Clinical trial NCT04774094
Conditions: Hospital-Acquired Pneumonia
Sponsor: Pfizer
Start date: 2021-05-21; Completion date: 2023-05-04
Enrollment: 235 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, single arm, open-label, multi-center clinical study evaluating the effectiveness and safety of CAZ-AVI in participants with HAP (including VAP), who have initiated treatment with CAZ-AVI in an inpatient hospital setting. The duration of antibiotic treatment with the CAZ-AVI is 7-14 days. Participants must receive intravenously (IV) CAZ-AVI in the hospital for at least 7 full days. There are no formal hypothesis tests planned for this study. The number and percent of participants having clinical cure, failure, and indeterminate at TOC visit in the cMITT analysis population will be summarized.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Zavicefta, Ceftazidime-Avibactam
Intervention descriptions: intervention 1: Participants will receive CAZ-AVI (2000 mg of ceftazidime and 500 mg of avibactam) administered by IV infusion in a volume of 100 mL at a constant rate over 2 hours.

Protocol documents:
Prot_000.pdf: 
Ceftazidime - Avibactam
Protocol C3591026
Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 1
A SINGLE ARM, OPEN-LABEL, MULTI-CENTER, INTERVENTIONAL STUDY
EVALUATING THE EFFICACY AND SAFETY OF CEFTAZIDIME-AVIBACTAM 
(CAZ-AVI) IN CHINESE ADULTS WITH HAP (INCLUDING VAP) 
Study Intervention Name:
Ceftazidime - Avibactam
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
C3591026
Phase:
4
Short Title: Efficacy and Safety of Ceftazidime-Avibactam (CAZ-AVI) in Chinese 
Participants With HAP (Including VAP)
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.
CCI


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PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 1
07 February 2022
•
Added “CT scan” in Disease 
characteristics of Section 1.3 SoA, 
footnote “g” and Section 5.1 Inclusion 
Criteria 4 as an acceptable standard of 
care in assessing presence of 
pulmonary infiltration to incorporate 
the PACL (version date 18 Dec 2020).
•
Rephrased the test frequency of 
estimated creatinine clearance on 
Visits 3-15 in Section 1.3 SoA and 
footnote “p”, “s” to keep consistent 
with that of serum creatinine so as to 
keep in line with amikacin 
prescription information.
•
Added wording of “If Day 1 and 
Screening Visit occur on the same 
calendar day, lab results from 
Screening Visit can be used on Day 1 
visit” on Section 1.3 SoA footnote “o”
to clarify the requirement when Day 1 
and Screening Visit occur on the same 
calendar day.
•
Wording change of “a second negative 
pregnancy test result will be required 
at the baseline visit prior the
participant’s receiving the CAZ-AVI” 
to “a second pregnancy test will be 
required at the baseline visit prior the 
participant’s receiving the CAZ-AVI.” 
in Section 1.3 SoA footnote “q” and 
Section 8.2.4 Pregnancy Testing to 
keep consistency throughout the 
protocol.
•
Wording change of Inclusion Criteria 
3 from “Onset of symptoms ≥48 hours 
after admission or <7 days after 
discharge from an inpatient acute or 
chronic care facility” to “Onset of 
signs and symptoms (including 
Inclusion Criteria 4, 6, and 7) ≥48 


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PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Summary and Rationale for Changes
hours after admission or <7 days after 
discharge from an inpatient acute or 
chronic care facility” in Section 5.1 
Inclusion Criteria to clarify the 
required time window of signs and 
symptoms onset. 
•
Added wording “prior enrollment” to 
clarify time frame of previous 
antibiotic exposure before enrollment 
in Exclusion Criteria 9 of Section 5.2 
Exclusion Criteria.
•
Wording change of “Acute Physiology 
and Chronic Health Evaluation 
(APACHE) II score >30 or <10 using 
the most recent available data” to 
“Acute Physiology and Chronic 
Health Evaluation (APACHE) II 
score >30 or <10 using the available 
data within 24 hours prior baseline” to 
clarify the requirement of time 
window of data used to calculate 
APACHE II score.
•
Wording change of “carbapenems and 
CAZ-AVI” to “carbapenems and/or 
CAZ-AVI” to clarify targeted 
population in the study to keep 
consistent of study population with 
Ph3 study.
•
Wording change of dose formulation 
in Section 6.1 Study Intervention(s) 
Administered from “lyophilized 
powder for solution for injections” to 
“powder for solution for injections” to
be in line with CAZ-AVI label and to 
incorporate content of PACL (version 
date 21 Jul 2021).
•
Added a footnote for Table 1 “Time 
windows of dose frequency are Q8H ± 
30mins, Q12H ± 30mins, Q24H ± 
30mins and time window of infusion 
time is 2 hours ± 10mins” in 
Section 6.1.


Ceftazidime - Avibactam
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Final Protocol Amendment 1, 07 February 2022
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Document History
Document
Version Date
Summary and Rationale for Changes
•
Changed requirement of blood glucose 
test from “fasting” to “non-fasting” in 
Section 10.2 Appendix 2: Clinical 
Laboratory Tests. Because participant 
may be screened at any time of the 
day of Screening Visit and it is needed 
that participant receive IMP as soon as 
possible after eligibility is confirmed. 
Local lab results at baseline can be lab 
results from Screening Visit if 
Screening Visit and baseline occur on 
the same calendar day. 
•
Added footnote “HCO3 or CO2-CP 
results in blood chemistry will be 
assessed only for those participants at 
sites which can perform the HCO3 or 
CO2-CP tests.” of HCO3 / CO2-CP in 
Section 10.2 Appendix 2: Clinical 
Laboratory Tests to incorporate 
content of PACL (version date 21 Jul 
2021). 
•
Added APACHE II Score Worksheet 
used for calculation when different 
units of test results generated by local 
lab and related formulas.  
Original protocol
2 September 2020
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
clarification letter.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
LIST OF FIGURES .................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................20
2.1. Study Rationale .......................................................................................................20
2.2. Background .............................................................................................................21
2.2.1. Clinical Overview.......................................................................................21
2.3. Benefit/Risk Assessment.........................................................................................22
2.3.1. Risk Assessment.........................................................................................22
2.3.2. Benefit Assessment.....................................................................................22
2.3.3. Overall Benefit/Risk Conclusion................................................................23
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................23
4. STUDY DESIGN.................................................................................................................25
4.1. Overall Design.........................................................................................................25
4.2. Scientific Rationale for Study Design.....................................................................25
4.3. Justification for Dose ..............................................................................................26
4.4. End of Study Definition ..........................................................................................26
5. STUDY POPULATION......................................................................................................26
5.1. Inclusion Criteria.....................................................................................................27
5.2. Exclusion Criteria....................................................................................................28
5.3. Lifestyle Considerations..........................................................................................30
5.3.1. Contraception..............................................................................................30
5.3.2. Controlled sodium diet ...............................................................................30
5.4. Screen Failures ........................................................................................................30
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ......................................................................................30
6. STUDY INTERVENTION..................................................................................................30
6.1. Study Intervention(s) Administered........................................................................31


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6.1.1. Administration............................................................................................31
6.1.1.1. Empiric Gram-positive agent ....................................................32
6.1.1.2. Empiric Gram-negative agent ...................................................33
6.2. Preparation/Handling/Storage/Accountability ........................................................35
6.2.1. Preparation and Dispensing ........................................................................37
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................37
6.3.1. Allocation to Study Intervention ................................................................37
6.4. Study Intervention Compliance...............................................................................37
6.5. Concomitant Therapy..............................................................................................37
6.5.1. Rescue Medicine.........................................................................................38
6.6. Dose Modification...................................................................................................38
6.7. Intervention After the End of the Study..................................................................38
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................38
7.1. Discontinuation of Study Intervention ....................................................................38
7.2. Participant Discontinuation/Withdrawal From the Study.......................................39
7.2.1. Withdrawal of Consent...............................................................................40
7.3. Lost to Follow-up....................................................................................................40
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................41
8.1. Efficacy Assessments..............................................................................................42
8.1.1. Clinical response.........................................................................................42
8.1.2. Microbiology assessments..........................................................................44
8.1.2.1. Specimen collection ..................................................................44
8.1.2.2. Defining the baseline respiratory specimen ..............................46
8.1.2.3. Microbiological response definitions........................................46
8.2. Safety Assessments .................................................................................................48
8.2.1. Physical Examinations................................................................................48
8.2.2. Vital Signs ..................................................................................................48
8.2.3. Clinical Safety Laboratory Assessments ....................................................49
8.2.4. Pregnancy Testing ......................................................................................49
8.3. Adverse Events and Serious Adverse Events..........................................................49
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......50


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8.3.1.1. Reporting SAEs to Pfizer Safety...............................................50
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................51
8.3.2. Method of Detecting AEs and SAEs ..........................................................51
8.3.3. Follow-up of AEs and SAEs.......................................................................51
8.3.4. Regulatory Reporting Requirements for SAEs...........................................51
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................52
8.3.5.1. Exposure During Pregnancy......................................................52
8.3.5.2. Exposure During Breastfeeding ................................................53
8.3.5.3. Occupational Exposure .............................................................54
8.3.6. Cardiovascular and Death Events...............................................................54
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................54
8.3.8. Adverse Events of Special Interest.............................................................55
8.3.8.1. Lack of Efficacy........................................................................55
8.3.9. Medical Device Deficiencies......................................................................55
8.3.10. Medication Errors.....................................................................................55
8.4. Treatment of Overdose............................................................................................56
8.5. Pharmacokinetics ....................................................................................................56
8.6. Pharmacodynamics..................................................................................................56
8.7. Genetics...................................................................................................................56
8.7.1. Specified Genetics ......................................................................................56
8.8. Biomarkers ..............................................................................................................56
8.9. Immunogenicity Assessments.................................................................................56
8.10. Health Economics .................................................................................................56
9. STATISTICAL CONSIDERATIONS ................................................................................57
9.1. Estimands and Statistical Hypotheses.....................................................................57
9.1.1. Estimands....................................................................................................57
9.1.2. Hypothesis ..................................................................................................58
9.2. Sample Size Determination.....................................................................................58
9.3. Analysis Sets ...........................................................................................................59
9.4. Statistical Analyses .................................................................................................60
9.4.1. General Considerations...............................................................................60


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9.4.2. Primary Endpoint(s)....................................................................................60
9.4.3. Secondary Endpoint(s)................................................................................60
9.4.4. Safety Analyses ..........................................................................................60
9.4.5. Other Analyse(s).........................................................................................61
9.5. Interim Analyses .....................................................................................................61
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............61
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................62
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............62
10.1.1. Regulatory and Ethical Considerations ....................................................62
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................62
10.1.2. Financial Disclosure .................................................................................63
10.1.3. Informed Consent Process ........................................................................63
10.1.4. Data Protection .........................................................................................64
10.1.5. Dissemination of Clinical Study Data ......................................................64
10.1.6. Data Quality Assurance ............................................................................65
10.1.7. Source Documents....................................................................................66
10.1.8. Study and Site Start and Closure ..............................................................67
10.1.9. Publication Policy.....................................................................................68
10.1.10. Sponsor’s Qualified Medical Personnel .................................................68
10.2. Appendix 2: Clinical Laboratory Tests .................................................................70
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................71
10.3.1. Definition of AE .......................................................................................71
10.3.2. Definition of SAE.....................................................................................72
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................73
10.3.4. Reporting of SAEs....................................................................................76
10.4. Appendix 4: Contraceptive Guidance ...................................................................77
10.4.1. Male Participant Reproductive Inclusion Criteria....................................77
10.4.2. Female Participant Reproductive Inclusion Criteria.................................77
10.4.3. Woman of Childbearing Potential ............................................................78
10.4.4. Contraception Methods.............................................................................78


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........81
10.6. Appendix 6: APACHE II Classification System...................................................83
10.7. Appendix 7: Calculation of Estimated Creatinine Clearance................................87
10.8. Appendix 8: Abbreviations ...................................................................................88
11. REFERENCES ..................................................................................................................91


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LIST OF TABLES
Table 1.
Recommended IV Doses for Participants With Estimated CrCL ≤
50 mL/min1...............................................................................................31
Table 2.
Definitions of Clinical Response at the EOT Visit...................................43
Table 3.
Definitions of Clinical Response at the TOC Visit ..................................43
Table 4.
Microbiological Response Categories ......................................................47
Table 5.
Emergent Infections..................................................................................48
Table 6.
Protocol Required Safety Laboratory Assessments..................................70
LIST OF FIGURES
Figure 1.
Study Outline............................................................................................15
Figure 2.
Algorithm for Stopping or Continuing Open-label Empiric Gram-
positive Agent Based on Baseline Culture Results at 48 Hoursa,b ..........33
Figure 3.
Algorithm for Stopping or Continuing Open-lable Empiric Gram-
negative Coverage With Amikacin Based on Baseline Culture 
Results and Susceptibility Results at 48 Hoursa,b....................................35


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Efficacy and Safety of Ceftazidime-Avibactam (CAZ-AVI) in Chinese 
Participants With HAP (Including VAP)
Rationale
Hospital-acquired pneumonia (HAP) is defined as pneumonia that occurs 48 hours or more 
after admission, without being in the incubation period of infection at the time of admission. 
Ventilator-associated pneumonia (VAP) is a sub-type of HAP and is defined as pneumonia 
that occurs 48 hours or more after mechanical ventilation in patients undergoing endotracheal 
intubation or tracheotomy1. In the United States (US), the incidence of hospital-acquired 
infections in hospitalized patients was 4%, of which pneumonia accounted for approximately 
21.8%2. According to the results of a cross-sectional survey of large-scale nosocomial 
infection in China, the incidence of hospital-acquired infections in hospitalized patients was 
approximately 3%-5%, among which the incidence of hospital-acquired lower respiratory 
tract infection was approximately 2%3,4.
The most common resistant Gram-negative pathogens causing HAP/VAP in China include 
extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant 
Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB) and 
carbapenem-resistant Pseudomonas aeruginosa (CRPA)1. Currently the options for the 
treatment of Gram-negative infections, especially multidrug resistant strains including 
extended-spectrum β-lactamases (ESBL) producers, are extremely limited. Hence, 
availability and development of new agents to treat these infections will be welcome addition 
to the existing treatment. 
In China, CAZ-AVI was approved by the National Medical Products Administration 
(NMPA) on 21 May 2019. Indications for adults approved include complicated 
intra-abdominal infection (cIAI), HAP (including VAP), and for the treatment of infections 
due to aerobic Gram-negative organisms in adult patients with limited treatment options.
This study is designed to 
 to 
further evaluate effectiveness of CAZ-AVI in Chinese patients with HAP, including VAP. 
.
CCI
CCI


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Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To estimate clinical 
response to CAZ-AVI in 
HAP patients. 
Using a composite estimand strategy to estimate the 
clinical response rate at the test of cure (TOC) visit in 
participants who meet minimum disease requirements 
(excluding participants not expected to respond to 
CAZ-AVI). Clinical response will be categorized as cure, 
failure, and indeterminate per investigator’s assessment. 
Intercurrent events of death on study Day 1 or Day 2, 
death on or before TOC visit where HAP is clearly non-
contributory, identification of an infectious complication 
of pneumonia between Day 1 and Day 2 inclusive 
triggering treatment with further antibiotics will be 
regarded as indeterminate clinical response. Intercurrent 
events of death between Day 3 and TOC visit inclusive, 
development of infectious complications of pneumonia 
after Day 2 until TOC visit triggering treatment with 
further antibiotics will be regarded as failure clinical 
response.

The proportion of 
participants with clinical 
cure at the TOC visit in 
the clinically modified 
intent-to-treat (cMITT) 
population. 
Secondary: 
Secondary:
Secondary: 

To estimate clinical 
response to CAZ-AVI in 
HAP patients, and HAP 
patients with 
demonstrated 
Gram-negative 
pathogens.
Using a composite estimand strategy to estimate the 
clinical response rate at the end of treatment (EOT) visit 
in participants who meet minimum disease requirements, 
and at the EOT and TOC visits in participants who meet 
minimum disease requirements and have demonstrated 
Gram-negative pathogens (excluding participants not 
expected to respond to CAZ-AVI for both target 
populations). Clinical response will be categorized as 
cure, failure, and indeterminate per investigator’s 
assessment. Intercurrent events of death on study Day 1 
or Day 2, death on or before EOT visit (or TOC visit 
accordingly) where HAP is clearly non-contributory, 
identification of an infectious complication of pneumonia 
between Day 1 and Day 2 inclusive triggering further 
antibiotics treatment will be regarded as indeterminate 
clinical response. Intercurrent events of death between 
Day 3 and EOT visit (or TOC visit accordingly) 
inclusive, development of infectious complications of 
pneumonia after Day 2 triggering further antibiotics 
treatment will be regarded as failure clinical response.

The proportion of 
participants with clinical 
cure at the EOT visit in 
cMITT population, and at 
the EOT, TOC visits in 
the microbiologically 
modified intent-to-treat 
(mMITT) population. 

To estimate the 
microbiologic response to 
CAZ-AVI.
Using a composite estimand strategy to estimate the 
per-patient and per-pathogen microbiological response 
rate at the EOT and TOC visits in participants who meet 
minimum disease requirements and have demonstrated 
Gram-negative pathogens. Microbiological response will 
be categorized as favorable (ie, eradication, or presumed 
eradication), unfavorable (persistence, persistence with 
increasing minimum inhibitory concentration [MIC], or 
presumed persistence), and indeterminate. Per-pathogen 
microbiological response will be summarized with the 
proportion of participants achieving favorable response 
by baseline pathogen type; per-patient microbiological 
response will be summarized with the proportion of 
participants achieving overall favorable response (ie, 

The proportion of 
participants with the 
favorable per-patient 
microbiologic response at 
the EOT and TOC visits 
in the mMITT 
population.

The proportion of 
favorable per-pathogen 
microbiologic responses 
at the EOT and TOC 
visits in the mMITT 
population.


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Objectives
Estimands
Endpoints
favorable for each of the baseline pathogen isolate). 
Intercurrent events of death or identification of an 
infectious complication of pneumonia triggering further 
antibiotics treatment such that an adequate source 
specimen is not available to culture will be regarded as 
an indeterminate microbiological response if clinical 
response is indeterminate, and will be regarded as a 
presumed eradication if a clinical cure is assessed.

To estimate the efficacy 
of CAZ-AVI in patients 
with pathogens resistant 
to ceftazidime. 
Using the same composite estimand strategies as the 
primary estimand and aforementioned secondary 
estimands to estimate the proportions of participants 
with clinical cure and with a favorable per-patient 
microbiological response at the EOT and TOC visits in 
participants who meet minimum disease requirements 
and have demonstrated Gram-negative pathogens that 
are resistant to ceftazidime.

The proportion of 
participants with clinical 
cure, and proportion of 
participants with 
favorable per-patient 
microbiologic response at 
the EOT and TOC visits 
in patients with 
pathogens resistant to 
ceftazidime in the 
mMITT population.

To estimate all-cause 
mortality for CAZ-AVI.
Using a treatment-policy estimand strategy in 
participants who meet minimum disease requirements, 
and in participants who meet minimum disease 
requirements and have demonstrated Gram-negative 
pathogens to estimate the proportion of participants with 
death at the TOC visit and Day 28 of the study. Any 
death that occurred after the first dose of study 
intervention through the nominal analysis timepoint will 
be included. A participant with the last known survival 
status that is before the nominal analysis timepoint or 
missing at the nominal analysis timepoint will be 
reported as an unknown status.

The proportion of 
participants with death 
due to any cause 
(all-cause mortality) at 
the TOC visit and at 
Day 28 in the cMITT and 
mMITT populations.

To evaluate the safety 
and tolerability of 
CAZ-AVI. 
N/A.

Assessment of treatment-
emergent adverse events 
(TEAEs) and safety-
related clinical laboratory 
tests and vital 
observations.
Overall Design
This is a prospective, single arm, open-label, multi-center clinical study evaluating the 
effectiveness and safety of CAZ-AVI in participants with HAP (including VAP), who have 
initiated treatment with CAZ-AVI in an inpatient hospital setting. The duration of antibiotic 
treatment with the study intervention is 7-14 days. Participants must receive intravenously 
(IV) study intervention in the hospital for at least 7 full days. 
Number of Participants
Approximately 235 participants will be enrolled to study intervention such that 
approximately 200 participants will be evaluable for clinical cure rate in the cMITT 
population. 


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Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Intervention Groups and Duration
Each participant is expected to complete the study, including follow-up, within 
approximately 6 weeks. The duration of antibiotic treatment with study intervention is 7-14 
days. Participants must receive IV study intervention for at least 7 days. At any time after 7 
days, the investigator will have the option to continue IV study intervention or discontinue 
study intervention completely. Total therapy should not exceed 14 days. 
Participants will receive CAZ-AVI 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered IV 
as 2 hours infusion every 8 hours (q8h). Dose adjustments for participants with creatinine 
clearance (CrCL) ≤50 mL/min will be applied based on the approved label (Section 6.1.1).
In addition, participants for whom baseline cultures are still pending at registration will 
receive empiric linezolid or vancomycin to cover for Gram-positive pathogens for 48 to 
72 hours after Day 1; continuation or discontinuation of Gram-positive coverage after this 
period will be dependent on the final culture results (Section 6.1.1.1).
Certain participants will receive empiric Gram-negative antibiotic coverage with amikacin 
for 48 to 72 hours after enrollment to cover for multi-drug resistant Gram-negative organisms 
while awaiting susceptibility results (Section 6.1.1.2). 
For participants who discontinue study intevention early, all subsequent scheduled 
assessments should be collected. The EOT visit should occur within 24 hours of study 
intervention discontinuation.
A participant may withdraw from the study at any time at his/her own request. The early 
discontinuation visit applies only to participants who are enrolled and then are prematurely 
withdrawn from the study. The participant will be permanently discontinued both from the 
study intervention and from the study at that time. 
Data Monitoring Committee or Other Independent Oversight Committee: 
None.
Statistical Methods
In general, categorical variables (such as clinical response, microbiological response, 
mortality, etc) will be summarized by number of participants (n), and proportion of 
participants in each category. In particular, clinical response rate and microbiological 
response (patient-level) rates will be presented with corresponding 2-sided 95% confidence 
intervals (CI). 












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2. INTRODUCTION
Ceftazidime-avibactam (CAZ-AVI) is a β-lactam/β-lactamase inhibitor developed as an IV 
administered compound for parenteral treatment of participants with infections caused by 
Gram-negative pathogens, including pathogens that are resistant to ceftazidime.
Hospital-Acquired Pneumonia
HAP is defined as pneumonia that occurs 48 hours or more after admission, without being in 
the incubation period of infection at the time of admission. VAP is a sub-type of HAP and is 
defined as pneumonia that occurs 48 hours or more after mechanical ventilation in patients 
undergoing endotracheal intubation or tracheotomy1. In the US, the incidence of 
hospital-acquired infections in hospitalized patients was 4%, of which pneumonia accounted 
for approximately 21.8%2. According to the results of a cross-sectional survey of large-scale 
nosocomial infection in China, the incidence of hospital-acquired infections in hospitalized 
patients was approximately 3%-5%, among which, the incidence of hospital-acquired lower 
respiratory tract infection was approximately 2%3, 4.
Antibiotic resistance of HAP in China
The most common resistant Gram-negative pathogens causing HAP/VAP in China include 
extended spectrum β-lactamase-producing Enterobacteriaceae, CRE, CRAB and CRPA1. 
Data from China multicenter bacterial resistance networks (ie, China surveillance network 
for bacterial resistance [CHINET], 2004-20155, and Chinese antimicrobial resistance 
surveillance of nosocomial infection [CARES], 20166) showed that the isolation rate of 
ESBL-producing Klebsiella pneumoniae and Escherichia coli was 25% ~ 35% and 45% ~ 
60% respectively, and the rate of CRE was 5% ~ 18% among various specimens (eg, blood, 
urine, sputum).
Ceftazidime-Avibactam
CAZ-AVI comprises ceftazidime, an established injectable third generation cephalosporin 
antimicrobial agent, and avibactam, a novel non-β-lactam β lactamase inhibitor with a 
spectrum including Ambler Class A ESBLs, Class A serine carbapenemases (eg, KPC), 
Class C (AmpC) enzymes, and some Class D (OXA) β-lactamase enzymes. It is not active 
against class B metallo-β-lactamases, and it is not active against Acinetobacter baumannii. 
CAZ-AVI has been developed as an IV administered compound for treatment of patients 
with infections caused by Gram-negative pathogens, including pathogens that are resistant to 
ceftazidime (CAZ-resistant). CAZ-AVI was approved by the Food and Drug Administration 
(FDA) in the US on 25 February 2015, and was approved in the European Union (EU) on 
24 June 2016. In China, CAZ-AVI was approved by the NMPA on 21 May 2019. Indications 
for adults approved include cIAI, HAP (including VAP), and for the treatment of infections 
due to aerobic Gram-negative organisms in adult patients with limited treatment options.
2.1. Study Rationale 
China has participated in 2 international Phase 3 clinical trials for CAZ-AVI that have been 
completed, including 1 study in patients with HAP (including VAP), which demonstrated the 
non-inferiority (NI) of CAZ-AVI to meropenem for the treatment of HAP/VAP, including 


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infections due to Gram-negative pathogens resistant to ceftazidime. No new safety concerns 
were identified.
The purpose of the study is to further evaluate effectiveness of CAZ-AVI in Chinese 
participants with HAP, including VAP. 
. 
2.2. Background
In the face of increasing global antibiotic resistance, there are limited therapeutic options for 
the treatment of resistant Gram-negative pathogens. There is an urgent need for new 
antibiotics to treat serious infections caused by Gram-negative bacteria proven or suspected 
to be caused by β-lactam resistant pathogens, including those producing ESBLs and KPCs.
A new therapeutic agent that is able to demonstrate similar efficacy and safety to the current 
carbapenem standard of care, including efficacy in patients with Enterobacteriaceae and 
P. aeruginosa infections and activity against key β-lactam resistant pathogens is an important, 
clinically significant addition to the currently limited armamentarium that is available to 
physicians.
The addition of avibactam to ceftazidime expands its antibacterial activity against pathogens 
possessing β-lactamases that are susceptible to inhibition by avibactam, while retaining the 
bactericidal activity of ceftazidime7; it therefore has the potential to restore the utility of 
ceftazidime in the clinical setting. Efficacy and safety has been demonstrated in clinical 
trials, including in infections caused by CAZ-resistant, but CAZ-AVI-susceptible pathogens.
In China, CAZ-AVI was approved by the NMPA on 21 May 2019. 
2.2.1. Clinical Overview
There are 18 completed Phase 1 clinical pharmacology studies, including:

13 studies with administration of avibactam alone and/or CAZ-AVI by IV infusion 
(including 1 study conducted in pediatric participants)

Avibactam PK data from 5 Phase 1 clinical pharmacology studies in the 
ceftaroline-avibactam (CXL) development program, as it has been demonstrated that 
there is no PK interaction between CXL and avibactam.
There are also 2 completed Phase 2 studies in adults (1 in complicated urinary tract infection 
[cUTI] and 1 cIAI) and 5 Phase 3 clinical studies:

RECLAIM, a double-blind study in adult participants with cIAI.

RECLAIM3, a double-blind study in adult Asian participants with cIAI.

REPRISE, an open-label study in adult participants with cUTI or cIAI, who had 
ceftazidime-resistant pathogens at baseline.
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
RECAPTURE, a double-blind study in adult participants with cUTI.

REPROVE, a double-blind study in adult participants with HAP, including VAP.
Across the CAZ-AVI Phase 3 studies in participants with cIAI, cUTI and HAP, CAZ-AVI 
(±metronidazole [MTZ]) at the proposed dose was effective in participants with both 
CAZ-susceptible and CAZ-resistant pathogens. The observed safety profile supports the use 
of CAZ-AVI in the approved indications in Chinese adults.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of CAZ-AVI may be found in the China local product document (LPD), which 
is the single reference safety document (SRSD) for this study. 
2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) CAZ-AVI 
Potential risks associated with 
CAZ-AVI include the following: 
Encephalopathy and 
neurological symptoms such as 
tremor, coma and seizures in 
patients with renal impairment 
who do not have their dose 
appropriately reduced
The potential risks are based on 
product labeling for CAZ-AVI.
This potential risk has been 
reported with ceftazidime when 
the dose has not been reduced in 
patients with renal impairment.
Eligibility criteria have been 
selected to ensure that only 
appropriate participants are 
included in the study (see 
Section 5).
The dose should be reduced 
according to the degree of renal 
impairment (see Section 6.1). In 
participants with renal 
impairment, close monitoring of 
estimated creatinine clearance is 
advised.
Study Procedures (Not applicable)
Other (Not applicable)
2.3.2. Benefit Assessment
Participants enrolled into this clinical study will have required hospitalization due to other 
illnesses and will have developed HAP that requires treatment with IV antibiotics. The 
potential benefit to participants in this study is that they will receive effective antibiotic 
therapy for their infection based on clinical practice. The potential benefit of the study, in 
general, is to further characterize the efficacy and safety of a novel antibiotic product in a 
large sample size in Chinese after marketing approval, that is an effective treatment for 
HAP/VAP in the face of the changing pattern of antibiotic resistance.


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2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with CAZ-AVI are justified by the 
anticipated benefits that may be afforded to participants with HAP, including VAP.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To estimate clinical 
response to CAZ-AVI in 
HAP patients. 
Using a composite estimand strategy to estimate the 
clinical response rate at the TOC visit in participants 
who meet minimum disease requirements (excluding 
participants not expected to respond to CAZ-AVI). 
Clinical response will be categorized as cure, failure, 
and indeterminate per investigator’s assessment. 
Intercurrent events of death on study Day 1 or Day 2, 
death on or before TOC visit where HAP is clearly 
non-contributory, identification of an infectious 
complication of pneumonia between Day 1 and Day 2 
inclusive triggering treatment with further antibiotics 
will be regarded as indeterminate clinical response. 
Intercurrent events of death between Day 3 and TOC 
visit inclusive, development of infectious complications 
of pneumonia after Day 2 until TOC visit triggering 
treatment with further antibiotics will be regarded as 
failure clinical response.

The proportion of 
participants with clinical 
cure at the TOC visit in 
the cMITT population. 
Secondary: 
Secondary:
Secondary: 

To estimate clinical 
response to CAZ-AVI in 
HAP patients, and HAP 
patients with 
demonstrated 
Gram-negative 
pathogens.
Using a composite estimand strategy to estimate the 
clinical response rate at the EOT visit in participants 
who meet minimum disease requirements, and at the 
EOT and TOC visits in participants who meet minimum 
disease requirements and have demonstrated 
Gram-negative pathogens (excluding participants not 
expected to respond to CAZ-AVI for both target 
populations). Clinical response will be categorized as 
cure, failure, and indeterminate per investigator’s 
assessment. Intercurrent events of death on study Day 1 
or Day 2, death on or before EOT visit (or TOC visit 
accordingly) where HAP is clearly non-contributory, 
identification of an infectious complication of 
pneumonia between Day 1 and Day 2 inclusive 
triggering further antibiotics treatment will be regarded 
as indeterminate clinical response. Intercurrent events of 
death between Day 3 and EOT visit (or TOC visit 
accordingly) inclusive, development of infectious 
complications of pneumonia after Day 2 triggering 
further antibiotics treatment will be regarded as failure 
clinical response.

The proportion of 
participants with clinical 
cure at the EOT visit in 
cMITT population, and 
at the EOT, TOC visits 
in the mMITT 
population. 


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Objectives
Estimands
Endpoints

To estimate the 
microbiologic response 
to CAZ-AVI.
Using a composite estimand strategy to estimate the 
per-patient and per-pathogen microbiological response 
rate at the EOT and TOC visits in participants who meet 
minimum disease requirements and have demonstrated 
Gram-negative pathogens. Microbiological response will 
be categorized as favorable (ie, eradication, or presumed 
eradication), unfavorable (persistence, persistence with 
increasing MIC, or presumed persistence), and 
indeterminate. Per-pathogen microbiological response 
will be summarized with the proportion of participants 
achieving favorable response by baseline pathogen type; 
per-patient microbiological response will be summarized 
with the proportion of participants achieving overall 
favorable response (ie, favorable for each of the baseline 
pathogen isolate). Intercurrent events of death or 
identification of an infectious complication of 
pneumonia triggering further antibiotics treatment such 
that an adequate source specimen is not available to 
culture will be regarded as an indeterminate 
microbiological response if clinical response is 
indeterminate, and will be regarded as a presumed 
eradication if a clinical cure is assessed.

The proportion of 
participants with the 
favorable per-patient 
microbiologic response 
at the EOT and TOC 
visits in the mMITT 
population.

The proportion of 
favorable per-pathogen 
microbiologic responses 
at the EOT and TOC 
visits in the mMITT
population.

To estimate the efficacy 
of CAZ-AVI in patients 
with pathogens resistant 
to ceftazidime.
Using the same composite estimand strategies as the 
primary estimand and aforementioned secondary 
estimands to estimate the proportion of participants 
with clinical cure and with a favorable per-patient 
microbiological response at the EOT and TOC visits in 
participants who meet minimum disease requirements 
and have demonstrated Gram-negative pathogens that 
are resistant to ceftazidime.

The proportion of 
participants with clinical 
cure, and proportion of 
participants with 
favorable per-patient 
microbiologic response 
at the EOT and TOC 
visits in patients with 
pathogens resistant to 
ceftazidime in the 
mMITT population.

To estimate all-cause 
mortality for CAZ-AVI.
Using a treatment-policy estimand strategy in 
participants who meet minimum disease requirements, 
and in participants who meet minimum disease 
requirements and have demonstrated Gram-negative 
pathogens to estimate the proportion of participants with 
death at the TOC visit and Day 28 of the study. Any 
death that occurred after the first dose of study 
intervention through the nominal analysis timepoint will 
be included. A participant with the last known survival 
status that is before the nominal analysis timepoint or 
missing at the nominal analysis timepoint will be 
reported as an unknown status.

The proportion of 
participants with death 
due to any cause 
(all-cause mortality) at 
the TOC visit and at 
Day 28 in the cMITT 
and mMITT populations.

To evaluate the safety 
and tolerability of 
CAZ-AVI. 
N/A.

Assessment of TEAEs 
and safety-related 
clinical laboratory tests 
and vital observations.


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4. STUDY DESIGN
4.1. Overall Design
This is a single arm, multi-center interventional study evaluating the effectiveness and safety 
of CAZ-AVI in Chinese adults with HAP (including VAP).
Approximately 235 participants will be enrolled. Each participant is expected to complete the 
study, including follow-up, within approximately 6 weeks. The study intervention will be 
administered IV for a minimum of 7 days and a maximum of 14 days. Participants must 
receive the study intervention for at least 7 days. At any time after 7 days, the investigator
will have the option to continue the study intervention or discontinue the study intervention 
completely. 
The participant is to return to the study center for the scheduled visits following discharge 
from the hospital. An overall clinical assessment, vital sign measurements, ventilation status 
and detailed pulmonary assessment will be performed at Day 1 (baseline), daily during 
treatment with IV therapy, and at the EOT, and TOC (21 to 25 calendar days from 
enrollment) visits. In addition to these visits, death and AEs will be assessed until the final 
protocol follow up (FPFU) visit (28 to 32 calendar days after the last dose of CAZ-AVI). The 
FPFU visit may be conducted either in person or by telephone contact (Figure 1).
Note: The investigors must continue to collect AEs and perform safety reporting 
responsibilities per protocol via telephone contact or other methods as appropriate if on-site 
vists interrupted by the COVID-19 pandemic.
4.2. Scientific Rationale for Study Design
This study is designed 
 to further evaluate effectiveness of 
CAZ-AVI in Chinese patients with HAP, including VAP. The NI of CAZ-AVI compared 
with meropenem was demonstrated in overall population in co-primary endpoints (clinical 
cure rate at TOC visit in clinically modified intent-to-treat [cMITT] and clinical evaluable 
[CE] population) in REPROVE study. Comparative data in Chinese subgroup showing a 
consistent trend are also available in REPROVE study. To utilize more of the possible 
participants and estimate/evaluate the efficacy of CAZ-AVI in a relative large sample size 
after the marketing approval, a descriptive estimation study is planned in China as 
 
.
Empiric agents have been selected to cover Gram-positive pathogens and multi-drug resistant 
Gram-negative pathogens which may exhibit resistance to CAZ-AVI. Empiric agents are 
defined as those antimicrobials administered to the participant prior to knowledge of the 
respiratory specimen culture and susceptibility results. CAZ-AVI may not adequately cover 
certain species of Gram-positive and Gram-negative organisms that can cause HAP. Because 
prompt delivery of antibiotic with activity against the etiologic agent has been shown to 
decrease morbidity and mortality among participants with HAP and because culture and 
susceptibility results are not known until approximately 48 to 72 hours after they are 
obtained, use of empiric coverage with agents that cover both resistant Gram-negative and 
Gram-positive organisms is standard clinical practice in many regions around the world. In 
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this study, empiric Gram-positive and Gram-negative agents will be used for all participants 
whose culture results are not available at the time of recruitment. After 48-72 hours, the 
criteria for discontinuing empiric antibiotics are outlined in Sections 6.1.1.1and 6.1.1.2.
Human reproductive safety data are limited for CAZ-AVI, but there is no suspicion of human 
teratogenicity based on the intended pharmacology of the compound. Therefore, the use of a 
highly effective method of contraception is required (see Appendix 4).
4.3. Justification for Dose
The intention for CAZ-AVI is that it will be active in participants with HAP or VAP caused 
by Gram-negative bacteria that express various non-metallo-β-lactamases. The dosing 
regimen for this study will be based on the approved dose recommended for treatment of 
HAP/VAP in the package insert, which was established following: (i) acquisition of 
preclinical data, including surveillance of minimum inhibitory concentrations (MICs) among 
Gram-negative bacteria isolated from nosocomial pneumonia participants and results from 
mouse infection models; (ii) measurements of penetration into epithelial lining fluid; and 
(iii) completion of the Phase 2 and Phase 3 clinical studies in participants with cIAI, cUTI or 
HAP.
For patients with changing renal function, doses of CAZ-AVI will be modified as needed in 
accordance with the approved package insert.
The doses of linezolid, vancomycin and amikacin should follow the local package insert.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants 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 participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants ≥18 and ≤90 years of age at Visit 1 (Screen 1).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and 
female (Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Onset of signs and symptoms (including Inclusion Criteria 4, 6, and 7) ≥48 hours 
after admission or <7 days after discharge from an inpatient acute or chronic care 
facility.
4. New or worsening infiltrate on chest X-ray or CT scan obtained within 48 hours 
prior to screening.
5. Respiratory specimen obtained for Gram stain and culture within 48 hours prior to 
screening, and after the onset of signs and symptoms of HAP (ideally before receipt 
of any systemic antibiotics).
6. At least 1 of the following systemic signs: 

Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C) 

White blood cell (WBC) count >10,000 cells/mm3, or WBC count <4500 
cells/mm3, or >15% band forms.
7. At least 2 of the following respiratory signs or symptoms: 

A new onset of cough (or worsening of cough). 

Production of purulent sputum or endotracheal secretions. 

Auscultatory findings consistent with pneumonia/pulmonary consolidation (eg, 
rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony). 

Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2 <60 mmHg 
while breathing room air).


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
A need for mechanical ventilation or, for already ventilated participants, acute 
changes made in the ventilator support system to enhance oxygenation, as 
determined by, for example arterial blood gas or worsening PaO2/FiO2. 
Informed Consent:
8. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1.
Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
2.
Participant has a past or current history of known or suspected Clostridium difficile
associated diarrhea (CDAD).
3.
Pulmonary disease that precludes evaluation of therapeutic response (including, but 
not limited to, lung cancer, active tuberculosis, cystic fibrosis, granulomatous disease, 
fungal pulmonary infection or recent pulmonary embolism)
4.
Participants with lung abscess, pleural empyema or post obstructive pneumonia.
5.
Participants receiving hemofiltration or peritoneal dialysis.
6.
Any allergy to cephalosporins regardless of seriousness of that reaction. Severe 
hypersensitivity to any other betalactams (eg, penicillins, monobactams or 
carbapenems). 
7.
Participant is expected to require a treatment course for HAP longer than 14 days.
Prior/Concomitant Therapy:
8.
Co-administration of CAZ-AVI with probenecid or chloramphenicol and 
co-administration of any systemic antibiotic other than per protocol is not allowed.
9.
The total duration of antibiotic exposure for antibiotics whose administration begins 
in the 48 hours prior enrollment is longer than 24 hours (eg, administration of more 
than 3 doses of a q8h antibiotic or more than 1 dose of a q24h antibiotic).


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
However, participants are still eligible for entry if ALL pathogens identified at 
baseline are resistant to ALL of the antibiotics received; or the total duration of 
antibiotic exposure* of the antibiotics for which ANY of the pathogens identified 
at baseline were found to be susceptible, in the ≤48 hours, is ≤24 hours.

AND the participant has shown objective signs of worsening despite therapy as 
demonstrated by at least 1 of the below:
o
Increased oxygen requirement 
o
Two of the following: increased dyspnea, increased purulent sputum, 
increased tachypnea, increased WBC count.
* This excludes antibiotics that are not systemically absorbed (eg, topical antibiotics, oral 
vancomycin).
Prior/Concurrent Clinical Study Experience:
10. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention 
used in this study (whichever is longer). 
Diagnostic Assessments:
11. Acute Physiology and Chronic Health Evaluation (APACHE) II score >30 or <10 
using the available data within 24 hours prior baseline.
12. When culture results from a 48 hours specimen period prior to screening are available 
[Note: This can be from any culture and not just the baseline culture], and any of the 
following is present:

The participant is found to have HAP caused by Gram-positive organisms without 
concomitant infection with a Gram-negative pathogen (polymicrobial infections 
with Gram-positive pathogens are permitted as long as a Gram-negative pathogen 
is also present).

The participant is found to have HAP caused by a Gram-negative species not 
expected to respond to CAZ-AVI (eg, Acinetobacter baumanii, Stenotrophomonas 
spp). Note: the participant is allowed to participate in the study if the investigator 
considers that the species is a colonizer which does not warrant specific treatment 
and other criteria are met.

The participant is found to have HAP caused by a Gram-negative pathogen 
demonstrating resistance to carbapenems and/or CAZ-AVI.


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Other Exclusions:
13. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
5.3. Lifestyle Considerations
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception). In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.3.2. Controlled sodium diet
Each vial contains a total of 6.44 mmol of sodium (approximately 148 mg), which is 
equivalent to 7.4% of the maximum daily sodium intake recommended by World Health 
Organization (WHO). The maximum daily dose of this product is equivalent to 22.2% of the 
maximum daily sodium intake recommended by the WHO. This should be considered when 
administering CAZ-AVI to participants who are on a controlled sodium diet.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). The 
pariticipants who are screen failures will not be re-screened. 
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration 
Not Applicable.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.


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For the purposes of this protocol, study intervention refers to CAZ-AVI.
6.1. Study Intervention(s) Administered
Intervention Name
Zavicefta (ceftazidime/avibactam or CAZ-AVI)
Type
Drug
Dose Formulation
Powder for solution for injections
Unit Dose Strength(s)
CAZ-AVI 2.5g: ceftazidime 2g + avibactam 0.5g
Dosage Level(s)
CAZ-AVI 2.5 g administered IV as 2 hours infusion every 8 hours 
(q8h).
Refer to Table 1 for participants with estimated CrCL ≤50 mL/min
Route of Administration
Infusion
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor 
Refer to IP manual
Packaging and Labeling
Study intervention will be provided in a sealed vial within a carton 
containing 1 vial per carton and is labeled in a way that is consistent 
with the study design and with the regulatory requirement in China.
Refer to IP manual
Table 1.
Recommended IV Doses for Participants With Estimated CrCL 
≤50 mL/min1
Estimated CrCL (mL/min)
Dose regimen2
Frequency4
Infusion time
31~50
1.25 g（1 g/0.25 g）
Every 8 hours
2 hours
16~30
0.94 g（0.75 g/0.19 g）
Every 12 hours
2 hours
6~15
0.94 g（0.75 g/0.19 g）
Every 24 hours
2 hours
≤53
0.94 g（0.75 g/0.19 g）
Every 48 hours
2 hours
1.
CrCL estimated using the Cockcroft-Gault formula.
2.
Dose recommendations are based on pharmacokinetic modelling.
3.
Ceftazidime and avibactam are removed by haemodialysis. Dosing of CAZ-AVI on haemodialysis days 
should occur after completion of haemodialysis.
4.
Time windows of dose frequency are Q8H ± 30mins, Q12H ± 30mins, Q24H ± 30mins and time window 
of infusion time is 2 hours ± 10mins.
6.1.1. Administration
Participants will receive CAZ-AVI (2000 mg of ceftazidime and 500 mg of avibactam) 
administered by IV infusion in a volume of 100 mL at a constant rate over 2 hours.
For participants with estimated CrCL ≤50 mL/min, please refer to Table 1.
The duration of antibiotic treatment with study intervention is 7-14 days. Participants must 
receive IV study intervention in the hospital for at least 7 days. At any time after 7 days, the 
investigator will have the option to continue IV study intervention or discontinue study 
intervention completely. Total therapy should not exceed 14 days.


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When protocol defined empiric antibiotics provided by Pfizer are scheduled to be delivered 
at the same time as study intervention after the first dose, they may be given after the 
delivery of study intervention or concurrently via an alternative IV line or lumen. See 
Sections 6.1.1.1 and 6.1.1.2 for specific details regarding the administration of the empiric 
Gram-positive and Gram-negative agents.
6.1.1.1. Empiric Gram-positive agent
Linezolid should be given to all participants in whom baseline cultures are still pending at 
registration as empiric Gram-positive coverage for 48 hours (unless culture results are not
available at 48 hours post-registration in which case, use may be extended for an additional
24 hours [to a maximum of 72 hours post-registration]). Under certain circumstances, there 
may be reasons why a specific participant cannot or should not receive linezolid and in this 
instance vancomycin should be used instead.
In the following circumstances, individual participants must receive vancomycin instead of 
linezolid (ie, there is a contraindication to linezolid):

Hypersensitivity to linezolid or any of its known components

Participant has taken a monoamine oxidase inhibitor within 2 weeks prior to 
enrollment

Participant has uncontrolled hypertension, pheochromocytoma, thyrotoxicosis or
carcinoid syndrome

Participant is taking any of the following types of medications: directly and indirectly
acting sympathomimetic agents (eg, pseudoephedrine), vasopressive agents (eg,
epinephrine, norepinephrine), dopaminergic agents (eg, dopamine, dobutamine)

Participant is taking any of the following medications: serotonin re-uptake inhibitors,
tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine or 
buspirone
In the following circumstances, individual participants may, at the investigator’s discretion, 
receive vancomycin instead of linezolid:

Myelosuppression (including anemia, leukopenia, pancytopenia, and
thrombocytopenia)

Participant is receiving insulin or oral hypoglycaemic agents for diabetes mellitus
Dosing for linezolid and vancomycin refer to package insert. Participants should receive 
Gram-positive agents for 48 hours. At 48 hours, the Gram-positive agent should be continued 
or stopped based on the etiologic pathogens identified in the baseline culture as described in 
Figure 2. If the etiologic pathogen has not been identified at 48 hours, therapy may be 
continued for an additional 24 hours (ie, 72 hours total of empiric Gram-positive therapy). 




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All participants should receive amikacin for 48 hours if susceptibility results from the 
baseline culture are not available prior to registration (a maximum of 72 hours if 
susceptibility results are still not available at 48 hours post-registration) except in instances 
where an individual participant has a contraindication to aminoglycoside use (namely, 
myasthenia gravis), or is at low risk of infection with multi-drug resistant Gram-negative 
organisms as defined by the absence of all of the following criteria:

Antimicrobial therapy in preceding 90 days

Current hospitalization of 5 days or more

Hospitalization for 2 days or more in the preceding 90 days (excluding current
hospitalization)

Residence in a nursing home or extended care facility
Dosing of amikacin refer to pakage insert. The CrCL should be measured daily and dose 
adjusted appropriately. 
Amikacin should be continued for 48 hours and then stopped or continued based on pathogen 
identification and carbapenem susceptibility results as outlined in Figure 3. If final baseline 
culture and carbapenem susceptibility results are not available at 48 hours, amikacin use may 
be extended an additional 24 hours such that a participant may receive a maximum of 
72 hours of total amikacin therapy. If a carbapenem non-susceptible Gram-negative pathogen 
has not been identified at 72 hours, amikacin should be stopped (see Figure 3).
For participants in whom amikacin continuation is indicated, the duration of therapy is at the 
discretion of the investigator, but cannot be longer than duration of study intervention. Study 
intervention with CAZ-AVI should continue for 7-14 days, regardless of the need for 
ongoing amikacin therapy.


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Figure 3.
Algorithm for Stopping or Continuing Open-lable Empiric Gram-negative 
Coverage With Amikacin Based on Baseline Culture Results and 
Susceptibility Results at 48 Hoursa,b
a.
For details regarding use of study intervention see Section 6.1.1.
b.
If cultures and susceptibility results are not available at 48 hours, empiric amikacin may be continued for an
additional 24 hours (ie 72 hours of total therapy).
c.
For participants in whom all Gram-negative pathogens are susceptible to meropenem, imipenem based on
local susceptibility results using local interpretive criteria.
d.
For participants in whom at least one Gram-negative pathogen is non-susceptible to meropenem, imipenem
or doripenem based on local susceptibility results using local interpretive criteria.
e.
If the investigator considers the carbapenem non-susceptible Gram-negative organism(s) to be a colonizer
which does not warrant treatment, empiric Gram-negative treatment with amikacin may be stopped.
f.
When no pathogen is identified, the participant will continue to receive CAZ-AVI and therefore, 
discontinuation of amikacin is strongly encouraged. However, in certain circumstances it would be
acceptable to continue the amikacin if the investigator feels it is in the best interest of the participant.
Reasons for continuing amikacin in this circumstance should be documented.
6.2. Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 


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2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3.
Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4.
Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5.
Study interventions should be stored in their original containers and in accordance 
with the labels.
6.
See the IP manual for storage conditions of the study intervention once reconstituted 
and/or diluted.
7.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
Investigational Product Accountability Log (IPAL) or sponsor-approved equivalent. 
All study interventions will be accounted for using a study intervention accountability 
form/record.
8.
Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. 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.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.


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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention for 
administration. Study intervention 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. A second staff member will verify the dispensing.
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Study Intervention
This is an open-label, single arm study. The investigator’s knowledge of the treatment should 
not influence the decision to enroll a particular participant or affect the order in which 
participants are enrolled.
Study intervention will be dispensed at the study visits summarized in the SoA.
Returned study intervention must not be redispensed to the participants.
6.4. Study Intervention Compliance
The site will complete the required dosage Preparation Record located in the IP manual. The 
use of the Preparation Record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system. The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose. This may be used in place of the Preparation Record after 
approval from the sponsor and/or designee.
The qualified study center personnel at the study center will administer IV study intervention 
and treatment compliance will be assured. The dose, date, and exact start and stop time of 
administration of the IV study intervention will be recorded and checked by the monitor at 
monitoring visits.
6.5. Concomitant Therapy
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
All prescription and over the counter medications, including herbal products and blood or 
other blood product transfusions, being taken by the participant from signed informed 
consent prior to registration (considered prior medications) and from registration through the 
FPFU visit (considered concomitant medications) must be documented on the appropriate 
pages of the electronic case report form (eCRF). Systemic antibiotics should be documented 
for the entire duration of the study (from 2 weeks prior to study entry through the FPFU 
visit).
The use of probenecid or chloramphenicol and any systemic antibiotic not specified by this 
protocol is not permitted after registration.


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The use of systemic antibiotics not specified by this protocol is not permitted after 
enrollment. The use of metronidazole (or any other antibiotic active solely against anaerobes) 
or oral vancomycin (or any other oral antibiotic that is not absorbed systemically) are 
considered acceptable.
Other medication, which is considered necessary for the participant’s safety and well being, 
may be given at the discretion of the investigator and recorded in the appropriate sections of 
the eCRF. Should a participant require immunosuppressive agents or chemotherapy after 
being enrolled to IV study intervention, the investigator should contact the Pfizer physician 
before initiating therapy. Continued receipt of study intervention will be determined based 
upon assessment of the safety risk to the participant. Participants should remain in the study 
and complete all scheduled protocol assessments.
Any participant planning to undergo surgical treatment not compatible with the aims of the 
study must not be enrolled. For participants who need to undergo a unplanned surgical 
procedure during the study, the reason for the surgery must be documented as an AE in the 
eCRF.
6.5.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with CAZ-AVI; standard medical 
supportive care must be provided to manage the AEs. 
6.6. Dose Modification 
For participants with moderate and severe renal impairment, will require dose modification 
which are outlined in Table 1. 
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Stopping criteria for individual participants include:

In the absence of any alternative explanation for an increase in the following
abnormalities, individual participants should be withdrawn if the following
criteria are met (see also Appendix 5):

ALT or AST >8 × ULN

ALT or AST >3 × ULN and either total bilirubin >2 × ULN or 
evidence of coagulopathy. Evidence of coagulopathy should be 
discussed with the Pfizer clinician where possible

ALT or AST >3 × ULN and with appearance of symptoms suggestive of 
new or progressive liver disease. Symptoms suggestive of new or 


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progressive liver disease should be discussed with the Pfizer clinician
where possible

Positive pregnancy test at any time during the study treatment period
Investigators should not discontinue a participant from study intervention on the basis of 
microbiologic results alone (ie, culture and susceptibility results) without evidence of failure. 
However, the investigator should frequently re-assess the risk/benefit ratio to the participant 
as additional data become available during the study.
For participants who discontinue study intervention early, all subsequent scheduled 
assessments should be collected. The EOT visit should occur within 24 hours of study 
intervention discontinuation.
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following:

Participant or legally recongnized representative decision. The participant is at any
time free to discontinue treatment, without prejudice to further treatment

Adverse event (eg, risk to participant, as judged by the investigator or Pfizer)

Severe noncompliance to study protocol, as judged by the investigator and/or Pfizer

Treatment failure

In the opinion of the investigator, it is not in the best interest of the participant to
continue the IV study intervention or at the request of Pfizer that the particant stops
participation.
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for safety. See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further follow-up;


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
Lost to follow-up;

Death;

Study terminated by sponsor;
The early discontinuation visit applies only to participants who are enrolled and then are 
prematurely withdrawn from the study. Participants should be questioned regarding their 
reason for withdrawal. 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
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.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention 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 participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants 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 study intervention 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 participant 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.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.


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The following actions must be taken if a participant fails to return to the site for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 


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investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must 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.
The total blood sampling volume for individual participants in this study is approximately 
135 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
8.1. Efficacy Assessments
8.1.1. Clinical response
To estimate clinical response to CAZ-AVI in HAP patients is the primary objective of this 
study. A clinical response assessment outcome will be assigned to each participant by the 
investigator at the EOT and TOC visits. Clinical response outcomes are success, failure and 
indeterminate, the definitions of which are respectively given in Table 2 and Table 3 for the 
EOT and TOC visits.


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Table 2.
Definitions of Clinical Response at the EOT Visit
Clinical response
Definition
Clinical Cure
Participants will be considered to be a success for clinical response if:

The participant is alive and all signs and symptoms of pneumonia have 
resolved or improved such that all antibacterial therapies for HAP/VAP
are stopped. No antibacterial therapy other than those outlined by the 
protocol has been administered for HAP prior to EOT.
Clinical Failure
Participants who meet any 1 of the following criteria will be considered to be a 
treatment failure for clinical response:

Mortality due to HAP/VAP between Day 3 of study intervention and the 
EOT visit inclusive.

Incomplete clinical resolution or worsening of HAP-specific signs and 
symptoms that requires additional antibacterial therapy for HAP at or 
before EOT.

Development of infectious complications of pneumonia such as 
empyema or lung abscess after Day 2.
Indeterminate
Participants who meet any 1 of the following criteria will be considered to be 
indeterminate for clinical response:

Participant lost-to-follow-up or assessment is not undertaken, such that a 
determination of clinical response cannot be made.

Death on or before the date of the EOT visit where HAP is clearly 
non-contributory.

Death on study Day 1 or Day 2.

Identification of an infectious complication of pneumonia such as 
empyema or lung abscess between Day 1 and Day 2 inclusive.
Table 3.
Definitions of Clinical Response at the TOC Visit
Clinical response
Definition
Clinical Cure
Participants will be considered to be a success for clinical response if:

The participant was not a clinical failure at EOT, and the participant is 
alive and all signs and symptoms of pneumonia have resolved or 
improved to an extent that no antibacterial therapy for HAP was taken 
between EOT and TOC inclusive.
Clinical Failure
Participants who meet any 1 of the following criteria will be considered to be a 
treatment failure for clinical response:

Designated as a clinical failure at an earlier time point (eg, EOT).

Mortality due to HAP between Day 3 of study intervention and the TOC 
visit inclusive.

Persistence, incomplete clinical resolution, worsening or recrudescence 
of HAP-specific signs and symptoms that requires initiation of 
antibacterial therapy for HAP between EOT and TOC, inclusive.


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Table 3.
Definitions of Clinical Response at the TOC Visit
Clinical response
Definition

Development of complications of HAP such as empyema or lung abscess 
at or before the TOC visit.
Indeterminate
Participants who meet any 1 of the following criteria will be considered to be 
indeterminate for clinical response:

Participant lost-to-follow-up on or before the TOC visit or the assessment 
is not undertaken, such that a determination of clinical response cannot 
be made.

Death on or before the date of TOC visit where HAP is clearly 
non-contributory.

Death on study Day 1or Day 2 inclusive.

Identification of an an infectious complication of pneumonia such as 
empyema or lung abscess between Day 1 and Day 2 inclusive.
8.1.2. Microbiology assessments
All microbiological assessments will be initiated at the local laboratory for specimen 
collection, shipment of isolates, and analysis of isolates according to the sections below and 
as outlined in more detail in the microbiology laboratory manual. All respiratory and blood 
pathogens must be shipped to the central reference laboratory for confirmation of 
microbiological assessments. A unstained Gram stain slide of each respiratory specimen must 
also be sent to the central reference laboratory.
All specimens should be processed according to recognized methods that culture for aerobic 
organisms8 following the standard operating procedures of the clinical microbiology 
laboratory at each study center. All cultured pathogens should be kept by the local laboratory 
at –20°C or colder (preferably at -70°C) until the end of the study or when contacted by the 
central reference laboratory.
8.1.2.1. Specimen collection
Respiratory specimens
Baseline respiratory cultures must be obtained within 48 hours prior to Day 1 and after 
development of signs and symptoms of HAP (ideally before receipt of any systemic 
antibiotics). An adequate and appropriate baseline respiratory culture specimen should be 
sent to the local laboratory for Gram stain, culture, identification, and in vitro susceptibility 
testing.
Appropriate specimens from ventilated participants include:

endotracheal aspirate

bronchalveoloar lavage (BAL)


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
mini BAL

Protected Brush Specimen (PBS) sample
Appropriate specimens from non-ventilated participants include:

expectorated or induced sputum

BAL

mini BAL

PBS sample
Note that there may be non-ventilated participants who develop HAP and subsequently 
require intubation and mechanical ventilation. If such participants require ventilation prior to 
Day 1, a specimen appropriate for the participant should be obtained even if the participant 
has already provided a sputum sample. In addition, participants undergoing bronchoscopy 
prior to Day 1 should provide a respiratory specimen during the procedure even if a sputum 
sample or endotracheal aspirate has already been obtained.
In the circumstances where more than one culture has been obtained after the onset of signs 
and symptoms of pneumonia in the 48 hours prior to Day 1, the baseline culture will be 
established as described in Section 8.1.2.2.
To be considered adequate, respiratory samples from expectorated or induced sputum must 
show <10 squamous epithelial cells and >25 polymorphonuclear neutrophils per 100 × field 
upon a Gram stain.
When clinically indicated, pleural fluid should be sampled for Gram stain, culture 
identification, in vitro susceptibility testing; isolates should be sent to the central laboratory 
for confirmation. Additionally, (when indicated) cell counts, pH and lactate dehydrogenase 
(LDH) of pleural fluid as well as serum LDH should also be obtained. It is not necessary to 
submit a Gram-stain slide of pleural fluid to the central lab.
If treatment is discontinued early because the participant is failing therapy or other reasons, 
an appropriate respiratory specimen for culture should be obtained, ideally after stopping the 
initial treatment but before the new treatment is administered. The eCRF should indicate 
whether or not a sample was obtained.
Blood specimens
Two sets of blood cultures should be collected (ie, 4 bottles) from different sites for aerobic 
and anaerobic incubation within 24 hours prior to Day 1. Each bottle should be inoculated 
with 10 to 15 mL of blood for a total of 40 to 60 mL per collection. One set of blood cultures 
should be obtained through a venipuncture. Organisms isolated in the blood at study entry 
will be assigned a microbiologic response similar to those given for pathogens isolated from 


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respiratory specimens (see Table 4 for list of response categories). If participants are 
bacteremic, repeat samples must be collected at least every 3 days until clearance of 
bacteremia has been documented. If repeat cultures have not been finalized negative by the 
time of the EOT visit, a set of repeat blood cultures should be obtained at the EOT visit. 
Blood cultures should also be obtained as clinically indicated. Details concerning the 
collection of blood cultures are provided in the microbiology laboratory manual.
8.1.2.2. Defining the baseline respiratory specimen
In some circumstances, participants may have multiple respiratory specimens obtained after 
the onset of signs and symptoms of pneumonia in the 48 hours prior to Day 1.
The baseline respiratory culture is defined as the last respiratory culture obtained via BAL, 
mini BAL or PBS prior to Day 1. If BAL, mini BAL or PBS specimens are not available, the 
baseline respiratory culture will be defined as the last respiratory culture obtained via 
endotracheal aspirate prior to Day 1. If none of these are available, the baseline culture is 
defined as the last sputum culture obtained prior to Day 1.
The status and/or results of the baseline respiratory culture (ie, whether the results are 
pending or known; pathogen(s) identification and/or the susceptibility profile of the 
identified pathogens) should be used to determine whether the protocol requirements for 
empiric Gram-positive or Gram-negative agents have been met as described in Section 6.1.1. 
Only baseline cultures should be used for determining the need for these agents.
8.1.2.3. Microbiological response definitions
The per-patient and per-pathogen microbiologic response of CAZ-AVI in the mMITT 
analysis sets at the the EOT and TOC visits is a secondary objective of this study.
Microbiological response will be assessed per-pathogen and per-patient according to the 
definitions listed in Sections 8.1.2.3.1 and 8.1.2.3.2, respectively. Microbiological outcome 
per-patient is based on outcome per-pathogen isolated at the initial visit (considered as 
causative) and on the isolation of pathogens during the course of treatment or the 
post-treatment period.
8.1.2.3.1. Per-pathogen microbiological assessments 
Microbiological response will be assessed separately for each pathogen after completion of 
all follow-up visits using the definitions listed in Table 4.
Microbiological responses other than “indeterminate” will be classified as “favorable” or 
“unfavorable”. Favorable microbiological response assessments include “eradication” and
“presumed eradication”. Unfavorable microbiological response assessments include 
“persistence” “persistence with increasing MIC” and “presumed persistence”. 
“Superinfection” and “new infection” will be considered separately.


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8.1.2.3.2. Per-patient (overall) microbiological response assessments
Overall microbiological response will also be assessed as “favorable” or “unfavorable” for 
each participant. For participants from whom only 1 causative pathogen is isolated, the 
overall microbiological response assessment will be based on the microbiological response 
assessment for that pathogen.
For participants from whom more than 1 baseline pathogen is isolated, the overall 
microbiological response assessment will be “favorable” only if the microbiological response 
assessment for each of the baseline pathogens isolated is “favorable”. The overall 
microbiological response assessment will be “unfavorable” if at least 1 of the microbiological 
response assessments is “unfavorable”.
8.1.2.3.3. Microbiological response
Each baseline pathogen will be categorized according to the definitions in Table 4.
Table 4.
Microbiological Response Categories
Microbiological response
Definition
Eradication
An adequate source specimen demonstrates absence of the 
original baseline pathogen.
Presumed eradication
An adequate source specimen was not available to culture 
and the participant was assessed as a clinical cure.
Persistence
-
Persistence with increasing MIC
Adequate source specimen demonstrates continued 
presence of the original baseline pathogen.
Continued presence of the causative organism in a culture 
of the respiratory infection obtained during or upon 
completion of treatment with IV study intervention, and the 
pathogen that was susceptible to IV study intervention 
pre-treatment displays a ≥4-fold higher MIC to IV study 
intervention after treatment with IV study intervention.
Presumed persistence
An adequate source specimen was not available to culture 
and the participant was assessed as a clinical failure.
Indeterminate
An adequate source specimen was not available to culture 
and the participant’s clinical response was assessed as 
indeterminate.
Microbiologic response for blood pathogens should be classified similarly to the 
classifications for baseline pathogens noted in Table 4.


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8.1.2.3.4. MIC among pathogens
The favorable per-pathogen microbiologic response at the EOT and TOC visits will be 
evaluated for MIC categories. The MIC categories to be used are: ≤0.008, 0.015, 0.03, 
0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, and >256 μg/mL.
8.1.2.3.5. Emergent infections
Pathogens first appearing after baseline in participants with a baseline pathogen are 
categorised in Table 5 and will be summarised separately.
Table 5.
Emergent Infections
Emergent infection
Definition
Super-infection
Emergence of new pathogen from an adequate respiratory specimen during 
treatment with study intervention associated with emergence or worsening of signs 
and symptoms of infection and a requirement for additional antibiotics.
New infection
Emergence of new pathogen from an adequate respiratory specimen after 
completion of study intervention associated with emergence or worsening of signs 
and symptoms of infection and a requirement for additional antibiotics.
Colonization
Isolation of an organism from an adequate respiratory specimen which is not 
associated with signs and symptoms of active infection, and does not require 
antimicrobial therapy.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded. If the participant’s actual height and weight are not 
available, the height and weight may be estimated for study use. All height and weight 
measurements should be recorded in the CRF as actual or estimated. 
A brief physical examination will include, at a minimum, assessments of the 
lungs.Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. Vital Signs
Tympanic or axillary temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.


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Blood pressure and pulse rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
rate and 1 blood pressure measurements.
8.2.3. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.4. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second pregnancy test will be required at the baseline visit prior the 
participant’s receiving the CAZ-AVI. Pregnancy tests will also be done whenever 1 
menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected) and at the end of the study. Pregnancy tests may also be repeated if 
requested by IRBs/ECs or if required by local regulations. If a urine test cannot be confirmed 
as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the 
participant must be excluded if the serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.


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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant or legally authorized representative will be questioned about the occurrence 
of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 


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awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1. will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information 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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.


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Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, 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. Details of the 
pregnancy will be collected after the start of study intervention and until a minimum 
of 28 calendar days after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 


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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.
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 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. 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 including 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 study intervention. 
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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact. 


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The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so 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.
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, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE. The information 
must be reported using the CT SAE Report Form. Since the information does not pertain to a 
participant 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.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
The following disease-related events (DREs) are common in participants with HAP, 
including VAP, and can be serious/life threatening:

Disease progression;
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE. These events will be recorded on the corresponding 
CRF page in the participant’s CRF within 24 hours 
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a DRE):

The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant.


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OR

The investigator considers that there is a reasonable possibility that the event was 
related to study intervention.
8.3.8. Adverse Events of Special Interest 
Not Applicable.
8.3.8.1. Lack of Efficacy
Not Applicable.
8.3.9. Medical Device Deficiencies 
Not Applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention 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
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
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 nonserious, are recorded on the AE page of the 
CRF. 


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of CAZ-AVI greater than specified in protocol in Section 6.1.1.1
will be considered an overdose.
The Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the medical monitor within 24 hours.
2.
Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of CAZ-AVI (whichever is 
longer).
3.
Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4.
Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Pharmacokinetic (PK) parameters are not evaluated in this study. 
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.


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9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a 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. Estimands and Statistical Hypotheses
9.1.1. Estimands
For the primary efficacy objective and the secondary efficacy objectives, except for 
estimating all-cause mortality, a composite estimand strategy will be used; for the secondary 
efficacy objective of estimating all-cause mortality, a treatment-policy estimand strategy will 
be used. 
Primary Efficacy Estimand:
A composite estimand strategy will be used to estimate the clinical response rate at the TOC 
visit in participants who meet minimum disease requirements (excluding participants not 
expected to respond to CAZ-AVI). Clinical response will be categorized as cure, failure, and 
indeterminate per investigator’s assessment. Intercurrent events of death on study Day 1 or 
Day 2, death on or before TOC visit where HAP is clearly non-contributory, identification of 
an infectious complication of pneumonia between Day 1 and Day 2 inclusive triggering 
treatment with further antibiotics will be regarded as indeterminate clinical response. 
Intercurrent events of death between Day 3 and TOC visit inclusive, development of 
infectious complications of pneumonia after Day 2 until TOC visit triggering treatment with 
further antibiotics will be regarded as failure clinical response. 
Secondary Efficacy Estimands:
•
To estimate clinical response to CAZ-AVI in HAP participants, and HAP participants 
with demonstrated Gram-negative pathogens:
A composite estimand strategy will be used to estimate the clinical response rate at 
the EOT visit in participants who meet minimum disease requirements, and at the 
EOT and TOC visits in participants who meet minimum disease requirements and 
have demonstrated Gram-negative pathogens (excluding participants not expected to 
respond to CAZ-AVI for both target populations). Clinical response will be 
categorized as cure, failure, and indeterminate per investigator’s assessment. 
Intercurrent events of death on study Day 1 or Day 2, death on or before EOT visit (or 
TOC visit accordingly) where HAP is clearly non-contributory, identification of an 
infectious complication of pneumonia between Day 1 and Day 2 inclusive triggering 
further antibiotics treatment will be regarded as indeterminate clinical response. 
Intercurrent events of death between Day 3 and EOT visit (or TOC visit accordingly) 
inclusive, development of infectious complications of pneumonia after Day 2 
triggering further antibiotics treatment will be regarded as failure clinical response.


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•
To estimate the microbiologic response to CAZ-AVI:
A composite estimand strategy will be used to estimate the per-patient and 
per-pathogen microbiological response rate at the EOT and TOC visits in participants 
who meet minimum disease requirements and have demonstrated Gram-negative 
pathogens. Microbiological response will be categorized as favorable (ie, eradication, 
or presumed eradication), unfavorable (persistence, persistence with increasing MIC, 
or presumed persistence), and indeterminate. Per-pathogen microbiological response 
will be summarized with the proportion of participants achieving favorable response 
by baseline pathogen type; per-patient microbiological response will be summarized 
with the proportion of participants achieving overall favorable response (ie, favorable 
for each of the baseline pathogen isolate). Intercurrent events of death or 
identification of an infectious complication of pneumonia triggering further 
antibiotics treatment such that an adequate source specimen is not available to culture 
will be regarded as an indeterminate microbiological response if clinical response is 
indeterminate, and will be regarded as a presumed eradication if a clinical cure is 
assessed.
•
To estimate the efficacy of CAZ-AVI in participants with pathogens resistant to 
ceftazidime:
Same composite estimand strategy as the primary estimand and aforementioned 
secondary estimands to estimate the proportion of participants with clinical cure and 
with favorable per-patient microbiological response at the EOT and TOC visits in 
participants who meet minimum disease requirements and have demonstrated 
Gram-negative pathogens that are resistant to ceftazidime.
•
To estimate all-cause mortality for CAZ-AVI:
A treatment-policy estimand strategy will be used in participants who meet minimum 
disease requirements, and in participants who meet minimum disease requirements 
and have demonstrated Gram-negative pathogens to estimate the proportion of 
participants with death at the TOC visit and Day 28 of the study. Any death that 
occurred after first dose of study intervention through the nominal analysis timepoint 
will be included. A participant with the last known survival status that is before the 
nominal analysis timepoint or missing at the nominal analysis timepoint will be 
reported as an unknown status.
9.1.2. Hypothesis
There are no formal hypothesis tests planned for this study.
9.2. Sample Size Determination
According to the enrollment experience of the previously completed Phase 3 HAP/VAP 
study (REPROVE) and feasibility assessment, and considering the enrollment window and 
number of research centers that may participate, it is estimated that approximately 235
patients will be enrolled. Assuming a 17% data loss rate based on previous clinical study 


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experience, approximately 200 patients are expected to be evaluable for clinical cure rate in 
the cMITT population. 
Below table shows the precision (ie, 95% confidence interval) with 200 evaluable patients 
assuming the observed clinical response rate ranging from 60% to 75%.
Evaluable Number
Clinical Cure Rate
95% Confidence 
Interval (CI)
Half Width of the 
95% CI
200
60%
(53.2%, 66.8%)
6.8%
200
65%
(58.4%, 71.6%)
6.6%
200
70%
(63.6%, 76.4%)
6.4%
200
75%
(69.0%, 81.0%)
6.0%
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant / Defined 
Analysis Set
Description
Enrolled assigned to study 
intervention 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study following 
completion of the informed consent process. Potential participants who 
are screened for the purpose of determining eligibility for the study, but 
do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.
Modified Intent-to-Treat 
(MITT) Analysis Set
It will consist of all enrolled patients who have minimum disease criteria 
and receive any amount of study intervention.
clinical Modified 
Intent-to-Treat (cMITT) 
Analysis Set
This is a subset of the MITT analysis set, and will include participants:
• whose (properly obtained) baseline respiratory or blood cultures 
demonstrate Gram-negative pathogens with or without concomitant 
Gram-positive pathogens (excluding patients with Gram-negative 
pathogens not expected to respond to either study intervention [ie, 
participants with only the following monomicrobial Gram negative 
infections: any of the Acinetobacter species; or any Legionella species; 
or Stenotrophomonas maltophilia; or Elizabethkingia 
meningoseptica]);
OR
• participants in whom no etiologic pathogens are identified from 
respiratory or blood cultures at baseline.
microbiological Modified 
Intent-to-Treat (mMITT) 
Analysis Set
It is a subset of the MITT analysis set, and will include participants:
who have a properly obtained respiratory culture demonstrating 
Gram-negative pathogens, excluding patients not expected to respond to 
CAZ-AVI (ie, patients with only the following monomicrobial Gram-
negative infections: any of the Acinetobacter species; or any Legionella
species; or Stenotrophomonas maltophilia; or Elizabethkingia 
meningoseptica). If baseline respiratory cultures are not available or do 
not identify a respiratory pathogen, but a Gram-negative organism known 
to cause pneumonia is identified from baseline blood cultures, the 
participant will qualify for the mMITT population.
Safety Analysis Set (SAS)
All participants who take at least 1 dose of study intervention. 
Participants will be analyzed according to the product they actually 
received.


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9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.4.1. General Considerations
This is an estimation study. The clinical response, micobiological response and all-cause 
mortality from participants treated with CAZ-AVI will be estimated at different visit time 
points and in various analysis populations. The corresponding 95% CIs for the response rates 
will be calculated. 
9.4.2. Primary Endpoint(s)
The number and percent of participants having clinical cure, failure, and indeterminate at 
TOC visit in the cMITT analysis population will be summarized. Responses missing at the 
analysis visit such as due to intercurrent events, loss to follow up, early discontinuation will 
follow the details stated in Section 8.1.1. Clincial cure rate and the corresponding 2-sided 
95% CI will be provided.
Results will be listed together with the Phase 3 clinical study REPROVE to observe the 
consistency trend. 
Subgroup analyses will be performed by demographics and baseline disease characteristics 
such as APACHE II score, systemic antibiotics use, type of microbial infection, bacteremic.
The subgroup results will be compared with same subgroups in the REPROVE study. Due to 
different study times, operations, drug resistance, etc, the comparisons of results between this 
study and REPROVE study will not be subject to statistical comparison.
9.4.3. Secondary Endpoint(s)
Same analysis as the primary efficacy endpoint will be performed for the secondary efficacy 
endpoints. In particular, clinical cure rate, microbiological favorable response (per-patient 
and per-pathogen), and all-cause mortality will be summarized by number of participants (n), 
proportion of participants with corresponding 2-sided 95% CI.
9.4.4. Safety Analyses
All safety analyses will be performed on the safety population. These will be presented in 
tabular and/or graphical format and summarized descriptively and will follow Pfizer 
standards as appropriate.
The MedDRA coding system will be used to classify all AEs with respect to system organ 
class and preferred term. All causality and treatment-related, Treatment-emergent AEs, 
discontinuation due to AEs and laboratory data abnormalities will be summarized with 
frequency and percentages. 


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Absolute and change from baseline in selected laboratory tests and vital signs will be 
summarized with number (n), mean, standard deviation, median, minimum, and maximum. 
Number and percentages of participants meeting the categorical criteria of laboratory 
abnormality will be presented.
9.4.5. Other Analyse(s) 
None.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. 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. 
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a data monitoring committee (DMC).


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor and submitted to an IRB/EC 
by the investigator and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. 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 study 
intervention, 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 participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.


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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. The participant or his/her legally authorized representative should be given sufficient 
time and opportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized 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.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.


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10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ 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 will 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 participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
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 results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.


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www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.


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The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. 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.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor 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 participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.


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Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.


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10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. 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, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol and study intervention identifiers, 
participant 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 participant’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 


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contact number is not intended for use by the participant directly, and if a participant calls 
that number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 6.
Protocol Required Safety Laboratory Assessments
Hematology
Coagulation
Chemistry
Urinalysisa
Arterial blood 
gasc
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total 
neutrophils 
(Abs)
Eosinophils 
(Abs)
Monocytes 
(Abs)
Basophils 
(Abs)
Lymphocytes 
(Abs)
Partial 
thromboplastin 
time
Prothrombin 
time
International 
normalized 
ratio (INR)
BUN/BU and 
creatinine
Glucose (non-
fasting)
Calcium
Sodium
Potassium
Chloride
HCO3 /
CO2-CPf
AST 
ALT
Total bilirubin
Alkaline 
phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte 
esterase
Urobilinogen
Urine bilirubin
Microscopy 
and cultureb
Arterial pH
Partial pressure 
of oxygen 
(PaO2)
Partial pressure 
of carbon 
dioxide 
(PaCO2)
Oxygen 
saturation
Bicarbonate 
(HCO3)
At screening 
only:
FSHd
Pregnancy 
test (β-hCG)e
a.
Urinalysis is for screening purposes only.
b.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
c.
Required for ventilated participants; recommended for non-ventilated participants.
d.
For confirmation of postmenopausal status only. High FSH level in the postmenopausal range must be 
used to confirm a postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT.
e.
Serum or urine β-hCG for female participants of childbearing potential.
f.
HCO3 or CO2-CP results in blood chemistry will be assessed only for those participants at sites which 
can perform the HCO3 or CO2-CP tests.
Investigators must document their review of each laboratory safety report.














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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s) :

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).

OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described below, during the intervention period 
and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s). If a highly effective method that is user dependent is 
chosen, a second effective method of contraception, as described below, must also
be used. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 


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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1.
Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2.
Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition, a

high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.


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1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. The spermatogenesis cycle is 
approximately 90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
In addition, one of the following effective barrier methods must also be used when 
option 6 or 7 are chosen above:

Male or female condom with or without spermicide;


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
Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede 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 laboratory 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 
participant’s individual baseline values and underlying conditions. Participants 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:

Participants 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 participants 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).


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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 participant 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 for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also 
be given to drawing a separate tube of clotted blood and an 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/paracetamol (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) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels 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.


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Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
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10.6. Appendix 6: APACHE II Classification System
APACHE II SCORE FORM
PHYSIOLOGIC VARIABLE
HIGH ABNORMAL RANGE
LOW ABNORMAL RANGE
+4
+3
+2
+1
0
+1
+2
+3
+4
1. Temperature (°C)
≥41
39–40.9
38.5–38.9
36–38.4
34–35.9
32–33.9
30–31.9
≤29.9
2. Mean arterial pressure (mm Hg)
≥160
130–159
110–129
70–109
50–69
≤49
3. Heart rate (ventricular response)
≥180
140–179
110–139
70–109
55–69
40–54
≤39
4. Respiratory rate (non-ventilated or
ventilated)
≥50
35–49
25–34
12–24
10–11
6–9
≤5
5. Oxygenation
A-aDO2 or PaO2 (mm Hg)
a) FiO2 ≥0.5:record A-aDO2
≥500
350–499
200–349
<200
b) FiO2 <0.5:record only PaO2
>70
61–70
55–60
<55
6. Arterial pH – If no ABGs record
Serum HCO3 below
≥7.7
7.6–7.69
7.5–7.59
7.33–7.49
7.25–7.32
7.15–7.24
<7.15
7. Serum Sodium (mmol/L)
≥180
160–179
155–159
150–154
130–149
120–129
111–119
≤110
8. Serum Potassium (mmol/L)
≥7
6–6.9
5.5–5.9
3.5–5.4
3–3.4
2.5–2.9
<2.5
9. Serum Creatinine (mg/dL)
Double points for acute renal
failure
≥3.5
2–3.4
1.5–1.9
0.6–1.4
<0.6
10. Hematocrit (%)
≥60
50–59.9
46–49.9
30–45.9
20–29.9
<20
11. White Blood Count (k/mm3)
≥40
20–39.9
15–19.9
3–14.9
1–2.9
<1
12. Glasgow Coma Scale
(Score = 15 minus actual GCS)
15 – GCS=
A.    Total Acute Physiology Score
(APS)
Sum of the 12 individual points =

Serum HCO3 (venous-mmol/L)
Not preferred, use if no ABGs
≥52
41–51.9
32–40.9
22–31.9
18–21.9
15–17.9
<15


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Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 84
Abbreviations: ABGs = arterial blood gases; CHP = Chronic Health Points; CV = cardiovascular; GCS = Glasgow Coma Score; 
PHT = pulmonary hypertension.
APACHE II Score Worksheet:

Abstract data from the 24 hour interval prior to baseline. 

Enter the value for each line item.  Calculate APACHE II score using most recent local laboratory results. 
APACHE II Worksheet instruction
A - Physiological components

Document one score for each of the physiological variables.  Then calculate and document the total APS. 

The following will be accepted as core temperatures: rectal, esophageal, bladder, tympanic, or central.  If the only temperature 
data available is from the oral or axillary routes, convert the temperature to an APACHE II core value using the following 
conversion factors:

Actual oral temperature (°C) + 0.5C= Rectal (core) temperature;


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Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 85

Actual axillary temperature (°C) + 1.0°C = Rectal (core) temperature.

For the MAP value, use arterial line data if available, otherwise calculate the MAP from the cuff pressure using the following 
formula:
MAP = 1/3 (SBP – diastolic blood pressure [DBP]) + DBP
(Example: BP 90/60, MAP = 1/3 (90 - 60) + 60 = 10 + 60 = 70)
Note:  If a DBP was not obtained, do not calculate a MAP, record “not done”.

Oxygenation

in case the FiO2 is >50%, calculate the alveolo-arterial oxygen difference (A-aDO2) using the following formula, use ABGs 
results:
A-aDO2=[(FiO2 (713)-(partial pressure of carbondioxide (PaCO2)/0.8)] - PaO2
(Example: FiO2=0.6; PaO2=56; and PaCO2=26
(0.6 x 713) minus (26 : 0.8) minus 56
427 - 32.5 = 395.3 - 56 = 339.3 = A-aDO2 (mm Hg)
To calculate use FiO2 (in decimal), PaCO2 (mm Hg) and PaO2 (mm Hg).

If the FiO2 is <50%, record the lowest PaO2.

In case there is no ABG available assume normal oxygenation (Variable score = 0).

Serum creatinine (μmol/L): double point score for acute renal failure.  Creatinine conversion from μmol/L to mg/dL to be:  
88.4 mol/L= 1 mg/dL.

WBC Count.  Record WBCs in 1000s (eg, a WBC count of 30000 cells/mm3 would be recorded as 30).


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Protocol C3591026
Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 86

Arterial PH should be substituted by serum bicarbonate (HCO3) if there are no ABGs available in the previous 24 hours.
B – Age Points

Circle the appropriate point for the subjects age range.
C - Chronic Health Points
If the subject has a history of severe organ system insufficiency or is immunocompromised assign chronic health points as follows: 

For nonoperative or emergency postoperative subjects: 5;

For elective postoperative patients: 2;

Subject does NOT have a history of severe organ system insufficiency and is NOT immunocompromised: 0.
They will receive the points only once (which means even if they have 2 criteria, the maximum is either 2 or 5).
GLASGOW COMA SCALE
For the GCS score, determine the lowest (worst) number for each of the 3 factors in the scale (eye opening, verbal response, and motor 
response).  Add together these 3 numbers, and then subtract this number from 15 to get the final GCS score.  The subject's neurological 
status during a single neurological assessment should be evaluated. 
Since it is not possible to assess the GCS in subjects who are sedated and paralyzed, by convention the GCS is regarded as normal, 
unless it is known that there was a brain injury prior to sedation.  In that case the last measured GCS is to be used; if there is no brain 
injury prior to sedation the GCS is 15, thus the neurologic score will be 0.


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Protocol C3591026
Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 87
10.7. Appendix 7: Calculation of Estimated Creatinine Clearance
CALCULATION OF THE ESTIMATED CREATININE CLEARANCE
Estimated creatinine clearance will be calculated using the following Cockcroft-Gault 
formula9. The weight obtained at Screening should be used to qualify for entry into the study. 
In order to determine the need to adjust the dose and/or dosing interval of IV study 
intervention to be administered, the patient’s estimated creatinine clearance must be 
calculated using the most recent serum creatinine value that was obtained at the local 
laboratory, the patient’s most recent actual (not ideal) body weight, and the Cockcroft-Gault 
formula.
Cockcroft-Gault formula:
Estimated creatinine clearance is calculated by Cockcroft-Gault as follows:
For serum creatinine in mg/dL:
estimated creatinine clearance = [(140 – age) × weight in kilograms] / [72 × serum creatinine
in mg/dL]
(× 0.85 if female)
For serum creatinine in μmol/L:
estimated creatinine clearance = [(140 – age) × weight in kilograms × constant] / [serum
creatinine in μmol/L]
where constant = 1.23 for males and 1.04 for females.


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Protocol C3591026
Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 88
10.8. Appendix 8: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
5-HT
serotonin
A-aDO2
alveolar-arterial oxygen difference
ABGs
arterial blood gases
Abs
absolute
AE
adverse event
ALT
alanine aminotransferase
APACHE
Acute Physiology and Chronic Health Evaluation 
APS
Acute Physiology Score
AST
aspartate aminotransferase
AVI
Avibactam
BAL
bronchalveoloar lavage
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
BU
blood urea
BUN
blood urea nitrogen
CARES
Chinese antimicrobial resistance surveillance of nosocomial 
infection 
CAZ
Ceftazidime
CDAD
Clostridium difficile associated diarrhea
CE
clinical evaluable
CFR
Code of Federal Regulations
CHINET
China surveillance network for bacterial resistance 
CHP
Chronic Health Points
CI
confidence intervals 
cIAI
complicated intra-abdominal infection 
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
cMITT
clinically modified intent-to-treat 
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019 
CRAB
carbapenem-resistant Acinetobacter baumannii
CrCL
creatinine clearance
CRE
carbapenem-resistant Enterobacteriaceae 
CRF
case report form
CRO
contract research organization
CRPA
carbapenem-resistant Pseudomonas aeruginosa
CSR
clinical study report
CT
computed tomography/clinical trial
CCI


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Protocol C3591026
Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
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Abbreviation
Term
cUTI
complicated urinary tract infection
CXL
ceftaroline-avibactam 
CV
cardiovascular
DBP
diastolic blood pressure
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DRE
disease-related event
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EMA
European Medicines Agency
EOT
end of treatment 
ESBL
extended-spectrum β-lactamases
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration 
FiO2
fraction of inspired oxygen 
FPFU
final protocol follow up 
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GCS
Glasgow Coma Score
GGT
gamma-glutamyl transferase
HAP
Hospital-Acquired Pneumonia 
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormone replacement therapy
ICD
informed consent document
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product 
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IV
intravenous(ly)
KPC
Klebsiella pneumoniae carbapenemases
LDH
lactate dehydrogenase
LFT
liver function test
LPD
local product document
MAP
mean arterial pressure
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume


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Protocol C3591026
Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 90
Abbreviation
Term
MedDRA
Medical Dictionary for Regulatory Activities
MIC
minimum inhibitory concentration
MITT
modified intent-to-treat 
mMITT
microbiologically modified intent-to-treat 
msec
millisecond
MTZ
metronidazole 
N/A
Not Applicable
NI
non-inferiority
NIMP
noninvestigational medicinal product
NMPA
the National Medical Products Administration 
 
PACL
Protocol Administrative Change Letter
PaO2
partial pressure of oxygen 
PBS
Protected Brush Specimen
PK
pharmacokinetic(s)
q8h
every 8 hours 
q24h
every 24 hours 
Qual
qualitative
RBC
red blood cell
SAE
serious adverse event
SAS
safety analysis set 
SAP
statistical analysis plan
SBP
systolic blood pressure
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TOC
test of cure 
ULN
upper limit of normal
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman of childbearing potential
VAP
Ventilator-Associated Pneumonia 
CCI


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Final Protocol Amendment 1, 07 February 2022
PFIZER CONFIDENTIAL
Page 91
11. REFERENCES
1. Shi Y, Huang Y, Zhang TT, et al. Chinese guidelines for the diagnosis and treatment of 
hospital-acquired pneumonia and ventilator-associated pneumonia in adults (2018 
Edition). J Thorac Dis. 2019;11(6):2581-2616.
2. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health 
care-associated infections. N Engl J Med. 2014;370(13):1198-1208.
3. Wu A, Wen X, Li C, et al. China national point prevalence survey on healthcare-
associated infection and antimicrobial use in 2012. 2014;13(1):8-15.
4. Ren N, Wen X-M, Wu A-H. Study on the changing trends in national nosocomial 
infection transection investigation results. Chinese Journal of Infection Control. 
2007;6:16-18.
5. Hu F-P, Guo Y, Zhu D-M, et al. Resistance trends among clinical isolates in China 
reported from CHINET surveillance of bacterial resistance, 2005–2014. Clinical 
microbiology and infection. 2016;22:S9-S14.
6. National Health and Family Planning Commission. Report on antimicrobial stewardship 
and current status of antimicrobial resistance in China (2017). Peking Union Medical 
College Publishing House; 2017.
7. Keepers TR, Gomez M, Celeri C, et al. Bactericidal activity, absence of serum effect, and 
time-kill kinetics of ceftazidime-avibactam against β-lactamase-producing 
Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrobial Agents and 
Chemotherapy. 2014;58(9):5297-5305.
8. Thomson RB Jr. Specimen collection, transport, and processing: bacteriology. In: Murray 
PR, editor. Manual of Clinical Microbiology. 9th ed. Washington, DC: ASM Press; 2007: 
291-333.
9. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.

SAP_001.pdf: 
Protocol C3591026 (Ceftazidime - Avibactam) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3591026
A SINGLE ARM, OPEN-LABEL, MULTI-CENTER, INTERVENTIONAL STUDY 
EVALUATING THE EFFICACY AND SAFETY OF CEFTAZIDIME-AVIBACTAM 
(CAZ-AVI) IN CHINESE ADULTS WITH HAP (INCLUDING VAP)
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
22 May 2023


Protocol C3591026 (Ceftazidime - Avibactam) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.1.1. Primary Estimand (E1) .................................................................................7
2.1.2. Secondary Estimand(s).................................................................................7
2.1.2.1. Estimand for Clinical Response (E1)..........................................7
2.1.2.2. Estimand for Microbiologic Response (E2)................................8
2.1.2.3. Estimand for Efficacy in Patients with Pathogens 
Resistant to Ceftazidime (E3)..............................................................8
2.1.2.4. Estimand for All-cause Mortality (E4)........................................8
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.1.1. Clinical Response .......................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................11
3.2.1. Microbiological Response ..........................................................................12
3.2.1.1. Per-Pathogen Microbiological Response ..................................12
3.2.1.2. Per-Patient Microbiological Response......................................14
3.2.1.3. MIC Among Pathogens.............................................................14
3.2.2. Emergent Infections....................................................................................14
3.2.3. All-cause Mortality.....................................................................................15
3.4. Baseline Variables...................................................................................................15
3.4.1. Subgroup Analysis Variables .....................................................................16
3.4.2. Other Baseline Variables............................................................................17
3.5. Safety Endpoints .....................................................................................................17
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3.5.1. Adverse Events...........................................................................................17
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................18
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.2. General Methods .....................................................................................................19
5.3. Impact Assessment of COVID-19 and Remote TOC Visits...................................20
5.4. Methods to Manage Missing Data ..........................................................................21
6. ANALYSES AND SUMMARIES ......................................................................................21
6.1. Primary Endpoint(s) ................................................................................................21
6.1.1. Clinical Response at the TOC visit in the cMITT population....................21
6.1.2. Sensitivity Analyses....................................................................................21
6.2. Secondary Endpoint(s) ............................................................................................22
6.2.1. Clinical Response at the EOT Visit in cMITT Population, and at 
EOT, TOC Visits in the mMITT Population ...................................................22
6.2.2. Microbiologic Response at the EOT and TOC visit...................................22
6.2.3. Clinical and Microbiologic Response in Participants with Pathogens 
Resistant to Ceftazidime ..................................................................................23
6.2.4. Emergent Infections....................................................................................23
6.2.5. All-Cause Mortality....................................................................................23
6.2.6. Safey Endpoints..........................................................................................23
6.4. Subset Analyses.......................................................................................................24
6.5. Baseline and Other Summaries and Analyses.........................................................24
6.5.1. Baseline Summaries....................................................................................24
6.5.2. Study Conduct and Participant Disposition................................................24
6.5.3. Concomitant Medications...........................................................................25
6.6. Safety Summaries and Analyses .............................................................................25
6.6.1. Adverse Events...........................................................................................25
6.6.2. Laboratory Data..........................................................................................26
6.6.3. Vital Signs ..................................................................................................26
6.6.4. Extent of Exposure and Compliance ..........................................................26
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6.7. COVID-19 related analyses.....................................................................................27
7. INTERIM ANALYSES.......................................................................................................27
8. REFERENCES ....................................................................................................................27
APPENDICES .........................................................................................................................28
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Definitions of Clinical Response at the EOT Visit...................................10
Table 3.
Definitions of Clinical Response at the TOC Visit ..................................11
Table 4.
Microbiological Response Categories ......................................................13
Table 5.
Emergent infections..................................................................................14
Table 8.
HEMATOLOGY......................................................................................31
Table 9.
CHEMISTRY ...........................................................................................32
LIST OF FIGURES
Figure 1.
Study Outline..............................................................................................9
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................28
Appendix 3. Criteria for Potentially Clinically Significant Lab Results .................................31
Appendix 5. List of Abbreviations...........................................................................................34
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Objectives
Estimands
Endpoints
of pneumonia after Day 2 until TOC visit triggering 
treatment with further antibiotics will be regarded as 
failure clinical response.
Secondary: 
Secondary:
Secondary: 

To estimate clinical 
response to CAZ-AVI in 
HAP patients, and HAP 
patients with 
demonstrated 
Gram-negative 
pathogens.

Using a composite estimand strategy to estimate the 
clinical response rate at the end of treatment (EOT) visit 
in participants who meet minimum disease 
requirements, and at the EOT and TOC visits in 
participants who meet minimum disease requirements 
and have demonstrated Gram-negative pathogens. 
Clinical response will be categorized as cure, failure, 
and indeterminate per investigator’s assessment. 
Intercurrent events of death on study Day 1 or Day 2, 
death on or before EOT visit (or TOC visit accordingly) 
where HAP is clearly non-contributory, identification of 
an infectious complication of pneumonia between Day 1 
and Day 2 inclusive triggering further antibiotics 
treatment will be regarded as indeterminate clinical 
response. Intercurrent events of death between Day 3 
and EOT visit (or TOC visit accordingly) inclusive, 
development of infectious complications of pneumonia 
after Day 2 triggering further antibiotics treatment will 
be regarded as failure clinical response.

The proportion of 
participants with clinical 
cure at the EOT visit in 
cMITT population, and at 
the EOT, TOC visits in 
the microbiologically 
modified intent-to-treat 
(mMITT) population. 

To estimate the 
microbiologic response to 
CAZ-AVI.

Using a composite estimand strategy to estimate the 
per-patient and per-pathogen microbiological response 
rate at the EOT and TOC visits in participants who meet 
minimum disease requirements and have demonstrated 
Gram-negative pathogens. Microbiological response 
will be categorized as favorable (ie, eradication, or 
presumed eradication), unfavorable (persistence, 
persistence with increasing minimum inhibitory 
concentration [MIC], or presumed persistence), and 
indeterminate. Per-pathogen microbiological response 
will be summarized with the proportion of participants 
achieving favorable response by baseline pathogen type; 
per-patient microbiological response will be 
summarized with the proportion of participants 
achieving overall favorable response (ie, favorable for 
each of the baseline pathogen isolate). Intercurrent 
events of death or identification of an infectious 
complication of pneumonia triggering further antibiotics 
treatment such that an adequate source specimen is not 
available to culture will be regarded as an indeterminate 
microbiological response if clinical response is 
indeterminate, and will be regarded as a presumed 
eradication if a clinical cure is assessed.

The proportion of 
participants with the 
favorable per-patient 
microbiologic response at 
the EOT and TOC visits 
in the mMITT 
population.

The proportion of 
favorable per-pathogen 
microbiologic responses 
at the EOT and TOC 
visits in the mMITT 
population.

To estimate the efficacy 
of CAZ-AVI in patients 
with pathogens resistant 
to ceftazidime. 

Using the same composite estimand strategies as the 
primary estimand and aforementioned secondary 
estimands to estimate the proportions of participants 
with clinical cure and with a favorable per-patient 
microbiological response at the EOT and TOC visits in 
participants who meet minimum disease requirements
and have demonstrated Gram-negative pathogens that 
are resistant to ceftazidime.

The proportion of 
participants with clinical 
cure, and proportion of 
participants with 
favorable per-patient 
microbiologic response at 
the EOT and TOC visits 
in participants with 
pathogens resistant to 
ceftazidime in the 
mMITT population.


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Objectives
Estimands
Endpoints

To estimate all-cause 
mortality for CAZ-AVI.

Using a treatment-policy estimand strategy in 
participants who meet minimum disease requirements,
and in participants who meet minimum disease 
requirements and have demonstrated Gram-negative 
pathogens to estimate the proportion of participants with 
death at the TOC visit and Day 28 of the study. Any 
death that occurred after the first dose of study 
intervention through the nominal analysis timepoint will 
be included. A participant with the last known survival 
status that is before the nominal analysis timepoint or 
missing at the nominal analysis timepoint will be 
reported as an unknown status.

The proportion of 
participants with death 
due to any cause 
(all-cause mortality) at 
the TOC visit and at 
Day 28 in the cMITT and 
mMITT populations.

To evaluate the safety 
and tolerability of 
CAZ-AVI. 

N/A.

Assessment of treatment-
emergent adverse events
(TEAEs) and safety-
related clinical laboratory 
tests and vital 
observations.
2.1.1. Primary Estimand (E1)
The primary estimand of this study will use the composite policy strategy to estimate the 
clinical response to CAZ-AVI accounting for both treatment adherence and response. The 
estimand is defined according to the primary objective and is in alignment with the primary 
endpoint. It includes the following 4 attributes:

Population: Patients who have hospital-acquired pneumonia (HAP);

Variable: Clinical response per investigator’s assessment at the TOC visit. Clinical 
response will be categorized as cure, failure, and indeterminate. Intercurrent events 
of death on study Day 1 or Day 2, death on or before TOC visit where HAP is clearly 
non-contributory, identification of an infectious complication of pneumonia between 
Day 1 and Day 2 inclusive triggering treatment with further antibiotics will be 
regarded as indeterminate clinical response. Intercurrent events of death between 
Day 3 and TOC visit inclusive, development of infectious complications of 
pneumonia after Day 2 until TOC visit triggering treatment with further antibiotics 
will be regarded as failure clinical response;

Intercurrent event: The intercurrent events are addressed as part of the variable 
definition;

Population-level summary: The proportion of participants with clinical cure at the 
TOC visit.
2.1.2. Secondary Estimand(s)
2.1.2.1. Estimand for Clinical Response (E1)
The primary estimand E1 will be used. The proportion of participants with clinical cure at 
the EOT and TOC visits will be the analysis variables.


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2.1.2.2. Estimand for Microbiologic Response (E2)
The secondary estimand for microbiologic response will use the composite policy strategy to 
estimate the per-patient and per-pathogen microbiological response rate to CAZ-AVI 
accounting for both treatment adherence and response. The estimand is defined according to 
the secondary objective and is in alignment with the secondary endpoints. It includes the 
following 4 attributes:

Population: Patients who have hospital-acquired pneumonia (HAP) and have 
demonstrated Gram-negative pathogens;

Variable: The per-patient and per-pathogen microbiological response at the EOT visit 
and TOC visit. Microbiological response will be categorized as favorable (ie, 
eradication, or presumed eradication), unfavorable (persistence, persistence with 
increasing MIC, or presumed persistence), and indeterminate. Intercurrent events of 
death or identification of an infectious complication of pneumonia triggering further 
antibiotics treatment such that an adequate source specimen is not available to culture 
will be regarded as an indeterminate microbiological response if clinical response is 
indeterminate, a presumed persistence if a clinical failure is assessed and a presumed 
eradication if a clinical cure is assessed.

Intercurrent event: The intercurrent events are addressed as part of the variable 
definition;

Population-level summary: Per-pathogen microbiological response will be 
summarized with the proportion of participants achieving favorable response by 
baseline pathogen type; per-patient microbiological response will be summarized 
with the proportion of participants achieving overall favorable response (ie, favorable 
for each of the baseline pathogen isolate).
2.1.2.3. Estimand for Efficacy in Patients with Pathogens Resistant to Ceftazidime (E3)
Using the same composite estimand strategies as the primary estimand and aforementioned 
secondary estimands to estimate the proportion of participants with clinical cure and with a 
favorable per-patient microbiological response at the EOT and TOC visits in participants 
who meet minimum disease requirements and have demonstrated Gram-negative pathogens 
that are resistant to ceftazidime.
2.1.2.4. Estimand for All-cause Mortality (E4)
The secondary estimand for all-cause mortality will use the treatment policy strategy to 
estimate the all-cause death rate regardless of whether an intercurrent event occurs. The 
estimand is defined according to the secondary objective and is in alignment with the 
secondary endpoints. It includes the following 4 attributes:

Population: Patients who have hospital-acquired pneumonia (HAP);

Variable: Death due to any cause at the TOC visit and Day 28;




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3.1.1. Clinical Response
Clinical response outcome assessments will be assigned to each participants by the 
investigator at the EOT and TOC visits Table 2 and Table 3 respectively). Clinical response
will be classified as clinical cure, clinical failure, or indeterminate based on clinical outcome.
A clinical failure occurring at an earlier time point (eg, EOT) will be carried forward to the 
TOC visit. If the clinical response at the TOC visit is missing, it will be considered as being
indeterminate unless there was a previous clinical failure, in which case the clinical response
will be considered as clinical failure at the TOC visit.
Table 2.
Definitions of Clinical Response at the EOT Visit
Clinical response
Definition
Clinical Cure
Participants will be considered to be a cure for clinical response if:

The participant is alive and all signs and symptoms of pneumonia have 
resolved or improved such that all antibacterial therapies for HAP/VAP are 
stopped. No antibacterial therapy other than those outlined by the protocol has 
been administered for HAPa prior to EOT.
Clinical Failure
Participants who meet any 1 of the following criteria will be considered to be a failure 
for clinical response:

Mortality due to HAP/VAP between Day 3 of study intervention and the EOT 
visit inclusive.

Incomplete clinical resolution or worsening of HAP-specific signs and 
symptoms that requires additional antibacterial therapy for HAP at or before 
EOT.

Development of infectious complications of pneumonia such as empyema or 
lung abscess after Day 2.
Indeterminate
Participants who meet any 1 of the following criteria will be considered to be 
indeterminate for clinical response:

Participant lost-to-follow-up or assessment is not undertaken, such that a 
determination of clinical response cannot be made.

Death on or before the date of the EOT visit where HAP is clearly 
non-contributory.

Death on study Day 1 or Day 2.

Identification of an infectious complication of pneumonia such as empyema 
or lung abscess between Day 1 and Day 2 inclusive.
a.
In addition to protocol-allowed antibacterial therapy with study drug and open-label empiric linezolid 
and aminoglycoside, narrow-spectrum Gram-positive agents (ie, agents without Gram-negative coverage 
- eg, linezolid, vancomycin) and metronidazole (or any other antibiotic active solely against anaerobes) 
initiated after enrollment for HAP are permitted (ie, do not constitute a clinical failure), but must not 
continue past EOT.


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Table 3.
Definitions of Clinical Response at the TOC Visit
Clinical response
Definition
Clinical Cure
Participants will be considered to be a cure for clinical response if:

The participant was not a clinical failure at EOT, and the participant 
is alive and all signs and symptoms of pneumonia have resolved or 
improved to an extent that no antibacterial therapy for HAP was 
taken between EOT and TOC inclusive.
Clinical Failure
Participants who meet any 1 of the following criteria will be considered to 
be a failure for clinical response:

Designated as a clinical failure at an earlier time point (eg, EOT).

Mortality due to HAP between Day 3 of study intervention and the 
TOC visit inclusive.

Persistence, incomplete clinical resolution, worsening or 
recrudescence of HAP-specific signs and symptoms that requires 
initiation of antibacterial therapy for HAP between EOT and TOC, 
inclusive.

Development of complications of HAP such as empyema or lung 
abscess at or before the TOC visit.
Indeterminate
Participants who meet any 1 of the following criteria will be considered to 
be indeterminate for clinical response:

Participant lost-to-follow-up on or before the TOC visit or the 
assessment is not undertaken, such that a determination of clinical 
response cannot be made.

Death on or before the date of TOC visit where HAP is clearly 
non-contributory.

Death on study Day 1or Day 2 inclusive.

Identification of an an infectious complication of pneumonia such 
as empyema or lung abscess between Day 1 and Day 2 inclusive.
3.2. Secondary Endpoint(s)

The proportion of participants with clinical cure at the EOT visit in cMITT 
population, and at the EOT, TOC visits in the mMITT population.

The proportion of participants with the favorable per-patient microbiologic response 
at the EOT and TOC visits in the mMITT population.

The proportion of favorable per-pathogen microbiologic responses at the EOT and 
TOC visits in the mMITT population.

The proportion of participants with clinical cure, and proportion of participants with 
favorable per-patient microbiologic response at the EOT and TOC visits in 
participants with pathogens resistant to ceftazidime in the mMITT population.


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
The proportion of participants with death due to any cause (all cause mortality) at the 
TOC visit and at Day 28 in the cMITT and mMITT populations.

Assessment of TEAEs and safety-related clinical laboratory tests and vital 
observations.
3.2.1. Microbiological Response
Baseline respiratory cultures will be obtained within 48 hours prior to Day1 and after 
development of signs and symptoms of HAP (ideally before receipt of any systemic 
antibiotics). For cases that there are multiple respiratory cultures, the baseline respiratory 
culture is defined as the last respiratory culture obtained via BAL, mini BAL or PBS prior to 
Day 1. If BAL, mini BAL or PBS specimens are not available, the baseline respiratory 
culture will be defined as the last respiratory culture obtained via endotracheal aspirate prior 
to Day 1. If none of these are available, the baseline culture is defined as the last sputum 
culture obtained prior to Day 1.
Baseline blood cultures will be defined as all the cultures ontained within 24 hours prior to 
Day 1.
All the pathogens identified from the baseline respiratory cultures and the baseline blood 
cultures will be treated as baseline pathogens.
Baseline microbiology susceptibility for each baseline pathogen is defined as the result with 
the highest MIC value or the worst susceptibility if no MIC value available.
Identification of pathogens and susceptibility results will be recorded by both the local 
microbiology laboratory and the central reference laboratory. The identification and 
susceptibility results of the central reference laboratory will be regarded as definitive. Data 
from local lab will be used only if the microbiology tests were not done in the central lab.
Microbiological response at the EOT and TOC visits will be assessed based on the pathogens
isolated at baseline and during the course of treatment or the post-treatment period in the 
mMITT population. Microbiological response will be assessed per-pathogen and per-patient 
(overall) according to the definitions as provided below.
Microbiological responses other than “indeterminate” will be classified as “favorable” or 
“unfavorable”. Favorable microbiological response assessments include “eradication” and 
“presumed eradication”. Unfavorable microbiological response assessments include 
“persistence” “persistence with increasing MIC” and “presumed persistence”. “Super
infection” and “new infection” will be considered separately.
3.2.1.1. Per-Pathogen Microbiological Response
The per-pathogen microbiological response will be categorized according to the following 
definitions presented in Table 4 for each baseline pathogen . Per-pathogen response will be 
derived for the pathogens seen in either respiratory sample or blood samples, and will also be 
derived separately for pathogens seen only in the blood sample. Appendix 2 contains a 


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clarification of the definitions in these 2 ways, based upon example scenarios following a 
particular pathogen “X” appearing in either the respiratory sputum sample or the blood 
sample.
Table 4.
Microbiological Response Categories
Microbiological responsea
Definition
Eradication
An adequate source specimenb demonstrates absence of the original 
baseline pathogen.
Presumed eradication
An adequate source specimenb was not available to culture and the 
participant was assessed as a clinical cure.
Persistence
-
Persistence with 
increasing MICc
Adequate source specimenb demonstrates continued presence of the original 
baseline pathogen.
Continued presence of the causative organism in a culture of the respiratory 
infection obtained during or upon completion of treatment with IV study 
intervention, and the pathogen that was susceptible to IV study intervention
pre-treatment displays a ≥4-fold higher MIC to IV study intervention after 
treatment with IV study intervention.
Presumed persistence
An adequate source specimenb was not available to culture and the 
participant was assessed as a clinical failure.
Indeterminate
An adequate source specimenb was not available to culture and the 
participant’s clinical response was assessed as indeterminate.
a. The microbiological outcome will be determined from cultures obtained at the EOT and TOC visit window
respectively.
b. When assessing a respiratory sputum sample, an adequate source specimen is required - any sample that
may yield the growth of pathogen eg, blood, respiratory specimens, or pleural fluid.
c. ‘Persistence with increasing MIC’ is a subset of ‘persistence’.

For the per-pathogen response in respiratory site or blood, the pathogens observed in 
respiratory or blood samples are “pooled”, so that a follow-up pathogen observed in 
either culture source would count as persistence.

Once persistence, persistence with increasing MIC, or presumed persistence is 
experienced for a pathogen (at or beyond EOT) it will be carried forward to any later 
visits with a favorable or indeterminate response.

Once eradication is observed for a blood pathogen, no further blood samples would 
be expected, and therefore the eradication will be carried forward to later visits with 
no blood sample collected.
An adequate sputum sample is defined as follows:


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
From expectorated or induced sputum, an adequate sample is one with <10 squamous 
epithelial cells and >25 polymorphonuclear neutrophils per low-power field upon a 
Gram stain; throat secretions are considered to be inadequate; all other specimens 
(endotracheal aspirate, BAL, mini-BAL, PBS) are considered to be adequate.
3.2.1.2. Per-Patient Microbiological Response
Per-patient (overall) microbiological response at the EOT and TOC visits will be determined
based on individual outcomes for each baseline pathogen, including those from respiratory 
and blood samples. 
For participants from whom only 1 causative pathogen is isolated, the overall 
microbiological response will be based on the microbiological response assessment for that 
pathogen. For participants from whom more than 1 baseline pathogen is isolated, the overall 
microbiological response (patient-level) will be favorable only if the microbiological 
response for each of the baseline pathogens isolated is favorable. The overall 
microbiological response will be unfavorable if any one of the baseline pathogens is 
unfavorable. The overall microbiological response will be indeterminate in all other 
situations.
3.2.1.3. MIC Among Pathogens
The CAZ-AVI MIC categories that will be used are: ≤0.008, 0.015, 0.03, 0.06, 0.12, 0.25, 
0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256 and >256 μg/mL. For ceftazidime MIC categories that 
will be used are: ≤0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, and >128 μg/mL. All 
categories above 32 μg/mL will be grouped as “>32” in summary tables. For the purposes of 
this study, MICs reported as 0.06 and 0.12 μg/ml are equivalent to 0.0625 and 0.125 μg/ml 
respectively. If a patient has more than 1 isolates tested for the same pathogen species, the 
highest MIC value to CAZ-AVI for that pathogen will be selected.
3.2.2. Emergent Infections
Pathogens first appearing after baseline in participants with a baseline pathogen are 
categorized in Table 5 and will be summarized separately.
Table 5.
Emergent infections
Emergent infection
Definition
Super-infection
Emergence of new pathogen from any specimena during treatment with
study therapy associated with emergence or worsening of signs and
symptoms of infection and a requirement for additional antibiotics.
New infection
Emergence of new pathogen from any specimena after completion of study
therapy associated with emergence or worsening of signs and symptoms of
infection and a requirement for additional antibiotics.
a. When assessing a respiratory sputum sample, an adequate source specimen is required.




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3.4.1. Subgroup Analysis Variables
The following baseline variables will be used in the subgroup analyses for primary efficacy 
endpoint of clinical cure rate in the cMITT population.

Type of infection (Non-VAP and VAP).

Baseline severity of disease (via APACHE II score) (10-19, 20-30).

Ventilated or non-ventilated at baseline.
Note: A patient is considered to be ‘ventilated’ if (i) the patient is VAP, or (ii) the 
patient is Non-VAP and is on a ventilator on the day of enrollment.

Type of infection will be further considered by assessment of early- and late-VAP 
(among the VAP participants; VAP development on day 3 or 4 of hospitalisation 
defines ‘early’; and VAP development on or after day 5 of hospitalisation defines 
‘late’).

Prior systemic antibiotic use (yes/no)
Note: ‘yes’ if the patient is considered to be ‘exposed’ to prior antibiotic therapy 
within 2 days before randomization.

Monomicrobial or polymicrobial infection (or no pathogen).
Note: Mostly, type of microbial infection will be derived from the baseline sputum 
culture result. If more than one pathogen is isolated from the baseline sputum culture 
result, then the microbial type would be considered as polymicrobial. Otherwise, the 
microbial type would be considered as monomicrobial. However, if other (ie, blood) 
culture results occur to show additional pathogen(s) different from sputum culture 
results by which participants are considered monomicrobial, then these participants
will be overridden as polymicrobial.

Bacteremic at baseline (yes/no).
Note: If a bacterial pathogen is reported from the baseline blood culture results, 
regardless of whether the same pathogen is found in the baseline sputum culture or 
not, the patient would be designated as “bacteremic at baseline”. Otherwise, the 
patient would be considered as “not bacteremic at baseline”.

Age (18-45; 46-64; 65-74; 75-90).

Gender (male, female).

Renal function category at baseline ( CrCl 16-50 mL/min, CrCl 51-150 mL/min, CrCl 
151+ mL/min).


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3.4.2. Other Baseline Variables
Demographic and baseline characteristics include the following (besides above variables that 
will be used for subgroup analysis):

Age (years);

Medical history;

Height (cm);

Weight (kg);

Body mass index (BMI) [kg/m2];

BMI category (<18.5, 18.5 - <25, 25 - <30, ≥30);

APACHE II score;

Number of prior systemic antibiotic use (1 antibiotic, 2 antibiotics, 3 or more 
antibiotics);

Baseline pathogens;

Estimated creatinine clearance (CrCl) [mL/min];

Gram stain (G+ alone, G- alone, or G-mixed (ie, both + and -)).
3.5. Safety Endpoints
The safety endpoints of this study are:

Incidence of adverse events by study period: treatment period [from first dose to 
EOT] and for the full study period [from first dose to FPFU];

Incidence of clincal laboratory abnormalities (defined as Potentially Clinically 
Significant [PCS] results) and summary of values and change from baseline in 
clinical laboratory measures by scheduled visit;

Measurements and change from baseline in vital sign measures by scheduled visit.
3.5.1. Adverse Events
An adverse event (AE) is any untoward medical occurrence in a study participant
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage. An adverse event is considered a 
Treatment-Emergent Adverse Event (TEAE) if the event started after the study medication 
start date and time.
Adverse events will be classified using the Medical Dictionary for Regulatory Activities
(MedDRA) to determine System Organ Class and Preferred Term.


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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Participant/Defined Analysis 
Set
Description
Enrolled 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study following 
completion of the informed consent process. Potential participants who 
are screened for the purpose of determining eligibility for the study, but 
do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol.
Modified Intent-to-Treat 
(MITT) Analysis Set
It will consist of all enrolled participants who have minimum disease 
criteriaa and receive any amount of study intervention.
clinical Modified 
Intent-to-Treat (cMITT) 
Analysis Set
This is a subset of the MITT analysis set, and will include participants:
• whose (properly obtained) baseline respiratory or blood cultures 
demonstrate Gram-negative pathogens with or without concomitant 
Gram-positive pathogens (excluding participants with Gram-negative 
pathogens not expected to respond to either study intervention [ie, 
participants with only the following monomicrobial Gram negative 
infections: any of the Acinetobacter species; or any Legionella species; 
or Stenotrophomonas maltophilia; or Elizabethkingia 
meningoseptica]);
OR
• participants in whom no etiologic pathogens are identified from 
respiratory or blood cultures at baseline.
microbiological Modified 
Intent-to-Treat (mMITT) 
Analysis Set
It is a subset of the MITT analysis set, and will include participants:
who have a properly obtained respiratory culture demonstrating 
Gram-negative pathogens, excluding participants not expected to respond 
to CAZ-AVI (ie, participants with only the following monomicrobial 
Gram-negative infections: any of the Acinetobacter species; or any 
Legionella species; or Stenotrophomonas maltophilia; or Elizabethkingia 
meningoseptica). If baseline respiratory cultures are not available or do 
not identify a respiratory pathogen, but a Gram-negative organism known 
to cause pneumonia is identified from baseline blood cultures, the 
participant will qualify for the mMITT population.
Safety Analysis Set (SAS)
All participants who take at least 1 dose of study intervention. 
Participants will be analyzed according to the product they actually 
received.
See Appendix 1 for a detailed list of analysis sets used for different estimand, endpoint and 
timepoint.
a. Minimum disease criteria for HAP will be determined based on the following inclusion 
criteria.
Inclusion Criteria 3:
Onset of signs and symptoms (including Inclusion Criteria 4, 6, and 7) ≥48 hours after 
admission or <7 days after discharge from an inpatient acute or chronic care facility.


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Inclusion Criteria 4:
New or worsening infiltrate on chest X-ray or CT scan obtained within 48 hours prior to 
screening.
Inclusion Criteria 6:
At least 1 of the following systemic signs:

Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C)

White blood cell (WBC) count >10,000 cells/mm3, or WBC count <4500 cells/mm3, 
or >15% band forms.
Inclusion Criteria 7:
At least 2 of the following respiratory signs or symptoms:

A new onset of cough (or worsening of cough).

Production of purulent sputum or endotracheal secretions.

Auscultatory findings consistent with pneumonia/pulmonary consolidation (eg, rales, 
rhonchi, bronchial breath sounds, dullness to percussion, egophony).

Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2 <60 mmHg while 
breathing room air).

A need for mechanical ventilation or, for already ventilated participants, acute 
changes made in the ventilator support system to enhance oxygenation, as determined 
by, for example arterial blood gas or worsening PaO2/FiO2.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
This is an estimation study. No formal hypothesis testing will be performed for this study. 
5.2. General Methods
All data will be presented for the single CAZ-AVI treatment arm. Descriptive statistics 
(number, mean, standard deviation [SD], median, minimum, and maximum) will be provided 
for continuous variables, and counts and percentages will be presented for categorical 
variables. The corresponding 95% CIs for the response rates will be calculated using 
Jeffrey’s method (Brown et al. 2001; Cai 2005).1,2 Listings of individual participat data will 
also be produced.
Categorical and qualitative variable summaries for safety will include the frequency and 
percentage of subjects who are in the particular category. In general, the denominator for the 


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percentage calculation will be based upon the total number of participants in the 
cooresponding analysis population.
5.3. Impact Assessment of COVID-19 and Remote TOC Visits
Per protocol, the investigors must continue to collect AEs and perform safety reporting 
responsibilities per protocol via telephone contact or other methods as appropriate if on-site 
vists interrupted by the COVID-19 pandemic. Protocol-specified safety laboratory tests may 
be performed at a local hospital if the study participant is unable to visit the study site, where 
allowable by law or local guidance.
As TOC visit is the primary endpoint visit, attention to the compliance of TOC visit should 
be paid, and mitigations to reduce the non-compliance rate during the study ongoing are 
applied. Although there are still some cases that the onsite TOC visit failed to be 
accomplished, of which some are due to COVID-19 related issues and the others are due to 
the participants’ personal issue such as body health status. For these cases, remote TOC visit 
assessment will be done, which may be based on the local hospital laboratory test or through 
telephone contact with the participants. PDs will be categorized as “Visit was done 
remotely”, and these PDs will be used to flag the participants during the data analysis and 
reporting stage.
To closely monitor the rate of remote TOC visit and limit its impact on the final results of 
this study, especially on the primary endpoint of clincal response at TOC visit, a threshold 
for TOC non-compliance was setup. 
The TOC non-compliance rate of 15% was set as the monitoring threshold by study team per 
below considerations:

The remote TOC visit will increase the rate of  “Indeterminate” clinical response due 
to lack of on site assessment information for the efficacy assessment. And these will 
impact the final results of clincal response rate. Referring to other CAZ-AVI studies, 
the rate of Indeterminate is about 9.0% in cMITT analysis set.

The TOC non-compliance will include cases for subjects who were not evaluated as 
clinical failure at EOT but didn’t complete the TOC visit on site, including: a. Remote 
visit via telephone only; b. Remote visit via telephone and local hospital visit. Also 
the rate of indeterminate will be accumulated in the rate of non-compliance.

To monitor the TOC non-compliance, we use the 10% which is close to the expected 
indeterminate rate as a reference. Meanwhile, considering the non-compliance may 
include some cases which are assessed as cure or failure per remote assessment, we 
extend the threshold to 15% to be the threshold for monitoring.
Data collected via remote assessments will be treated the same as data collected via on-site 
visits including the primary endpoint of clinical response at TOC visit, which will be 
included in the primary analysis (Section 6.1.1) regardless of the events of COVID-19 


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pandemic or remote TOC visits. Besides the primary analysis, sensitivity analyses will be 
performed to show the impact of these events (Section 6.1.2).
5.4. Methods to Manage Missing Data
For efficacy data, missing data due to intercurrent events, loss to follow up, early 
discontinuation will be handled following the details stated in Section 3.1.1 and 
Section 3.2.1. For clinical response assessments that are not done or missing at TOC visit due 
to individual reasons other than the intercurrent events captured in the endpoints’ definitions, 
the clinical response of failure at the EOT visit will be carried forward to the TOC visit, 
otherwise it will be handled the same as an event of loss to follow up as stated in Section 
3.1.1. For microbiological response assessments that are not done or missing at TOC visit, if 
a pathogen is assessed as persistence or persistence with increasing MIC at the EOT visit, 
this assessment will be carried forward to the TOC visit. Oherwise it will be handled per 
Section 3.2.1.
For safety data, missing dates will be programmatically handled according to Pfizer 
standards.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Clinical Response at the TOC visit in the cMITT population

Estimand strategy: Composite policy strategy estimand E1 (Section 2.1.1).

Analysis set: cMITT population (Section 4).

Analysis methodology: Jeffrey’s method (Brown et al. 2001; Cai 2005)1,2 will be used to 
calculate the 95% CIs for the response rate (Section 5.2).  

Intercurrent events and missing data: These have been accounted for in the estimand
(Section 2.1.1), the definition of clinical response (Section 3.1.1) and methods to handle 
missing data (Section 5.4).

The number and percent of participants having clinical cure, failure, and indeterminate at 
TOC visit in the cMITT analysis population will be summarized. Clincial cure rate and 
the corresponding 2-sided 95% CI will be provided.

Results will be listed together with the Phase 3 clinical study REPROVE to observe the 
consistency trend.
6.1.2. Sensitivity Analyses
A sensitivity analysis of clinical response at TOC visit will be performed by removing the 
participants with remote TOC visits recorded as protocol deviations. Same method for the 
primary analysis in Section 6.1.1 will be applied.


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Another sensitivity analysis of clinical response at TOC visit will be performed by removing 
participants with remote TOC visits who didn’t have any signs or symptom information 
collected at the TOC visit. Same method for the primary analysis in Section 6.1.1 will be 
applied.
6.2. Secondary Endpoint(s)
6.2.1. Clinical Response at the EOT Visit in cMITT Population, and at EOT, TOC 
Visits in the mMITT Population

Estimand strategy: Composite policy strategy estimand E1 (Section 2.1.2.1).

Analysis set: cMITT population and the mMITT population (Section 4).

Analysis methodology: Jeffrey’s method (Brown et al. 2001; Cai 2005)1,2 will be used to 
calculate the 95% CIs for the response rate (Section 5.2).

Intercurrent events and missing data: These have been accounted for in the estimand 
(Section 2.1.2.1), the definition of clinical response (Section 3.1.1) and methods to handle 
missing data (Section 5.4).

The number and percent of participants having clinical cure, failure, and indeterminate at 
EOT visit in the cMITT analysis population and at EOT and TOC visits in the mMITT 
population will be summarized. Clincial cure rate and the corresponding 2-sided 95% CI 
will be provided.
6.2.2. Microbiologic Response at the EOT and TOC visit

Estimand strategy: Composite policy strategy estimand E2 (Section 2.1.2.2).

Analysis set: mMITT population (Section 4).

Analysis methodology: Jeffrey’s method (Brown et al. 2001; Cai 2005)1,2 will be used to 
calculate the 95% CIs for the per-patient and per-pathogen microbiological response rate
(Section 5.2).  

Intercurrent events and missing data: These have been accounted for in the estimand 
(Section 2.1.2.2), the definition of microbiological response (Section 3.2.1) and methods 
to handle missing data (Section 5.4). 

The number and percent of participants having favorable, unfavorable, and indeterminate
microbiological response at the EOT and TOC visits will be summarized. Per-pathogen 
microbiological response will be summarized with the proportion of participants 
achieving favorable response by baseline pathogen; per-patient microbiological response 
will be summarized with the proportion of participants achieving overall favorable
response (ie, favorable for each of the baseline pathogen isolate). Per-patient and 
per-pathogen (if numbers permit) favorable microbiological response rate and the 
corresponding 2-sided 95% CI will be provided.


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6.2.3. Clinical and Microbiologic Response in Participants with Pathogens Resistant to 
Ceftazidime

Estimand strategy: Composite policy strategy estimand E3 (Section 2.1.2.3).

Analysis set: the subpopulation of participants with pathogens resistant to ceftazidime in 
the mMITT population (Section 4).

Analysis methodology: Jeffrey’s method (Brown et al. 2001; Cai 2005)1,2 will be used to 
calculate the 95% CIs for the clinical cure rate and the favorable per-patient 
microbiologic reponse rate (Section 5.2).  

Intercurrent events and missing data: These have been accounted for in the estimand
(Section 2.1.2.3), the definition of clinical and microbiological response (Section 3.1.1
and Section 3.2.1) and methods to handle missing data (Section 5.4). 

The number and percent of participants having clinical cure, failure, and indeterminate 
and having favorable, unfavorable, and indeterminate microbiological response at the 
EOT and TOC visits will be summarized. Clincial cure rate and the per-patient favorable
microbiological response rate and the corresponding 2-sided 95% CI will be provided.
6.2.4. Emergent Infections
The number and percentage of patients who reported at least 1 superinfection or new 
infection will be summarized for the mMITT analysis sets.
6.2.5. All-Cause Mortality

Estimand strategy: Treatment policy strategy estimand E4 (Section 2.1.2.4).

Analysis set: Same analyses will be done in the cMITT and mMITT populations 
respectively (Section 4).

Analysis methodology: Jeffrey’s method (Brown et al. 2001; Cai 2005)1,2 will be used to 
calculate the 95% CIs for the all-cause mortality (Section 5.2).  

Intercurrent events and missing data: These have been accounted for in the estimand
(Section 2.1.2.4). 

The number and percent of participants with death due to any cause at the TOC visit and 
at Day 28 will be summarized. And the corresponding 2-sided 95% CI for all cause 
mortality will be provided.
6.2.6. Safey Endpoints
The details of safety analyses are described in the Section 6.6.




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6.5.3. Concomitant Medications 
All prior and concomitant medications will be summarized. Systemic antibiotic medications 
will be summarized and listed separately.
6.6. Safety Summaries and Analyses
All safety analyses will be performed on the safety population. Standard summary tables and 
listings will be generated using Pfizer’s Clinical Data Analysis and Reporting System 
(CDARS) for the following parameters: adverse events, lab parameters (hematology, blood 
chemistry, and urinalysis), vital signs, discontinuations from study, discontinuations from 
treatment and treatment duration.
Unless otherwise noted, AEs will be sorted by MedDRA hierarchy (alphabetically by SOC, 
then HLGT, HLT and PT, however only SOC and PT will be displayed in the summary 
tables).
6.6.1. Adverse Events
All TEAEs will be summarized separately for the study periods (treatment period [from first 
dose to the EOT visit] and for the full study period [from first dose to the end of study). 
TEAEs will be summarized by number and percent by system organ class (SOC) and 
preferred term (PT). 
The following summaries for the CAZ-AVI treatment will be presented:

Any TEAE;

Any SAE;

TEAEs leading to death;

TEAEs leading to discontinuation;

Severe TEAEs.
The number and percentage of participants experiencing the AEs will be summarized for the 
CAZ-AVI treatment as following:

Summary of TEAEs by system organ class and preferred term;

Summary of TEAEs by system organ class and preferred term, split by highest 
reported intensity;

Summary of drug-related TEAEs by system organ class and preferred term;

Summary of TEAEs leading to discontinuation by system organ class and preferred 
term;


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
Summary of SAEs by system organ class and preferred term,
Appropriate listings of SAEs, AEs, AEs that led to discontinuation and AEs leading to death 
will be presented. Non-TEAEs will be included in the listing. Listings of the details of all 
deaths will also be presented.
6.6.2. Laboratory Data
Laboratory data for hematology and clinical chemistry will be summarized as described in 
Section 5.2 by study visit for observed values and for the corresponding change from 
baseline (CFB) values. Frequencies of potentially clinically significant values occurring 
during the clinical study will also be presented (hematology and clinical chemistry). 
Potentially clinically significant criteria are outlined in Appendix 3.
Shifts from low, normal, and high relative to the normal range between baseline and each 
post-baseline time point will be evaluated for hematology and clinical chemistry laboratory 
parameters. 
In addition, a summary table will be presented which will indicate the number of subjects 
who separately meet the laboratory criteria for potential Hy’s Law after the start of study 
treatment at any time up to the EOT visit and up to the FPFU visit: The AST, ALT, total 
bilirubin and ALP elevations can occur at any time in the specific review period and do not 
need to occur simultaneously.
A listing of participants with elevations in any one of the AST, ALT, Total bilirubin 
parameters will be also presented. ie, Participants with a value of ≥3xULN for ALT or AST 
or a value of ≥2xULN for Total bilirubin. This listing will contain all the ALT, AST, Total 
bilirubin and ALP study data for such participants.
Listings of values for each patient will be presented with abnormal or out-of-range values 
flagged. Local laboratory test values will be listed for each patient.
6.6.3. Vital Signs
Vital signs will be summarized for the observed values and for the corresponding CFB values 
at each applicable visit for the single CAZ-AVI treatment group.
Vital signs for all participants will be listed.
6.6.4. Extent of Exposure and Compliance
Exposure to study drug during the treatment period will be summarized for the safety 
analysis set.
Exposure (in days) to study therapy will be summarized. In addition, the number of IV 
infusions and the number of each individual component of study therapy will be summarized 
by baseline renal status (categories based on CrCl as outlined in Section 0).


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Descriptive statistics (number of patients, mean, SD, minimum, median and maximum value) 
of treatment compliance will be presented for CAZ-AVI treatment group using the cMITT 
and safety analysis sets.
Compliance over the whole treatment period will be calculated as follows:
Compliance =   Actual Number of Doses Received     * 100 
                                      Planned Number of Doses
The planned number of doses can be counted based on the total number of planned doses 
recorded in the CRF.
A subject is considered compliant if between 80% and 120% of the planned number of doses 
is received. Interruption in therapy is considered non-compliance only if the compliance 
criteria described above is not met. Medication compliance will be summarized (n, mean, 
standard deviation, median, minimum and maximum). The compliance will also be 
summarized in the following categories: <80%, ≥ 80% to 120%, and >120% by the number 
and percentage of subjects.
6.7. COVID-19 related analyses
In addtion to the above planned sensitivity analyses in Section 6.1.2 regarding COVID-19 
impact to the primary endpoint, the analyses specified below will also be provided to reflect 
the impact of COVID-19 pandemic. 
Protocol deviations related to COVID-19 will be listed. The discontinuations from study or 
study drug due to COVID-19 will be summarized. And the treatment emergent COVID-19 
related adverse events will be summarized by SOC and PT.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. 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. 
8. REFERENCES
1.
Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. 
Statistical Science 2001, 16 (2):101-117.
2.
Cai TT. One-sided confidence intervals in discrete distributions. J Stat Plan Inference 
2005;131(1):63-68.


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APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint/Variable
Analysis Set
Statistical Method
Timepoint
Objective
Estimand
Clinical Cure
cMITT
Summary of Proportion
95% CI for Response Rate
TOC
Primary Endpoint
E1
Clinical Cure
cMITT
Summary of Proportion
95% CI for Response Rate
EOT
Secondary Endpoint
E1
Clinical Cure
mMITT
Summary of Proportion
95% CI for Response Rate
EOT and TOC
Secondary Endpoint
E1
Microbiologic Response
mMITT
Summary of Proportion
95% CI for Response Rate
EOT and TOC
Secondary Endpoint
E2
Clinical Cure and Favorable 
Per-patient Microbiologic 
Response
participants with pathogens 
resistant to ceftazidime in 
the mMITT population
Summary of Proportion
95% CI for Response Rate
EOT and TOC
Secondary Endpoint
E3
Death
cMITT and mMITT
Summary of Proportion
95% CI for mortality
TOC and Day 28
Secondary Endpoint
E4






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Appendix 3. Criteria for Potentially Clinically Significant Lab Results
Table 8.
HEMATOLOGY
PCS Low Decrease; if both Below LLN 
and % Decrease from Baseline
PCS High Increase: if both Above ULN 
and % Increase from Baseline
Parameter
Lower Limit 
% decrease from 
baseline
Upper Limit
% increase from 
baseline
Hemoglobin 
<0.8 × LLN
>20%
>1.3 × ULN
>30%
Hematocrit
<0.8 × LLN
>20%
>1.3 × ULN
>30%
Erythrocyte count 
(RBC)
<0.8 × LLN
>20%
>1.3 × ULN
>30%
Leukocytes (WBC)
<0.65 × LLN  
>60%
>1.6 × ULN
>100%
Neutrophils
<0.65 × LLN  
>75%
>1.6 × ULN
>100%
Lymphocytes
<0.25 × LLN  
>75%
>1.5 × ULN
>100%
Eosinophils
N/A 
N/A
>4.0 × ULN
>300%
Monocytes
N/A 
N/A
>4.0 × ULN
>300%
Basophils
N/A 
N/A
>4.0 × ULN
>300%
Platelets count
<0.65 × LLN 
>50%
>1.5 × ULN
>100%
LLN = lower limit of normal range provided by the local laboratory; ULN = upper limit of normal range 
provided by the local laboratory; RBC = red blood cell; WBC = white blood cell; N/A = not applicable.


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Table 9.
CHEMISTRY
PCS Low Decrease; if both Below LLN 
and % Decrease from Baseline
PCS High Increase: if both Above ULN 
and % Increase from Baseline
Parameter
Lower Limit 
% decrease from 
baseline
Upper Limit
% increase from 
baseline
Bicarbonate 
<0.7 × LLN
>40%
>1.3 × ULN
>40%
Sodium 
<0.85 × LLN
>10%
>1.1 × ULN
>10%
Potassium 
<0.8 × LLN
>20%
>1.2 × ULN
>20%
Phosphorus  
<0.5 × LLN
>50%
>3.0 × ULN
>200%
Chloride 
<0.8 × LLN
>20%
>1.2 × ULN
>20%
Calcium 
<0.7 × LLN
>30%
>1.3 × ULN
>30%
Alkaline 
phosphatase
<0.5 × LLN  
>80%
>2.0 × ULN
>100%
ALT 
N/A
N/A
>3.0 × ULN
>200%
AST 
N/A
N/A
>3.0 × ULN
>200%
Gamma-glutamyl 
transferase
N/A
N/A
>3.0 × ULN
>200%
Total bilirubin 
N/A
N/A
>2.0 × ULN
>150%
Direct bilirubin 
N/A
N/A
>2.5 × ULN
>150%
Glucose, fasting
<0.6 × LLN  
>40%
>3.0 × ULN
>200%
Glucose, 
nonfasting
<0.6 × LLN  
>40%
>3.0 × ULN
>200%
Total protein 
<0.5 × LLN
>50%
>1.5 × ULN
>50%
Albumin 
<0.5 × LLN
>50%
>1.5 × ULN
>50%
Creatinine 
N/A
N/A
>2.0 × ULN
>100%
Urea nitrogen 
(BUN)
<0.2 × LLN  > 
200%
>100%
>3.0 × ULN
>200%
LLN = lower limit of normal range provided by the local laboratory; ULN = upper limit of normal range 
provided by the local laboratory; N/A = not applicable; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; BUN = blood urea nitrogen.


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CCI


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Appendix 5. List of Abbreviations
Abbreviation
Term
AE
adverse event
ALP
llkaline phosphatase
ALT
alanine aminotransferase
APACHE
Acute Physiology and Chronic Health Evaluation
AST
aspartate aminotransferase
BAL
bronchalveoloar lavage
BMI
Body mass index
BUN
blood urea nitrogen
CAZ-AVI
ceftazidime-avibactam
CDARS
Clinical Data Analysis and Reporting System
CFB
change from baseline
CI
confidence interval
cMITT
clinical modified intent-to-treat
CrCL
creatinine clearance
EOT
end of treatment
FPFU
final protocol follow up
HAP
hospital-acquired pneumonia
HLGT
High-Level Group Terms
HLT
High-Level Terms
IV
intravenously
LLN
lower limit of normal range
MedDRA
Medical Dictionary for Regulatory Activities
MIC
minimun inhibitory cocentration
MITT
modified intent-to-treat
mMITT
microbiological modified intent-to-treat
N/A
not applicable
NG
no growth
PBS
Protected Brush Specimen
PCS
Potentially clinically significant
PT
Preferred Term
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD
Standard deviation
SOC
System Organ Class
TEAE
treatment-emergent adverse event
TOC
test of cure
ULN
upper limit of normal range
VAP
ventilator-associated pneumonia
WBC
white blood cell