Clinical trial NCT04040621
Conditions: Hospitalized Children With Suspected or Confirmed Nosocomial Pneumonia
Keywords: nosocomial pneumonia, NP
Sponsor: Pfizer
Start date: 2020-06-15; Completion date: 2021-05-07
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, multinational, open label single dose pharmacokinetic (PK) study enrolling at least 32 subjects. The study aims to characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ AVI in pediatric subjects aged 3 months to less than 18 years who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia, including ventilator associated pneumonia.

Detailed description:
This is a multicenter, multinational, open label single dose pharmacokinetic (PK) study enrolling at least 32 subjects. The study aims to characterize the PK of CAZ AVI and assess its safety and tolerability following a single intravenous (IV) infusion. Subjects will be hospitalized pediatric patients who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia (NP), including ventilator associated pneumonia (VAP). The study will consist of a Screening visit (Visit 1, Day 1), during which consent will be obtained and subject eligibility will be confirmed, a Baseline/Treatment visit (Visit 2, Day 1) during which subjects will receive a single IV infusion of CAZ AVI, and then two follow up assessment visits at 24 hours (Visit 3, Day 2) and 48 hours (Visit 4, Day 3). Blood samples for PK analyses (0.5 mL per sample) will be obtained over 22 hours for Cohort 1 (7 samples), over 13 hours for Cohort 2 (6 samples), and over 6 hours for Cohorts 3 and 4 (4 samples). Additionally, for subjects who are undergoing bronchoalveolar lavage (BAL) for clinical purposes and for whom informed consent is obtained specifically for BAL, an epithelial lining fluid (ELF) sample will be collected for estimation of CAZ AVI concentrations.

Arms: arm 1: This arm includes 4 cohorts
Interventions: intervention 1: Ceftazidime-avibactam
Intervention descriptions: intervention 1: Single intravenous infusion of ceftazidime-avibactam over 2 hours. Dosage will vary depending upon age, weight and renal function.

Protocol documents:
Prot_000.pdf: 
Ceftazidime-Avibactam (CAZ-AVI)
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A PHASE 1, OPEN-LABEL, SINGLE-DOSE STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
CEFTAZIDIME-AVIBACTAM (CAZ-AVI) IN CHILDREN FROM 3 MONTHS TO 
LESS THAN 18 YEARS OF AGE WHO ARE HOSPITALIZED AND RECEIVING
SYSTEMIC ANTIBIOTIC THERAPY FOR SUSPECTED OR CONFIRMED 
NOSOCOMIAL PNEUMONIA, INCLUDING VENTILATOR-ASSOCIATED 
PNEUMONIA
Investigational Product Number:
PF-06947386
Investigational Product Name:
Zavicefta (Ceftazidime-Avibactam)
United States (US) Investigational New 
Drug (IND) Number:
101,307
European Clinical Trials Database 
(EudraCT) Number:
2018-002841-12
Protocol Number:
C3591025
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Original 
protocol
17 September
2018
Not applicable (N/A)
Amendment 1
12 June 2019
In addition to minor administrative changes and 
clarifications, protocol amendment 1 includes the 
following:
As needed in the document, text was updated to indicate 
that when screening assessment procedures are 
performed the day prior to the dose of CAZ-AVI, 
weight is also to be collected at day of dose 
administration.  The weight collected on the date of dose 
administration will be used to properly calculate the 
dose of CAZ-AVI to be administered.
The protocol summary, the introduction and study 
design were updated to include the CAZ-AVI pediatric 
approval in children from 3 months of age and older in 
2019 received in the US for the treatment of cIAI (when 
combined with metronidazole), and for the treatment of 
cUTI.  Text now also has been updated to show that 
CAZ-AVI has received regulatory approval in 51 
countries worldwide.
Text has been updated to show that this study is planned 
to be performed at approximately 43 sites and 14 
countries in the Americas, Europe, and Asia.
At the Screening Visit (Day -1 to 1), text was updated to 
clarify that standard of care assessments performed will 
not replace the study specific Screening and Baseline 
laboratory assessments.  
Study Design text was updated to provide a definition of 
nosocomial pneumonia as pneumonia with onset ≥48 
hours after admission or within 7 days of discharge from 
an inpatient care facility, including ventilator-associated 
pneumonia (VAP), defined as a parenchymal lung 
infection arising ≥48 hours after endotracheal intubation 
and mechanical ventilation.  
Inclusion Criteria text for criterion 4b was update to 
clarify that the imaging result of “new or worsening 
infiltrate” was not limited to X-ray, but could be 


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Document
Version Date
Summary of Changes and Rationale
demonstrated on chest X-ray or other imaging modality 
that had been performed as part of the subject’s medical 
care.
Pharmacokinetic (PK) Blood Sample Assessments for 
all cohorts was updated so that the first PK sample is 
obtained at the end of CAZ-AVI infusion/flush +0 to 5 
minutes. End time of IV flush has been added to the 
data points to be collected at the Baseline Visit.  Text 
was also updated to clarify that the PK sample obtained 
immediately after the CAZ-AVI infusion/flush must not 
be drawn from any lumen of a catheter used for drug 
delivery.
Pharmacokinetics Analysis (Primary Endpoint) text in 
the objectives and endpoint section has been updated to 
show that plasma concentration of ceftazidime and of 
avibactam will be listed, and summarized by nominal 
time for all cohorts, using appropriate descriptive 
statistics such as number, mean, standard deviation 
(SD), minimum, median, maximum, geometric mean, 
and coefficient of variation.  The text update also 
clarifies that the NCA PK parameters will be 
summarized for Cohorts 1 and 2 using descriptive 
statistics. Text was updated to use the term nominal 
time for all cohorts so that the primary endpoint related 
to plasma concentration now describes CAZ and AVI 
plasma concentration by nominal time. 
Tertiary/Exploratory Endpoints text updated to state 
endpoint as CAZ and AVI ELF:plasma concentration 
ratios, and to clarify that this collection is considered for 
subjects who have BAL after bronchoscopy. Text also 
clarified  that lab results will be medically reviewed.  
End of Trial text was updated to define the end of the 
study as the last visit of the last patient undergoing the 
study, or the date of study closure in the case of early 
study termination, whichever date is later.  Text was 
also updated to state that the study may be terminated at 
individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), 
or if recruitment is slow.”  


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
PROTOCOL SUMMARY.........................................................................................................8
SCHEDULE OF ACTIVITIES................................................................................................11
1. INTRODUCTION ...............................................................................................................13
1.1. Mechanism of Action/Indication.............................................................................13
1.2. Background .............................................................................................................14
1.3. Rationale for Conducting this Study.......................................................................14
1.4. Dose Rationale ........................................................................................................15
1.5. Benefit/Risk and Ethical Assessment......................................................................17
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................18
3. STUDY DESIGN.................................................................................................................18
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................20
4.1. Inclusion Criteria.....................................................................................................20
4.2. Exclusion Criteria....................................................................................................21
4.3. Randomization Criteria ...........................................................................................23
4.4. Lifestyle Requirements ...........................................................................................23
4.4.1. Contraception..............................................................................................23
4.5. Sponsor’s Qualified Medical Personnel..................................................................24
5. STUDY TREATMENTS.....................................................................................................24
5.1. Allocation to Treatment ..........................................................................................24
5.2. Breaking the Blind ..................................................................................................24
5.3. Subject Compliance.................................................................................................25
5.4. Investigational Product Supplies.............................................................................25
5.4.1. Dosage Form(s) and Packaging..................................................................25
5.4.2. Preparation and Dispensing........................................................................25
5.5. Administration.........................................................................................................26
5.6. Investigational Product Storage ..............................................................................26
5.7. Investigational Product Accountability...................................................................27
5.7.1. Destruction of Investigational Product Supplies ........................................27


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5.8. Concomitant Treatment(s).......................................................................................27
6. STUDY PROCEDURES .....................................................................................................28
6.1. Screening and Enrollment .......................................................................................28
6.1.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1)..............................28
6.2. Study Period ............................................................................................................30
6.2.1. Visit 2, Study Day 1....................................................................................30
6.2.2. Visit 3, Study Day 2, 24 Hour Follow-Up Assessment..............................31
6.2.3. Visit 4, Study Day 3, 48 Hour Follow-Up Assessment..............................31
6.2.4. Late Follow-up (LFU) ................................................................................32
6.3. Subject Withdrawal.................................................................................................32
7. ASSESSMENTS..................................................................................................................34
7.1. Pregnancy Testing...................................................................................................34
7.2. Pharmacokinetics ....................................................................................................35
7.2.1. Pharmacokinetic (PK) Blood Sample Collection .......................................35
7.2.2. Collection of BAL Fluid Samples ..............................................................37
7.3. Safety Assessments .................................................................................................37
7.3.1. Laboratory Safety Assessments..................................................................37
7.4. Blood Volume .........................................................................................................38
8. ADVERSE EVENT REPORTING......................................................................................39
8.1. Requirements...........................................................................................................39
8.1.1. Additional Details on Recording Adverse Events on the CRF...................40
8.1.2. Eliciting Adverse Event Information..........................................................40
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................41
8.1.4. Time Period for Collecting AE/SAE Information......................................41
8.1.5. Causality Assessment .................................................................................41
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................42
8.2. Definitions...............................................................................................................42
8.2.1. Adverse Events...........................................................................................42
8.2.2. Abnormal Test Findings .............................................................................43
8.2.3. Serious Adverse Events ..............................................................................43
8.2.4. Hospitalization............................................................................................44


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8.3. Severity Assessment................................................................................................45
8.4. Special Situations ....................................................................................................45
8.4.1. Protocol-Specified Serious Adverse Events...............................................45
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................45
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................47
8.4.4. Medication Errors .......................................................................................49
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................50
9.1. Sample Size Determination.....................................................................................50
9.2. Efficacy Analysis ....................................................................................................50
9.3. Pharmacokinetic Analysis (Primary Endpoint).......................................................50
9.3.1. BAL Analysis (Exploratory Endpoint).......................................................52
9.4. Safety Analysis (Secondary Endpoint) ...................................................................52
9.5. Interim Analysis ......................................................................................................53
9.6. Data Monitoring Committee ...................................................................................53
9.7. Safety Review Committee.......................................................................................53
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................53
11. DATA HANDLING AND RECORD KEEPING .............................................................54
11.1. Case Report Forms/Electronic Data Record .........................................................54
11.2. Record Retention...................................................................................................54
12. ETHICS..............................................................................................................................55
12.1. Institutional Review Board/Ethics Committee......................................................55
12.2. Ethical Conduct of the Study ................................................................................55
12.3. Subject Information and Consent..........................................................................55
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................57
13. DEFINITION OF END OF TRIAL...................................................................................57
14. SPONSOR DISCONTINUATION CRITERIA ................................................................57
15. PUBLICATION OF STUDY RESULTS..........................................................................57
15.1. Communication of Results by Pfizer ....................................................................57
15.2. Publications by Investigators ................................................................................58
16. REFERENCES ..................................................................................................................60


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LIST OF TABLES
Table 1.
Identity of Investigational Product .......................................................................25
Table 2.
CAZ-AVI Doses in Relationship to Age, Weight, and Renal Function...............26
Table 3.
Cohort 1 - Schedule for PK Assessments.............................................................36
Table 4.
Cohort 2 - Schedule for PK Assessments.............................................................36
Table 5.
Cohorts 3 and 4 - Schedule for PK Assessments..................................................37
Table 6.
Laboratory Safety Tests........................................................................................38
Table 7.
Volume of Blood to be Drawn from Each Subject...............................................39
LIST OF FIGURES
Figure 1.
Study Outline........................................................................................................19
APPENDICES
Appendix 1. Abbreviations......................................................................................................62


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PROTOCOL SUMMARY
Background and Rationale
Ceftazidime is an injectable third generation cephalosporin antibiotic which has been in 
clinical use worldwide for more than 25 years for the treatment of infections caused by 
aerobic Gram-negative pathogens.  Ceftazidime has been shown to be safe and effective in 
adult and pediatric patients (neonates to adolescents <18 years of age) for a range of 
indications.  However, over the past 15 years, resistance to ceftazidime has been increasing 
worldwide. The most common mechanism of resistance is bacterial production of 
β-lactamases, in particular, extended spectrum β-lactamases (ESBLs).
In order to counter ceftazidime resistance and restore antibacterial activity to ceftazidime, a 
combination product has been developed in which ceftazidime is combined with avibactam, a 
novel non-β-lactam β-lactamase inhibitor.  Although avibactam itself possesses no intrinsic 
antibacterial activity, it has been shown to restore activity of ceftazidime against clinically 
relevant β-lactamases of class A and class C varieties, including extended spectrum 
β-lactamases (ESBLs) and serine-based Klebsiella pneumoniae carbapenemases (KPCs) and 
AmpC producing strains.  Although avibactam has no inhibitory effect on class B 
metallo-β-lactamases, it does inhibit the activity of some class D β-lactamases (eg, OXA-48 
type carbapenemase).  A fixed dose combination of ceftazidime and avibactam (CAZ-AVI) 
was approved for use in adults in the United States in 2015, and for use in children three 
months of age and older (with cIAI in combination with metronidazole, or cUTI) in 2019, 
under the brand name AVYCAZ.1 A fixed dose combination of ceftazidime and avibactam 
(CAZ-AVI) was approved for use in adults in Europe in 2016 under the brand name 
Zavicefta.2  This fixed-dose combination of CAZ-AVI is currently being evaluated globally 
for pediatric use.
Study Sites and Number of Subjects Planned
This study is planned to be performed at approximately 43 sites and 14 countries in the 
Americas, Europe, and Asia.
The study will enroll approximately 32 children aged 3 months to <18 years who are 
hospitalized and receiving systemic antibiotic therapy for suspected or confirmed nosocomial 
pneumonia (NP), also known as hospital-acquired pneumonia (HAP), including the subtype 
of ventilator-associated pneumonia (VAP).1
                                                
1 Note that the word “bacterial” is sometimes added to these descriptions, ie, hospital-acquired bacterial 
pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) to emphasize the bacterial nature 
of pneumonia requiring antibacterial treatment.  Throughout this document the disease entity will be referred 
to using the traditional nomenclature of HAP/VAP.


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Subjects will be divided into 4 age cohorts, all enrolling simultaneously:
Objectives and Endpoints
Primary Objective:
Primary Endpoints:

To characterize the pharmacokinetics 
(PK) of a single intravenous dose of 
CAZ-AVI in pediatric subjects aged 
3 months to less than 18 years who 
are receiving systemic antibiotic 
therapy for suspected or confirmed 
nosocomial pneumonia, including 
ventilator-associated pneumonia.

CAZ and AVI Plasma concentrations by 
nominal time.

CAZ and AVI PK parameters calculated by 
non-compartmental analysis (Cohorts 1 and 
2 only).
Secondary Objective:
Secondary Endpoints:

To evaluate the safety and tolerability 
of a single intravenous dose of 
CAZ-AVI in pediatric subjects aged 
3 months to less than 18 years with 
nosocomial pneumonia, including 
ventilator-associated pneumonia.

Safety and tolerability endpoints include 
adverse events (AEs), serious adverse events 
(SAEs), deaths, discontinuations due to AEs 
and laboratory abnormalities.
Exploratory Objectives:
Exploratory Endpoints:

To determine CAZ-AVI 
concentrations in bronchial epithelial 
lining fluid (ELF) by bronchoalveolar 
lavage (BAL) from subjects 
undergoing bronchoscopy for their 
clinical management if bronchoscopy 
with BAL is performed within the PK 
sampling interval after CAZ-AVI 
infusion.

CAZ and AVI ELF:plasma concentration 
ratios.
Cohort
Age
Number
1
Age 12 years to <18 years
n=8
2
Age 6 years to <12 years
n=8
3
Age 2 years to <6 years
n=8
4
Age 3 months to <2 years
(born ≥37 weeks gestational age)
n=8
4a
Age 1 year to <2 years
n=4
4b
Age 3 months to <1 year
n=4


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Study Design
This is a multicenter, multinational, open-label single-dose pharmacokinetic (PK) study 
enrolling at least 32 subjects.  The study aims to characterize the PK of CAZ-AVI and assess 
its safety and tolerability following a single intravenous (IV) infusion.  Subjects will be 
hospitalized pediatric patients who are receiving systemic antibiotic therapy for suspected or
confirmed nosocomial pneumonia (NP) defined as pneumonia with onset ≥48 hours after 
admission or within 7 days of discharge from an inpatient care facility, including 
ventilator-associated pneumonia (VAP), defined as a parenchymal lung infection arising 
≥48 hours after endotracheal intubation and mechanical ventilation.  Subjects will be enrolled 
in 4 cohorts of descending age, each consisting of at least 8 evaluable subjects.  An evaluable 
subject is one who has received the complete single IV dose of CAZ-AVI and provided PK 
blood samples at 50% of the sampling time points. The definition of an evaluable subject is 
used for enrollment purposes only, and it does not impact the definition of the PK analysis 
set in Section 9.3.  Each subject will receive a single IV dose of CAZ-AVI administered as 
an infusion over a 120 minute period.  Blood samples will be collected from all subjects at 
the end of/after the infusion to evaluate the PK of ceftazidime and avibactam.  Subjects will 
be followed for 48 hours after the end of the infusion.
The study will consist of a Screening visit (Visit 1, Day -1 to 1), during which consent will 
be obtained and subject eligibility will be confirmed, a Baseline/Treatment visit (Visit 2, 
Day 1) during which subjects will receive a single IV infusion of CAZ-AVI, and then two 
follow-up assessment visits at 24 hours (Visit 3, Day 2) and 48 hours (Visit 4, Day 3). Blood 
samples for PK analyses (0.5 mL per sample) will be obtained over 22 hours for Cohort 1 
(7 samples), over 13 hours for Cohort 2 (6 samples), and over 6 hours for Cohorts 3 and 
4 (4 samples). A Late Follow-up (LFU) visit, that may be performed by telephone, will be 
conducted 28-35 days after the CAZ-AVI infusion in order to identify, assess, and record any 
new Serious Adverse Event (SAE).  
In addition to routine clinical monitoring all available safety and tolerability data from each 
cohort will be reviewed by a Safety Review Committee (SRC) after the first 4 subjects in 
each cohort are enrolled.  The SRC will consist of the study team physician, international 
coordinating Investigator or delegate, global safety risk lead or delegate, therapeutic area 
director or delegate and the clinical pharmacologist/pharmacometrician or delegates.  Any 
SRC recommendation to alter the conduct of the study or modify dosing will be incorporated 
into a protocol amendment, as appropriate, and forwarded to regulatory authorities.






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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Ceftazidime is an injectable bactericidal third generation cephalosporin antibiotic which has 
been in clinical use worldwide for more than 25 years.  Ceftazidime is approved for the 
treatment of aerobic Gram-negative bacterial infections in adults and children including 
neonates (from birth).  Many years of experience using ceftazidime have accrued in 
numerous countries worldwide and its tolerability profile is well characterized.  Included 
among the infections treated by ceftazidime are complicated urinary tract infection (cUTI) 
caused by P. aeruginosa, Enterobacter spp., Proteus spp., Klebsiella spp., and E. coli; 
complicated intra-abdominal infection (cIAI), including peritonitis, caused by E. coli, 
Klebsiella spp., Staphylococcus aureus (methicillin-susceptible strains); and lower 
respiratory tract infections caused by P. aeruginosa, Klebsiella spp. E. coli, Enterobacter spp, 
and S. aureus (methicillin susceptible strains).  Ceftazidime is also approved for use in a wide 
range of other infections, including, but not limited to complicated skin and soft tissue 
infections (cSSTI), bone and joint infections, bronchopulmonary infections in cystic fibrosis, 
and bacteremias (Fortum Summary of Product Characteristics [SmPC] 2016;4 FORTAZ 
United States Package Insert [USPI] 2014).5  Like other β-lactam antibiotics, ceftazidime is 
susceptible to hydrolysis by β-lactamases, in particular, extended spectrum β-lactamases 
(ESBLs), thereby rendering it inactive.  The high and increasing prevalence of β-lactam 
resistance worldwide over the last 15 years has reduced the utility of ceftazidime in many 
countries.
Avibactam is a novel, non β-lactam, β-lactamase inhibitor.  Beta-lactamase inhibition by 
avibactam is effected through the formation of a stable covalent carbamoyl linkage to the 
enzyme complex.  Although avibactam itself possesses no intrinsic antibacterial activity, it 
has been shown to restore in vitro activity of ceftazidime against Class A, Class C and some 
Class D β-lactamases (eg OXA-48 type carbapenemse) restoring activity against pathogens 
commonly associated with cIAI, cUTI, and nosocomial pneumonia (NP).  Avibactam, when 
combined with ceftazidime, has also been shown to be active against strains that express a 
combination of β-lactamase types, as well as strains that are concomitantly resistant to other 
antibacterial classes such as fluoroquinolones.  Unlike currently available β-lactamase 
inhibitors, avibactam does not induce β-lactamase production (Miossec, Claudon, et al., 
2013).6
A fixed dose combination of ceftazidime-avibactam (referred to hereafter as CAZ-AVI) was 
approved for use in adults by the FDA on 25 February 2015, and in children three months of 
age and older (cIAI in combination with metronidazole, or cUTI) on 18 Mar 2019 and is 
marketed under the tradename AVYCAZ.1  On 24 June 2016, the European Commission 
granted European Union marketing authorization for the use of CAZ-AVI in adults under the 
tradename Zavicefta.2  The fixed dose combination ceftazidime-avibactam is currently being 
evaluated for pediatric use.


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CAZ-AVI has received regulatory approval in 51 countries worldwide. CAZ-AVI is 
indicated in the US and Europe for the treatment of adults with complicated intra-abdominal 
infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired 
pneumonia (HAP), including ventilator associated pneumonia (VAP).  It is also indicated in 
Europe for the treatment of infections due to aerobic Gram-negative organisms in adult 
patients with limited treatment options.  CAZ-AVI is indicated in the US for the treatment of 
children three months of age and older with cIAI when used in combination with 
metronidazole, and in children with cUTI.
1.2. Background
Ceftazidime-avibactam is currently being evaluated for use in pediatric patients.  Single-dose 
PK of CAZ-AVI was previously investigated in Study D4280C00014, which included the 
same age cohorts as the present study, but did not target specific types of infection and 
enrolled only a few children with pneumonia.  CAZ-AVI was subsequently evaluated at 
multiple doses in children with cIAI (D4280C00015/C3591004) and cUTI 
(D4280C00016/C3591005), corresponding to two of the approved indications for CAZ-AVI 
in adults.
1.3. Rationale for Conducting this Study
The long-established efficacy and safety of ceftazidime in children, the mode of action of 
avibactam, the available Phase 2 clinical data for CAZ-AVI in pediatrics, and the established 
efficacy and safety of CAZ-AVI for the treatment of HAP/VAP in adults provide a strong 
rationale for extending the evaluation of CAZ-AVI into the pediatric HAP/VAP population.  
This study will extend the pediatric evaluation of CAZ-AVI into children with HAP/VAP, 
the third indication for CAZ-AVI in adults.  Observed PK data from the adult Phase 3 studies 
in patients with cIAI (Studies D4280C00001 and D4280C00005, Mazuski, Gasink, et al 
2016)7 and HAP/VAP (Study D4281C00001, Torres, Zhong, et al 2018)8 suggest that the 
plasma PK of both ceftazidime and avibactam are comparable in patients with cIAI and NP 
following the administration of CAZ-AVI 2000 mg/500 mg as a 120 minute infusion. The 
present study will confirm whether the plasma PK of ceftazidime and avibactam in children
with NP are comparable with the plasma PK in children with cIAI and cUTI.
Based on the assumptions that the disease, mechanism of action, and the PK/PD are the same 
in pediatric and adult HAP/VAP patients; the appropriate dose of CAZ-AVI for pediatric 
patients will be one that achieves comparable plasma exposures to those in adults.  If the 
adult dose is efficacious, the same exposure in pediatric patients should also be associated 
with clinical efficacy.  CAZ-AVI is expected to provide positive clinical outcomes in those 
pediatric HAP/VAP patients infected with pathogens resistant to β-lactam antibiotics due to 
the presence of avibactam sensitive β-lactamases.  Therefore, CAZ-AVI has the potential to 
address the significant unmet clinical need associated with antibiotic resistance in pediatric
HAP/VAP patients.
As an exploratory endpoint in this study in a limited number of subjects who are undergoing 
bronochoscopy with bronchoalveolar lavage (BAL) for clinical purposes, and for whom
informed consent is obtained specifically for the collection of BAL samples, an epithelial 


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lining fluid (ELF) sample will be collected for estimation of CAZ-AVI concentrations.  An 
adult BAL study in normal volunteers has shown that both ceftazidime and avibactam 
penetrate dose-proportionally into ELF, with ELF exposure to both drugs being about 30% of 
plasma exposure (Nicolau, Siew, et al., 2015).9  Since the clinical efficacy of CAZ-AVI has 
been demonstrated in adults with HAP/VAP, ELF penetration is known to be adequate to 
achieve efficacy, and plasma exposure is validated as a suitable surrogate target.
The inclusion and exclusion criteria for this study have been chosen in order to select 
appropriate pediatric patients who are being treated for suspected or confirmed HAP/VAP 
infection.  The PK sampling and safety assessments are judged to be sufficient to fulfill the 
primary and secondary objectives of the study.
1.4. Dose Rationale
Dosing for this study is based on modelling and simulation study CAZ-MS-PED-02 
(Pediatric Investigation Plan [PIP] Study 7) which included data from the adult Phase 1, 2, 
and 3 studies including studies of cIAI, cUTI, and NP, and three prior pediatric studies: 
1) D4280C00014, an open-label, single-dose study in hospitalized pediatric patients from 
3 months to <18 years of age receiving systemic antibiotic therapy for suspected or 
confirmed infection; 2) D4280C00015/C3591004 a phase 2, single-blind, randomized, 
multicenter, active-controlled, multiple-dose study of CAZ-AVI when given in combination 
with metronidazole and compared with meropenem in hospitalized pediatric patients from 
3 months to <18 years of age with cIAI; and 3) D4280C00016/C3591005 a phase 2, 
single-blind, randomized, multicenter, active-controlled, multiple-dose study of CAZ-AVI 
compared with cefepime in hospitalized pediatric patients from 3 months to <18 years of age 
with cUTI.
In all population pharmacokinetic (PK) analyses both CAZ and AVI concentration time 
courses have been well described by a linear 2-compartment PK model with first-order 
elimination.  Simulations based on the final population described above were used to provide 
dose recommendations for all pediatric patients from pre-term neonates to <18 years of age 
with normal renal function in addition to pediatric patients 2 to <18 years of age with mild, 
moderate, or severe renal impairment.  Per dose regimen and age scenario sets of 
1,000 pediatric PK parameters were simulated with between-subject variability simulated 
non-parametrically through resampling of individual random effect estimates from the final 
CAZ and AVI models.  The exposure target was defined as achieving at least 50 percent of 
time on treatment that CAZ and AVI are simultaneously above the minimum inhibitory 
concentration (MIC) of 8 mg/mL for CAZ and Critical threshold concentration (CT) of 
1.0 mg/L for AVI, respectively.  The Probability of Target Attainment (PTA) was defined as 
the probably of achieving the exposure target.  The PTA for PK/PD CAZ MIC 8 mg/L and 
AVI CT 1.0 mg/L is the same joint PK/PD target used to support approval in adults.
A range of mg/kg doses were simulated, with the total dose capped at the absolute adult 
CAZ-AVI label doses of 2000/500 mg every 8 hours over a 120 minute infusion for normal 
renal function/mild renal impairment (or adjusted label dose for moderate renal impairment).  
Simulations were based on steady-state exposures; however, single CAZ-AVI doses will be 
administered in this study.


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The doses for this study (see Table 2) when administered q8h as a 120 minute intravenous 
[IV] infusion were predicted to achieve ≥92% PTA in NP, which is above the target PTA of 
90%.  In subjects with normal renal function, average exposure (Cmax and AUC) were 
predicted to be comparable to or higher than corresponding adult reference values.  Average 
ceftazidime maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) values ranged from 110-124% and 97-110%, respectively, 
of corresponding adult reference values.  Average avibactam Cmax and AUC values were 
126-148% and 112-129%, respectively, of corresponding adult reference values.  
Additionally, these values were below the average for CAZ Cmax and AUC and AVI AUC 
and slightly higher for AVI Cmax as compared to the adult with mild renal impairment 
population, which are the group with the highest ceftazidime and avibactam exposures that 
have been studied in Phase II and III clinical studies, with data suggesting that CAZ-AVI is 
well-tolerated in this adult reference population (Muller, et al., 2013).10
In mild renal impairment (CrCL ≥50 to <80 mL/min/1.73 m2), the dose of 
CAZ-AVI 50/12.5 mg/kg when administered q8h as a 120 minute intravenous [IV] infusion 
(subjects ≥2 years of age) was predicted to achieve ≥99% PTA in NP, which is well above 
the target PTA of 90%.  In subjects with mild renal impairment, average exposure (Cmax and 
AUC) were predicted to be comparable to or higher than corresponding adult reference 
values.  For the CAZ-AVI 50/12.5 mg/kg q8h dose, the CAZ Cmax and area under the plasma 
concentration-time curve from time 0 to 24 hours (AUC0-24) were between 108 and 124% and 
between 98 and 112% respectively, of the values for adult subjects with mild renal 
impairment. The AVI Cmax and AUC0-24 were between 124 and 148% and between 111 and 
131% respectively, of the values for adult subjects with mild renal impairment.  As noted 
previously, the lack of a dose adjustment is consistent in adult patients with mild renal 
impairment.  Although not assessed in CAZ-MS-PED-02, the study doses in subjects 
≥3 months to <6 months and ≥6 months to <2 years are 40/10 mg/kg and 50/12.5 mg/kg, 
respectively, consistent with dosing in mild renal impairment for Studies 
D4280C00015/C3591004 and D4280C00016/C3591005.
In moderate renal impairment (CrCL ≥30 to <50 mL/min/1.73 m2), the dose of CAZ-AVI 
25/6.25 mg/kg when administered q8h as a 120 minute intravenous [IV] infusion (subjects
≥2 years of age) was predicted to achieve ≥99% PTA in NP, which is well above the target 
PTA of 90%.  In subjects with moderate renal impairment, average exposure (Cmax and AUC) 
were predicted to be comparable to or higher than corresponding adult reference values.  For 
the 25/6.25 mg/kg q8h dose, the CAZ Cmax and AUC0-24 were between 114 and 149% and 
between 99 and 143% respectively, of the values for adult subject with mild renal 
impairment. The AVI Cmax and AUC0-24 were between 134 and 171% and between 114 and 
154% respectively, of the values for adult subjects with mild renal impairment. Although not 
assessed in CAZ-MS-PED-02, doses in subjects ≥3 months to <6 months and ≥6 months to 
<2 years in this study are 20/5 mg/kg and 25/6.25 mg/kg, respectively, consistent with dosing 
in moderate renal impairment for Studies D4280C00015/C3591004 and 
D4280C00016/C3591005.  These doses are 50% of the total daily dose for normal subjects 
which are consistent with the dose adjustment applied in adult patients with moderate renal 
impairment.  


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As noted previously, these are the same doses as used in the recently completed pediatric 
studies with CAZ-AVI in cIAI (D4280C00015/C3591004) and cUTI 
(D4280C00016/C3591005).  The doses for this study are listed Table 2.  For the ceftazidime 
component these doses are within the mg/kg/day range of the approved doses of 30-50 mg/kg
q8h for children 1 month to 12 years (FORTAZ USPI 2014)5 and 100-150 mg/kg/day in 
three divided doses for children <40 kg (Fortum SmPC 2016).4
1.5. Benefit/Risk and Ethical Assessment
The potential benefit of the study, in general, is the confirmation that a novel antibiotic 
combination product is an appropriate treatment for infections in children, including 
nosocomial pneumonia, in the face of the changing pattern of antibiotic resistance.  The 
subjects enrolled into this clinical study will have infections that are of sufficient severity to 
require hospitalization and treatment with systemic antibiotics. CAZ-AVI will not be used in 
this study to treat the infection for which the patient has been admitted as this is not a 
therapeutic study.
The risk considerations for this study encompass the known and potential risks for the 
development product CAZ-AVI and its component products ceftazidime and avibactam.
The full risk profile for ceftazidime is described in the prescribing information for the 
product (refer to local ceftazidime product labeling).  Important risks as laid out in the 
warnings and precautions in product labeling for ceftazidime include the following:

Elevated levels of ceftazidime used in patients with renal impairment have been 
associated with neurological sequelae such as tremor, myoclonus, seizures, 
encephalopathy and coma.
The adverse events (AEs) described below for ceftazidime may occur with multiple
administrations and are unlikely to occur with the single dose that subjects in this study will 
be receiving:

Antibiotic-associated diarrhea, Clostridium difficile diarrhea, colitis, and 
pseudomembranous colitis;

Bacterial overgrowth with nonsusceptible organisms.
The risks for CAZ-AVI in children have not been fully elucidated; however, it is assumed 
that known or potential risks for CAZ-AVI should include those identified in the approved 
local label for CAZ-AVI, eg the US Package Insert (USPI) (AVYCAZ, 2019)1 or the EU 
Summary of Product Characteristics (SmPC) (Zavicefta, 2018).2  Thus far, no unique risks 
have been identified for the combination of ceftazidime and avibactam in children.  In 
recently completed study D4280C00015/C3591004, CAZ-AVI plus metronidazole was well 
tolerated for the treatment of pediatric patients 3 months of age to <18 years of age with 
cIAI.  Highly favorable clinical and microbiological response rates were observed across all 
patients in the study and against the predominant cIAI pathogens (E. coli and P. aeruginosa), 
and no new safety concerns were identified.  In recently completed study 


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D4280C00016/C3591005 CAZ-AVI was generally well tolerated and appeared effective for 
the treatment of pediatric patients 3 months of age to <18 years of age with cUTI, and no 
new safety concerns were identified.  Side effects identified for the avibactam component of 
CAZ-AVI include injection site redness and injection site bruising.
Additional information for CAZ-AVI may be found in the single reference safety document 
(SRSD), which for this study is the CAZ-AVI Investigator Brochure (IB).
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
Primary Endpoint:

To characterize the pharmacokinetics 
(PK) of a single intravenous dose of 
CAZ-AVI in pediatric subjects aged 
3 months to less than 18 years who are 
receiving systemic antibiotic therapy for 
suspected or confirmed nosocomial 
pneumonia, including 
ventilator-associated pneumonia.

CAZ and AVI plasma concentrations
by nominal time.

CAZ and AVI PK parameters 
calculated by non-compartmental 
analysis (Cohorts 1 and 2 only).
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
a single intravenous dose of CAZ-AVI 
in pediatric subjects aged 3 months to 
less than 18 years with nosocomial 
pneumonia, including 
ventilator-associated pneumonia.

Safety and tolerability endpoints
include adverse events (AEs), serious 
adverse events (SAEs), deaths, 
discontinuations due to AEs and 
laboratory abnormalities.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):

To determine CAZ-AVI concentrations 
in bronchial epithelial lining fluid (ELF) 
by bronchoalveolar lavage (BAL) from 
subjects undergoing bronchoscopy for 
their clinical management if 
bronchoscopy is performed within the 
PK sampling interval after CAZ-AVI 
infusion.

CAZ and AVI ELF:plasma 
concentration ratios.
3. STUDY DESIGN
This is a multicenter, multinational, open-label single-dose PK study enrolling approximately 
32 subjects.  This study is planned to be performed at approximately 43 sites and 
14 countries in the Americas, Europe, and Asia.  The study outline is shown in Figure 1.


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This study aims to characterize the PK of CAZ-AVI and assess its safety and tolerability 
following a single IV infusion.  Subjects will be hospitalized pediatric patients who are 
receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia 
(NP), defined as pneumonia with onset ≥48 hours after admission or within 7 days of 
discharge from an inpatient care facility, including ventilator-associated pneumonia (VAP), 
defined as a parenchymal lung infection arising ≥48 hours after endotracheal intubation and 
mechanical ventilation.  Subjects will be enrolled in 4 cohorts of descending age, each 
consisting of at least 8 evaluable subjects.  An evaluable subject is one who has received the 
complete single IV dose of CAZ-AVI and provided PK blood samples at ≥50% of the 
sampling time points. The definition of an evaluable subject is used for enrollment purposes 
only, and does not impact the definition of the PK analysis set in Section 9.3.  Each subject 
will receive a single IV dose of CAZ-AVI administered as an intravenous infusion over a 
120 minute period.  Blood samples will be collected from all subjects after the infusion to 
evaluate the PK of ceftazidime and avibactam.  Subjects will be followed for 48 hours after 
the end of the infusion.
The study will consist of a Screening visit (Visit 1, Day -1 to 1), during which consent will 
be obtained and subject eligibility will be confirmed, a Baseline/Treatment visit (Visit 2, 
Day 1) during which subjects will receive a single IV infusion of CAZ-AVI, and then two 
follow-up assessment visits at 24 hours (Visit 3, Day 2) and 48 hours (Visit 4, Day 3).  A 
Late Follow-up (LFU) telephone visit will be conducted 28-35 days after the CAZ-AVI 
infusion to identify, assess, and record any new Serious Adverse Event (SAE).  Blood 
samples for PK analyses (0.5 mL per sample) will be obtained over 22 hours following the 
CAZ-AVI infusion for Cohort 1 (7 samples), over 13 hours for Cohort 2 (6 samples), and 
over 6 hours for Cohorts 3 and 4 (4 samples).  A Late Follow-up (LFU) visit, that may be 
performed by telephone, will be conducted 28-35 days after the CAZ-AVI infusion in order 
to identify, assess, and record any new Serious Adverse Event (SAE).  
In addition to routine clinical monitoring all available safety and tolerability data from each 
cohort will be reviewed by a Safety Review Committee (SRC) after the first 4 subjects in 
each cohort are enrolled.  The SRC will consist of the study team physician, international 
coordinating Investigator or delegate, global safety/risk lead or delegate, therapeutic area 
director or delegate and the clinical pharmacologist/pharmacometrician or delegates.  Any 
SRC recommendation to alter the conduct of the study or modify dosing will be incorporated 
into a protocol amendment, as appropriate, and forwarded to regulatory authorities.
Figure 1.
Study Outline
Assess
PK
Day -1 to 1
ICD and 
screening the 
day of or day
before infusion
of CAZ-AVI
Day 1
Infusion of 
CAZ-AVI 
over 120 
minutes
Day 2
24 hour 
Follow
-up
Late 
Follow-up 
(telephone)
28-35 days 
after 
CAZ-AVI
Day 3
48 hour 
Follow
-up


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4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
Investigator’s study team before subjects are included in the study.  
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject’s parent(s), legal guardian, or legally acceptable representative has been 
informed of all pertinent aspects of the study.  As appropriate per local requirements 
informed assent of subjects must also be documented.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
3. Male or female children age ≥3 months to <18 years at Screening:
a.
Cohort 1: age 12 years to <18 years;
b. Cohort 2: age 6 years to <12 years;
c.
Cohort 3: age 2 years to <6 years;
d. Cohort 4: age 3 months to <2 years (must be born ≥37 weeks gestational age).
4. Hospitalized, receiving systemic antibiotic therapy for the treatment of a suspected or 
confirmed HAP, including VAP, meeting the following criteria, and expected to 
require hospitalization until after the follow-up evaluations are completed on Day 3 
(48 hours after the end of infusion):
a.
Onset of symptoms ≥48 hours after admission or <7 days after discharge from an 
inpatient acute or chronic care facility;
b. Evidence of new or worsening infiltrate as demonstrated on chest X-ray or other 
imaging modality that has been performed as part of the subject’s regular medical 
care;


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c.
At least 1 of the following systemic signs prior to the initiation of treatment for 
Nosocomial Pneumonia:
i.
Fever (temperature >38°C) or hypothermia (rectal/core temperature 
<35°C);
ii.
White blood cell (WBC) count >10,000 cells/mm3, or WBC count 
<4,500 cells/mm3, or >15% band forms.
d. At least 2 of the following respiratory signs or symptoms:
i.
A new onset of cough (or worsening of cough);
ii.
Production of purulent sputum or endotracheal secretions;
iii.
Auscultatory findings consistent with pneumonia/pulmonary consolidation 
(eg, rales, rhonchi, bronchial breath sounds, dullness to percussion, 
egophony);
iv.
Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2
<60 mmHg while breathing room air);
v.
A need for mechanical ventilation or, for already ventilated subjects, acute 
changes made in the ventilator support system to enhance oxygenation, as 
determined by, for example arterial blood gas or worsening PaO2/FiO2.
5. Likely to survive the current illness or hospitalization.
6. Sufficient IV access (peripheral or central) to receive study drug and dedicated access 
for PK sampling.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the Investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
2. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
3. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the subject inappropriate for entry into this 
study.


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4. Past or current history of epilepsy or seizure disorder (excluding childhood febrile 
seizures.
5. Severe renal impairment defined as creatinine clearance (CrCL) ≤30 mL/min/1.73 m2
calculated using the child’s measured height (length) and serum creatinine with the 
Bedside Schwartz equation (Schwartz, Munoz, et al., 2009):3
CrCL (mL/min/1.73 m2) =
6. Documented history of any hypersensitivity or allergic reaction to any β-lactam 
antibiotic.
7. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who are sexually active and unwilling or 
unable to use a highly effective method of contraception as outlined in this protocol 
for the duration of the study and for at least 28 days after the last dose of CAZ-AVI.
8. Acute hepatitis in the prior 6 months, a prior history of cirrhosis, acute hepatic failure, 
or acute decompensation of chronic hepatic failure; and/or any of the following blood 
test results, for any individual, when assessed for eligibility:
a.
Bilirubin >3 × upper limit of normal (ULN), unless isolated hyperbilirubinemia is 
directly related to the acute infection or due to known Gilbert’s disease;
b. ALT or AST >3 × ULN values used by the laboratory performing the test. 
Subjects with values >3 × ULN and <5 × ULN are eligible if this value is acute 
and directly related to the infectious process being treated. This must be 
documented;
c.
ALP >3 × ULN. Subjects with values >3 × ULN and <5 × ULN are eligible if this 
value is acute and directly related to the infectious process being treated. This 
must be documented.
9. Any condition (eg, septic shock, burns, cystic fibrosis, acute hemodynamic 
instability, including those conditions not responding to pressor support) that would 
make the patient, in the opinion of the Investigator, unsuitable for the study (eg, 
would place a patient at risk; compromise the quality of the data; or interfere with the 
absorption, distribution, metabolism, or excretion of CAZ-AVI).
10. Receipt of a blood or blood component or scheduled for transfusion within the PK 
sampling period (eg, red blood cells, fresh frozen plasma, platelets) transfusion during 
the 24-hour period before enrollment.
11. Body mass index (BMI) below the 5th percentile or above the 95th percentile for 
height, age, and weight except for children <2 years of age as BMI is not considered a 
screening tool for healthy weight in children under 2 years of age.


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12. Treatment with ceftazidime within 12 hours of CAZ-AVI administration or treatment 
with ceftazidime within 24 hours of CAZ-AVI administration in subjects with renal 
impairment (CrCL ≤50 mL/min/1.73 m2).
13. Treatment with potent inhibitors of OAT1 and/or OAT3 (eg, probenecid, 
p-aminohippuric acid (PAH), or teriflunomide).
4.3. Randomization Criteria
This study is not randomized.  All enrolled subjects will receive a single dose of CAZ-AVI.  
The Investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
4.4. Lifestyle Requirements
4.4.1. Contraception
All fertile male subjects and female subjects who are of childbearing potential who are, in the 
opinion of the Investigator, sexually active and at risk for pregnancy with their partner(s), 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the single dose of 
investigational product.  The Investigator or his or her designee will confirm that the subject 
has selected an appropriate method of contraception from the list of permitted contraception 
methods (see below).  At time points indicated in the Schedule of Activities, the Investigator 
or designee will instruct the subject of the need to use highly effective contraception 
consistently and correctly and document the conversation, and the subject’s affirmation, in 
the subject’s chart.  In addition, the Investigator or designee will instruct the subject to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the subject or partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject 
plans to remain on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate. 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject. 


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Additionally, all sexually active male subjects must agree to prevent potential transfer to and 
exposure of partner(s) to drug through ejaculate by using a condom consistently and 
correctly, beginning with the time of dose of investigational product and continuing for at 
least 28 days after the dose of investigational product.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the Investigator site, and contact details for a contact center in the 
event that the Investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by Investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the Investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the Investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the Investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).  
For this study, the investigational product is Zavicefta (ceftazidime-avibactam [CAZ-AVI]).
5.1. Allocation to Treatment
This is an unblinded, single treatment arm PK study.  All subjects will receive CAZ-AVI.
5.2. Breaking the Blind
This is an open-label study.  Blinding procedures are not applicable.


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5.3. Subject Compliance
Qualified study center personnel will administer the IV study treatment and assure treatment 
compliance.  At a minimum the dose, date, and exact start and stop time of administration of 
the IV study treatment will be recorded in the appropriate sections of the Case Report Form 
(CRF) and checked by the monitor at monitoring visits.  Deviations from study treatment will 
be reported and documented.
5.4. Investigational Product Supplies
All sites will be provided with an Investigational Product (IP) Manual containing detailed 
instructions on the receipt, storage, dispensing, preparation, and administration of the 
investigational product, as outlined below.  If there is any conflict between this protocol and 
the IP Manual regarding the handling of the investigational product, the IP Manual will 
control.
5.4.1. Dosage Form(s) and Packaging
The investigational product, Zavicefta (ceftazidime 2 g/avibactam 0.5 g), will be supplied by 
Pfizer as a white to yellow powder for concentrate for solution for infusion in a 20 mL glass 
vial.  Each vial contains a fixed dose combination of ceftazidime pentahydrate equivalent to 
2 g ceftazidime and avibactam sodium equivalent to 0.5 g avibactam.
Table 1.
Identity of Investigational Product
Investigational product
Dosage form and strength
Zavicefta (ceftazidime-avibactam)
2 g/0.5 g powder for concentrate for solution for 
infusion
5.4.2. Preparation and Dispensing
Detailed instructions for the preparation of CAZ-AVI powder for concentrate for solution for 
infusion will be provided in the separate IP Manual.  The investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.  The 
preparation and administration of all sterile products must be performed using aseptic 
technique.  
Ceftazidime/avibactam powder for concentrate for solution for infusion vials should be 
reconstituted with 10 mL of sterile water for injection.  After reconstitution, 1 mL of solution 
contains 167.3 mg of ceftazidime and 41.8 mg of avibactam.  The reconstituted solution is 
pale yellow and free of particles.  Each vial is for single use only and should be used 
immediately after reconstitution.  The reconstituted solution in the vial should be diluted with
a compatible diluent for administration in an IV bag or IV syringe at the appropriate 
concentration for intravenous infusion.
Any unused product or waste material should be disposed of in accordance with local 
requirements.


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5.5. Administration
The single dose intravenous infusion of CAZ-AVI is based on age and weight of the subject, 
with adjustment according to renal function, as detailed in Table 2.  Administration should be 
via either an appropriately sized sterile syringe and calibrated syringe pump or IV infusion 
bag and calibrated IV pump over 120 minutes.  The 120 minute infusion should be followed 
by an IV flush of the line.   Details regarding drug administration will be provided in the IP 
Manual.
Table 2.
CAZ-AVI Doses in Relationship to Age, Weight, and Renal Function
Cohort
Age range
Body 
weight
CAZ-AVI dose
CrCL 50 mL/min/1.73 m2
CAZ-AVI dose
CrCL 30 to <50 mL/min/1.73 m2
1a
12 years to
<18 years
40 kg
2000 mg CAZ
500 mg AVI
1000 mg CAZ
250 mg AVI
1a
12 years to
<18 years
<40 kg
50 mg/kg CAZ
12.5 mg/kg AVI
25 mg/kg CAZ
6.25 mg/kg AVI
2a
6 years to
<12 years
40 kg
2000 mg CAZ
500 mg AVI
1000 mg CAZ
250 mg AVI
2a
6 years to
<12 years
<40 kg
50 mg/kg CAZ
12.5 mg/kg AVI
25 mg/kg CAZ
6.25 mg/kg AVI
3a
2 years to
<6 years
All
50 mg/kg CAZ
12.5 mg/kg AVI
25 mg/kg CAZ
6.25 mg/kg AVI
4b
1 year to
<2 years
All
50 mg/kg CAZ
12.5 mg/kg AVI
25 mg/kg CAZ
6.25 mg/kg AVI
4b
6 months to
<1 year
All
50 mg/kg CAZ
12.5 mg/kg AVI
25 mg/kg CAZ
6.25 mg/kg AVI
4b
3 months to
<6 months
All
40 mg/kg CAZ
10 mg/kg AVI
20 mg/kg CAZ
5.0 mg/kg AVI
a.
Subjects considered for entry into the study will be within the body mass index (BMI) range between the 
5th percentile and ≤95th percentile according to height, weight, and age.
b.
BMI will not be calculated for children <2 years of age as BMI is not considered a screening tool for 
healthy weight in children under 2 years of age.
5.6. Investigational Product Storage 
The Investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  
See the Investigational Product Manual for storage conditions of the product once 
reconstituted and/or diluted.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.


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Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.7. Investigational Product Accountability 
The Investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.7.1. Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the Investigator site, the 
Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
Prescribed antibiotics used to treat the subject’s infection should be continued or modified 
according to the Investigator’s decision.


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All prescription and over-the-counter medications being taken by the subject for 5 days prior 
to study entry (considered prior treatment) and from enrollment through Day 2 and Day 3 
(follow-up period) (considered concomitant treatments) must be documented on the 
appropriate pages of the CRF.  For Cohort 3 and 4 subjects who are being breast fed, record 
all medications taken by the lactating mother for 3 days before the CAZ-AVI infusion 
through Day 3.
Other medication that is considered necessary for the subject’s safety and well-being may be 
given at the discretion of the Investigator and recorded in the appropriate sections of the 
CRF.  Subjects who have completed study dose of CAZ-AVI infusion and are in the 
follow-up period should remain in the study as they are not actively on study dose of 
CAZ-AVI, but being followed for outcomes.
Treatment with probenecid within 48 hours of CAZ-AVI administration is not permitted as 
this could interfere with the CAZ-AVI PK assessment.  In vitro, avibactam is a substrate of 
OAT1 and OAT3 transporters which might contribute to the active uptake from the blood 
compartment, and thereby its excretion.  As a potent OAT inhibitor, probenecid inhibits OAT 
uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the 
elimination of avibactam when co-administered.
Treatment with ceftazidime within 12 hours of CAZ-AVI administration, or treatment with 
ceftazidime within 24 hours of CAZ-AVI administration in subjects with renal impairment 
(CrCL ≤50 mL/min/1.73 m2) is not permitted.
6. STUDY PROCEDURES 
Study periods are defined in Figure 1.  Details of the study plan and procedures are provided 
in the Schedule of Activities and are described in detail by visit in the following sections.
6.1. Screening and Enrollment
Prior to any study-specific procedures, the subject’s parent or parents (depending on local 
requirements) or legally acceptable representative must provide written informed consent and 
the subject must provide informed assent as appropriate per local requirements.  Either 
written assent or documented verbal assent may be obtained according to local requirements.  
During the screening period, subjects will be assessed regarding eligibility criteria.  Subjects 
who do not meet all of these criteria must not be enrolled in the study.
6.1.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1)
Each subject will undergo Screening assessment procedures on the day of or one day prior to 
the dose of CAZ-AVI.  These will serve as the baseline assessments and can be completed on 
the same calendar day as Day 1, prior to CAZ-AVI infusion, but must be completed no 
earlier than the day before the start of CAZ-AVI infusion. When screening assessment 
procedures are performed the day prior to the dose of CAZ-AVI, weight is also to be 
collected at day of dose administration.  The weight collected on the date of dose 
administration will be used to properly calculate the dose of CAZ-AVI to be administered.


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If additional assessments are conducted per standard of care prior to the first infusion of 
CAZ-AVI the assessments closest to the infusion will be considered baseline.
Potential subjects who do not meet enrollment criteria may, as appropriate, repeat screening 
evaluations at a later time for possible enrollment into the study.
6.1.1.1. Clinical Assessments
1. Obtain informed consent and assent as appropriate.  At selected sites, if subjects will 
undergo BAL as part of their clinical management, separate consent and assent as 
appropriate must be obtained for collection of BAL fluid for CAZ-AVI analysis.
2. Review inclusion and exclusion criteria.
3. Collect demographics.
4. Collect medical and surgical history.
5. Review prior and concomitant treatments.
6. Perform complete physical examination, including height and weight. Body mass 
index (kg/m2) will be calculated as the ratio of weight in kg/(height in cm/100)2. The 
BMI will not be calculated for children <2 years of age as BMI is not considered a 
screening tool for healthy weight in children under 2 years of age.
7. Measure vital signs including supine blood pressure, pulse rate, respiratory rate, and 
temperature (oral, rectal, or tympanic, as appropriate). Vital signs will be measured 
at the following time points: before infusion and 2, 4, 6, 12, 24 and 48 hours after the 
end of the CAZ-AVI infusion. Additional vital signs may also be taken as needed.
8. Record oxygen saturation, if available.
9. Monitor for AEs and SAEs.
10. Obtain results of chest x-ray (CXR), computerized tomography scan (CT scan), or 
other imaging tests (eg, MRI, ultrasound) if performed diagnostically as part of the 
subject’s regular medical care for the current diagnosis of pneumonia up to before 
screening.
11. For subjects who the Investigator determines are of childbearing potential and are 
sexually active confirm that highly effective contraception is being used.
6.1.1.2. Laboratory Assessments
1. Obtain a blood sample for clinical chemistry and hematology assessments (see
Table 6 for details of laboratory assessments).  
2. Obtain a urine sample for routine analysis.


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3. Creatinine clearance will be determined using the Bedside Schwartz equation [eGFR 
(ml/min/1.73 m2) = 0.413 * (length (cm)/serum creatinine (mg/dL)], Schwartz, 
Munoz, et al., 2009.3
4. Obtain a blood or urine pregnancy test with a sensitivity of at least 25 mIU/mL for 
β-hCG for females who have achieved menarche. If the test is positive, the subject
must be excluded.
6.2. Study Period
6.2.1. Visit 2, Study Day 1
Study Day 1 is the day of CAZ-AVI infusion and PK assessment.  Screening and Baseline
activities may be combined if entry requirements can be completed jointly on the same 
calendar day.
6.2.1.1. Clinical Assessments
1. Review prior and concomitant treatments.
2. Measure vital signs including supine blood pressure, pulse rate, respiratory rate, and 
temperature. Vital signs will be measured at the following time points: before 
infusion and 2, 4, 6, 12, 24, and 48 hours after the end of the CAZ-AVI infusion. 
Additional vital signs may also be taken prn.
3. Collect weight.
4. Record oxygen saturation, if available.
5. Record adjunctive therapeutic procedures (eg, endotracheal aspiration, 
bronchoscopy), if performed.
6. Obtain results of CXR, CT scan, or other imaging tests (eg, MRI, ultrasound) if 
performed as part of the subject’s regular medical care.
7. For subjects who the Investigator determines are of childbearing potential and are 
sexually active confirm that highly effective contraception is being used.
8. Monitor for AEs and SAEs.
6.2.1.2. Laboratory Assessments
1. Obtain PK blood samples according to the detailed schedule in Section 7.2.1, Table 3, 
Table 4, or Table 5.
2. For those who have provided consent, obtain blood sample (0.5 mL) for plasma urea 
concentration in comparison to the BALF urea concentration for any subject 
undergoing BAL as part of their clinical management during the blood PK sampling 
interval.


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3. For those who have provided consent, BAL fluid collection to be performed at 
selected sites only for subjects undergoing bronchoscopy as part of their clinical 
management during the time window for collection of PK blood samples after 
CAZ-AVI infusion.  A matching blood sample to replace one of the PK blood 
samples is to be collected at the same time as the BAL, along with a blood sample for 
blood urea analysis.
6.2.1.3. Study Therapy Administration
1. Infusion of CAZ-AVI IV over a 120 minute (±10 min) period, according to the cohort 
as indicated in Table 2.  The 120 minute infusion should be followed by an IV flush 
of the line.  Details regarding drug administration will be provided in the IP Manual.  
The dose should be calculated based on the subject’s weight at Baseline (Day 1).  To 
support the use of population PK modeling the actual dose amount of CAZ-AVI 
administered, the accurate date and time of start and end of the IV infusion, end time 
of IV flush, and the actual blood sample times are required.
6.2.2. Visit 3, Study Day 2, 24 Hour Follow-Up Assessment
6.2.2.1. Clinical Assessments
1. Review concomitant treatments.
2. Measure vital signs including supine blood pressure, pulse rate, respiratory rate, and 
temperature.  Vital signs will be measured at the following time points: pre-infusion 
and 2, 4, 6, 12, 24 and 48 hours after the end of the CAZ-AVI infusion.  Additional 
vital signs may also be taken prn.
3. Record oxygen saturation, if available.
4. Record adjunctive therapeutic procedures (eg, endotracheal aspiration, 
bronchoscopy), if performed.
5. Obtain results of CXR, CT scan, or other imaging tests (eg, MRI, ultrasound) if 
performed as part of the subject’s regular medical care.
6. For subjects who the Investigator determines are of childbearing potential and are 
sexually active confirm that highly effective contraception is being used.
7. Monitor for AEs and SAEs.
6.2.3. Visit 4, Study Day 3, 48 Hour Follow-Up Assessment
6.2.3.1. Clinical Assessments
1. Review concomitant treatments.
2. Perform complete physical examination, including weight.


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3. Measure vital signs including supine blood pressure, pulse rate, respiratory rate, and 
temperature.  Vital signs will be measured at the following time points: pre-infusion 
and 2, 4, 6, 12, 24 and 48 hours after the end of the CAZ-AVI infusion.  Additional 
vital signs may also be taken prn.
4. Record oxygen saturation, if available.
5. Record adjunctive therapeutic procedures (eg, endotracheal aspiration, 
bronchoscopy), if performed.
6. Obtain results of CXR, CT scan, or other imaging tests (eg, MRI, ultrasound) if 
performed as part of the subject’s regular medical care.
7. For subjects who the Investigator determines are of childbearing potential and are 
sexually active confirm that highly effective contraception is being used.
8. Monitor for AEs and SAEs.
6.2.3.2. Laboratory Assessments
1. Obtain a blood sample for clinical chemistry and hematology assessments
(see Table 6 for details of laboratory assessments).
2. Obtain a urine sample for routine analysis.
3. Creatinine clearance will be determined using the Bedside Schwartz equation [eGFR 
(ml/min/1.73 m2) = 0.413 * (length (cm)/serum creatinine (mg/dL)], Schwartz, 
Munoz, et al., 2009.3
4. Obtain a blood or urine pregnancy test with a sensitivity of at least 25 mIU/mL for 
β-hCG for females who have achieved menarche.
6.2.4. Late Follow-up (LFU)
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the subject 
may be done via a phone call.
6.3. Subject Withdrawal
In this single-dose study, the study drug infusion should not be discontinued before the 
120 minute administration is complete unless the following events occur:

Subject decision. The subject or the subject’s parent(s) or other legally acceptable 
representative(s) is at any time free to discontinue treatment infusion, without 
prejudice to further treatment;


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
Clinically significant AE, as judged by the Investigator;

Investigator evaluation and decision.
Subjects are at any time free to withdraw from the study (CAZ-AVI and assessments), 
without prejudice to further treatment (withdrawal of consent).  The subject or parent(s), or 
other legally acceptable representative(s), will always be asked about the reason(s) and the 
presence of any AEs.  If possible, the subject will be seen and assessed by an Investigator at 
the time of withdrawal.  Adverse events and serious adverse events (SAEs) will be followed 
up.
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.
Subjects should notify the Investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the Investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up:
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the Investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the Investigator may use a Sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the Investigator should be reported and 
documented in the subject’s medical records.


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Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the subject return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the Investigator 
upon consultation with the Sponsor.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the Investigator that may make it unfeasible to 
perform the test. In these cases the Investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
Investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the Investigator site prior 
to initiation of the study.
7.1. Pregnancy Testing
For female subjects of childbearing potential, as determined by the Investigator, a serum or 
urine pregnancy test, with sensitivity of at least 25 mIU/mL for β-hCG, will be performed 
locally at the screening visit, Visit 1, and the 48 hour assessment, Visit 4.  A negative 
pregnancy test result is required before the subject may receive CAZ-AVI.  Pregnancy tests 
may also be repeated if requested by institutional review boards (IRBs)/ethics committees 
(ECs) or if required by local regulations.


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Urine pregnancy tests must be sensitive to at least 25 mIU/mL for β-hCG and will be 
conducted with the test kit provided by the central laboratory in accordance with instructions 
provided in its package insert.  Subjects who have missed a menstrual period or who show an 
indeterminate or positive result on the urine test may not further progress in the study until 
pregnancy is ruled out using further diagnostic testing (eg, a negative quantitative serum 
pregnancy test conducted at a certified laboratory).
7.2. Pharmacokinetics
Sparse PK sampling, especially for pediatric patients younger than 12 years of age, has been 
employed to minimize blood sampling requirements. The use of analgesic creams to 
minimize discomfort is permitted as per standard of care. An indwelling catheter may be 
used for the repeated PK sampling, to minimize the discomfort; this catheter/port will not be 
used for administration of any medication. Prior to obtaining each sample the saline used to 
flush the catheter will be discarded.
7.2.1. Pharmacokinetic (PK) Blood Sample Collection
Samples may be obtained by venipuncture, through a saline/heparin lock, peripherally 
inserted central catheter, or through a central line.  A site other than the infusion site is 
preferred; however, samples may be drawn from the same site as the infusion site, by use of a 
multi-lumen catheter, with the exception of the blood drawn immediately after the infusion
which must not be drawn from any lumen of a catheter used for drug delivery. In cases 
where a multi-lumen catheter is used for drug delivery and blood draws, the PK blood 
samples, other than the first PK sample collection performed at the end of CAZ-AVI 
infusion/flush, must be taken from a lumen that was NOT used for drug delivery. Detailed 
instructions for PK sample collection will be provided in the Laboratory Manual.
Venous blood samples for the determination of CAZ-AVI PK for each cohort are presented 
in Table 3, Table 4, and Table 5 for Cohort 1, Cohort 2, and Cohorts 3 and 4, respectively.  
The actual date and time of collection of each sample will be recorded in the CRF.
Detailed instructions for the collection, labeling, storage, and shipment of samples will be 
provided in the Laboratory Manual.
For total blood volume collection see Section 7.4.
Leftover plasma could be used to assess concentrations of endogenous biomarkers for drug 
transporters and/or drug metabolizing enzymes.  Any results from such analyses may be 
reported separately from the CSR.


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Table 3.
Cohort 1 - Schedule for PK Assessments
Nominal time
Nominal 
Time Post-
Dose (TPD)
Blood 
volume
End of CAZ-AVI infusion/flush +0 to 5 minutes
2 hours
0.5 mL
30 minutes after the end of the CAZ-AVI infusion/flush
±5 minutes
2 hours, 
30 minutes
0.5 mL
1.5 hours after the end of the CAZ-AVI infusion/flush
±15 minutes
3 hours, 
30 minutes
0.5 mL
3 hours after the end of the CAZ-AVI infusion/flush
±30minutes
5 hours
0.5 mL
6 hours after the end of the CAZ-AVI infusion/flush
±30 minutes
8 hours
0.5 mL
10 hours after the end of the CAZ-AVI infusion/flush
±30 minutes
12 hours
0.5 mL
22 hours after the end of the CAZ-AVI infusion/flush
±30 minutes
24 hours
0.5 mL
Table 4.
Cohort 2 - Schedule for PK Assessments
Nominal time
Nominal 
Time 
Post-Dose
(TPD)
Blood 
volume
End of CAZ-AVI infusion/flush +0 to 5 minutes
2 hours
0.5 mL
15 to 45 minutes after the end of the CAZ-AVI infusion/flush
2 hours, 
15 minutes
0.5 mL
1 to 2 hours after the end of the CAZ-AVI infusion/flush
3 hours
0.5 mL
2 to 3 hours after the end of the CAZ-AVI infusion/flush
4 hours
0.5 mL
4 to 6 hours after the end of the CAZ-AVI infusion/flush
6 hours
0.5 mL
11 to 13 hours after the end of the CAZ-AVI infusion/flush
13 hours
0.5 mL


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Table 5.
Cohorts 3 and 4 - Schedule for PK Assessments
Nominal time
Nominal 
Time 
Post-Dose
(TPD)
Blood 
volume
End of CAZ-AVI infusion/flush + 0 to 5 minutes
2 hours
0.5 mL
15 to 45 minutes after the end of the CAZ-AVI infusion/flush
2 hours, 
15 minutes
0.5 mL
2 to 3 hours after the end of the CAZ-AVI infusion/flush
4 hours
0.5 mL
4 to 6 hours after the end of the CAZ-AVI infusion/flush
6 hours
0.5 mL
7.2.2. Collection of BAL Fluid Samples
At selected sites, subjects who are undergoing bronchoscopy with BAL as part of their 
clinical management any time during the blood PK sampling interval, should have a portion 
of the BAL fluid which is not required for the subject’s medical care retained for PK 
analysis.  For these subjects a blood PK sample should be obtained at the same time as the 
BAL fluid collection, to replace one of the designated blood PK samples.  Additionally, a 
0.5 mL blood sample should be obtained for plasma urea concentration in comparison to the 
BALF urea concentration. 
Sites performing BAL will follow their standard local procedures for the lavage, recording 
the location of the lavage and volumes instilled.  Immediately after completion of the lavage, 
BAL aspirates should be pooled and the volume recorded.  After removing aliquots for local 
culture, cell count, and differential as per standard practice, the remaining pooled BALF 
should be placed on ice and centrifuged at 400 x g for 5 minutes. BALF supernatant will be 
collected without disturbing the pellet and one 3 mL aliquot of BALF supernatant will be 
prepared in a separate tube for bioanalysis of avibactam and ceftazidime, and one 3 mL 
aliquot of BALF supernatant for analysis of urea.  Detailed instructions for the collection, 
labeling, storage, and shipment of BALF samples will be provided in the Laboratory Manual.
7.3. Safety Assessments
Subjects must be evaluated by a physician or an appropriately trained health care 
professional at every visit, and the evaluation must be documented.  The procedures 
discussed below will be completed at the designated visits.
7.3.1. Laboratory Safety Assessments
Blood samples and urine samples will be collected at baseline and the 48 hour assessment 
(Visit 4).  Samples may also be collected at any time during study participation if clinically 
indicated.


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The following laboratory tests will be measured:
Table 6.
Laboratory Safety Tests
Chemistry panel
Hematology panel
Urinalysis
Sodium 
Potassium 
Chloride 
Bicarbonate
Creatinine
BUN
Glucose, nonfasting
Calcium
Phosphorus
Magnesium
Alkaline phosphatase 
GGT 
AST
ALT
Creatine kinase 
LDH
Total bilirubin 
Indirect bilirubin 
Hematocrita
Hemoglobin
Red Blood Cell count
White Blood Cell count
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Neutrophils, immature
Platelets
Mean cell volume
Mean cell hemoglobin
β-hCG Pregnancy Test 
(blood or urine) for femalesb
Appearance (color, 
clarity)
Bilirubin
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Microscopic
     Red blood cells
     White blood cells
     Casts
     Crystals
     Bacteria, yeast, 
parasites
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; 
GGT, gamma glutamyltransferase; INR, international normalized ratio; LDH, lactate dehydrogenase; PTT, 
partial thromboplastin time.
a.
If a subject’s hemoglobin or hematocrit decreases significantly (in the Investigator’s judgement) after 
administration of the CAZ-AVI infusion, a workup for hemolytic anemia should be performed per standard 
of care.
b.
Required for females of childbearing potential, as determined by the Investigator.  Either a serum or urine 
pregnancy test is acceptable with a sensitivity of at least 25 mIU/mL for β-hCG.
7.4. Blood Volume
Table 7 shows the total volume of blood that will be drawn from each subject for the 
purposes of the study, apart from blood that is taken as part of subject’s normal standard of 
care.  This protocol complies with European Union’s recommendations for blood loss 
associated with pediatric research (Anonymous, 2017)11 and the World Health Organization 
guidelines “Blood Sample Volumes in Child Health Research: Review of Safe Limits” 
(Howie, 2011).12


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Table 7.
Volume of Blood to be Drawn from Each Subject
Assessment
Sample 
volume
(mL)
All Cohorts
Number
of 
samples
Total 
volume 
(mL)
Safety
Clinical Chemistry
2a
2
4a
Hematology
2
2
4
Pharmacokinetics
Cohort 1 (≥12 to <18 years)
0.5
7
3.5
Cohort 2 (≥6 to <12 years)
0.5
6
3
Cohort 3 (≥2 to <6 years)
0.5
4
2
Cohort 4 (≥3 months to <2 years)
0.5
4
2
Total Cohort 1
11.5a,b
Total Cohort 2
11a,b
Total Cohort 3
10a
Total Cohort 4
10a
a.
Subjects undergoing BAL will have one addition 0.5 mL blood sample obtained for plasma urea 
concentration at the time of the BAL.
b.
Female subjects of childbearing potential will have either a serum or urine pregnancy test performed at the 
screening visit (Visit 1), and the 48 hour assessment (Visit 4); each serum pregnancy test requires an 
additional 2 mL blood sample. 
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
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Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the Investigator are to be reported 
regardless of whether the event is determined by the Investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the Investigator does not become 
immediately aware of the occurrence of an event, the Investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the Investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the Investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The Investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian/legally acceptable representative.  In 
addition, each study subject/parent(s)/legal guardian/legally acceptable representative will be 
questioned about the occurrence of AEs in a non-leading manner.


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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the Investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the Investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the Investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 


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(evidence) or arguments to suggest a causal relationship should be provided.  If the 
Investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor.  If the Investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.  
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;


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
Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);


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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the Investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the Investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”


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In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor.
The subject should return to the Investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 


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anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of Investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.


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
If a subject or subject’s partner becomes or is found to be pregnant during the 
subject’s treatment with the investigational product, the Investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the Investigator must 
submit information regarding environmental exposure to a Pfizer product in a 
pregnant woman (eg, a subject reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) to Pfizer Safety using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred 
and within 24 hours of awareness of the exposure.  The information submitted should 
include the anticipated date of delivery (see below for information related to 
termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the Investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.

Additional information regarding the EDP may be requested by the Sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, 
the Investigator will provide the subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document in the 
source documents that the subject was given the Pregnant Partner Release of 
Information Form to provide to his partner.


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8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the Investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the Investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the Investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.


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In the event of a medication dosing error, the Sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the Sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The primary objective of this study is to evaluate the pharmacokinetics, safety, and 
tolerability of a single dose of CAZ-AVI in children with HAP/VAP. The study is not 
powered for inferential statistical analysis.  The sample size of 32 subjects is considered 
adequate to evaluate the pharmacokinetics of CAZ-AVI in this population.
9.2. Efficacy Analysis
There is no assessment of efficacy in this single dose study.
9.3. Pharmacokinetic Analysis (Primary Endpoint)
The PK analysis set will consist of all subjects who received a complete IV study dose of 
CAZ-AVI and have at least 1 ceftazidime and/or avibactam plasma measurement available.  
The definition of an evaluable subject from Section 3 (one who has received the complete 
single IV dose of CAZ-AVI and provided PK blood samples at ≥50% of the sampling time 
points) is used for enrollment purposes only, and it does not impact the definition of the PK 
analysis set. 
Plasma concentrations of CAZ and AVI will be listed, and summarized by nominal time 
using appropriate descriptive statistics such as number, mean, standard deviation (SD), 
minimum, median, maximum, geometric mean, and coefficient of variation.
Individual plasma concentration profiles, using the PK analysis set for Cohorts 1 to 4, will be 
presented graphically using actual sample collection time on both linear and semilogarithmic 
scales, showing all patients on a single plot for each cohort and analyte.  Median 
concentration-time profiles will be presented on both linear and semilogarithmic scales using 
nominal time for both ceftazidime and avibactam.  Additional graphical presentations of PK 
data may be included at the discretion of the clinical pharmacologist.


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In addition, PK parameters of ceftazidime and avibactam will be calculated by 
non-compartmental analysis (NCA) using actual PK sampling times following single dose 
administration of CAZ-AVI for Cohorts 1 and 2 as follows:
Parameter
Definition
Method of Determination
AUC0-8
Area under the plasma 
concentration-time profile 
from time 0 to 8 hours.
Linear/Log trapezoidal rule.
AUCinf
a
Area under the plasma 
concentration-time profile 
from time 0 to infinity.
Linear/Log trapezoidal rule.
AUCinf = AUClast + (Clast*/ kel), where Clast* is 
the estimated concentration at the time of the 
last quantifiable concentration and kel is the 
terminal phase rate constant calculated by a 
linear regression of the log-linear 
concentration-time curve.  Only those data 
points judged to describe the terminal log-linear 
decline will be used in the regression.
AUClast
Area under the plasma 
concentration-time profile 
from time 0 to the last 
quantifiable concentration.
Linear/Log trapezoidal rule.
Cmax
Maximum plasma 
concentration.
Observed directly from data.
Tlast
Time of last quantifiable 
plasma concentration.
Observed directly from data.
Tmax
Time for Cmax.
Observed directly from data.
t½
a
Terminal elimination 
half-life.
Loge(2)/kel.
CLa
Clearance.
Dose/AUCinf.
Vss
a
Volume of distribution at 
steady-state.
Volume of distribution at steady state is 
calculated as: Vss = CL × MRT.
Mean residence time (MRT) is calculated as: 
MRT = AUMCinf/AUCinf - (infusion time/2).
Area under the first moment curve from 0 time 
to infinity (AUMCinf) is calculated as:
AUMCinf = AUMClast + ((t × Cest
1*)/kel) + 
(Cest
1*/kel2)
1Cest = e(-KEL × Tlast) × KELC0 , where C0 is the
back-extrapolated concentration at time zero.
Vz
a
Volume of distribution 
during terminal phase.
Dose/(AUCinf × kel).
a.
If data permit.


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These NCA PK parameters will be summarized for Cohorts 1 and 2 using descriptive 
statistics.
Further, the avibactam and ceftazidime concentration, pediatric patient demographics, and 
disease status data from Cohorts 1 to 4 will be combined with the data from appropriate 
previous clinical studies in pediatric patients and/or adults for a population PK analysis.  The 
actual dosing and plasma sampling times will be used for the analysis.  Individual 
compartmental PK parameters for pediatric patients in Cohorts 1 and 2 with available 
avibactam and ceftazidime plasma concentration data will be calculated by the empirical 
Bayesian estimate, and individual non-compartmental PK parameters such as Cmax, minimum 
concentration (Cmin), area under the plasma concentration-time curves at steady-state 
(AUCss), and t½, will be derived from the determined avibactam and ceftazidime 
concentration time courses.
A stand-alone population PK modelling and simulation analysis plan will be prepared and the 
results will be reported in a stand-alone report outside of the clinical study report.
9.3.1. BAL Analysis (Exploratory Endpoint)
Ceftazidime and avibactam ELF:plasma concentration ratios (for available matching ELF 
and plasma samples) will be provided.  It is anticipated that interpretation of these ELF 
concentration results will be problematic due to the variability of BAL sampling (no standard 
timing of sample collection in relation to dosing) and the small sample size.  As a result, ELF 
drug concentration data will not be used for decision-making purposes and will be considered 
exploratory only.
9.4. Safety Analysis (Secondary Endpoint)
The safety analysis set will consist of all subjects who received any amount of IV study dose 
of CAZ-AVI.  No inferential statistical tests will be performed for any safety analyses.  For 
each safety parameter, the last assessment made before the first dose of study therapy will be 
used as the baseline for all analyses.  Summaries of demographics and other baseline 
characteristics will be provided.  The incidence of AEs, SAEs, deaths, and discontinuations 
due to AEs will be summarized by system organ class and preferred term according to the 
Medical Dictionary for Regulatory Activities (MedDRA), by relationship to study therapy, 
and by severity.  All recorded AEs will be listed and tabulated by system organ class, 
preferred term and for each cohort.  Adverse events occurring from the start of study dose of 
CAZ-AVI infusion up to 48 hours after the end of infusion, and up to the end of the study
(LFU) will be summarized by preferred term and system organ class using the MedDRA 
vocabulary (Version 14.0 or higher) by cohort.  Descriptive statistics of observed results and 
the change from baseline to selected post baseline time points will be presented for clinical 
laboratory results and vital signs.  Tabulations and listings of data for vital signs, physical 
examinations, and clinical laboratory tests will be presented with abnormal or out-of-range 
values flagged.  Potentially clinically significant laboratory results will be summarized.


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9.5. Interim Analysis
No formal interim analysis will be conducted for this study. However, as this is an 
open-label study, the Sponsor may conduct unblinded reviews of the data during the course 
of the study for the purpose of safety assessment, facilitating pharmacokinetic
(PK)/pharmacodynamic (PD) modeling, and/or to support clinical development.
9.6. Data Monitoring Committee 
This study will not have an external data monitoring committee (E-DMC).  
9.7. Safety Review Committee
This study will use an Internal Safety Review Committee which will be known as the Safety 
Review Committee (SRC).  The SRC will consist of the study team physician, international 
coordinating Investigator or delegate, global safety/risk lead or delegate, therapeutic area 
director or delegate and the clinical pharmacologist/pharmacometrician or delegate. The 
SRC will assess safety and tolerability after the first 4 subjects in each cohort are enrolled.  
With the exception of the international coordinating Investigator or delegate, all members of 
the SRC will be members of the Sponsor organization.  Other team members may be asked to 
join as needed.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
Investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the Investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The Investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the Investigator will cooperate with Pfizer 
or its agents to prepare the Investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The Investigator site and 
Investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The Investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the Investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs[/Data Collection Tools (DCTs)] are securely stored at the study site in encrypted 
electronic and/or paper form and will be password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts.
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the Investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
Investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent/assent documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports).  The 
records should be retained by the Investigator according to the ICH guidelines, according to 
local regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  
The investigator must ensure that the records continue to be stored securely for so long as 
they are retained.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
Investigator, another institution, or an independent third party arranged by Pfizer. 


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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The Investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the
IRB/EC should be retained in the Investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the Investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be 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.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any
reports, publications, or other disclosures, except where required by applicable law.
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  


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The Investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.
The Investigator must ensure that each study subject’s parent(s), legal guardian, or legally 
acceptable representative is fully informed about the nature and objectives of the study, the 
sharing of data relating to the study and possible risks associated with participation, including 
the risks associated with the processing of the subject’s personal data.  The investigator 
further must ensure that each study subject’s parent(s), legal guardian, or legally acceptable 
representative is fully informed about his or her right to access and correct his or her personal 
data and to withdraw consent for the processing of his or her personal data.
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
Investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the Investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained or waived.  If assent is obtained verbally, it must be documented in the source 
documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.  
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed. The Investigator will retain the original of each subject's signed consent/assent 
document.


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the Investigator will inform Pfizer immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
The end of the study is defined as the last visit of the last patient undergoing the study, or the 
date of study closure in the case of early study termination, whichever date is later.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
ceftazidime-avibactam at any time.
If a study is prematurely terminated, Pfizer will promptly notify the Investigator.  After 
notification, the Investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.


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PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
Principal Investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the Investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The Investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the Investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The Investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the Investigator agrees that the first publication is 
to be a joint publication covering all Investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the Investigator is free to publish separately, subject to the other 
requirements of this section.


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For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other
issues.


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16. REFERENCES
1.
AVYCAZ. (ceftazidime-avibactam) [United States Package Insert]. Allergan USA, Inc., 
Irvine, CA 92612. 2019.
2.
Zavicefta. (ceftazidime-avibactam) [European Summary of Product Characteristics]. 
Pfizer Ireland Pharmaceuticals, Ringaskiddy, County Cork, Ireland. 2018.
3.
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 
2009;20(3):629-637.
4.
Fortum (ceftazidime) [European Summary of Product Characteristics]. 
GlaxoSmithKline, UK; June 2016.
5.
FORTAZ (ceftazidime for injection) [United States Package Insert]. GlaxoSmithKline, 
Research Triangle Park, NC. January 2014.
6.
Miossec C, Claudon M, Levasseur P, Black MT. The beta-lactamase inhibitor 
avibactam (NXL104) does not induce ampC beta-lactamase in Enterobacter cloacae. 
Infection & Drug Resistance. 2013;6:235-240.
7.
Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, 
Newell P, Pachl J. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole 
Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results 
From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect 
Dis.62(11):1380-1389.
8.
Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, Song J, Taylor D, Laud PJ, 
Stone GG, Chow JW. Ceftazidime-avibactam versus meropenem in nosocomial 
pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, 
double-blind, phase 3 non-inferiority trial. The Lancet Infectious Diseases. 
2018;18(3):285-295.
9.
Nicolau DP, Siew L, Armstrong J, Li J, Edeki T, Learoyd M, Das S. Phase 1 study 
assessing the steady-state concentration of ceftazidime and avibactam in plasma and 
epithelial lining fluid following two dosing regimens. J Antimicrob 
Chemother.70(10):2862-2869.
10.
Muller AE, Punt N, Mouton JW. Optimal exposures of ceftazidime predict the 
probability of microbiological and clinical outcome in the treatment of nosocomial 
pneumonia. J Antimicrob Chemother. 2013;68(4):900-906.
11.
Anonymous. Ethical considerations for clinical trials on medicinal products conducted 
with minors: Recommendations of the expert group on clinical trials for the 
implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal 
products for human use. European Commission. 2017.


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12.
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull 
World Health Organ. 2011;89(1):46-53.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-24
area under the plasma concentration time profile from time 0 to 
24 hours
AUC0-8
area under the plasma concentration time profile from time 0 to 
8 hours
AUCinf
area under the plasma concentration time profile from time 0 to 
infinity
AUClast
Area under the plasma concentration time profile from time 0 to 
the last quantifiable concentration
AUCss
area under the plasma concentration-time curves at steady-state
AVI
avibactam
BAL
bronchoalveolar lavage
BALF
bronchoalveolar lavage fluid
BMI
body mass index
CAZ
ceftazidime
CAZ-AVI
ceftazidime-avibactam
CBC
complete blood count
cIAI
complicated intra-abdominal infection
CK
creatine kinase
CL
systemic plasma clearance
Cmax
maximum (or peak) plasma concentration
Cmin
minimum (or trough) plasma concentration
CrCL
creatinine clearance
CRF
case report form
CSA
clinical study agreement
CSR
clinical study report
cSSTI
complicated skin and soft tissue infection
CT
clinical trial
CTA
clinical trial application
CT scan
computerized tomography scan
cUTI
complicated urinary tract infection
CXR
chest x-ray
DCT
data collection tool
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
EC
ethics committee
E-DMC
external data monitoring committee 


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Abbreviation
Term
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rete
ESBL
extended spectrum -lactamase
EU
European Union
EudraCT
European Clinical Trials Database
ELF
epithelial lining fluid
FDA
Food and Drug Administration
GA
gestational age
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HAP
hospital acquired pneumonia
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRQL
health-related quality of life
IB
Investigator Brochure
ICH
International Conference on Harmonisation
ID
identification code
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
IV
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
KPCs
Klebsiella pneumoniae carbapenemases
LFT
liver function test
LFU
late follow-up
LSLV
last subject last visit 
MedDRA
medical dictionary for regulatory activities
MIC
Minimal inhibitory concentration (lowest drug concentration that 
prevents visible microorganism growth)
MRI
magnetic resonance image
N/A
not applicable
NCA
non-compartmental analysis
NP
nosocomial pneumonia
OAT
organic anion transporters
PCD
primary completion date
PD
Pharmacodynamics(s)
PI
Principal Investigator
PIP
Pediatric Investigation Plan
PK
pharmacokinetic
PT
prothrombin time


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Abbreviation
Term
PTA
probability of target attainment
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SmPC
summary of product characteristics
SRC
safety review committee
SRSD
single reference safety document
TBili
total bilirubin
TPD
Time post-dose
t½
terminal plasma half-life
Tlast
time of last quantifiable plasma concentration
Tmax
time of maximum plasma concentration
ULN
upper limit of normal
US
United States
USPI
United States package insert
VAP
ventilator associated pneumonia
Vss
volume of distribution at steady state
Vz
volume of distribution at the terminal phase
WBC
white blood cell


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SAP_001.pdf: 
Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol C3591025
A PHASE 1, OPEN-LABEL, SINGLE-DOSE STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
CEFTAZIDIME-AVIBACTAM (CAZ-AVI) IN CHILDREN FROM 3 MONTHS TO 
LESS THAN 18 YEARS OF AGE WHO ARE HOSPITALIZED AND RECEIVING
SYSTEMIC ANTIBIOTIC THERAPY FOR SUSPECTED OR CONFIRMED 
NOSOCOMIAL PNEUMONIA, INCLUDING VENTILATOR-ASSOCIATED 
PNEUMONIA
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
02-Aug-2019


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................5
2.2.1. Sample Size Determination ..........................................................................6
2.2.2. Schedule of Activities...................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoints - PK ............................................................................................9
3.2. Secondary Endpoints - Safety ...................................................................................9
3.3. Other Endpoints – ELF by BAL ...............................................................................9
3.4. Baseline Variables...................................................................................................10
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Adverse Events...........................................................................................10
3.5.2. Laboratory Data..........................................................................................10
3.5.3. Vital Signs, Height and Weight..................................................................10
4. ANALYSIS SETS ...............................................................................................................10
4.1. Full Analysis Set .....................................................................................................11
4.2. Per Protocol Analysis Set........................................................................................11
4.3. Safety Analysis Set..................................................................................................11
4.4. Pharmacokinetics Analysis Set ...............................................................................11
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.2. General Methods .....................................................................................................11
5.3. Methods to Manage Missing Data ..........................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................11
6.1. Primary Endpoint(s) – PK.......................................................................................11
6.2. Secondary Endpoints - Safety .................................................................................14
6.3. Other Endpoint – ELF by BAL...............................................................................14


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
6.4. Subset Analyses.......................................................................................................14
6.5. Baseline and Other Summaries and Analyses.........................................................15
6.6. Safety Summaries and Analyses .............................................................................15
6.6.1. Adverse Events...........................................................................................15
6.6.2. Laboratory Data, Vital Signs, Physical Examination.................................15
6.6.3. Study Treatment Exposure .........................................................................15
6.6.4. Prior and Concomitant Medications...........................................................16
7. INTERIM ANALYSES.......................................................................................................16
7.1. Introduction .............................................................................................................16
7.2. Interim Analyses and Summaries............................................................................16
7.3. Data Monitoring Committee ...................................................................................16
7.4. Safety Review Committee.......................................................................................16
8. APPENDICES .....................................................................................................................17
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Overview of the Protocol Visits and Procedures........................................7
Table 3.
Schedule for PK Assessments.  Nominal Times for Each Cohort..............9
Table 4.
PK parameters – non-compartmental analysis .........................................13
Table 5.
Expected Age Ranges for Cohorts 4a and 4b ...........................................17
Table 6.
Expected age ranges for cohorts 1, 2 and 3 ..............................................18
LIST OF FIGURES
Figure 1.
Study Outline..............................................................................................6
APPENDICES
Appendix 1. Imputation of Incomplete Date of Birth and Derivation of Age - Cohort 4 .......17
Appendix 2. Imputation of Incomplete Date of Birth and Derivation of Age –
Cohorts 1, 2 and 3.....................................................................................18


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 4
1. VERSION HISTORY
Table 1.
Summary of Changes
SAP Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Version 1.0
27-Mar-2019
Original 
17-Sep-2018
Not 
Applicable
This is the first version of this SAP
Version 2.0
02-Aug-2019
Amendment 1
12-Jun-2019
Changes 
were made 
for 
consistency 
with wording 
used in 
protocol 
amendment
Section 2 (Study Design): Updated texts in italics in several places from this section for 
consistency with the changes in protocol amendment

Section 2.2: clarification of the following: definition of nosocomial pneumonia, 
definition of evaluable subject for enrollment purposes, and late follow up visit.

Section 2.2.2: Updated schedule of assessments.
Section 3 (Endpoints): Adjusted description of endpoints, which were also streamlined in 
protocol amendment

Section 3.1 Text for primary endpoints has been updated.

Section 3.1: Table 3 has been changed to reflect adjustments made in protocol to PK 
Blood Sample Assessments.

Section 3.3 Text for ELF by BAL endpoint has been updated.

Section 3.4 (Baseline variables): added text from protocol clarifying Screening 
(Day -1 to 1) and baseline assessments. Same change applies to Section 3.5.3.
Section 6 (Analyses and Summaries): text was streamlined 

Section 6.1 (Primary Endpoint – PK) and Section 6.3 (Other Endpoint – ELF by 
BAL): Provided further clarification regarding the summary of these endpoints.

Section 6.3 (Other Endpoint – ELF by BAL): added explanation on the derivation of 
CAZ and AVI ELF:plasma concentration ratios.

Section 6.5 (Baseline Summaries): provided definition of renal impairement.

Section 6.6.2. (Laboratory Data): clarified that laboratory results will be medically 
reviewed.

Sections 6.6.3 and 6.6.4 were added to describe summaries of study treatment 
exposure and prior/ concomitant medications, respectively.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 5
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3591025.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Note: in this document any text taken directly from the protocol is italicized.
2.1. Study Objectives
Primary Objective:

To characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ-AVI 
in pediatric subjects aged 3 months to less than 18 years who are receiving systemic 
antibiotic therapy for suspected or confirmed nosocomial pneumonia, including 
ventilator-associated pneumonia.
Secondary Objective:

To evaluate the safety and tolerability of a single intravenous dose of CAZ-AVI in 
pediatric subjects aged 3 months to less than 18 years with nosocomial pneumonia, 
including ventilator-associated pneumonia.
Tertiary/Exploratory Objective:

To determine CAZ-AVI concentrations in bronchial epithelial lining fluid (ELF) by 
bronchoalveolar lavage (BAL) from subjects undergoing bronchoscopy for their 
clinical management if bronchoscopy with BAL is performed within the PK sampling 
interval after CAZ-AVI infusion.
2.2. Study Design
This open label, single dose, PK study aims to characterize the PK of CAZ-AVI and assess its 
safety and tolerability following a single IV infusion.  Subjects will be hospitalized pediatric 
patients who are receiving systemic antibiotic therapy for suspected or confirmed 
nosocomial pneumonia (NP), defined as pneumonia with onset ≥48 hours after admission or 
within 7 days of discharge from an inpatient care facility, including ventilator-associated 
pneumonia (VAP), defined as a parenchymal lung infection arising ≥48 hours after 
endotracheal intubation and mechanical ventilation.  Subjects will be enrolled in 4 cohorts of 
descending age, each consisting of at least 8 evaluable subjects. An evaluable subject is one 
who has received the complete single IV dose of CAZ AVI and provided PK blood samples at 
≥50% of the sampling time points. The definition of an evaluable subject is used for 
enrollment purposes only, and does not impact the definition of the PK analysis set in 
Section 4.4.  Each subject will receive a single IV dose of CAZ-AVI administered as an 
intravenous infusion over a 120 minute period.  Blood samples will be collected from all 
subjects after the infusion to evaluate the PK of ceftazidime and avibactam.  Subjects will be 
followed for 48 hours after the end of the infusion.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 6
The study will consist of a Screening visit (Visit 1, Day -1 to 1), during which consent will be 
obtained and subject eligibility will be confirmed, a Baseline/Treatment visit (Visit 2, Day 1) 
during which subjects will receive a single IV infusion of CAZ-AVI, and then two follow-up 
assessment visits at 24 hours (Visit 3, Day 2) and 48 hours (Visit 4, Day 3).  A Late 
Follow-up (LFU) telephone visit will be conducted 28-35 days after the CAZ-AVI infusion to 
identify, assess, and record any new Serious Adverse Event (SAE).  Blood samples for PK 
analyses (0.5 mL per sample) will be obtained over 22 hours following the CAZ-AVI infusion 
for Cohort 1 (7 samples), over 13 hours for Cohort 2 (6 samples), and over 6 hours for 
Cohorts 3 and 4 (4 samples). A Late Follow up (LFU) visit, that may be performed by 
telephone, will be conducted 28-35 days after the CAZ AVI infusion in order to identify, 
assess, and record any new Serious Adverse Event (SAE).  The study outline is shown in 
Figure 1.
Figure 1.
Study Outline
Subjects will be divided into 4 age cohorts, all enrolling simultaneously:
Cohort
Age
Number
1
Age 12 years to <18 years
n=8
2
Age 6 years to <12 years
n=8
3
Age 2 years to <6 years
n=8
4
Age 3 months to <2 years (born ≥37 weeks gestational age)
n=8
       4a
     Age 1 year to <2 years
     n=4
       4b
     Age 3 months to <1 year
     n=4
2.2.1. Sample Size Determination
This study is not powered for inferential statistical analysis.  The sample size of 32 subjects is 
considered adequate to evaluate the pharmacokinetics of CAZ-AVI in this population.
Assess
PK
Day -1 to 1
ICD and 
screening the 
day of or day
before infusion
of CAZ-AVI
Day 1
Infusion of 
CAZ-AVI 
over 120 
minutes
Day 2
24 hour 
Follow
-up
Late 
Follow-up 
(telephone)
28-35 days 
after 
CAZ-AVI
Day 3
48 hour 
Follow
-up




Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8
a.
Screening (Day -1 to 1 ) assessments will serve as baseline and can be completed on the same calendar day as Day 1, prior to CAZ-AVI infusion, but must 
be completed no earlier than the day before the start of CAZ-AVI infusion. If Screening and Baseline assessments are performed on different days, weight 
should be collected at both Screening and Baseline, and weight at Baseline should be used to calculate dose.
b.
BMI will only be calculated at screening.  The BMI will not be calculated for children <2 years of age as BMI is not considered a screening tool for healthy
weight in children under 2 years of age.
c.
Vital signs (blood pressure, pulse rate, respiratory rate and temperature) will be taken at the following time points: before infusion and at 2, 4, 6, 12, 24, 
and 48 hours after the end of CAZ-AVI infusion.  Additional vital signs may be taken as needed.
d.
At screening, obtain results of CXR, CT scan, or other imaging tests (eg, MRI, ultrasound) if performed as diagnostically part of the subject’s regular 
medical care for the current diagnosis of pneumonia.
e.
If clinically indicated.
f.
Blood sample (0.5 mL) for blood urea analysis to be collected at the time of BAL only for subjects undergoing BAL as part of their clinical management.
g.
Creatinine values will be used to calculate CrCL using the Bedside Schwartz equation [eGFR (ml/min/1.73 m2) = 0.413 * (length(cm)/serum creatinine 
(mg/dL)], Schwartz, Munoz, et al., 2009.
h.
A serum or urine pregnancy test with sensitivity for human chorionic gonadotropin (hCG) of at least 25 mIU/mL to be performed on all female subjects of 
childbearing potential (postmenarcheal), as determined by the Investigator.
i.
PK samples will be drawn at time points indicated in Tables 3, 4 and 4 of the protocol for Cohort 1, Cohort 2, and Cohorts 3 and 4, respectively.
j.
BAL fluid collection to be performed at selected sites only for subjects undergoing bronchoscopy with BAL as part of their clinical management during the 
time window for collection of PK blood samples after CAZ-AVI infusion.  A matching blood sample to replace one of the PK blood samples is to be collected 
at the same time as the BAL, along with a blood sample for blood urea analysis.
k.
Review prior and concomitant treatments.  For Cohort 3 and 4 subjects who are being breast fed, record all medications taken by the lactating mother for 
3 days before the CAZ-AVI infusion through Day 3.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints - PK

CAZ and AVI plasma concentrations by nominal time.

CAZ and AVI PK parameters calculated by non-compartmental analysis (NCA) 
(Cohorts 1 and 2 only). 
Table 3.
Schedule for PK Assessments. Nominal Times for Each Cohort
Cohort 1
Cohort 2
Cohorts 3 and 4
End of CAZ-AVI 
infusion/flush + 0 to 5 
min (TPD 2h)
End of CAZ-AVI 
infusion/flush + 0 to 5 
min (TPD 2h)
End of CAZ-AVI 
infusion/flush + 0 to 5 
min (TPD 2h)
30 min after the end of 
infusion/flush ± 5 min
(TPD 2h 30)
15-45 min after the end 
of  infusion/flush
(TPD 2h 15)
15-45 min after the end 
of  infusion/flush
(TPD 2h 15)
1.5h after the end of 
infusion/flush ± 15 min
(TPD 3h 30)
1-2h after the end of 
infusion/flush (TPD 3h)
2-3h after the end of 
infusion/flush (TPD 4h)
3h after the end of 
infusion/flush ± 30min 
(TPD 5h)
2-3h after the end of 
infusion/flush (TPD 4h)
4-6h after the end of 
infusion/flush (TPD 4h)
6h after the end of 
infusion/flush ± 30 min 
(TPD 8h)
4-6h after the end of 
infusion/flush (TPD 6h)
10h after the end of 
infusion/flush ± 30 min 
(TPD 12h)
11-13h after the end of 
infusion/flush (TPD 13h)
22h after the end of 
infusion/slush ± 30 min 
(TPD 24h)
The nominal time post-dose (TPD) as collected in the CRF is indicated in parenthesis
3.2. Secondary Endpoints - Safety

Safety and tolerability endpoints include adverse events (AEs), serious adverse events 
(SAEs), deaths, discontinuations due to AEs and laboratory abnormalities.
3.3. Other Endpoints – ELF by BAL
CAZ and AVI ELF:plasma concentration ratios.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 10
3.4. Baseline Variables
Baseline will be defined as the latest measurement taken prior to start of IV study drug.
Screening (Day -1 to 1) assessments will serve as baseline and can be completed on the same 
calendar day as Day 1, prior to CAZ AVI infusion, but must be completed no earlier than the 
day before the start of CAZ AVI infusion.  
3.5. Safety Endpoints
Clinical Data Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPs) will 
be used for the analysis of standard safety data. 
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to treatment if:

the event occurs for the first time on or after the start of study treatment and was not 
seen prior to the start of treatment, or

the event was observed prior to the start of study treatment but increased in severity 
during treatment.
The start of study treatment is defined as the start time of the infusion of IV study drug. Any 
adverse event that meets the requirements described above will be considered treatment 
emergent. 
3.5.2. Laboratory Data
Laboratory data include hematology, blood chemistry, urinalysis and CrCL estimation, and 
will be collected at screening and at visit 4 (day 3, 48h assessment). Additional collection 
may be performed at Visit 2 (day 1) for those with BAL: Blood sample (0.5 mL) for blood 
urea analysis to be collected at the time of BAL only for subjects undergoing BAL as part of 
their clinical management.
3.5.3. Vital Signs, Height and Weight
Vital signs include blood pressure, pulse rate, respiratory rate and temperature and will be 
taken at the following time points: before infusion and at 2, 4, 6, 12, 24, and 48 hours after 
the end of CAZ-AVI infusion. Height will be collected at screening and weight will be 
collected at screening, baseline and at the 48h assessment. If Screening and Baseline 
assessments are performed on different days, weight should be collected at both Screening 
and Baseline, and weight at Baseline should be used to calculate dose and for summarization 
purposes.  
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 11
4.1. Full Analysis Set
Not applicable, as there is no assessment of efficacy in this single dose study.
4.2. Per Protocol Analysis Set 
Not applicable.
4.3. Safety Analysis Set
The safety analysis set will consist of all subjects who received any amount of IV study dose 
of CAZ AVI.  
4.4. Pharmacokinetics Analysis Set
The PK analysis set will consist of all subjects who received a complete IV study dose of CAZ 
AVI and have at least 1 ceftazidime and/or avibactam plasma measurement available. All 
PK summaries will be presented using the PK analysis set.
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis will be performed after dataset release.
5.1. Hypotheses and Decision Rules
The primary objective of this study is to evaluate the pharmacokinetics, safety, and 
tolerability of a single dose of CAZ-AVI in children with HAP/VAP.  The study is not
powered for inferential statistical analysis.  
5.2. General Methods 
Descriptive methods will be used to summarize all data. In general summaries will be 
presented overall and by cohort.
Descriptive methods for binary data will include counts and percentages. 
In general, descriptive statistics for continuous data will include mean, standard deviation, 
median, minimum and maximum observed values. Continuous NCA PK parameters will 
also be summarized using geometric mean, and coefficient of variation.  
5.3. Methods to Manage Missing Data
In general, missing values will not be imputed. Partial date handling will be done according 
to CaPs. Imputation of incomplete date of birth for the purposes of deriving age will follow 
the algorithm in Appendix 1.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s) – PK
Plasma concentrations of CAZ and AVI will be listed, and summarized by nominal time using 
appropriate descriptive statistics such as number, mean, SD, minimum, median, maximum, 
geometric mean, and coefficient of variation.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 12
Individual plasma concentration profiles, using the PK analysis set for Cohorts 1 to 4, will 
be presented graphically using actual sample collection time on both linear and 
semilogarithmic scales, showing all patients on a single plot for each cohort and analyte.  
Median concentration time profiles will be presented on both linear and semilogarithmic 
scales using nominal time for both ceftazidime and avibactam.
In addition, PK parameters of ceftazidime and avibactam will be calculated by NCA using 
actual PK sampling times following single dose administration of CAZ-AVI for 
Cohorts 1 and 2 as described in Table 4.
For Cohorts 1 and 2 the NCA PK parameters will be summarized using descriptive statistics. 
Further, the avibactam and ceftazidime concentration, pediatric patient demographics, and 
disease status data from Cohorts 1 to 4 will be combined with the data from appropriate 
previous clinical studies in pediatric patients and/or adults for a population PK analysis.  
The actual dosing and plasma sampling times will be used for the analysis.  Individual 
compartmental PK parameters for pediatric patients in Cohorts 1 and 2 with available 
avibactam and ceftazidime plasma concentration data will be calculated by the empirical 
Bayesian estimate, and individual non-compartmental PK parameters such as Cmax, minimum 
concentration (Cmin), area under the plasma concentration time curves at steady state 
(AUCss), and t½, will be derived from the determined avibactam and ceftazidime 
concentration time courses.
A stand alone population PK modelling and simulation analysis plan will be prepared and 
the results will be reported in a stand alone report outside of the clinical study report.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 13
Table 4.
PK parameters – non-compartmental analysis
Parameter
Definition
Method of Determination
AUC0-8
Area under the plasma 
concentration-time profile 
from time 0 to 8 hours
Linear/Log trapezoidal rule
AUCinf
a
Area under the plasma 
concentration-time profile 
from time 0 to infinity
Linear/Log trapezoidal rule
AUCinf = AUClast + (Clast*/ kel), where Clast* is the 
estimated concentration at the time of the last 
quantifiable concentration and kel is the terminal 
phase rate constant calculated by a linear 
regression of the log-linear concentration-time 
curve.  Only those data points judged to describe the 
terminal log-linear decline will be used in the 
regression
AUClast
Area under the plasma 
concentration-time profile 
from time 0 to the last 
quantifiable concentration
Linear/Log trapezoidal rule
Cmax
Maximum plasma 
concentration
Observed directly from data
Tlast
Time of last quantifiable 
plasma concentration
Observed directly from data 
Tmax
Time for Cmax
Observed directly from data 
t½ 
a
Terminal elimination 
half-life
Loge(2)/kel
CL a
Clearance
Dose/AUCinf
Vss
a
Volume of distribution at 
steady-state
Volume of distribution at steady state is calculated 
as: Vss = CL × MRT
Mean residence time (MRT) is calculated as: MRT 
= AUMCinf/AUCinf - (infusion time/2)
Area under the first moment curve from 0 time to 
infinity (AUMCinf) is calculated as:
AUMCinf = AUMClast + ((t × Cest
1
*)/kel) + 
(Cest
1
*/kel2)
1Cest = e(-KEL × Tlast) × KELC0 , where C0 is the
back-extrapolated concentration at time zero
Vz
a
Volume of distribution 
during terminal phase
Dose/(AUCinf × kel)
a.
If data permit.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 14
6.2. Secondary Endpoints - Safety
The evaluation of safety and tolerability of a single IV dose of CAZ-AVI in this pediatric 
population is a secondary objective of this study. Safety endpoints are AEs, SAEs, deaths 
and discontinuations due to AEs, and laboratories abnormalities, therefore they will be 
summarized as per the CaPs standards. Further details are presented in Section 6.6.
6.3. Other Endpoint – ELF by BAL
CAZ and AVI ELF:plasma concentration ratios are defined as the ELF concentrations
divided by the respective plasma concentration. This formula is only applicable for subjects 
who have BAL after bronchoscopy.
CAZ and AVI ELF:plasma concentration ratios are part of an exploratory objective for this 
study. Ceftazidime and avibactam ELF:plasma concentration ratios (for available matching 
ELF and plasma samples) will be listed. A listing of CAZ and AVI concentrations in BAL 
and urea concentrations in BAL and plasma will also be provided.  
Parameter
Definition
Method of Determination
CBAL
Drug Concentration in BAL*
Observed directly from data
Curea,BAL
Urea concentration in BAL
Observed directly from data
Curea,p
Urea concentration in blood plasma
Observed directly from data
CELF
concentration in ELF
CBAL× (Curea,p/Curea,BAL)
* note that drug concentration is for both CAZ and AVI.
Example:

CBAL: CAZ concentration in BAL is 10 ng/mL

Curea,BAL: Urea concentration in BAL is 3 ng/mL

Curea,p: Urea concentration in plasma is 15 ng/mL

CELF: CAZ concentration in ELF would be 50 ng/mL [calculated 10 x (15/3)]
CAZ and AVI ELF:plasma concentration ratios are part of an exploratory objective for this 
study. These ratios will be listed along with the CAZ and AVI concentrations in BAL and 
urea concentration in BAL and in blood plasma (for available matching ELF and plasma 
samples).  
6.4. Subset Analyses 
No subset analyses will be done for this study.


Protocol C3591025 (PF 06947386)
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PFIZER CONFIDENTIAL
Page 15
6.5. Baseline and Other Summaries and Analyses
CaPs standards will be used for the analysis of standard safety data:

demographics;

baseline characteristics (physical measurements, primary diagnosis, renal 
impairement: CrCL >= 50 and CrCL >=30 to <50 mL/min/1.73 m2);

medical and surgical history;

physical examination;

prior and concomitant treatments.
6.6. Safety Summaries and Analyses
No inferential statistical tests will be performed for any safety analyses.  
6.6.1. Adverse Events
The incidence of AEs, SAEs, deaths, and discontinuations due to AEs will be summarized by 
system organ class and preferred term according to the Medical Dictionary for Regulatory 
Activities (MedDRA), by relationship to study therapy, and by severity.  
All recorded AEs will be listed and tabulated by system organ class, preferred term and for 
each cohort.  Adverse events occurring from the start of study dose of CAZ-AVI infusion up 
to 48 hours after the end of infusion, and up to the end of the study (LFU) will be summarized 
by preferred term and system organ class using the MedDRA vocabulary (Version 14.0 or 
higher) by cohort.  
6.6.2. Laboratory Data, Vital Signs, Physical Examination
For each safety parameter, the last assessment made before the first dose of study therapy 
will be used as the baseline for all analyses.  
Descriptive statistics of observed results and the change from baseline to selected post 
baseline time points will be presented for clinical laboratory results and vital signs.  
Tabulations and listings of data for vital signs, physical examinations, and clinical 
laboratory tests will be presented with abnormal or out-of-range values flagged.  
Potentially clinically significant laboratory results will be summarized. Laboratory data will 
be medically assessed for potential clinically significance, and summarized in the clinical 
study report through listings.
6.6.3. Study Treatment Exposure
Treatment exposure to CAZ-AVI will be summarized displaying counts and percentages of 
subjects who were exposed to each category of CAZ-AVI dose administered.


Protocol C3591025 (PF 06947386)
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PFIZER CONFIDENTIAL
Page 16
6.6.4. Prior and Concomitant Medications
Prior and concomitant medications received by the subject (and for the mothers of breast-fed 
subjects in cohorts 3 and 4) will be summarized using standard summaries.
7. INTERIM ANALYSES
7.1. Introduction
This is an open-label, single arm study.  All the interim analyses described in this section are 
for descriptive purposes.
7.2. Interim Analyses and Summaries
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label study, the Sponsor may conduct unblinded reviews of the data during the course 
of the study for the purpose of safety assessment, facilitating pharmacokinetic 
(PK)/pharmacodynamic (PD) modeling, and/or to support clinical development.
7.3. Data Monitoring Committee 
This study will not have an external data monitoring committee (E-DMC).  
7.4. Safety Review Committee
This study will use an Internal Safety Review Committee which will be known as the Safety 
Review Committee (SRC).  The SRC will consist of the study team physician, international 
coordinating Investigator or delegate, global safety/risk lead or delegate, therapeutic area 
director or delegate and the clinical pharmacologist/pharmacometrician or delegate.  The 
SRC will assess safety and tolerability after the first 4 subjects in each cohort are enrolled.  
With the exception of the international coordinating Investigator or delegate, all members of 
the SRC will be members of the Sponsor organization.  Other team members may be asked to 
join as needed.


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
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8. APPENDICES 
Appendix 1. Imputation of Incomplete Date of Birth and Derivation of Age - Cohort 4
For subjects in Cohort 4 date of birth will be collected as month and year (ie, day will be 
unknown). Imputation of incomplete date of birth (DOB) will be done using the following 
data available from the case report form: month and year of birth from the in complete DOB, 
date of informed consent, expected age in months for cohorts 4a and 4b.

Step 1. Find a range of plausible DOBs based on the known month and year of birth 
from the incomplete DOB;

Step 2. Find a range of plausible DOBs based on the date of informed consent and the 
expected age in months for each cohort according to Table 5;

Step 3. Determine the range of possible DOBs based on the intersection of the two 
ranges in Steps 1 and 2a;

Step 4. Use the midpoint of the range of possible DOBs in Step 3 as the imputed 
DOB; derive age in months by subtracting the imputed DOB from the date of 
informed consent, and dividing by 30.42.
Note: 
a. if the ranges of plausible DOBs found in Steps 1 and 2 are not overlapping and the data for incomplete DOB 
and date of informed consent are confirmed by the site to be correct, this represents a protocol deviation on the 
age of patients. In this case, the range of possible DOBs in Step 3 will be determined based on the range from 
Step 1 and the date of informed consent, without taking the expected age of the cohorts into consideration.
For example, a patient from Cohort 4a:

incomplete DOB of Aug2017, date of informed consent 01Dec2018;

Step 1 range: 01Aug2017 to 31Aug2017;

Step 2 range: 02Dec2016 (i.e., almost 2 years old) to 01Dec2017 (ie, 1 year old);

Step 3 range: 01 to 31Aug2017;

Step 4: imputed DOB is 16Aug2017, derived age is 472 days, or 15.5 months.
Table 5.
Expected Age Ranges for Cohorts 4a and 4b
Cohort
Age Range
Expected age in 
Months
4a
Age 1 year to <2 years
12 to <24
4b
Age 3 months to <1 year
3 to <12


Protocol C3591025 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 18
Appendix 2. Imputation of Incomplete Date of Birth and Derivation of Age –
Cohorts 1, 2 and 3
For subjects in Cohorts 1, 2 and 3 date of birth will be collected only as year (i.e., both day 
and month will be unkown). Imputation of incomplete date of birth (DOB) will be done 
using the following data available from the case report form: year of birth from the 
incomplete DOB, date of informed consent, expected age in years cohorts 1, 2 and 3.

Step 1. Find a range of plausible DOBs based on the year of birth from the 
incomplete DOB;

Step 2. Find a range of plausible DOBs based in the date of informed consent and the 
expected age in years for each cohort according to Table 6;

Step 3. Determine the range of possible DOBs based on the intersection of the two 
ranges in Steps 1 and 2a;

Step 4. Use the midpoint of the range of possible DOBs in Step 3 as the imputed
DOB; derive age in years by subtracting the imputed DOB from the date of informed 
consent, and dividing by 365.25.
Note: 
a. if the ranges of plausible DOBs found in Steps 1 and 2 are not overlapping and the data for incomplete DOB 
and date of informed conset are confirmed by the site to be correct, this represents a protocol deviation on the 
age of patients. In this case, the range of possible DOBs in Step 3 will be determined based on the range from 
Step 1 and the date of informed consent, without taking the expected age of the cohorts into consideration.
For example, a patient from Cohort 1:

incomplete DOB UNK/UNK/2006, and informed consent date 01Jul2018;

Step 1 range: 01Jan2006 to 31Dec2006;

Step 2 range: 02Jul2000 (ie, is almost 18 years old) to 01Jul2006 (ie, 12 years old);

Step 3 range: 01Jan2006 to 01Jul2006;

Step 4: imputed DOB is 01Apr2006, derived age is 4474 days, ie, 12.2 years.
Table 6.
Expected age ranges 
for cohorts 1, 2 and 3
Cohort
Age Range in years
1
Age 12 years to <18 years
2
Age 6 years to <12 years
3
Age 2 years to <6 years