiotics. If a) discrepancies 
occur between the results obtained at the central laband those obtained at the local labor b) 
microorganismsthat are isolated at the local labdo not survive shipping to the central lab, a 
sponsorrepresentative or delegate mayrequest to shipa second sample of the isolate in 
question. In the instance of differences in pathogen identification or susceptibilities, the 
central reference laboratory results will take precedence over the local laboratory results. 
The data obtained at the central reference labwill be used to determine descriptively a) the 
pathogen(s) causing the patient’s infection and b) the efficacy of the study therapy at the 
pathogen level.Local laboratory results may be used if a microorganism does not survive 
shipping or is not recoverable from the local laboratory. The central reference lab will transfer 
all microbiological data directly to CTCC where they will be merged into the study database
(without being entered in the eCRF). The isolate ID number will be used to match the data 
obtained at the central lab with the data obtained at the local lab. Details will be described in a 
data transfer agreement.
5.2
Safety assessments
Safety and tolerability assessment will be undertaken on individual patient and cohort basis, 
for the earlypatient safety and PK review, through a determination of serious adverse events 
(SAE) and adverse events (AE) based on signs and symptoms, examinations and laboratory 
tests. If deterioration in a laboratory value or vital sign is associated with clinical signs or 
symptoms, the sign or symptom will be reported as an adverse event (AE) and the associated 
laboratory result or vital sign will be considered as additional information. For details on AE 
definition and reporting see section6.
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5.2.1
Laboratory safety assessments
Blood and urine safety samples for determination of clinical chemistry, haematology and 
urinalysis will be taken at the following sampling time pointsas described in section 4: at 
screening, at baseline (note: baseline assessment only required if Visit 1 and Visit 2 are 
separated by surgery OR are >12 hours apart); days 4, 7, 10, and 13(+/-1 day); end of therapy 
(EOT; within 24 hours after end of last infusion), test of cure (TOC; day 25 +/-3 days), and 
latefollow-up (LFU; day 35 +/-3 days).
Safety samples will be sent to the central laboratory for analysis. The date andtime of 
collection will be recorded on the patient’s eCRF.The results of safety lab sampling will be 
made available to the investigators. The laboratory safety variables tobe measured at the 
central laboratory are displayed in Table 3. 
For eligibility assessment (additional determination of serum creatinine / calculation of CrCl, 
serum pregnancy test (orurine pregnancy testfor preliminary enrolment if serum test result is 
not available at screening), AST, ALT, ALP, total bilirubin, hematology as defined in section 
3.1and 3.2), local laboratory test results will be usedand entered in the eCRF.
Hepatic and renal function should be closely monitored throughout the treatment period. AST, 
ALT, ALP, GGT, total bilirubin and creatinine clearance will beassessed daily in the local lab
and the values entered in the eCRF. TheCrCl value (calculated by the Cockcroft-Gault 
formula using serum creatinine; see Appendix E)will be reviewed and, where necessary, the 
ATM-AVI dose will be adjusted (see section 7.2). Following review of AST, ALT, ALP, 
GGTand total bilirubin values,additional measures as listed in sections 6.7.3and 3.9will be 
initiated where required. 
Furthersafety samples may be collected if clinically indicated at the discretion of the 
investigatorand analysed in the local laboratory of the study site.
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Table 3: 
Laboratory Safety Variables
Clinical chemistry
Hematology
Urinalysis
Alanine aminotransferase
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase
β-hCGa
Bicarbonate
Blood urea nitrogen 
Calcium, total 
Chloride 
Creatinine b
Gamma glutamyl transferase 
(local lab only)
Glucose (nonfasting)
Inorganic phosphorus 
Potassium 
Sodium 
Bilirubin (total, direct and 
indirect) 
Total protein 
Hematocrit 
Hemoglobin
INR (local lab only)
Platelet count
Red blood cell count 
White blood cell count (total and 
differential)
Appearance (color, clarity)
Bilirubin
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific gravity
Urobilirubin 
Microscopic examination:
Red blood cells
White blood cells
Casts
Crystals
Bacteria, yeast cells, or parasites
Other
Blood culturesc
aβ-hCG:β-human chorionic gonadotropin; will be determined for woman of childbearing potential at screening 
(visit 1) and LFU only.
bfollowing each determination of serum creatinine until LFU(inclusive), also the estimate creatinine clearance 
will be calculated.
csamples for blood cultures should be taken at eligibility/screening and asclinically indicated thereafter (e.g. if 
previous blood cultures were positive). See section 4.
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalitiesand criteria for intensified monitoring and/or discontinuation of study 
drug (see sections 3.9and 6.7.3). The laboratory results should be signed and dated and 
retained at study centre as source data for laboratory variables. For information on how AEs 
based on laboratory tests shouldbe recorded and reported, see section6.3.6.
For each determinationof serum creatinineuntil EOT (inclusive), also the estimate creatinine 
clearance will be calculated as defined according to Appendix E. The investigator will assess 
the patient’s eligibility regarding renal function continuously during the study (for criteria and 
timing see section 6.7.2and the Study Plan detailing the procedures. For monitoring of liver-
related laboratory parameters, see section 6.7.3. For discontinuation of individual patients 
based on laboratory safety assessments, see section 3.9.
5.2.2
Physical examination
A complete physical examination will be performed as scheduled and displayed in the Study 
Plan detailing the procedures. The physical examinations will include an assessment of the 
following: general appearance including site of infection, skin, head and throat (head, eyes, 
ears, nose, and throat), lymph nodes, respiratory, cardiovascular, abdomen including wound 
examination, musculoskeletal, and neurological systems.
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Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
62(99)
If pathologic findings emerge or worsen compared to the physical examination at screening, 
these findings should be documented as AEs on the respective page of the eCRF. Ifthe 
findings meet the criteria for an SAE, procedures for reporting such events should be followed 
(refer to section 6.4).
Height and weight will be measured at the screening visit, and the body mass index will be 
calculatedas the ratio of weight in kg/(height in cm/100)
2. If these assessments cannot be 
performed due to the patient’s clinical condition, they may be done later (as soon as possible).
After the screening visit, weight should be measured as clinically indicated.
Adetailed focused (abdominal)assessment will be performed at screening, at baseline (note: 
baseline assessmentonly required if Visit 1 and Visit 2 are separated by surgery OR are >12 
hours apart), daily during treatment with IV study therapy, at the EOT,TOC, and LFU visits.
5.2.3
ECG
Standard 12-lead ECGs (triplicates for each recording time point) will be recorded and 
assessed at Visit 2 (baseline), Day 3 and EOT (seeTable 1). Two recordings will be taken on 
Day 3; one within 30 minutes of the end of the ATM-AVI infusion and one just prior to 
starting the next infusion. One recording only isrequired at Visit 2 (baseline) and EOT. The 
ECGs should be standard 12-lead ECGs with a lead II rhythm strip with the patient in the 
supine position after the patient has rested in this position for 10 minutes.If clinically 
indicated, additional ECG recordings can be made at the discretion of the investigator as 
unscheduled assessments. A single independent third party using uniform techniques will 
carry out formal analysis and reporting of ECG data for purposes of the study. For adverse 
event reporting of ECG abnormalities see section 6.3.6.
5.2.4
Vital signs
Vital sign measurements (including blood pressure, heart rate, body temperature and 
respiratory rate) should be assessed at Screening, Baseline, daily while the patient is receiving 
IV study therapy, at EOT, at TOC, and at the LFU visit (seeTable 1).
The investigator should make an assessmentof the available results with regard to clinically 
relevant abnormalities. The results should be signed and dated and retained at study centre as 
source data. For information on how AEs based on vital signs should be recorded and 
reported, see section 6.3.6.
5.2.4.1
Blood pressure and heart rate
Supine blood pressure and heart rate will be measured using a semiautomatic blood pressure 
recording device with an appropriate cuff size. The patients will be required to rest in a supine 
position for at least 10 minutes prior to heart rate and blood pressure measurements. 
5.2.4.2
Body temperature
Body temperature will be measured using an automated thermometer. The patient’s body 
temperature will be evaluated at least twice a day (suggested at least 8 hours apart) and the 
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
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actual time of body temperature collection will be recorded. Fever will be defined as a body 
temperature >38°C. For each individual patient, the method of temperature measurement 
ideally should be consistent for the duration of the study.
5.2.4.3
Respiratory rate
Respiratory rate will be collected in breaths per minute.
5.2.5
Safety and PK Assessmentsby the Scientific Advisory Committee
5.2.5.1
Early safety assessment –Cohort 1 review
The safety and tolerability of the ATM-AVI dosing regimen (500 mg ATM plus 137 mg AVI 
loading dose by IV infusion over a 30 minute period, immediately followed by a maintenance 
dose of 1500 mg ATM plus 410 mg AVI by IV infusion overa 3 hour period every 6hours)
will be assessed based on the impact on patient liver transaminases. The assessment will be 
both a per patient assessment throughout the study period and per a cohort review of thefirst 
10 patients having completed all PK and safety assessments.
The initial safety review(together with the parallel evaluation of thepharmacokinetics of 
ATM-AVI –see section 5.3.3) will be assessed by the SACand the sponsor and input to a 
decision on whether
(a)
the study is discontinued, or
(b)
the remainder of the study will continue with the same dose regimen for patients 
with normal renal function or mild renal impairment (CrCl >50 mL/min), or
(c)
patients in Cohort 2 with normal renal function or mild renal impairment (CrCl>50 
mL/min)will receive the higher AVI dose (loading dose of ATM 500 mg / AVI 167 
mg, followed by maintenance doses of ATM 1500 mg / AVI 500 mg)
and
(d)
patientswith moderate renal impairment (CrCl 31to 50 mL/min) should be 
included and administered the proposed dosing regimen for these patients as 
described in section 7.2.
5.2.5.2 Second safety assessment –Cohort 2 review
In the eventthat the AVI dose is increased in Cohort 2, a second safety and PK review will 
occur once at least10 patients in Cohort 2 have completed all safety and PK assessments.The 
assessment will be both a per patient assessment throughout the study period and per a cohort 
review of thefirst 10 patients in Cohort 2 having completed all PK and safety assessments.
The secondsafety review(together with the parallel evaluation of the pharmacokinetics of 
ATM-AVI –see section 5.3.3) will be assessed by the SAC and the sponsorand input to a 
decision on whether
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
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a) the remainder of the study (Cohort 3) will continue at the same (higher AVI dose)
regimen, or
b) the remainder of the study will continue (Cohort 3) with the lower AVI dose regimen 
for patients with CrCl > 50 mL/min and for patients with CrCl 31-50 mL/min, 
respectively(as described in section7.2), and
c) the dose regimen selected is confirmed for the development of ATM-AVI.
5.2.5.3 Criteria for immediate progression
The criteria for immediate progression after the safety reviewsare as follows:
All transaminase rises are asymptomatic and rapidly reversibleupon end of (or 
discontinuation of) therapy.

Individual patient transaminase elevations:

Patients with normal baseline transaminases (elevations <5xULN)

Patients with baseline transaminase >3xULN and <5xULN documented 
as being directly related to infection being treated (inclusion criteria) -
elevations no higher than 8xULN
No morethan 2 individuals have transaminase elevation as described above
If the criteria for immediate progression are met, investigators will be informed of the decision 
to continue recruiting as soon as feasible (within a timeframe to be confirmed).The 
pharmacokinetic data will be evaluated when available but will not be required to confirm the 
decision for immediate progression.
5.2.5.4 Criteria for stop and review
The criteria for stop and review before enrolment of furtherpatients are as follows: 
Any one transaminase elevation is not rapidly reversible (in the absence of an alternative 
explanation for transaminase elevation) 
Between 3 to 5 individuals have a transaminase elevation as described in section 5.2.5.3
Any one patient meets the following individual transaminase discontinuation criteria in the 
absence of an alternative explanation:
Patients with initial normal baseline transaminases progressing to:

ALT or AST ≥3×ULN and evidence of coagulopathy 

ALT or AST ≥3×ULN with symptoms suggestive of new or progressive 
liver disease 
Patients with initial baseline transaminases >3xULN and <5xULN, documented as 
being directly related to infection being treated,progressing to:
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Date 29 March 2017
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
ALT or AST ≥ 5×ULN and evidence of coagulopathy 

ALT or AST ≥ 5×ULN with symptoms suggestive of new or progressive 
liver disease 
In the event of a stop and review before progression, available pharmacokinetic data will be 
evaluated to determine the relationship between exposure andtransaminase elevation. More 
extensive modelling may be required to determine if a change in dose is required and to 
identify an appropriate dose for the remaining patients.
5.2.5.5
Criteria for non-progression
The criteria for non-progression after the safety reviewof Cohort 1 are as follows:
1 patient meets Hy’s Law criteria (see Appendix D)
More than one transaminase rise is not rapidly reversible (in the absence of an alternative 
explanation for transaminase elevation) 
More than 5 individuals have a transaminase rise as described in section 5.2.5.3
Three or more patients meet the following individual transaminase discontinuation criteria 
in the absence of an alternative explanation:
Patients with normal baseline transaminases

ALT or AST ≥3×ULN and evidence of coagulopathy 

ALT or AST ≥3×ULN with symptoms suggestive of new or progressive 
liver disease 
Patients with baseline transaminases >3xULN and <5xULN documented as being 
directly related to infection being treated

ALT or AST ≥5×ULN and evidence of coagulopathy 

ALT or AST ≥5×ULN with symptoms suggestive of new or progressive 
liver disease 
If any one of the above criteria for non-progression occurs before 10 patients have been 
recruited for the early safety review, then the study will be stopped. If any one of the above 
criteria for non-progression occurs before or at the time of the 10 patient safety review in 
Cohort 2, then dosing at the higher AVI dose will be stopped and the data reviewed prior to a 
decision to continue with recruitment at the lower AVI dose.Further criteria for 
discontinuation of the study are listed in section 3.11. Discontinuation criteria for individual 
patients are listed in section 3.9. 
All patients observed with transaminase elevation will be monitored where required as per the 
criteria outlined in section 6.7.3.
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
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Date 29 March 2017
66(99)
5.3
Pharmacokinetics
5.3.1
Collection of samples
Blood samples (3 mL per sample) for plasma PK analysis of ATM-AVI will be collected at 
the times presented in Table 4and Figure 3, Figure 4and Figure 5. The sampling plan is based 
on the dosing schedule as described in section 7.2. Samples will be drawn from the opposite 
arm to that which is used for drug infusions. For detailed information on handling of samples 
and blood volume, see section 5.6and Laboratory Manual.
All patients will undergo sparse pharmacokinetic sampling on Day 1 of treatment. On Day 4, 
the first twenty five (25) patients will undergo intensive pharmacokinetic sampling. The 
remaining 15 patients will have a sparse PK sampling regimen onDay 4. The date, starting 
and end time of infusion and exact time of collection of each sample will be recorded in the 
eCRF. To provide greater flexibility, Day 4 intensive and sparse PK samples can be collected
on Day 4 ± 1 day, when steady state concentrations of ATM-AVI will have been attained.
Table 4:
Pharmacokinetic ATM-AVI Sample Collection Time Points
Day
Sample time
Day 1
All patients: sparse sampling (4 samples/patient)
Sample 1:0h (within 1h before start of loading dose)
Sample 2: within 5 min before the end of the loading dose infusion
Sample 3: anytime within the 15 minutes prior to the end of the second IV 
infusion (3.25h –3.5h after start of loading dose infusion)
Sample 4: within 5-6 h afterstart of loading dose infusion
Day 4
First 25 patients: intensive sampling (11 samples/patient)
Trough (within 10 min prior to IV infusion start), 0.5h 1, 2, 3 (within 15 
minbefore IV infusion stop), 3.25, 3.5. 3.75, 4, 5, and 6 h after start of IV 
infusion (just before start of next infusion)
Remaining 15 patients: sparse sampling (3 samples/patient)
Sample 1: within 1 h of start of IV infusion 
Sample 2:within the15min prior to theend ofIV infusion (within 2.75 to 
3h after start of IV infusion)
Sample 3:within 5-6 hafterstart of IV infusion (within one hour prior to 
start the next infusion)
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Drug Substance ATM-AVI
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Figure 3
Sampling regimen on Day 1
Figure 4
Sampling regimen on Day 4 –intensive sampling
Figure 5
Sampling regimen on Day 4 –sparse sampling
5.3.2
Determination of drug concentrationin plasma
Samples for determination of ATM and AVI concentrations in plasma will be analysed by 
Covance on behalf of the sponsor, using an appropriate validated bioanalytical method. Full 
details of the bioanalytical methods used will be described in a separate bioanalytical report. 
All samples within the known stability of the analytes of interest (i.e., ATM and AVI) at time 
of receipt by the bioanalytical laboratory will be analysed.
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Drug Substance ATM-AVI
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Date 29 March 2017
68(99)
Incurred sample reproducibility analysis will be performed alongside the analysis of the PK 
samples and reported in a separate bioanalytical report. Additional analyses may be conducted 
on the biological samples to further investigate thepresence and/or identity of drug 
metabolites. Results from such analyses may also be reported separately from the CSR.For 
analysis of pharmacokinetic data, see section 8.5.4.
5.3.3 
Early patient review and second safety and PK assessment–evaluation of the 
pharmacokinetics of ATM and AVI
Data fromthe first 10patients having completed all PK and safety assessments (with 
normal/mild renal impairment status) in Cohort 1 (and in Cohort 2 in the event that AVI dose 
escalation has occurred) will be assessed to provide confirmation of the pharmacokinetic 
profile of ATM-AVI in patients in comparison to the profile previously observed in healthy 
human volunteers, when administered via a loading dose followed by a maintenanceinfusion 
regimen (q6h, 3h infusion). These patients will have sparse sampling on Day 1 and intensive 
sampling on Day 4, as described in Table 4. The reviewswill contribute to the parallel safety 
and tolerability assessment in order to provide input forthe decisions listed insection 5.2.5.
Scheduled protocol (i.e.not actual) plasma PK sampling times will be used in the PK 
calculations for the early safety & PK review. Pharmacokinetic sampling will continue, if 
there is a positive decision to proceed (see section 5.2.5)to complete the full data set of
40patients. 
5.3.4
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
orsix months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses, see section 5.6.1.
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
5.4
Pharmacodynamics
See section5.1.1.
5.5
Pharmacogenetics: not applicable
Pharmacogenetic samples will not be taken during the study.
5.6
Biological sampling procedures
Samples for safety, microbiological and PK analyses will be collected asper the inclusion 
criteria, Study Plan (Table 1) and PK sampling schedule (Table 4). The volume of blood to be 
drawn from each patient is displayed in Table 5. Prior to any sampling, the patient’s (or 
legally acceptablerepresentative’s) informed consent to the use and storage of donated 
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Drug Substance ATM-AVI
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biological samples is to be obtained (as part of the Informed Consent Form). Allsamples will 
be processed and analysed using sensitive and validated bioanalytical methods.
The number of samples taken, as well as the volume required for each analysis, may be 
changed during the study as new data on ATM-AVI become available. The results of safety 
lab sampling (clinical chemistry, hematology) will bemade available to the investigators. 
Similarly, the results of microbiological blood cultures obtained for study purposes will be 
made available to the investigators without delay.
The total volume of blood that will be drawn from each patient in this study is presented in 
Table 5:
Table 5: 
Volume of blood to be drawn from each patient
Assessment
Sample volume 
(mL)
Number of 
samples
Total volume (mL)
Safety
Clinical chemistry
5
min. 6, max. 10a
min. 30, max. 50
Hematology
2.5
min. 6, max. 10a
min. 15, max. 25
Renal and hepatic function
2.5
max. 14e
max. 35e
Pregnancy testb
2.5
2
0 or 5
Pharmacokinetic sampling
3
7 or 15c
21 or 45
Blood culture
10
4d
40
Total
106–200
a
Number of samples depends on clinical response (duration of therapy: 5 –14 days) and timing of surgery relative to 
screening. Sampling time points: screening(local AND central lab),baseline(if Visit 1 and Visit 2 are separated by 
surgery or occur >12 hours apart), study days 4, 7, 10, and 13(+/-1 day); end of therapy (EOT;within 24 hoursafter
end of last infusion), test of cure (TOC; day 25 +/-3 days), and latefollow-up (LFU; day 35 +/-3 days).
b
Determination of β-human chorionic gonadotropin (β-hCG)for woman of childbearing potential at screening (visit 1) 
and LFU only.
c
Number of samples depends on which PK sampling regimen the patient will undergo (see Table 4).
d
Blood cultures willbe taken at eligibility / screeningregardless of whether they are indicated for standard care.If the 
culture is positive at enrolment, additional samples will be collected as clinically indicated.Each blood culture will 
consist of 2 sets of 20 ml (10mlin aerobic bottle and 10ml in anaerobic bottle). The blood samples must be taken 30 
min apart or at the same time from 2 different venepuncture sites (e.g. peripheral and central line).
e
Hepatic and renal function (AST, ALT, ALP, GGT, total bilirubin andCrCl)will be assessed daily in the local lab
during treatment. The number of additional samples depends on the duration of therapy(5 –14 days) and on the 
number of samples taken anyway for the clinical management of the patient. On treatment days where clinical 
chemistry samples are taken for routine clinical management of the patient, these samples should be used to assess 
AST, ALT, ALP, GGT, total bilirubin, CrCl, and the values entered in the eCRF, in order to avoid additional sampling 
for study purposes.
5.6.1
Storage, re-use and destruction of biological samples
Samples will be disposed of after the CSR has been finalized, unless retained for future 
analyses or research projects. Key samples for exploratory biomarker research ormetabolite 
identificationand/or analysis may be retained at an sponsorassigned Biobank, at the central 
laboratory, or possibly a COMBACTE-CARE partner laboratoryon behalf of the sponsorfor 
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a maximum of 15 years from the date of the Last Subject’s Last Visit, after which they will be 
destroyed. The results from investigation will not be reported in the CSR but separately in a 
scientific report or publication.
5.6.2 
Labelling and shipment of biological samples
The investigator will ensure that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’. Any samples identified as Infectious 
Category A materials are not to be shipped and no further samples will be taken from the 
patient unless agreed upon by the sponsorand the appropriate labelling, shipping, and 
containment provisions are approved.
Samples must be collected, labelled, processed, analysed, stored and transported to the 
relevant storage site, as indicated in the Laboratory Manual. Tubes will be labelled with the 
study number, sample description and date and time of collection. The date and time of the 
sample collection will be recorded in the source documents and in the appropriate section of 
the eCRF. 
An isolate ID number will be allocated to all pathogen isolates obtained at the local
microbiologicallab. Samples of all isolates will be sent to the central reference lab (see 
section 5.1.2).PK samples will be shipped periodically from the study centers to the 
responsible (sponsor-approved) laboratory at agreed intervals.
Samples should be shipped in batchesif possible. Logistics should be coordinated between 
involved parties to ensure that samples will arrive during working hours. A requisition sheet 
should accompany the shipment that details the study number, centre number, enrolment 
number, date of sample collection, and a unique identifier for each of the samples in the 
shipment. Detailed instructions for sample processing and shippingare given in the study site 
manual and in the laboratory manual.
5.6.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigatorsat each study centre keepfull traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keepdocumentation of receipt of arrival.The sample receiver keeps full traceability of the 
samples while in storage and during use until used or disposed of or until further shipment and 
keeps documentation of receipt of arrival.
The sponsorkeeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. Samples retained for further use are 
registered in the sponsor’sBiobank system during the entire life cycle.
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5.6.4
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented. If samples are already analysed,the 
sponsoris not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, the patient may be 
withdrawn from further study participation at the discretion of the investigator.
The investigator:

Ensures that the sponsoris notified immediately of a patient’s withdrawal of 
informed consent to use donated samples

Ensures that biological samples from that patient, if stored at the study center, are 
immediately identified, disposed of or destroyed, and the action documented

Ensures the laboratories holding the samples are informed about the withdrawn 
consent immediately and that samples are disposed of or destroyed, the action 
documented, and the signed document returned to the study center

Ensures that the patient and the sponsorare informed about the sample disposal.
The sponsorverifies that the laboratories holding the samples are informed about the 
withdrawn consent immediately and that samples are disposed of or destroyed and the action 
documented and returned to the study center.
6.
SAFETY REPORTING AND MEDICALMANAGEMENT
The investigator is responsible for ensuring that all study centre personnel involved in the 
study are familiar with the content of this section. Thisis of the utmost importance.
Safety and tolerability assessment will be undertaken on individual patient and cohort basis 
through a determination of serious adverse events and adverse events based on signs and 
symptoms, examinations and laboratory tests. 
6.1
Definition of adverse event
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (e.g.,nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no IV study treatment has been administered.
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The term AE is used to include both serious and non-serious AEs.
6.2
Definitionof serious adverse event
A serious adverse event is an AE occurring during any study phase after the patient has signed 
the ICF(i.e., treatment, follow-up)that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing 
hospitalisation excluding hospitalization due to worsening or failure of 
treatment for primary infection under study

Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may 
require medical intervention to prevent one of the outcomes listed above, 
including suspected transmission of an infectious agent via the IV study 
therapy 
Cases of liver dysfunction that meet Hy’s Law criteria are defined and reported as SAEs, 
using the “important medical event” seriousness criterion if no other criteria are applicable 
(see Appendix D). For further guidance on the definition of a SAE, see Appendix B.
6.3
Recording ofadverse events
Planned procedures or hospitalizations should not be recorded as SAEs, but complications 
arising from planned procedures or hospitalization / prolongation of hospitalizations meeting a 
seriousnesscriterion should be recorded and reported as SAEs.
6.3.1 
Time period for collection of adverse events
Adverse Events and Serious Adverse Events mustbe collected for each patient from the time 
when informed consent is obtained at screening untilthe latefollow-up visit (irrespective of 
whether the last follow-up visit attended by the patient is TOC or LFU; i.e. at the latest until 
Day 38). 
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment (LFU) will be 
followed up by the investigator for as long as medically indicated, i.e. until the 
event is resolved or stabilized. Pfizer/CTCC retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
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6.3.3
Variables 
The following variables will be collect for each AE;

AE (verbatim)

Date and time when the AE started and stopped

Maximum intensity:
mild (awareness of sign or symptom, but easily tolerated)
moderate (disturbing but still tolerable)
severe (intolerable)

Whether the AE is serious or not

Investigator causality rating against the IV study therapy (yes or no)

Action taken with regard to the IV study therapy

AE caused subject’s withdrawal from study (yes or no)

Outcome of the AE
In addition, the following variables will be collected for SAEs:

Onset date (date AE met seriousnesscriteria)

Detection date (date the investigator became aware of the SAE)

AE is serious due to:
(a)
Death; if fatal outcome, the following will be collected:
Date of death
Autopsy performed
Primary/secondary cause of death
(b)
Life threatening
(c)
Inpatient hospitalization or prolongation of existing hospitalization (note: patients 
will be hospitalized at study entry. A planned hospitalization and the initial 
hospitalization that made the patient eligible for the study will not be considered an
SAE but if the hospitalization is prolonged due to an AE, the hospitalization 
becomes anSAE)
Date of hospitalization
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Date of discharge
(d)
Result in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions
(e)
Congenital abnormality or birth defect
(f)
Important medical event

Suspected transmission of an infectious agent via investigational medicinal product 

Causality assessment in relation to study procedures

Causality assessment in relation to other medication

Description of SAE.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2. An AE of severe 
intensity isnot necessarily to be considered as serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not anSAE unless it meets the criteria 
shown in section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be anSAE when it satisfies the criteria 
shown in section 6.2.
6.3.4
Causality collection
The investigatorwill assess causal relationship between IV study therapy and each AE, and
answer ‘yes’ or ‘no’ to the question ‘Doyou consider that there is a reasonable possibility that 
the event may have been caused by the IV study therapy?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. A guide to the interpretation of the causality question is found in Appendix 
B.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study center personnel: “Have you had any health problems since the
previous visit or when you were last asked?” and “Have you had any new symptoms?” or 
revealed by observation will be collected and recorded in the eCRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) rather than recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
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6.3.6 
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital sign measurements will be 
summarized in the CSR. Deterioration as compared with screening or baseline assessmentsin 
protocol-mandated laboratory values, vital signs, ECGs and safety assessments should 
therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason for 
discontinuation of treatment with the IV study therapy.
If deterioration in a laboratory value, vital sign or ECG assessment is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result or vital sign will be considered as additional information. Wherever possible, 
the reporting investigator uses the clinical, rather than the laboratory term (e.g., anaemia 
versus low haemoglobin value). In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AE(s). Deterioration 
of a laboratory value, which is unequivocally due todisease progression, should not be 
reported as an AE or SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the screening assessment will be reported as an AE.
6.3.7
Hy’s Law
The investigator is responsible for, without delay, determining whether the patient meets 
potential Hy’s law criteria (according to European Commission: Product information 
Zavicefta 2016
European Commission: Community register of medicinal products for human use. Product 
information Zavicefta 2 g/0.5 g powder for concentrate for solution for infusion. Accessed on 
13 July 2016. Available at http://ec.europa.eu/health/documents/community-
register/2016/20160624135109/anx_135109_en.pdf
FDA 2009): 
A Potential Hy’s Law (PHL) caseis defined as any situation where a patienthas an increase in 
both AST orALT≥3xULN andtotal bilirubin ≥ 2xULN, irrespective of the patient’s alkaline 
phosphatase value, at any point during the study following the start of study medication. 
A Hy’s Law (HL) caseis defined as a patient with an increase in serumAST or ALT  ≥3x 
ULN together withtotal bilirubin ≥2x ULN, where no other reason than the IMP can be found 
to explain the combination of increases, e.g., elevated serum ALP indicating cholestasis,viral 
hepatitis, another drug.
For PHL and Hy’s Law the elevation in transaminases must precede orbe coincident with 
(i.e., on the same day) the elevation in total bilirubin, but there is no specified timeframe 
within which the elevations in transaminases and total bilirubinmust occur. Details regarding 
the actions required in the cases of increases in ALT, AST, and total bilirubin can be found in 
Appendix D.
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Other cases where a subject shows elevations in liver biochemistry may require further 
evaluation (see sections 5.2.5and 6.7.3). If a patient reaches an ALT or AST ≥5 × ULN, the 
patient may continue with the IMP as planned unless discontinuation criteria as described in 
section 3.9are met. The patient should be seen within 48 hours to instigate enhanced follow-
up and monitoring as defined in section 6.7.3. Also patients with ALT or AST ≥3.0 x ULN 
and bilirubin ≥1.5 x ULNwill require enhanced follow-up and monitoring as defined in 
section 6.7.3.
6.3.8 
Exceptions from standard adverse event collection
Where there is deterioration in the condition for which the IV study therapy is being used, 
there may be uncertainty as to whether this is lack of efficacy, disease progression or 
constitutes an AE. In such cases, unless the Pfizer/CTCCor reporting physician considers 
that the study treatment contributed to the deterioration or local regulations state to the 
contrary, the deterioration should be compared with the definitions below and considered to 
be either lack of effect (section 6.3.8.1) or disease progression (section 6.3.8.2) and not an AE.
6.3.8.1
Lack of effect
Insufficient therapeutic effect will be captured as an efficacy outcome. Instances of, or 
discontinuation due to insufficient therapeutic effect (i.e., lack of efficacy) should not be 
collected as AEs. A clinical failure should not be recorded as an AE.
6.3.8.2
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which ATM-AVI is being studied. It may be an increase in the severity of the 
disease under study (cIAI) and/or increases in the symptoms of the disease. Expected 
progression of the disease under study and /or expected progression of signs and symptoms of 
the disease under study, unless more severe in intensity or more frequent than expected for the 
patient’s condition should not be reported as an AE. Any event or extended hospitalization 
that is unequivocally due to disease progression must not be reported as an SAE unless it is 
believed that the study drug actively contributed to the progression of the disease (i.e., not by 
way of insufficient therapeutic effect). Events, which are unequivocally due to disease 
progression, should not be reported as an AE.
6.4
Reporting of serious adverse events
All SAEs will be reported, whether or not considered causally related to the IV study therapy 
or to the study procedures. All SAEs will be recorded in the eCRF.
Any SAE occurring in the course of the study must be reported by the investigators or 
qualified designeeto the CTCC pharmacovigilance centre on the SAE Report Form within24 
hours of investigator’s awarenessof it. Contact details of the CTCC pharmacovigilance 
centre and applicable emergency contacts are given in section 6.10.
The designated Pfizer CTCC Pharmacovigilance representatives will work with the 
investigator (and national coordinator/medical monitor if required) to ensure that all the 
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necessary information is provided to Pfizer Safety within 24 hours of investigator’s 
awarenessDetails regarding the handling of incoming SAE reports at CTCC are defined in 
the study specific Safety Handling Plan.
For all serious adverse events where important or relevant information is missing, active 
follow-up will be undertaken immediately by the investigator. Investigators or other study 
center personnel will inform Pfizer /CTCC Pharmacovigilance representatives of any follow-
up information on a previously reported SAE within24 hours of when he or she becomes 
aware of it.
The reference document for definition of expectedness/listedness is the latest version of the IB 
for the IV study medication ATM-AVI.
Pfizer will provide regulatory authorities with safety updates/reports according to local 
requirements, including suspected and unexpected serious adverse reactions, where relevant. 
The national coordinator is responsible for reporting of such cases to the respective Ethics 
Committees and investigators.
6.4.1
Other significant adverse events
During the evaluation of the AE data, a CTCC or Pfizermedically qualified expert will 
review the list of AEs that were not reported as SAEs or discontinuation of IV study therapy 
due to AEs. Basedon the Pfizerphysician or CTCC physician (as a Pfizerdelegate) 
judgment, significant AEs of particular clinical importance may, after consultation with the 
Pfizerphysician, be considered other significant AEs and reported as such in the CSR. A 
similar review of other data from laboratory tests, vital signs, ECGs, and other safety 
assessments will be performed for identification of other significant AEs.
Examples of these are marked haematological and other laboratory abnormalities and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment.
6.5
Overdose
Overdose is defined as a dose of study drug administered to a patient in excess of that 
specified in the IB for that product, unless specified otherwise in the clinical study protocol. 
Overdose does not automatically make an AE serious but if the consequences of the overdose 
are serious for example death or hospitalization, the event is serious and should be reported as 
such.
According theSmPC (ER Squibb & Sons Limited 2014), there have been no reported cases of 
ATM overdosage or intoxicationbut there is no post marketing pharmacovigilance data 
available. If necessary, ATM may be cleared from the serum by haemodialysis and/or 
peritoneal dialysis. ATM has been shown to be cleared from the serum by continuous 
arteriovenous hemofiltration.
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In a Phase II study in the ceftazidime-AVI development programme, a patient was 
accidentally treated with 1000 mg of AVI in one IV dosing (ceftazidime was also overdosed). 
No clinical symptoms or changes in laboratory values were observed for this patient.
Inadvertent misdosing, such as administration of a higher dose than stated in the protocol, 
should be followed up expectantly. Patients misdosed or overdosed (when defined) should be 
treated with appropriate supportive care until recovery.
If an overdose or intoxication on the IV study therapy occurs in thecourse of the study, then 
the investigator or other site personnel will inform appropriatePfizer/CCTCrepresentatives
immediately, or no later than 24 hoursof when he or she becomes aware of it.
The designated Pfizer/CCTCrepresentative will work with theinvestigator to ensure that all 
relevant information is provided to Pfizer Safetywithin the time limits given below.
Recording an overdose will be done according to the following:
An overdose with associated AE(s)is to be recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRFand on the overdose eCRFmodule.Relevant 
information regarding any corresponding SAE(s)related to the overdose mustbe 
forwarded toPfizer /CTCC pharmacovigilance representativesfor data entry in the safety 
database.An overdose without associated symptoms is also to be recorded on the 
overdose eCRF module.

For overdoses associated with a SAE, the standard SAE reporting timelines apply, see 
section 6.4.
6.6
Pregnancy
If a patient becomes pregnant during the course of the study, ATM-AVIshould be 
discontinued immediately. All pregnancies and outcomes of pregnancy occurring from the 
date of the first dose of study drug until 3 months after the last dose of study drug should be 
reported to Pfizer and CTCC within 24 hoursof awarenessand documented as specified in 
section 6.6.1.
6.6.1
Maternal exposure
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IV 
study therapy may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs.The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other study center 
personnel will report this information toPfizerCTCC pharmacovigilance centre in the 
Pregnancy Report Formwithin 24 hoursfrom when he or she becomes aware of it. Outside 
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the CTCC pharmacovigilance business hours, the investigator should utilise themedical 
emergency contacts for reporting. Contact details of the CTCC pharmacovigilance centre, its 
business hours and applicable emergency contacts are given in section 6.10.
The designated Pfizer/CTCC representatives will work with the investigator (and national 
coordinator/medical monitor if required) to ensure that all relevant information is provided to 
Pfizer Safety within 24 hours of investigator’s awareness. The same timelines apply when 
outcome information is available.
The “Pregnancy Report” module in the eCRF will be used to report the pregnancy and the 
“Pregnancy Outcome” safety module will be used to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of 
any pregnancy occurring from the date of the first dose of study drug until 3 months after the 
last dose of study drug must be reported to Pfizer Safety/CCTCwithin 24 hours of 
investigator’s awarenessand documented as specified in Section 6.6.1.
6.7
Medical management and monitoring during the study
6.7.1 
Coagulation and concomitant use of anticoagulants
Prolongation of prothrombin time has been reported rarely in patients receiving ATM. In 
addition, numerous cases of increased activity of oral anticoagulants have been reported in 
patients receiving antibiotics, including β-lactams. Severe infection or inflammation, and the 
age and general condition of the patient appear to be risk factors. Appropriate monitoring 
(according to applicable medical guidelines and institutional standard of care) should be 
undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral 
anticoagulants may be necessary to maintain the desired level of anticoagulation.
6.7.2
Renal function
CrClwill be monitored throughout the study. Determination of creatinine will be part ofeach 
safety lab until LFU inclusive, i.e. every 3 days (+/-1 day) until end of IV study therapy(as 
defined inTable 1), followed by calculation of CrCl at the central lab.For eligibility 
assessment, CrCl needs to be calculatedat the study site, based on the creatinine value 
determined at local lab (see section 4and Appendix E).In addition, a daily control of 
creatinine and CrCl will be done in the local lab during treatment (see section 4.1.3and 5.2.1
for details).
Only patients with normal renal function or mild renal impairment (CrCl >50 mL/min)will be 
recruited until completion of the early safety and PK review. If CrCl falls to ≤ 50 mL/min in 
one of these patients, the IV study therapy should be stopped and the patient followed up to 
the end of the study.
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Provided the results of the early patient review confirm the eligibility of patients with CrCl of 
31 –50 mL/min, the IV study therapy should be stopped and the patient followed up to the 
end of the studyif CrCl falls to ≤ 30 mL/min(see section 3.9).
6.7.3
Monitoring of liver-related laboratory parameters
For patients withsignificant elevations in liver-related laboratory parametersidentified in 
study visit samplesafter enrolment,but not meeting individual discontinuation criteria, an 
intensified monitoringplanwill be instigatedas follows: 

If a patient reaches an ALT or AST ≥5 x ULN and has notmet the discontinuation 
criteria, the following enhanced monitoring and patient follow-up will be instigated 
within a 48 hour period:
Collection of clinical and historical information to determine the cause of ALT 
and/or AST elevations;
If required, the daily assessment of AST, ALT, ALP, GGTandtotal bilirubin
during treatment (see sections 4.1.3and 5.2.1) will be continued after end of 
treatmentuntil the peak value has been reached as documentedby a decline in 
the values and the patient shows clinical improvement;
The frequency of testing will decrease to weekly or less if abnormalities 
stabilize after end of treatment, or if study drug has been discontinued and 
patient is asymptomatic. Patientswill be followed, including laboratory testing, 
until resolution.

Patients with ALTorAST≥3 x ULN andtotal bilirubin >1.5 × ULN or with an 
ALP increase of 100% from baseline will qualify for intensified monitoring of 
detailed liver chemistry (including ALP, ALT, AST, gamma glutamyl transferase 
[GGT], and total bilirubin)
Sampling aimed at identifying the cause of changes observed during routine monitoring 
should be done for all patients fulfilling intensified monitoring criteria. Liver enzymes should 
be monitored at least every 24hours until the elevated levels return to within the normal limits 
or are stable, as judged by the Principal Investigator. 
For patient review of liver-related laboratory parameters, see section 5.2.5. For definition and 
handling of Hy’s law cases, see section 6.3.7and Appendix D.
6.8
Management of IMP related toxicities
For handling of patients having received an overdose and showing IMP related toxicities, see 
section 6.5.
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83(99)
7.2
Dose and treatment regimens
The duration of treatment with IV study therapy is 5 to 14 days where a full day is defined as 
a 24 hour period. From the study start, only patients with normal renal function or mild renal 
impairment (i.e. CrCl >50 mL/min; see Appendix E) will be eligible. The proposed 
administration of ATM-AVI for these patients (Cohort 1) is a loading dose (500 mg ATM plus 
137 mg AVI by intravenous [IV] infusion over a 30 minute period), immediately followed by 
a dose of 1500 mg ATM plus 410 mg AVI by IV infusion over a 3 hour period every 6 hours 
(maintenance infusion). The targeted total dose on Day 1 will be 6500 mg ATM and 1777 mg 
AVI. For the following (full) days, this will be 6000 mg ATM / 1640 mg AVI. 
In addition, anaerobic coverage for cIAI will be provided by administration of 500 mg 
metronidazole, infused over 1 hour. Metronidazole will be administered every 8 hours, 
starting after the first ATM-AVI maintenance infusion and maintained until end of IV study 
therapy.
The PK, safety and tolerability of the dosing regimen described above will be assessed in a 
first cohort of 10 patients(Cohort 1); i.e. recruitment into this initial cohort of patients will 
continue until 10 patients with CrCl >50mL/min have completed all scheduled PK and safety 
assessments. 
In the event that a higher AVI dose will be administered in Cohort 2(see section 1.4), all 
patients with normal renal function or mild renal impairment (CrCl > 50 mL/min) will receive 
a loading dose (500 mg ATM plus 167 mg AVI by intravenous [IV] infusion over a 30 minute 
period), immediately followed by a dose of 1500 mg ATM plus 500 mg AVI by IV infusion 
over a 3 hour period every 6 hours (maintenance infusion). Patients will also receive 500 mg 
metronidazole infused over 1 hour every 8 hours (q8h), starting after the first ATM-AVI 
maintenance infusion.
Patients in Cohort 2 with moderate renal impairment (CrCl31 -50 mL/min) will receive 
either;
A loading dose consistent with Cohort 1 (500 mg ATM plus 137 mg AVI by 
intravenousinfusion over a 30 minute period), immediately followed by an extended
loading infusion of 1500 mg ATM plus 410 mg AVI over a 3 hour period. The 
maintenance infusions (starting 3 hours after stop of the extendedloading infusion) 
will be 750 mg ATM plus 205 mg AVI over a 3 hour period (to be administered every 
6 hours). The targeted total dose on Day 1 will be 4250 mg ATM: 500 mg (loading 
dose) + 1500 mg (extended loading infusion) + 3x 750 mg = 2250 mg (maintenance 
infusion)and 1162 mg AVI: 137 mg (loading dose) + 410 mg (extended loading 
infusion) + 3x 205 mg (maintenance infusion). From Day 2 onwards, the targeted total 
daily dose will be 3000 mg ATM (4x 750 mg maintenance infusion)/ 820 mg AVI(4x 
205 mg maintenance infusion).
Or
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A loading dose consistent with a higher AVI dose in Cohort 2 (500 mg ATM plus 167 
mg AVI by intravenous infusion over a 30 minute period), immediately followed by an
extended loading infusion of 1500 mg ATM plus 500 mg AVI over a 3 hour period. 
The maintenance infusions (starting 3 hours after stop of the extendedloading 
infusion) will be 750 mg ATM plus 250 mg AVI over a 3 hour period (to be 
administered every 6 hours). The targeted total dose on Day 1 will be 4250 mg ATM: 
500 mg (loading dose) + 1500 mg (extended loading infusion) + 3x 750 mg = 2250 mg 
(maintenance infusion)and 1417 mg AVI: 167 mg (loading dose) + 500 mg (extended 
loading infusion) + 3x 250 mg (maintenance infusion). From Day 2 onwards, the 
targeted total daily dose will be 3000 mg ATM(4x 750 mg maintenance infusion)/ 
1000 mg AVI(4x 250 mg maintenance infusion).
In the case that renal functionrecovers or deteriorates in Cohort 2 or 3 patients (i.e., local or 
central lab results show CrCl increases from 31 –50 mL/min at baseline to >50 mL/min, or 
decreasesfrom >50 mL/min at baseline to 31 –50 mL/min) during the treatment period, the 
dose of ATM-AVI should be adjusted by the investigator to meet the applicable dose regimen
(see above), based on the latest CrCl value.
In view of the primary objectives of this trial (assessment of ATM-AVI pharmacokinetics and 
patient safety), it is important that all IV study therapies are administered at a constant flow 
rate while strictly adhering to the dosing information given above.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling 
(European Commission GMP Guideline 2010). Label text will be translated into local 
language. The pharmacist at the study center will prepare and label the individual IV infusions 
according to the handling instructions.
7.4
Storage
All IV study therapy should be kept in a secure place under appropriate storage conditions. 
The storage conditionswill be stated on the study drug labelling and in the pharmacy manual.
7.5
Compliance
Qualified study center personnel will administer the IV study therapy and assure treatment 
compliance. The dose, date, and exact start and stop time of administration of theIV study 
therapy will be recorded in the appropriate sections of the eCRF and checked by the monitor 
at monitoring visits.
7.6
Accountability
The IV study therapy provided for this study will be used only as directed in the study 
protocol.
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Intravenous study therapy will be dispensed to the investigator or medically qualified 
personnel by the study center pharmacist. Intravenous study therapy will only be prepared / 
administered to patients by qualified pharmacy personnel / medically qualified personnel who 
have been appropriately trained to prepare / administer IV study therapy. Written 
authorization of study personnel to administer IMPmust be documented on the Delegation of 
Authority Log in one of 2 ways:

All study staff trained and authorized by the investigator to prepare / administer IV 
study therapy are listed on the Delegation of Authority Log, 
OR

The nurse manager(s)/supervisor(s) and study pharmacists authorized by the 
investigator are listed on the Delegation of Authority Log as the person(s) 
responsible for ensuring that the nursing/pharmacy staff are appropriately trained on 
IV study therapy preparation/administration prior to preparing/administering it, and 
for maintaining current and complete training documentation at all times.
Written documentation of training of IV study therapy administration and pharmacy study 
center personnel will be kept current throughout the study, and ongoing training will be 
provided by study center personnel as assigned by the investigator on the Delegation of 
Authority Log. It is the investigator’s responsibility to ensure that all documentation remains 
current and complete throughout the study. The investigator will document how he or she will 
ensure staff are adequately trained before they perform the infusion, and he or she will ensure 
that there is a system in place that will guarantee supervision of the study therapy 
administration process and patient safety (e.g., study therapy will only be administered to 
patients under supervision of an investigator). Source documentation should clearly indicate 
who administered the infusion. Records of IV study therapy usage should include the 
identification of the patientto whom the IV study therapy was administered, the quantity and 
date of administration, and a record of unused IV study therapy. The investigator/pharmacist 
is responsible for maintaining accurate IV study therapy accountability records throughout the 
study on the relevant forms provided by the sponsor/CTCC. Each administration of IV study 
therapy will be documented in the eCRF.
It is the investigator’s responsibility to establish a system for handling study treatments, 
including investigational medicinal products, to ensure that:

Deliveries of such products are correctly received by a responsible person (e.g., 
pharmacist).

Deliveries are recorded.

Intravenous study therapy is handled and stored safely and properly.

Intravenous study therapy provided for this study is used only as directed in the 
study protocol.
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
Study center personnel account for all study drugs received at the study center, 
dispensed for the patient, and returned to the pharmacy. Any discrepancies should 
be documented, investigated, and appropriately resolved.

The CTCC representative or delegate performs complete IV study therapy 
accountability during each monitoring visit, including verifying documentation of 
receipt, dispensing, return, and destruction of IV study therapy and consistency of 
this documentation with physical inventory.

At the end of the study, study center personnel account for all unused IV study 
therapy and for appropriate destruction or return of all unused IV study therapy to a 
designated facility or the sponsorfor destruction. Destruction procedures must be 
approved by the sponsor. It must be possible to reconcile delivery records with 
records of IV study therapy use and destroyed/returned stock. The investigator or 
pharmacist should sign certificates of delivery and return.
7.7
Concomitant and other treatments 
Both ATM (Mattie 1994) and AVI (see IB) are predominantly eliminated by the kidney, partly 
by active tubular excretion. Probenecid and furosemide interfere with the active tubular 
excretion, resulting in increased plasma concentrations of the study drugs.While these 
increases are considered to beclinically insignificant(ER Squibb & Sons Limited 2014), 
concomitant administration of probenecid and/or furosemide should still be avoided if at all 
possible during IV study therapy. Patients being treated with probenecid are not eligible for 
this study (see Exclusion criteria). Based on current knowledge, further relevant drug-drug 
interactions with regard to ATM-AVI administration in this study are not to be expected (see 
section1.3).
All prescription and over the counter medications being taken by the patient for the 2 weeks 
prior to study entry (considered prior treatment) and from enrolmentthrough the LFU visit 
(considered concomitant treatments) must be documented on theappropriate pages of the 
eCRF. Systemic antibiotics should be documented for the entire duration of the study (from 2 
weeks prior to enrolmentthrough the LFU visit).Also application of topical antibacterial and 
antifungal agents and antibiotic peritoneal lavageneed to be recorded in the eCRF.
If Enterococcusspecies or MRSA is one of the pathogens suspected or isolated and, in the
opinion of the investigator, specific therapy is indicated, then vancomycin,linezolid,or 
daptomycin may be added to the study regimens according to the usualpractice of the 
investigator. Information on contraindications, special warnings and precautions and 
interactions with other medicinal products and other forms of interaction are available in the 
respective Summaries of Product Characteristics (SmPCs) for these products and investigators 
are recommended to refer to these for further prescribing information. If vancomycin, 
linezolid, or daptomycin are started empirically tocover MRSA or Enterococcusspecies, and 
if final culture results did not isolate MRSA orEnterococcus species, then the investigator 
should discontinue the additional Gram-positivecoverage that was empirically added.
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Other than vancomycin, linezolid, or daptomycin, which are permitted for treatment of 
suspected or isolated MRSA or Enterococcus species, the use of other systemic antimicrobials 
not specified by this protocol is not permitted duringthe studywith the following exceptions:
If a new infection develops at a remote site (i.e., outside of the abdomen)between the date and 
time of enrolmentand the LFU visit, and the investigator considersaddition of non-study 
antibiotics essential to the safety and wellbeing of the patient, additional antibiotics may be 
added(see also table below in this section). 
Also it is anticipated that in instances of suspected clinical failure, alternative or additional 
antibiotic therapy to treat the cIAI may be required. Prior to administering additional or 
alternative antibiotics the investigator should contact the national coordinating investigator to 
confirm the clinical evaluation andmicrobiological identification of an isolate not coveredby 
ATM-AVI and metronidazole. It is anticipated that in instances of suspected clinical failure, 
alternative or additional antibiotic therapy to treat the cIAI may be required, and where rescue 
therapy is provided the patient should be assessed as a clinical failure.An appropriate 
antibiotic should be selected, taking into account results of sensitivity testing(see also table 
below in this section). 
Also antifungal therapy to treat the cIAI should be avoided unless clinically indicated.
All actions related to the administration of concomitant antibiotics should be documented in 
the eCRF.
Further medication (other than that described above), which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the investigatorwithout 
delay but should also be documented inthe eCRF.
If analgesic medication is needed for pain, the use of analgesics without antipyretic properties 
is preferred. Should a patient require immunosuppressive agents or chemotherapy after 
enrolment, the investigator should contact the sponsor’sphysician or delegate before initiating 
therapy. Continued patient study participation will be determined based upon assessment of 
the safety risk to the patient if he or she were to continue in the study. Patients who have 
already completed the IV study therapy should remain in the study until LFU assessment as 
they are not activelyon study therapy but being followed up for outcomes.
Restricted Medication/Class of drug:
Usage:
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Systemic anti-infective drugs*(antibiotics and 
antifungal drugs) 
*other than vancomycin, linezolid, or 
daptomycin which are permitted for treatment 
of suspected or isolated MRSA or 
Enterococcusspecies
Prior to administration:
contact national coordinating investigator 
obtain a microbiological specimen from the 
infection site
confirm infection due to a pathogen not 
covered by ATM-AVI and metronidazole
review result of sensitivity testing
select appropriate antibiotic drug, taking the 
above into account as well as the 
corresponding Summary of Product 
Characteristics (SmPC) for further 
prescribing information
Analgesic medication
Drugs without antipyretic properties arepreferred
Prohibited Medication/Class of drug:
Probenecid
Prohibited from enrolment to end of IV study therapy
7.8
Post study access to study treatment
At the end of the study, the sponsor will not continue to supply study drug to subjects or 
investigators unless the sponsor chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
8.
STATISTICAL ANALYSES
8.1
Statistical considerations
This is a prospective, open-label, multicenter study to determine the PK, safety and 
tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of hospitalized patients. 
Analyses will be performed by the sponsoror its representatives. A comprehensive Statistical 
Analysis Plan (SAP) will be prepared prior to first patientincluded and any subsequent 
amendments will be documented, with final amendments completed prior to data base lock.
8.2
Sample size estimate
Up to 40 patients will be enrolled into the study in total. Althoughthe study is not powered to 
perform statistical tests, assessment of safety and complete PK assessments from at least 30 
patients with cIAI, is considered sufficient to adequately confirm the PK and safety profile of 
ATM-AVI in a population with a representative burden of disease. It is expected that 10 
patients in Cohort 1 (and 10 patients in Cohort 2 if the higher AVI dose is used) having 
completed all safety assessments are sufficient for an initial review of key safety criteria of 
ATM-AVI,in order to progress with the continuedtreatment ofpatients.
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8.3
Definitions of analysis sets
The modified intent to treat (MITT) population will include all enrolled patients who receive 
any amount of study drug.
The microbiologically modified intent-to treat (mMITT) population is a subset of the MITT 
population and includes all enrolled patients who have a diagnosis of cIAI and have an intra-
abdominal pathogen at baseline (regardless of susceptibility to the study drug).For example, a 
reason for exclusion from the mMITT population may be (amongst others) lack of a pathogen 
collected from a surgical procedure at baseline, whether that be because the surgery was not 
performed, or was performed outside protocol time frame (as defined ininclusion criteria; see 
section 3.1).
The pharmacokinetic (PK) population includes all patients who have at least 1 plasma 
concentration data assessment available for ATM-AVI, no fundamental violations of the 
inclusion and exclusion criteria and no important protocol violations affecting assessment of 
PK as defined in the finalised Statistical Analysis Plan. The reason for exclusion will be listed 
for all subjects in question.
8.3.1
Efficacy analysis set
There are twoefficacy analysis sets: the MITT and mMITTpopulation (for definition see 
section 8.3).
8.3.2
Safety analysis set
The safety analysis set is the MITT population (for definition see section 8.3).
8.3.3
PK analysis set
The PK analysis set is the PK population (for definition see section 8.3).
8.4
Outcome measures for analyses
The primary outcome measureswill be (see also section 2):

ATM and AVI concentrations in plasma (samples to be collected for 6 
hours after the start of an ATM-AVI 3 hour infusion).They will be 
analyzed in the PK analysis set.

Derived PK parameters Cmax, tmax, AUC(0-6), AUC(0-last), tlast, t1/2, 
Vss, Vzand CL for the patients undergoing intensive sampling on day 4. 
They will be analyzed in the PK analysis set.

Safety and tolerability as assessed by adverse events, physical 
examination, vital signs, ECGs, and laboratory assessments. They will be 
analyzed in the safety analysis set.
The secondary outcome measures will be:
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
Proportion of patients with clinical cure at the TOC visit. This will be 
analyzed inthe MITT and mMITT populations.

Correlation of derived PK parameters for ATM-AVI and clinical cure at 
TOC. This will be analyzed in the mMITTpopulation.
The exploratory outcome measures will be:

Estimates of model parameters and their precision, goodness-of-fit, 
individual and mean predictions.
8.5
Methods for statistical analyses
The followingcharacteristicswill be summarised in the safety population:demographics (age, 
sex, and race), medical and surgical history, description of cIAI, baseline assessments of 
clinical signs and symptoms, microbiological assessment of primary infection site or blood, 
IV study therapy administrationand baseline pathogens.MIC frequencies for each infecting 
species isolated from either the abdominal site or blood at baseline will be reported. Pathogens 
isolated from cultures obtained post-baseline will be listed. 
No confirmatory interim analysis is planned. However, in the early patient review,the PK and 
safety aspects will be assessed as displayed in section 5.2.5and 5.3.3. 
8.5.1
Analysis of the primary variables
Descriptive statistical analyses will be performed. Number of observations, arithmetic mean, 
standard deviation (SD), median, firstquartile, thirdquartile, minimum, and maximum will be 
given for quantitative variables. If reasonable, geometric mean and coefficient of variation 
will also be given. Absolute and relative frequencies are given for qualitative variables. If 
variables are measured over time, each time point will be summarized. Summaries of the 
number and frequency of AEs will be presented. 95% confidence intervals will be given 
where reasonable. Full details of the PK analysis will be given in the Pharmacokinetic 
Analysis Plan.
Adverse events occurring from the first dose of IV study therapy up to the LFU visit will be 
summarized by preferred term, system organ class, relationship to IV study therapy and 
severity. Summaries and listings of death, AEs, SAEs, other significant AEs, and AEs that led 
to discontinuation or withdrawal will be presented.
8.5.2
Analysis of the secondary variables
The number and percentage of patients with clinical cure (shown with 80% and 95% 
confidence intervals) will be tabulated for the MITT and mMITT analysis set. Key patient 
subgroups (e.g. the group of patientswith extended-spectrum β-lactamase [ESBL]-phenotype 
pathogens) will be summarised in the same way, and illustrated graphically as a forest plot.
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The proportion of clinical cure at the TOC visit will be determined excluding any patients 
with concomitant antibiotics not administered for failure (mMITT).Refer to section 7.7for 
rules relating to concomitant medication.
8.5.3
Exploratory analysis
The possible relationship between exposure to ATM-AVI and both efficacy and safety 
outcomeswill be explored graphically. Moreover, complex PK/PD modelling (e.g. 
NONMEM) will be done to describe the general trend and variability in the observed data but 
also to better understand underlying mechanisms of drug action and the interaction with the 
physiologic system; to predict tested and untested doses and dosing regimens (Nielsen et al. 
2013). 
No inferential statistical tests will be implemented, given the small sample sizes with respect 
to any efficacy objective.
8.5.4
Evaluation of pharmacokineticsand of pharmacokinetic -pharmacodynamic 
relationships
The following section8.5.4.1describes the analysis of the first25 patients undergoing 
intensive PK sampling. Section8.5.4.2describes the population PK/PD analysis that will 
include data from all patients in the study with one or more PK sample collected (see sections 
5.3.1and 8.3). The early safety and PKreview (see section 5.3.3) will not be reported as part 
of the CSR.
8.5.4.1 Evaluation of the pharmacokinetics of ATM and AVI
The actual sampling times will be used in all final plasma PK parameter calculations. 
Pharmacokinetic parameters will be derived for the 25 patients with intensive plasma 
sampling using non-compartmental methodswith Phoenix®WinNonlin 6.3, or higher (Certara 
L.P., St. Louis, Missouri); or SAS®Version 9.2, or higher (SAS Institute, Inc., Cary, North 
Carolina).
Key PK parameters and a non-compartmental PK report will be summarized in the Clinical 
Study Report (CSR)or in an appendix to CSR. 
8.5.4.2
Population pharmacokinetic/pharmacodynamic analyses
The final data may be pooled with data from other studies to conduct population PK analysis 
(using NONMEM version VII or higher). Using these parameter estimates (mean PK 
parameters including inter-individual variance estimates)Monte-Carlo simulations will be 
undertaken and potential PK/PD relationships will be explored. A detailed population PK/PD 
analysis plan will be prepared prior to any such analysis/es, the results of which will be 
reported separately.
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9.
STUDY AND DATA MANAGEMENT
9.1
Pre-study activities
Before the first patient is entered into the study in an investigational study center, a Sponsor 
representative (or delegate) will

Determine the adequacy of the facilities (including study personnel)

Determine availability of appropriate patients for the study

Discuss with the investigator(s) and other personnel involved in the study their 
responsibilities with regard to protocol adherence and study conduct and the role 
and responsibilities of the COMBACTE-CARE, the sponsor, the delegated 
Academic Research Organisation (CTCC)and further parties involved in the 
conduct of the study.This will be documented in a Clinical Study Agreement 
between the involved parties.
9.2
Training of study site personnel
Before the first subject is entered into the study, asponsor and COMBACTE-CAREdelegate 
will conduct an on-site initiation visit to review and discuss the requirements of the Clinical 
Study Protocol and related documents with the investigational staff and also train them in any 
study specific procedures and system(s) utilized. The web based Electronic Data Capture 
(EDC) system TrialMaster (OmniComm Systems, Inc.) will be trained by eLearning.
The investigator will ensure that appropriate training relevant to the study is given to all of the 
study center personnel, and that any new information relevant to the performance of this study 
is forwarded to the study center personnel involved. The investigator will maintain a record of 
all individuals involved in the study (medical, nursing, and other study center personnel).
9.3
Monitoring of the study
The monitoring of this study will be coordinated byCTCC. All German trial sites will be 
monitored by CTCC. Trial sites outside of Germany will be monitored by local COMBACTE-
CARE partners or delegates assigned by the sponsor,according to the monitoring manual 
developed by CTCC. Details will be defined inthe study specific responsibility split and in 
the study-specific monitoring manual.
The trial sites will be monitored to ensure the quality of the data collected. The objectives of 
the monitoring procedures are to ensure that the study subject’s safety and rights as a study 
participant are respected, that accurate, valid and complete data are collected, and that the 
study is conducted in accordance with the study protocol, the principles of GCP and local 
legislation.
During the study, the monitor will have regular contacts with the study site, including 
telephone contacts and on-site visits to:
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
Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the study center personnel is adhering to the protocol, that 
data are being accurately and timely recorded in the eCRFs, that 
biological samples are handled in accordance with the Laboratory 
Manual and that study drug accountability checks are being performed

Perform source data verification (a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating subjects. This will require direct access to all original 
records foreach subject (e.g., clinic charts, laboratory printouts, 
electronic and paper-based medical records)

Ensure withdrawal of informed consent to the use of the subject’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the subject (see section 5.6.4)
All investigators need to agree that a monitor will regularly visit the trial site and assure that 
the monitor will receive appropriate support in his/her activities during the monitoring visits. 
The monitor will be available between visits if the investigator(s) or other trial site personnel 
need information and advice about the study conduct. The informed consent form includes a 
statement that the monitor has the right –while observing the provisions of data protection 
legislation –to compare data of the case report forms with the trial subject’s medical records.
A monitoring visit report will be prepared for each visit, describing the progress of the clinical 
study and any problems as well as proposed corrective and preventive actions. 
Detailed information (e.g. frequency and duration of monitoring visits, source data 
verification etc.) will be described in the study specific monitoring manual.
9.3.1
Source data
Original records such as clinic charts, laboratory printouts as well as electronic and paper-
based medical records are source documents which contain source data necessary for 
verification of the study data documented in the eCRF. The location of the source data will be 
documented trial site specific. Refer to the Clinical Study Agreement for location of source 
data.
9.3.2
Study agreements
The investigator at each center should comply with all the terms, conditions, and obligations 
of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this clinical study protocol and the Clinical Study Agreement, the 
terms of clinical study protocol shall prevail with respect to the conduct of the study and the 
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treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements betweenCOMBACTE-CARE/sponsor /CTCC and the investigator should be in 
place before any study-related procedures can take place or patients are enrolled.
9.3.3
Archiving of study documents
The investigator will follow the principles outlined in the Clinical Study Agreement (CSA), 
ICH-GCP and local regulations.
9.4
Study timetable and end of study
The end of the study is defined as the last visit of the last patient participating in the study.
This definition appliesfor the entire study, not for a specific region.
The study is expected to start infirst quarter 2016 and to end by fourthquarter 2017.The 
investigators will be notified by the Sponsor when recruitment is complete.
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP or if recruitment is slow. The sponsormay also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with ATM-AVI (see section 3.11).
9.4.1
Clinical Study Report
The Clinical Study Report or Synopsis will be submitted to competent authoritiesand ethics 
committees within 12 months after the end of the study (as defined above) as applicable, 
according to local requirements.
9.5
Data management 
Data management will be performed by CTCC, accordingto the Data Management Manual.
The data collected through third party sources will be obtained, imported into the study 
database and reconciled against study data, including the PK data. For the early patient review 
as described in section 5.3.3, PK data may additionally besent directly to the sponsor.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Medications will be classified according to the sponsor’sDrug Dictionary. All coding will be 
performed by CTCC separate from the study database. The codes will be merged with the 
study data by the biometrician.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the Data Validation Plan (manual checks) and the 
Database Specification (automatic checks). Quality control procedures will be applied to each 
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stage of data handling to ensure that all data are reliable and have been processed correctly. 
When all data have been coded, validated, reconciled, signed and locked, clean file will be 
declared and the final database willbe locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study willbe conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, may be accompanied by a 
separate document that incorporates) wording that complies with relevant data protection and 
privacy legislation.All data collected for this study will be handled according to ICH-GCP 
and further applicable (e.g. local)regulations.
10.3
Ethics and regulatory review
An Ethics Committee (EC) or Institutional Review Board (IRB) should approve the final 
study protocol and amendments to protocol where applicable, including the final version of 
the Informed Consent Form and any other written information or materials to be provided to 
the patients. The investigator will ensure the distribution of these documents to the applicable 
EC or IRB, and to the study center personnel.
The opinion of the EC/IRB should be given in writing. The investigator should receive the 
written approval and send a copy thereof to the sponsor/CTCC prior to enrolment of any 
patient into the study. The EC should approve all advertising used to recruit patients for the 
study. If required by local regulations, the protocol should be re-approved by the Ethics 
Committee annually.
The sponsorshouldapprove any modifications to the Informed Consent Form that are needed 
to meet local requirements.
Before enrolment of any patient into the study, the final study protocolis approved by the 
national regulatory authority or a notification to the national regulatory authority is done, 
according to local regulations. The sponsorwill handle the distribution of alldocuments 
requested bythe national regulatory authorities.
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The sponsorwill provide regulatory authorities with safety updates/reports according to local 
requirements, including suspected and unexpected serious adverse reactions(SUSARs), where 
relevant. Reporting of such cases to the respective Ethics Committees and investigators will 
be done by CTCC.
10.4
Informed consent
The investigator(s) at each centrewill:

Ensure that each patient is given full and adequate oral and written information 
about the nature, purpose, and possible risks and benefits of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure thatpatients who are unable to provide informed consent atScreening and 
who are entered into the study by the consent of a legally acceptable representative 
provide their own informed consent for continuing to participate in the study as 
soon as possible on recovery, as applicable in accordance with national and local 
regulations.

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
investigator’s study file

Ensure a copy of the signed Informed Consent Form is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the investigator and 
the sponsor.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol (revised clinical study protocol).
The amendment is to be approved by the relevant EC/IRB and, if applicable, also by the 
national regulatory authority before implementation. Local requirements are to be followed 
for revised protocols.
The sponsor/CTCC will distribute any subsequent amendments and new versions of the 
protocol to each investigator. For distribution to Ethics Committee see Section 10.1.
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If a protocol amendment requires a change to a centre’s Informed Consent Form, the 
sponsor/CTCC and the centre’s Ethics Committee are to approve the revised Informed 
Consent Form before the revised form is used. 
The sponsor may change the ICF at any time to include extra safety information as deemed 
necessary. A patient will be re-consented if a new ICF is approved while the patient is still 
involved in study activities that are impacted by the changes to the ICF.
If local regulations require, any administrative change will be communicated to or approved 
by the competent EC/IRB.
10.6
Audits and inspections
Authorized representatives of the sponsor/CTCC, a regulatory authority, or an EC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the ICH, and any applicable regulatory requirements. The investigator 
will contact the sponsor/CTCC immediately if contacted by a regulatory agency about an 
inspection at the center.
11.
LIST OF REFERENCES
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Metronidazole 500 mg / 100 ml Intravenous Infusion. United Kingdom Summary of Product 
Characteristics. Caxton Way, Thetford, Norfolk, UK: The Company, eMC 2015. Available at 
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CLSI document M2
Clinical and Laboratory Standards Institute. Performance standards for antimicrobial 
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Cockcroft and Gault 1976
Cockcroft DW, Gault HM. Prediction of creatinine clearance from serum creatinine. Nephron. 
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Crandon and Nicolau 2013
Crandon JL, Nicolau DP: Human Simulated Studies of Aztreonam and Aztreonam-Avibactam 
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El Guinaidy MA, Nawishy S, Abd el Bary M, Sabbour MS. Single-dose pharmacokinetics of 
aztreonam in healthy volunteers and renal failure patients. J Chemother. 1989 Jun;1(3):164-9.
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EMA 2011
EMA Guideline on the evaluation of medicinal products indicated for treatment of bacterial 
infections. European Medicines Agency 2011, London, UK (EMA/CPMP/EWP/558/95 Rev 2, 
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ER Squibb & Sons Limited 2014
ER Squibb & Sons Limited. Azactam (ATM) 1g or 2g Powder for Solution for Injection or 
Infusion (vial). United Kingdom Summary of Product Characteristics. Uxbridge, UK: The 
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Accessed 8 July 2015
European Commission GMP Guideline 2010
European Commission EudraLex Volume 4: EU Guidelines to Good Manufacturing Practice, 
Medicinal Products for Human and Veterinary Use. Annex 13: Investigational Medicinal 
Products, 03 February 2010.
European Commission: Product information Zavicefta 2016
European Commission: Community register of medicinal products for human use. Product 
information Zavicefta 2 g/0.5 g powder for concentrate for solution for infusion. Accessed on 
13 July 2016. Available at http://ec.europa.eu/health/documents/community-
register/2016/20160624135109/anx_135109_en.pdf
FDA 2009
Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), July 2009
FDA 2015
Guidance for Industry: Complicated Intra-Abdominal Infections: Developing Drugs for 
Treatment, U.S. Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), February 2015.
FDA prescribing info: AVYCAZTM2015
Highlights of prescribing information. U.S. Department of Health and Human Services, Food 
and Drug Administration, September 2015. Accessed 22 October 2015. Available at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206494s001lbl.pdf
IMI 2015
Innovative Medicines Initiative ND4BB Topic 5: Clinical development of antibacterial agents 
for Gram-negative antibiotic resistant pathogens. http://www.imi.europa.eu/webfm_send/913
(last accessed: 29 June 2015).
Lucasti et al. 2013
Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and 
safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of 
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Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
99(99)
complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-
blind, Phase II trial. J Antimicrob Chemother 2013; 68(5):1183-92.
Magiorakos et al. 2012
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CC, et al. 
Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international 
expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 
2012; 18: 268–281.
Mattie 1994
Mattie H. Clinical pharmacokinetics of aztreonam. An update.Clin Pharmacokinet. 1994 Feb;
26(2):99-106.
Mihindu et al. 1983
Mihindu JC, Scheld WM, Bolton ND, Spyker DA, Swabb EA, Bolton WK. Pharmacokinetics 
of aztreonam in patients with various degrees of renal dysfunction. Antimicrob Agents 
Chemother. 1983 Aug; 24(2): 252-61.
Murray et al 2007
Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, editors. Manual of Clinical 
Microbiology. Washington DC; American Society for Microbiology; 2007 (Available upon 
request).
Nielsen et al. 2013
Nielsen EI, Friberg LE. Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. 
Pharmacol Rev. 2013;65(3):1053-90).
Nordmann et al. 2013
Nordmann P, Poirel L. Strategies for identification of carbapenemases-producing 
Enterobacteriaceae. J. Antimicrob Chemother. 2013; 68 (3):487-489.
Solomkin et al. 2010
Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, Baron EJ, et al. 
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. 
Clinical Infectious Diseases 2010; 50:133–64.
Tarral et al. 2015
Tarral A, Merdjan H. Effect of Age and Sex on the Pharmacokinetics and Safety of 
Avibactam in Healthy Volunteers. Clin Ther. 2015;37:877-886.
Vinks et al. 2007
Vinks AA, van Rossem RN, Mathôt RA, Heijerman HG, Mouton JW. Pharmacokinetics of 
aztreonam in healthy subjects and patients with cystic fibrosis and evaluation of dose-
exposure relationships using monte carlo simulation. Antimicrob Agents Chemother. 2007 
Sep; 51(9): 3049-55.
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Revised Clinical Study Protocol
Drug Substance ATM-AVI
Pfizer/AstraZeneca Study Code C3601001/D4910C00009
Edition Number Final 3.0
Date 29 March 2017
100(100)
Walsh et al. 2011
Walsh TR, Weeks J, Livermore SM, Toleman MA. Dissemination of NDM-1 positive bacteria 
in the New Delhi environment and its implications for human health: an environmental point 
prevalence study. Lancet Infect Dis 2011;11(5):355-62
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Statistical Analysis Plan 
Study code: D4910C00009 
Edition number: V03 D02 
Date: 07.04.2016 
 
 
Page 2 of 29 
 
 
 
 
 
Approved by 
 
Prof. 
 
Principal Investigator 
 
 
 
 
Place and date 
 
Signature 
Dr. 
  
Statistician, CTCC 
 
 
 
 
Place and date 
 
Signature 
 MSc 
Statistician, AstraZeneca 
 
 
 
 
Place and date 
 
Signature 
PPD
PPD
PPD
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Date: 07.04.2016 
 
 
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Contents 
 
1 
Background .................................................................................................................... 4 
1.1 
Trial objective .......................................................................................................... 5 
1.2 
Trial design ............................................................................................................. 5 
1.3  
Number of subjects ................................................................................................. 6 
2 
Analysis sets .................................................................................................................. 8 
2.1 
Definitions ............................................................................................................... 8 
2.2 
Application .............................................................................................................. 8 
2.3 
Major protocol deviations for definition of PK population ......................................... 8 
3 
Trial centres ................................................................................................................... 9 
4 
Analysis variables......................................................................................................... 10 
4.1 
Demography and baseline characteristics ............................................................. 10 
4.2 
Primary variable .................................................................................................... 10 
4.2.1 
Definition of AEs and SAEs ............................................................................ 13 
4.3 
Secondary variables14 
4.3.1 
Clinical cure ................................................................................................... 14 
5 
Handling of missing values and outliers ........................................................................ 16 
6 
Statistical analyses / methods ...................................................................................... 16 
6.1 
Patients ................................................................................................................. 16 
6.2 
Demography and baseline characteristics ............................................................. 16 
6.3 
Prior or concomitant medication, surgery and diseases ......................................... 16 
6.4 
Microbiology .......................................................................................................... 18 
6.5 
Exposition to treatment/Compliance ...................................................................... 19 
6.6 
Primary analysis .................................................................................................... 20 
6.6.1 
ATM-AVI concentrations and PK parameters ................................................. 20 
6.6.2 
Adverse Events and Serious Adverse Events ................................................ 21 
6.6.3 
Laboratory safety assessment ........................................................................ 21 
6.6.4 
Physical examinations .................................................................................... 22 
6.6.5 
Resting ECG .................................................................................................. 22 
6.6.6 
Vital signs ....................................................................................................... 22 
6.7 
Secondary analyses .............................................................................................. 23 
6.8 
Planned subgroup analyses .................................................................................. 23 
6.9 
Early patient review ............................................................................................... 23 
6.9.1 
Criteria for immediate progression .................................................................. 24 
6.9.2 
Criteria for stop and review............................................................................. 24 
6.9.3 
Criteria for non-progression ............................................................................ 25 
7 
Deviations from the protocol ......................................................................................... 26 
8 
Interpretation of results ................................................................................................. 26 
9 
Data problems .............................................................................................................. 26 
10 Software ....................................................................................................................... 26 
11 References ................................................................................................................... 27 
12 Appendices .................................................................................................................. 28 
12.1 Reference ranges of laboratory parameters .......................................................... 28 
12.2 Expected pathogens and their possible groupings ................................................ 28 
12.3 Planned tables, listing, graphics ............................................................................ 29 
12.4 Criteria for clinical significance of changes from baseline ...................................... 29 
 
 
 
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List of tables 
 
Table 1 
Study Plan detailing the procedures .................................................................... 7 
 
List of figures 
 
Figure 1 
Study Outline ....................................................................................................... 6 
 
 
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1 
Background 
1.1 
Trial objective 
The objective of this Phase IIa, patient pharmacokinetics (PK) study is to investigate the PK, 
tolerability and safety of aztreonam-avibactam (ATM-AVI) in patients with a serious bacterial 
infection and to provide dose confirmation for Phase III clinical trials. The 
Pharmacokinetic/Pharmacodynamic (PK/PD) data generated will contribute to a robust 
package of data, supported by prior experience with ATM and AVI administered separately, 
and validated by qualitative data for the combination from a proposed randomized Phase III 
clinical trial in patients with infections suspected to be caused by these specific but rare 
pathogens. [CSP section 2, p.28] 
1.2 
Trial design 
This is a prospective, open-label, single-arm, dose-confirming multicenter Phase IIa study to 
determine the PK, safety and tolerability of ATM-AVI in the treatment of hospitalized patients 
with a complicated intra-abdominal infection (cIAI). Forty adult patients with a diagnosis of 
cIAI and the need for a surgical intervention will be enrolled. The surgical intervention may 
take place within 24 hours before or after administration of the first dose of study drug. After 
obtaining written informed consent and confirming eligibility, patients will be assigned the 
following treatment: 
From the study start, only patients with normal renal function or mild renal impairment (i.e. 
creatinine clearance (CrCl) >50 mL/min) will be eligible. The proposed administration of 
ATM-AVI for these patients is a loading dose (500 mg ATM plus 137 mg AVI by intravenous 
[IV] infusion over a 30 minute period), immediately followed by a dose of 1500 mg ATM plus 
410 mg AVI by IV infusion over a 3 hour period every 6 hours (maintenance infusion). The 
targeted total dose on Day 1 will be 6500 mg ATM and 1777 mg AVI. From Day 2 onwards, 
this will be 6000 mg ATM / 1640 mg AVI. For anaerobic coverage, patients will also receive 
500 mg metronidazole infused over 1 hour every 8 hours (q8h), starting after the first ATM-
AVI maintenance infusion. 
The PK, safety and tolerability of the dosing regimen described above will be assessed in a 
first cohort of 10 patients (see section 6.8). 
Patients with moderate renal impairment (CrCl of 31 to 50 mL/min) must not be included prior 
to the completion of the 10 patient safety review and subsequent confirmation of an 
appropriate dosing regimen. Patients with a creatinine clearance of 31 – 50 mL/min will be 
eligible if the results of the early PK and safety review (along with respective PK modelling) 
• 
support inclusion of such patients and 
• 
confirm a specific dosing regimen to be amended to the protocol. 
Intravenous study therapy (ATM-AVI) plus metronidazole will be continued for a period of 
time (5 to 14 full days, where a full day is defined as a 24-hour period) deemed appropriate 
by the investigator based on the patient’s clinical response. After at least 5 full days of IV 
study therapy and at the discretion of the investigator, all study therapies may be 
discontinued if the patient has shown significant clinical improvement. 
It is anticipated that each patient will complete the study, including the Late Follow-up (LFU) 
visit. In the event that the patient is discharged from the hospital before the End of Treatment 
(EOT), Test of Cure (TOC), or LFU visit, they will return to the study centre for their 
scheduled assessment. If treatment with antibiotics is required beyond 14 days, the 
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2 
Analysis sets 
2.1 
Definitions 
The modified intent-to-treat (MITT) population will include all enrolled patients who receive 
any amount of study drug. 
The microbiologically modified intent-to-treat (mMITT) population is a subset of the MITT 
population and includes all enrolled patients who have a diagnosis of cIAI (i.e. meet inclusion 
criterion 4; CSP, p. 31-32) and have an intraabdominal pathogen at baseline (regardless of 
susceptibility to the study drug). For example, a reason for exclusion from the mMITT 
population would be (amongst others) lack of a pathogen collected from a surgical procedure 
at baseline, whether that be because the surgery was not performed, or was performed 
outside protocol time frame  (see inclusion criteria, with an extra tolerance of ±1 hour around 
the specified time intervals). 
The pharmacokinetic (PK) population includes all patients who have at least 1 plasma 
concentration data assessment available for ATM-AVI, no fundamental violations of the 
inclusion and exclusion criteria and no important protocol deviations affecting assessment of 
PK as defined in section 2.3. The reason for exclusion will be listed for all subjects in 
question. [CSP section 8.3, p.81] 
2.2 
Application 
There are two efficacy analysis sets: the MITT and mMITT population. The safety analysis 
set is the MITT population. The PK analysis set is the PK population. 
2.3 
Major protocol deviations for definition of PK population 
Patients who fail to qualify according to the following inclusion/exclusion criteria will be 
excluded from the PK analysis set [CSP sections 3.1 and 3.2, p.29-36]: 
• 
Inclusion criterion 4: diagnosis of cIAI 
• 
Exclusion criterion 3: prior (within 3 months of starting study medication) or 
concomitant administration of another investigational medication 
• 
Exclusion criterion 25: current probenecid treatment 
These criteria have been selected as essential for restricting the PK population because 
they relate either to the fundamental target population (cIAI) of the study or to the 
pharmacokinetic system being studied. 
Patients with the following protocol deviations will be excluded from the PK analysis set: 
• 
taking prohibited medication, i.e. probenecid 
 
 
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3 
Trial centres 
The study takes place in 22 trial centres in Germany, France and Spain. Each side is 
expected to recruit two patients. 
Site code 
Country 
Organisation 
France 
France 
France 
France 
France 
France 
Germany 
Germany 
Germany 
Germany 
Germany 
Germany 
Spain 
Spain 
Spain 
Spain 
Spain 
Spain 
Spain 
Spain 
Spain 
Spain 
 
 
 
PPD
PPD
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4 
Analysis variables 
4.1 
Demography and baseline characteristics 
The demographic and baseline variables are measured at visit 1 (day -1 to 0) or 2 (day 1). 
The following demographic variables will be analysed:  
• 
Age [years] 
• 
Sex [male, female] 
• 
Ethnicity [Hispanic/non-Hispanic] 
• 
Race [caucasian/white, black, Asian] 
• 
Smoking status [never smoker, ex-smoker, smoker] 
• 
Cumulative pack years 
• 
Ex-smoker since [years] 
• 
Alcohol history (number of glasses of beer, wine, spirits per week) 
The following baseline variables will be analysed: 
• 
Height [cm] 
• 
Weight [kg] 
• 
Body mass index [kg/m2] (computed as Weight [kg]/(Height [cm]/100)2) 
• 
Physical examination 
• 
Vital signs 
• 
Infection-related signs and symptoms 
• 
Diagnosis 
• 
Location of infection 
• 
Infection due to complications of previous abdominal surgery 
• 
Infection due to complication of previous treatment failure 
• 
Pathogens identified at baseline: genus and (if identified) species 
• 
Monomicrobial (manifestation of only one bacterial species from any source of 
infection [cIAI site or blood]) or polymicrobial (manifestation of more than one 
bacterial species from any source of infection [cIAI site or blood]) bacterial species 
• 
Minimum inhibitory concentrations (MIC) of each tested antimicrobial agent for each 
tested pathogen: possible values are ≤0.008, 0.015, 0.03, 0.0625, 0.125, 0.25, 0.5, 1, 
2, 4, 8, 16, 32, 64, 128, 256, >256 μg/ml. 
• 
Disk zone of ATM-AVI for each tested pathogen 
4.2 
Primary variable 
The PK analyses of the concentration (µg/mL) data for ATM and AVI respectively, will be 
performed by Standard Operating Procedures; Work Instructions will be used as the default 
methodology if not otherwise specified.  The actual sampling times will be used in the final 
PK parameter calculations. Nominal sampling times (see CSP Table 4 below) will be used for 
all interim PK analyses. All PK computations will be performed using Phoenix®WinNonlin 6.2, 
or higher (Certara L.P., St. Louis, Missouri); or SAS® Version 9.2, or higher (SAS 
Institute,Inc., Cary, North Carolina). Pharmacokinetic parameters will be derived using non-
compartmental methods. 
The primary outcome measures will be: 
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• 
Derived PK parameters for ATM and AVI, respectively: 
o Cmax: Maximum plasma concentration 
o tmax: Time of observed maximum concentration 
o AUC(0-6): Area under the plasma concentration vs. time curve from time point 
zero up to 6 hours 
o AUC(0-last): Area under the plasma concentration vs. time curve from time point 
zero up to the last measured concentration above Limit of quantification (LOQ) 
o tlast: Time of last measured concentration above LOQ 
o t1/2: Plasma elimination half-life 
o Vss: Apparent volume of distribution at steady state after IV administration 
o Vz: Volume of distribution during terminal phase after IV administration and  
o CL: clearance 
for the first 25 patients undergoing intensive sampling on day 4. They will be analysed 
in the PK analysis set. 
The pharmacokinetic sampling schedule is displayed below: 
Day 
Sample time 
Day 1 
All patients: sparse sampling (4 samples/patient) 
Sample 1: 0h (within 1h before start of loading dose) 
Sample 2: within 5 min before the end of the loading dose infusion 
Sample 3: anytime within the 15 minutes prior to the end of the second IV infusion 
(3.25h – 3.5h after start of loading dose infusion) 
Sample 4: within 5-6  h after start of loading dose infusion  
Day 4 
First 25 patients: intensive sampling (11 samples/patient) 
Trough (within 10 min prior to IV infusion start), 0.5h 1, 2, 3 (within 15 min before 
IV infusion stop), 3.25, 3.5. 3.75, 4, 5, and 6 h after start of IV infusion (just before 
start of next infusion)  
Remaining 15 patients: sparse sampling (3 samples/patient) 
Sample 1: within 1 h of start of IV infusion  
Sample 2: within the 15min prior to the end of IV infusion (within 2.75 to 3 h 
after  start of IV infusion) 
Sample 3: within 5-6 h after start of IV infusion (within one hour prior to start the 
next infusion) 
[CSP Table 4, p.60] 
Safety and tolerability as assessed by 
• 
Number and severity of adverse events and serious adverse events 
• 
Physical examination (at EOT and TOC) 
o Weight [kg] (only if clinically relevant change from baseline) 
o General appearance  
o Skin, head, eyes, ears, nose, throat  
o Lymph nodes  
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o Respiratory  
o Cardiovascular Abdomen  
o Musculoskeletal  
o Neurological Other  
All variables (except weight) are classified as normal or abnormal (clinical 
significance [yes, no] if abnormal). 
• 
Vital signs (daily assessment, day 2-14 = visit 3-15; EOT, TOC, LFU) 
o Systolic blood pressure [mmHg] 
o Diastolic blood pressure [mmHg] 
o Heart rate [beats/min] 
o Respiratory rate [breaths/min] 
o Temperature [°C] 
• 
ECGs 
• 
Laboratory assessments (baseline, day 4, 7, 10, 13, EOT, TOC, LFU and possibly 
further samples as clinically indicated to be analysed at the local laboratory) 
 
Clinical chemistry 
o 
Alanine aminotransferase 
o 
Albumin  
o 
Alkaline phosphatase  
o 
Aspartate aminotransferase 
o 
β-hCG (β-human chorionic gonadotropin; will be determined for woman 
of childbearing potential at screening (visit 1) and LFU only) 
o 
Bicarbonate 
o 
Blood urea nitrogen  
o 
Calcium, total  
o 
Chloride  
o 
Creatinine 
o 
Estimated creatinine clearance (to be calculated by study center 
personnel following each determination of serum creatinine until EOT 
(inclusive) according to CSP Appendix E. TOC and LFU: Calculation of 
CrCl only if clinically indicated.  
o 
Glucose (nonfasting) 
o 
Inorganic phosphorus  
o 
Potassium  
o 
Sodium  
o 
Bilirubin (total, direct and indirect)  
o 
Total protein 
 
Hematology 
o 
Hematocrit  
o 
Hemoglobin 
o 
Platelet count 
o 
Red blood cell count  
o 
White blood cell count (total and differential) 
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 
Urinalysis 
o 
Appearance (color, clarity) 
Bilirubin 
o 
Glucose 
o 
Ketones 
o 
Leukocyte esterase 
o 
Nitrite 
o 
pH 
o 
Protein 
o 
Specific gravity 
o 
Urobilirubin  
o 
Microscopic examination: 
Red blood cells 
White blood cells 
Casts 
Crystals 
Bacteria, yeast cells, or parasites 
 
Other 
o 
Blood culture (baseline and as clinically indicated thereafter) 
 They will be analysed in the safety analysis set. 
4.2.1 Definition of AEs and SAEs 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram). For the purposes of the present study, an AE can include an 
undesirable medical condition occurring at any time following informed consent, even if no IV 
study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
A serious adverse event (SAE) is an AE occurring during any study phase after the patient 
has signed the ICF (i.e., treatment, follow-up) that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation excluding 
hospitalization due to worsening or failure of treatment for primary infection under 
study 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defect  
• 
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above, including suspected 
transmission of an infectious agent via the IV study therapy 
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Liver dysfunction criteria: 
• 
A Potential Hy’s Law case is defined as any situation where a patient has an increase 
in both AST or ALT ≥3xULN and total bilirubin ≥ 2xULN, irrespective of the patient’s 
alkaline phosphatase value, at any point during the study following the start of study 
medication. 
• 
A Hy’s Law case is defined as a patient with an increase in serum AST or ALT 
≥3xULN together with total bilirubin ≥2x ULN, where no other reason than the IMP 
can be found to explain the combination of increases, e.g., elevated serum ALP 
indicating cholestasis, viral hepatitis, another drug. 
For potential and Hy’s Law cases the elevation in transaminases must precede or be 
coincident with (i.e., on the same day) the elevation in total bilirubin, but there is no 
specified timeframe within which the elevations in transaminases and total bilirubin must 
occur. 
[CSP Appendix D] 
The following cases of liver dysfunction are defined and reported as AE or SAE: 
(1) Hy’s law case: SAE 
(2) Potential Hy’s law case with an alternative explanation which is clinically significant: 
AE, or if seriousness criteria are met at any time, SAE 
(3) Potential Hy’s law cases where more than 3 weeks elapse without further 
confirmatory information: SAE (report term ‘Hy’s law’). 
Planned procedures or hospitalizations should not be recorded as SAEs, but complications 
arising from planned procedures or hospitalization / prolongation of hospitalizations meeting 
a seriousness criterion should be recorded and reported as SAEs. 
Adverse Events and Serious Adverse Events must be collected for each patient from 
informed consent until the late follow-up visit (irrespective of whether the last follow-up visit 
attended by the patient is TOC or LFU; i.e. at the latest until Day 38). 
[CSP section 6, p.65-71] 
4.3 
Secondary variables 
The secondary outcome measures will be: 
• 
Proportion of patients with clinical cure at the TOC visit. This will be analysed in the 
MITT and mMITT populations. 
• 
Correlation of derived PK parameters for ATM-AVI and clinical cure at TOC. This will 
be analysed in the mMITT population. 
4.3.1 Clinical cure 
Clinical cure is defined as follows: 
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Clinical 
Response 
Definition 
Cure 
Complete resolution or significant improvement of signs and symptoms of 
the index infection (cIAI) such that no further antimicrobial therapy, drainage, 
or surgical intervention is necessary and does not meet any of the failure 
criteria listed below. 
Failure 
Patients who meet any 1 of the following criteria will be considered a 
treatment failure: 
• 
Death related to intra-abdominal infection 
• 
Patient who received treatment with additional antibiotics for ongoing 
symptoms of cIAI (including patients prematurely discontinued from 
study therapy due to an adverse event who require additional 
antibiotics for cIAI) 
• 
Patient previously met criteria for failure (i.e. prior to respective visit) 
• 
Persisting or recurrent infection within the abdomen documented by 
the findings at re‑intervention either percutaneously or operatively 
(exception: the re-intervention was already planned at initial surgery 
to check proper infection/focus control, occurs within 96 hours after 
enrolment, does not show deterioration and includes fascial closure) 
• 
Post-surgical wound infections defined as an open wound with signs 
of local infection such as purulent exudates, erythema, or warmth that 
requires additional antibiotics and/or non-routine wound care 
Indeterminate Study data are not available for evaluation of efficacy for any reason, 
including: Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response cannot be made 
Abbreviations: cIAI, complicated intra-abdominal infection; EOT: End of Treatment (with study 
therapy); LFU: Late follow-up; TOC: Test of Cure. 
[CSP table 2, p.52] 
In order to confirm the clinical response classification (cure, failure or indeterminate) of a 
patient, all criteria for failure (see table above) will be checked. This will involve data from 
clinical response assessment (at EOT and TOC), mortality assessment (at EOT and TOC), 
concomitant antibiotic medication, study completion/discontinuation, surgical procedure and 
post-operative wound examination. Doubtful cases will be listed for scrutiny by the study 
physician. 
The proportion of patients with clinical cure is defined as the number of patients in the 
efficacy analysis set (MITT or mMITT population respectively) with clinical cure at TOC visit 
divided by the total number of patients in the efficacy analysis set. Indeterminate or missing 
assessment will be included in the denominator for calculation of Patients in the efficacy 
analysis set. 
Any patients with a missing assessment at TOC visit (along with any other reasons leading to 
an assignment of indeterminate response) will be regarded as failures in the calculation of 
the proportion cured. 
 
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5 
Handling of missing values and outliers 
Because of the small sample size and the explorative nature of the study missing values will 
not be imputed. Because the data will only be reported descriptive outliers will not be 
removed from the dataset. 
 
6 
Statistical analyses / methods 
Because of the explorative nature of the study no complicated statistical methods will be 
used for the analysis of the data. The tables, figures and listing used for the analysis are 
displayed in the TFL document in the appendix 12.3. 
6.1 
Patients 
The study population will be described as follows: 
• 
number (and percentage) of patients enrolled (overall and by country and site), 
received treatment, completed treatment and completed the study with reasons for 
not receiving treatment, discontinuing treatment and withdrawal from the study 
• 
number and percentage of patients with at least one important protocol deviation and 
reason for protocol deviation 
• 
number and percentage of patients in the safety, efficacy and PK analysis set and 
reasons of exclusion 
6.2 
Demography and baseline characteristics 
If not stated otherwise the last measurement before the first dose is the baseline value. 
Demographic and baseline variables will be summarised as follows: 
• 
for quantitative variables: number of observations, arithmetic mean, standard 
deviation (SD), median, 1st quartile, 3rd quartile, minimum and maximum 
• 
for qualitative variables: absolute and relative frequencies 
6.3 
Prior or concomitant medication, surgery and diseases 
Both ATM and AVI are predominantly eliminated by the kidney, partly by active tubular 
excretion. Probenecid and furosemide interfere with the active tubular excretion, resulting in 
increased plasma concentrations of the study drugs. While these increases are considered to 
be clinically insignificant, concomitant administration of probenecid is prohibited and 
furosemide should be avoided if at all possible during IV study therapy. Patients being 
treated with probenecid are not eligible for this study. Based on current knowledge, further 
relevant drug-drug interactions with regard to ATM-AVI administration in this study are not to 
be expected. 
All prescription and over the counter medications being taken by the patient for the 2 weeks 
prior to study entry (considered prior treatment) and from enrolment through the LFU visit 
(considered concomitant treatments) must be documented on the appropriate pages of the 
eCRF. Systemic antibiotics should be documented for the entire duration of the study (from 2 
weeks prior to enrolment through the LFU visit). Also application of topical antibacterial and 
antifungal agents and antibiotic peritoneal lavage need to be recorded in the eCRF. 
If Enterococcus species or MRSA is one of the pathogens suspected or isolated and, in the 
opinion of the investigator, specific therapy is indicated, then open-label vancomycin, 
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linezolid, or daptomycin may be added to the study regimens according to the usual practice 
of the investigator. If vancomycin, linezolid, or daptomycin are started empirically to cover 
MRSA or Enterococcus species, and if final culture results did not isolate MRSA or 
Enterococcus species, then the investigator should discontinue the additional Gram-positive 
coverage that was empirically added. 
The use of other systemic antimicrobials not specified by this protocol is not permitted during 
the study. However, if a new infection develops at a remote site (i.e., outside of the 
abdomen) between the date and time of enrolment and the LFU visit, and the investigator 
considers addition of non-study antibiotics essential to the safety and wellbeing of the 
patient, additional antibiotics may be added. 
Also it is anticipated that in instances of suspected clinical failure, alternative or additional 
antibiotic therapy to treat the cIAI may be required. Prior to administering additional or 
alternative antibiotics the investigator should contact the national coordinating investigator to 
confirm the clinical evaluation and microbiological identification of an isolate not covered by 
ATM-AVI and metronidazole. It is anticipated that in instances of suspected clinical failure, 
alternative or additional antibiotic therapy to treat the cIAI may be required, and where 
rescue therapy is provided the patient should be assessed as a clinical failure. An 
appropriate antibiotic should be selected, taking into account results of sensitivity testing. 
Also antifungal therapy to treat the cIAI should be avoided unless clinically indicated. 
All actions related to the administration of concomitant antibiotics should be documented in 
the eCRF. 
Further medication (other than that described above), which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the investigator without 
delay but should also be documented in the eCRF. 
If analgesic medication is needed for pain, the use of analgesics without antipyretic 
properties is preferred. Should a patient require immunosuppressive agents or chemotherapy 
after enrolment, the investigator should contact the AstraZeneca physician or delegate 
before initiating therapy. Continued patient study participation will be determined based upon 
assessment of the safety risk to the patient if he or she were to continue in the study. 
Patients who have already completed the IV study therapy should remain in the study until 
LFU assessment as they are not actively on study therapy but being followed up for 
outcomes. 
Restricted Medication/Class of drug: 
Usage: 
Systemic anti-infective drugs* (antibiotics 
and antifungal drugs)  
*other than vancomycin, linezolid, or 
daptomycin which are permitted for 
treatment of suspected or isolated MRSA 
or Enterococcus species 
Prior to administration: 
• 
contact national coordinating investigator 
• 
obtain a microbiological specimen from 
the infection site 
• 
confirm infection due to a pathogen not 
covered by ATM-AVI and metronidazole 
• 
review result of sensitivity testing 
• 
select appropriate antibiotic drug, taking 
the above into account as well as the 
corresponding Summary of Product 
Characteristics (SmPC) for further 
prescribing information 
Analgesic medication 
Drugs without antipyretic properties are 
preferred 
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Prohibited Medication/Class of drug: 
 
Probenecid 
Prohibited from enrolment to end of IV study 
therapy 
[CSP section 7.7, p.79-80] 
All medical/surgical events prior to start of the study will be listed for each patient by date. 
Additionally, disease related events prior to study start will be tabulated by system organ 
class. 
The prior (within the last two weeks before the study) and concomitant medication and 
antibiotic medication will be listed for each patient by date. Number and percentage of 
patients with prior and concomitant antibiotic medication will be given. 
All prior systemic antibiotic and concomitant medications will be coded using the AZ Drug 
dictionary medication code and summarized by ATC classification and preferred term. 
6.4 
Microbiology 
The local laboratory must identify all aerobic bacterial pathogens to the genus and species 
level using confirmatory (not presumptive) identification methods from blood, intraabdominal 
or other specimens. Antimicrobial susceptibility should be determined for each aerobic 
pathogen isolated according to local practices. In addition, a disk diffusion test for ATM-AVI 
must be performed on each aerobic isolate using CLSI methods. The local laboratory can 
perform any additional testing on further agents as they normally do to provide susceptibility 
results of isolated aerobic microorganisms. 
All anaerobic bacterial pathogens must be identified to at least the genus level. If the local 
laboratory cultures and performs susceptibility testing on anaerobic organisms, it should 
follow CLSI methodologies by either broth microdilution (Bacteroides fragilis group) or agar 
dilution with minimum inhibitory concentration (MIC) testing only (not disk diffusion) on 
metronidazole. 
However, all anaerobic isolates must be sent to the central reference laboratory for 
confirmation of identification and susceptibility testing. 
The investigator should record information on all specimens according to the microbiological 
investigator’s manual supplied by the central reference laboratory. All specimens collected at 
baseline or post baseline should be entered in the eCRF with regards to a) day, time and site 
of sampling b) local identification for each pathogen and c) disc susceptibility / MIC to the 
study therapy for each pathogen. 
The central reference laboratory will confirm pathogen identifications and susceptibility test 
results on all clinical isolates reported and shipped by the local laboratory. Thus, the central 
laboratory is responsible for the definitive identification for each microbiological organism and 
determination of MICs for ATM-AVI and comparator antibiotics. If a) discrepancies occur 
between the results obtained at the central lab and those obtained at the local lab or b) 
microorganisms that are isolated at the local lab do not survive shipping to the central lab, an 
AstraZeneca representative or delegate may request to ship a second sample of the isolate 
in question. In the instance of differences in pathogen identification or susceptibilities, the 
central reference laboratory results will take precedence over the local laboratory results. 
The data obtained at the central reference lab will be used to determine descriptively a) the 
pathogen(s) causing the patient’s infection and b) the efficacy of the study therapy at the 
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pathogen level. Local laboratory results may be used if a microorganism does not survive 
shipping or is not recoverable from the local laboratory. The central reference lab will transfer 
all microbiological data directly to CTCC where they will be merged into the study database 
(without being entered in the eCRF). The isolate ID number will be used to match the data 
obtained at the central lab with the data obtained at the local lab. Details will be described in 
a data transfer agreement. 
Adequate samples are defined as samples from pus, tissue, peritoneal fluid or swab 
collected at surgical intervention, or blood; data analysis will be restricted to adequate 
samples. 
Number and percentage of patients with pathogenic organisms identified at baseline will be 
summarized separately according to specimen type (intra-abdominal, blood) and shown by 
categorization into gram positive / gram negative and aerobes / anaerobes. Patients with 
pathogens categorized as Enterobacteriaceae will also be summarised. 
Number and percentages of patients having monomicrobial or polymicrobial infections at 
baseline will be summarised. 
Disk zone diameters from local lab will be categorised into susceptible, intermediate and 
resistant and will be tabulated. MIC from central lab will be tabulated as well (in case of 
multiple isolates with the same pathogen, that with the highest MIC will be reported). The 
isolates will be classified and tabulated as well. 
Any pathogenic organisms identified post-baseline will be listed. 
6.5 
Exposition to treatment/Compliance 
The exposure (in days; calculated as “last dose date – first dose date + 1”) to study therapy 
will be listed by patient. If the treatment duration is less than 5 days or beyond 14 days, the 
patient will be flagged. Additionally, the number of IV infusions and the number of each 
individual component of study therapy (ATM, AVI, metronidazole) will be summarized by 
baseline renal function (normal renal function/mild renal impairment (CrCl >50 mL/min) and 
moderate renal impairment (CrCl of 31 to 50 mL/min). 
Compliance for each IV therapy will be calculated as follows: (sum of actual infusions / 
expected infusion) × 100. The overall compliance will be an average of the ATM, AVI and 
metronidazole compliance. 
The number of expected infusions for each IV therapy will be calculated as A/B rounded to 
the nearest integer with 
• 
A: “stop date and time of the last dose of maintenance IV therapy – start date and 
time of the first dose of maintenance IV therapy” in hours 
• 
B: interval of infusion (6 for ATM and AVI, 8 for metronidazole) 
For ATM and AVI it is necessary to add 1 for the loading dose. 
These analyses will be performed in the safety analysis set. 
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•The number of NQ values (n below LLOQ) will be reported for each time point. 
Data from subjects excluded from the PK analysis set will be included in the data listings, but 
not in the descriptive statistics. 
6.6.2 Adverse Events and Serious Adverse Events 
The numbers and percent of patients with AEs occurring from the time when informed 
consent is obtained at screening up to the late follow-up visit will be summarised with 
absolute and relative frequencies. The following summaries will be presented: 
• 
Overall summary of AEs 
• 
Incidence of AEs by system organ class (SOC) and preferred term 
• 
Incidence of AEs by SOC, preferred term, and relationship to study therapy 
• 
Incidence of AEs by SOC, preferred term, and severity 
AEs which occur before the first dose of study medication will be identified as such in 
frequency tables (by inserting the corresponding frequency of such AEs in parentheses) and 
in listings. 
In addition, AE will be summarized by patients who received other antibiotics (i.e. excluding 
ATM-AVI, metronidazole) at any time during the treatment period versus those who did not 
receive antibiotics during the treatment period. In this summary all adverse events will be 
included regardless of whether they occurred prior to starting the antibiotic or not. 
A summary for deaths up to LFU visit will be presented; all deaths up to LFU visit with key 
patient information will be presented in a listing. Adverse events with outcome of death up to 
LFU visit will be summarized by system organ class and by preferred term; all adverse 
events with outcome of death up to LFU visit for key patient information will be presented in a 
listing. 
Incidence of SAEs up to LFU visit will also be presented by system organ class (SOC) and 
preferred term; all SAEs up to LFU visit for key patient information will be presented in 
listings. 
Incidence of adverse events of special interest will also be presented for each category by 
preferred term. Categories include: AEs potentially related to drug-induced liver injury, 
clostridium difficile colitis and hypersensitivity/anaphylaxis 
Incidence of AEs leading to discontinuation of investigational product by SOC and preferred 
term will be presented in a table and the patients discontinued the investigational product 
due to AEs will also be presented in a data listing. 
 
6.6.3 Laboratory safety assessment 
Central laboratory data for chemistry, hematology, and urinalysis will be summarized and 
plotted (box plots) by scheduled visit for the observed values and for the corresponding 
change from baseline (CFB) values. Continuous laboratory parameters will be summarized 
as number of observations, arithmetic mean, standard deviation (SD), median, 1st quartile, 3rd 
quartile, minimum and maximum. If a patient has multiple results for a particular test at a 
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particular visit, the first non-missing value will be used for the summary. Summaries will be 
based on data of the central lab unless the data are missing, in which case local lab data will 
be used if available. 
In addition, the following summaries at each applicable visit will also be provided: 
• 
Shift tables (from baseline) showing the number and percentages of patients on 
treatment at the applicable visit with low, normal, or high values for hematology, 
chemistry and coagulation tests, defined according to the LLN and ULN provided by 
the respective laboratory; for urinalysis negative (or normal), trace and positive will be 
tabulated. 
• 
The numbers and percentage of patients with potentially clinically significant 
abnormal values based on percent CFB using the criteria for potentially clinical 
significance detailed in appendix 12.4, by scheduled assessments and separately by 
scheduled as well as unscheduled. 
In addition, a summary table will be presented which will indicate the number of patients who 
separately meet the criteria for potential Hy’s Law or Hy’s Law (section 4.2.1 above) after the 
start of study treatment at any time up to the LFU visit: 
The AST, ALT, total bilirubin and ALP elevations can occur at any time in the specific review 
period and do not need to occur simultaneously. 
A listing of patients with a value of ≥3xULN for ALT or AST or a value of ≥2xULN for total 
bilirubin in any one of the AST, ALT, total bilirubin parameters will be also presented. This 
listing will contain all the ALT, AST, total bilirubin and ALP study data for such patients. 
6.6.4 Physical examinations 
The numbers and percentage of patients with normal or abnormal assessment for each body 
system will be displayed by scheduled assessment. The abnormal results at the applicable 
post-baseline visits will be further classified into two categories: 1) same as baseline and 2) 
new or aggravated. 
All the physical examination data will be listed. 
6.6.5 Resting ECG 
The number and percentage of patients within overall ECG interpretation category (normal, 
abnormal) for baseline and post-baseline (day 3 and EOT) by visit will be summarized. 
The number of patients with normal, abnormal ECG interpretation shift results from baseline 
to the EOT visit will be provided. 
ECG variables (PR, QRS, QT, QTcB mean, QTcF mean) all visits will be listed for all patients 
with abnormal results or shifts.  
6.6.6 Vital signs 
Vital signs will be summarized (number of observations, arithmetic mean, standard deviation 
(SD), median, 1st quartile, 3rd quartile, minimum and maximum) and plotted (box plots) for the 
observed values and for the corresponding change from baseline (CFB) values at each 
applicable visit. 
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Vital signs for all patients will be listed. 
6.7 
Secondary analyses 
The number and percentage of patients with clinical cure (shown with 80% and 95% 
confidence intervals), clinical failure and indeterminate response at the TOC visit will be 
tabulated for the efficacy analysis set in both the MITT and mMITT populations). 
The association of derived PK parameters for ATM-AVI and clinical cure at TOC will be 
analysed in the mMITT population. The PK descriptive statistics and plots will be produced 
separately for each clinical response group and informally compared.  
Patients with extended-spectrum β-lactamase [ESBL]-phenotype pathogens will be 
summarised in the same way, and illustrated graphically as a forest plot. As an exploratory 
analysis, the proportion of clinical cure at the TOC visit will be determined excluding any 
patients with concomitant antibiotics (mMITT). 
No inferential statistical tests will be implemented, given the small sample sizes with respect 
to any efficacy objective. 
6.8 
Planned subgroup analyses 
A subgroup analysis will explore differences according to sex. The following outcomes will be 
analysed comparatively in males and females: 
• 
ATM and AVI plasma concentrations (time series plots) 
• 
Derived PK parameters (summary statistics) 
• 
Severe AEs, SAEs, clinically significant lab values, vital signs, physical examination 
and ECG results 
• 
Clinical cure rates 
In accordance to Lucasti et al (2013, 2014) a male-female ratio of 2:1 is expected. From a 
clinical point of view no pharmacological or physiological differences between sexes are 
expected because metabolism of ATM-AVI mainly depends on renal function that is 
influenced by severity of disease and age. 
Similarly, subgroup analyses will be performed for renal function (normal, mild, moderate 
according to amendment of inclusion criteria) and for age. 
6.9 
Early patient review 
The safety and tolerability of the ATM-AVI dosing regimen (500 mg ATM plus 137 mg AVI 
loading dose by IV infusion over a 30 minute period, immediately followed by a maintenance 
dose of 1500 mg ATM plus 410 mg AVI by IV infusion over a 3 hour period every 6 hours) 
will be assessed based on the impact on patient liver transaminases. The assessment will be 
both a per patient assessment throughout the study period and per a cohort review of the 
first 10 patients having completed all PK and safety assessments. 
The initial safety review (together with the parallel evaluation of the pharmacokinetics of 
ATM-AVI) will be assessed by a scientific advisory committee and AstraZeneca and input to 
a decision on whether 
a) the remainder of the study will continue with the same dose regimen for patients with 
normal renal function or mild renal impairment (CrCl >50 mL/min) 
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b) patients with moderate renal impairment (CrCl 31 to 50 mL/min) should be included 
and administered the dosing regimen to be confirmed by amendment to the protocol 
c) the dose regimen is confirmed as the regimen for the ATM-AVI Phase III program. 
[CSP section 5.2.5, p.57-59] 
6.9.1 Criteria for immediate progression 
The criteria for immediate progression beyond the initial 10 patients are as follows: 
• 
All transaminase rises are asymptomatic and rapidly reversible upon end of (or 
discontinuation of) therapy. 
Individual patient transaminase elevations: 
o Patients with normal baseline transaminases (elevations ≥ 3xULN but < 
5xULN) 
o Patients with baseline transaminase > 3xULN and < 5xULN documented as 
being directly related to infection being treated (inclusion criteria) - elevations 
≥ 5xULN but < 8xULN 
• 
No more than 2 individuals have transaminase elevation as described above 
If the criteria for immediate progression are met, investigators will be informed of the decision 
to continue recruiting as soon as feasible (within a timeframe to be confirmed). The 
pharmacokinetic data will be evaluated when available but will not be required to confirm the 
decision for immediate progression. 
[CSP section 5.2.5.1] 
6.9.2 Criteria for stop and review 
The criteria for stop and review before progression beyond the initial 10 patients are as 
follows: 
• 
Any one transaminase elevation is not rapidly reversible (in the absence of an 
alternative explanation for transaminase elevation)  
• 
Between 3 to 5 individuals have a transaminase elevation as described in section 
6.9.1 
• 
Any one patient meets the following individual transaminase discontinuation criteria in 
the absence of an alternative explanation: 
Patients with initial normal baseline transaminases progressing to: 
o ALT or AST ≥ 3×ULN and evidence of coagulopathy 
o ALT or AST ≥ 3×ULN with symptoms suggestive of new or progressive liver 
disease 
Patients with initial baseline transaminases > 3xULN and < 5xULN, documented as 
being directly related to infection being treated, progressing to: 
o ALT or AST ≥ 5×ULN and evidence of coagulopathy 
o ALT or AST ≥ 5×ULN with symptoms suggestive of new or progressive liver 
disease 
In the event of a stop and review before progression, available pharmacokinetic data will be 
evaluated to determine the relationship between exposure and transaminase elevation. More 
extensive modelling may be required to determine if a change in dose is required and to 
identify an appropriate dose for the remaining patients. 
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[CSP section 5.2.5.2] 
6.9.3 Criteria for non-progression 
The criteria for non-progression beyond the initial 10 patients are as follows: 
• 
1 patient meets Hy’s Law criteria 
• 
More than one transaminase rise is not rapidly reversible (in the absence of an 
alternative explanation for transaminase elevation) 
• 
More than 5 individuals have a transaminase rise as described in section 6.9.1 
• 
Three or more patients meet the following individual transaminase discontinuation 
criteria in the absence of an alternative explanation: 
Patients with normal baseline transaminases 
o ALT or AST ≥ 3×ULN and evidence of coagulopathy 
o ALT or AST ≥ 3×ULN with symptoms suggestive of new or progressive liver 
disease 
Patients with baseline transaminases > 3xULN and < 5xULN documented as being 
directly related to infection being treated 
o ALT or AST ≥ 5×ULN and evidence of coagulopathy 
o ALT or AST ≥ 5×ULN with symptoms suggestive of new or progressive liver 
disease 
If any one of the above criteria for non-progression occurs before 10 patients have been 
recruited for the early safety review, then the study will be stopped.  
These criteria are to be interpreted by the scientific advisory committee in the light of all 
relevant clinical data on the patients concerned. The statisticians will translate the criteria to 
a programmable algorithm to indicate the numbers of patients fulfilling each of the 
component criteria, in order to assist the committee. 
[CSP section 5.2.5.3] 
For the early patient review the following will be presented: 
• 
Diagnosis [listing] 
• 
Safety local lab values (primarily AST, ALT, ALP, TBili, CrCl) [listing with flag for out 
of range values, graphs] 
• 
Safety central lab values (primarily AST, ALT, ALP, TBili, CrCl) [listing with flag for out 
of range values, graphs*] 
• 
PK parameters [listing, summary table] 
• 
ATM and AVI concentrations [listing, graph] 
As required for critical cases (such as potential Hy’s law, discontinuations, withdrawals, 
deaths, SAE): 
• 
AEs and SAEs [listing] 
• 
Concomitant medication [listing] 
• 
Patient profiles for potential Hy's Law cases 
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• 
Patient profiles for study drug discontinuations and withdrawals 
• 
Patient profiles for any overdose or pregnancy report eCRFs 
• 
Vital signs [listing with flag for out of range values, summary table] 
• 
ECG [listing, graph]* 
* direct from respective online portal as far as possible  
7 
Deviations from the protocol 
Not applicable 
8 
Interpretation of results 
No complex statistical methods are used in the study, therefore (from a statistical point of 
view) there are no special issues concerning the interpretation of the results. Because of the 
small sample size a careful interpretation of the results is essential. 
9 
Data problems 
Not expected. Will be recorded in a separate document. 
10 Software 
SAS 9.4 (SAS Institute Inc., Cary, NC, USA) will be used for the analysis of the data. Mainly 
the SAS procedure PROC TABULATE, PROC REPORT and PROC SGPLOT will be used to 
generate the TFL. Own macros will be validated according to IMSIE SOPs before using them 
for the analysis. 
 
 
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11 References 
• 
Clinical Study Protocol of REJUVENATE, Version 2.0, 02.03.2016 
• 
Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the 
efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem 
in the treatment of complicated intra-abdominal infections in hospitalized adults: 
results of a randomized, doubleblind, Phase II trial. J Antimicrob Chemother. 
2013;68(5):1183-92. 
• 
Lucasti C, Hershberger E, Miller B, Yankelev S, Steenbergen J, Friedland I, 
Solomkinc J. Multicenter, double-blind, randomized, Phase II trial to assess the safety 
and efficacy of ceftolozane-tazobactam plus metronidazole compared with 
meropenem in adult patients with complicated Intra-abdominal infections. 
Antimicrobial Agents and Chemotherapy. 2014;58(9):5350-7. 
 
 
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12 Appendices 
12.1 Reference ranges of laboratory parameters 
For all local laboratory parameters, upper and lower normal limits are entered in the eCRF 
together with the measured values. 
For central laboratory parameters, limits are specified in the Covance document 
D4910C00009_RefRanges_20160308.xlsx. 
Physical examination results are assessed as normal/abnormal and (if abnormal) clinically 
significant yes/no in the eCRF. 
Vitals signs will be assessed by the investigator with regard to clinical abnormality and the 
result entered in the eCRF. 
 
12.2 Expected pathogens and their possible groupings 
 
The following common pathogens are expected in this study. This list will be used for 
frequency tables, according to which pathogens actually occur: 
 
Gram-negative bacteria 
• 
Escherichia coli 
• 
Citrobacter koseri 
• 
Enterobacter cloacae 
• 
Klebsiella pneumoniae 
• 
Klebsiella oxytoca 
• 
Proteus mirabilis 
• 
Proteus vulgaris 
• 
Providencia stuartii 
• 
Serratia marcescens 
• 
Pseudomonas aeruginosa 
Anaerobes 
• 
Bacterioides fragilis group 
• 
Bacterioides spp. 
• 
Finegoldia magna 
• 
Peptostreptococcus spp. 
• 
Prevotella spp. 
• 
Fusobacterium spp. 
Gram-positive bacteria 
• 
Staphylococcus aureus 
• 
Viridans streptococci (anginosus group) 
• 
Enterococcus faecalis/faecium 
• 
Coagulase-negative Staphylococci 
 
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The following groupings of isolates may be employed for frequency tables and listings 
according to the information available and observed frequencies: 
• 
Carbapenem non-susceptible isolates 
• 
Colistin non-susceptible isolates 
• 
Multidrug-resistant isolates 
• 
MBL-producing isolates 
• 
ESBL-producing isolates 
 
12.3 Planned tables, listing, graphics 
See separate TFL document 
 
12.4 Criteria for clinical significance of changes from baseline 
See separate document 
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