Clinical trial NCT04882085
Conditions: Urinary Tract Infection Acute Pyelonephritis Hospital Acquired Pneumonia Ventilator-associated Pneumonia Bacteremia Intra-abdominal Infection
Sponsor: Pfizer
Start date: 2021-08-26; Completion date: 2023-08-31
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, randomized, multi-center, interventional, active-controlled Phase 4 study to evaluate the efficacy and safety of CAZ-AVI versus BAT in the treatment of infected participants with selected infection types (Hospital Acquired Pneumonia \[HAP\] (including Ventilator-Associated Pneumonia \[VAP\]); Complicated Urinary-Tract Infection \[cUTI\]; Complicated Intra-Abdominal Infection \[cIAI\]; Bloodstream Infection \[BSI\]) due to carbapenem-resistant Gram-negative pathogens in China.This study will be an estimation study. The statistical inference will be based on point estimate and confidence interval.

Detailed description:

Arms: arm 1: ceftazidime 2g plus avibactam 0.5g arm 2: Based on investigative site practice and local epidemiology and guideline
Interventions: intervention 1: Zavicefta, Ceftazidime-Avibactam intervention 2: Best Available Treatment
Intervention descriptions: intervention 1: CAZ-AVI 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered IV as a 2 hour infusion every 8 hours. Dose adjustments are available for participants with CrCL ≤50 mL/min. intervention 2: main treatment expected to be used as either monotherapy or in combination are colistin, tigecycline, fosfomycin, amikacin, and meropenem

Protocol documents:
Prot_000.pdf: 
Ceftazidime-Avibactam 
Protocol C3591033 
Protocol Amendment 1, 02 June 2022 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
AN OPEN-LABEL, RANDOMIZED, MULTI-CENTER, ACTIVE-CONTROLLED 
STUDY TO ESTIMATE THE EFFICACY AND SAFETY OF 
CEFTAZIDIME-AVIBACTAM (CAZ-AVI) VERSUS BEST AVAILABLE 
TREATMENT (BAT) IN THE TREATMENT OF INFECTIONS DUE TO 
CARBAPENEM-RESISTANT GRAM-NEGATIVE PATHOGENS IN CHINESE 
ADULTS 
 
 
Study Intervention Number: 
PF-06947386 
Study Intervention Name: 
Ceftazidime-Avibactam 
US IND Number: 
N/A 
 
EudraCT Number: 
N/A 
Protocol Number: 
C3591033 
Phase: 
4 
Short Title: The Efficacy and Safety of Ceftazidime-Avibactam (CAZ-AVI) Versus 
Best Available Treatment (BAT) in the Treatment of Infections due to Carbapenem- 
resistant Gram-negative Pathogens in Chinese Adults 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


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Protocol C3591033 
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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 
Substantial or 
Nonsubstantial 
Amendment 
1 
02 June 
2022 
• Based on real clinical practice and 
the definition of best available 
treatment, added investigator’s 
standard of care in line with local 
guidelines as the dose and 
frequency selection criteria of BAT 
administration on the basis of the 
LPD in section 4.1, section 4.2 and 
section 6.1.1.2. 
Substantial 
• During the COVID-19 pandemic, 
for reducing risk to participants, the 
following changes have been 
incorporated in section 1.3 and 
section 6.1: 
1. If participants are unable to visit 
study sites due to COVID-19 
pandemic or local policies, the 
investigators must continue to 
collect AEs and perform safety 
reporting responsibilities per 
protocol via telephone contact or 
other methods as appropriate 
(Section 1.3 note “v”). 
2. 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. 
Local laboratory reference ranges 
need to be documented (Section 1.3 
note “i”). 
3. If the sponsor cannot provide study 
drugs centrally due to COVID-19 
pandemic, and the investigator 
assesses that the participant should 
receive study drugs continuously, 
Non-substantial 
Non-substantial 
Substantial 


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Protocol C3591033 
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Document History 
Document 
Version 
Date 
Summary and Rationale for Changes 
Substantial or 
Nonsubstantial 
the study drugs can be provided 
with local sourcing (Section 6.1). 
• Updated CAZ-AVI information to 
align with new version of LPD in 
section 5.3.2. 
Non-substantial 
• Typographical errors were corrected 
in section 1.3 and section 5.1.1 per 
PACL dated 22 Jul 2021 and 
22 Dec 2021. 
Non-substantial 
• Based on the guideline and local 
clinical practice, white blood cell 
count is an objective criterion for 
infectious disease diagnosis and 
efficacy assessment. Added “white 
blood cell count in hematology or 
urine test” as objective symptoms or 
signs in section 5.1 inclusion 
criterion 3 per PACL dated 
22 Jul 2021. 
Non-substantial 
• It is understood that the additional 
unstained sputum smears cannot be 
obtained for specimens from the 
screening visit which have been 
completed based on the standard of 
care at site. Clarification added that 
the additional unstained gram stain 
slide is not required in screening 
visit in section 10.8 per PACL dated 
22 Jul 2021. 
Non-substantial 
• Changed the end of reviewing 
concomitant therapy from “TOC” to 
“LFU” in section 6.5 to keep 
consistency with section 1.3 per 
PACL dated 22 Dec 2021. 
Non-substantial 


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Protocol Amendment 1, 02 June 2022 
PFIZER CONFIDENTIAL 
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Document History 
Document 
Version 
Date 
Summary and Rationale for Changes 
Substantial or 
Nonsubstantial 
• Modified the format of Table 11 in 
section 10.2 to keep the format 
consistent and ensure clarity per 
PACL dated 22 Dec 2021. 
Non-substantial 
Original 
protocol 
02 Dec 
2020 
N/A 
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 change 
letter(s). 


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PFIZER CONFIDENTIAL 
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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..................................................................................................................... 16 
1.3. Schedule of Activities .............................................................................................. 17 
2. INTRODUCTION ................................................................................................................ 23 
2.1. Study Rationale ........................................................................................................ 23 
2.2. Background .............................................................................................................. 24 
2.2.1. Clinical Urgent clinical needs /Treatment status ........................................ 24 
2.2.2. Clinical Overview ....................................................................................... 25 
2.3. Benefit/Risk Assessment ......................................................................................... 25 
2.3.1. Risk Assessment ......................................................................................... 26 
2.3.2. Benefit Assessment ..................................................................................... 27 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 27 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ............................................................ 27 
4. STUDY DESIGN ................................................................................................................. 29 
4.1. Overall Design ......................................................................................................... 29 
4.2. Scientific Rationale for Study Design ..................................................................... 30 
4.3. Justification for Dose ............................................................................................... 31 
4.4. End of Study Definition ........................................................................................... 32 
5. STUDY POPULATION ...................................................................................................... 33 
5.1. Inclusion Criteria ..................................................................................................... 33 
5.1.1. Additional Inclusion Criteria ...................................................................... 34 
5.2. Exclusion Criteria .................................................................................................... 37 
5.2.1. Additional Exclusion Criteria ..................................................................... 38 
5.3. Lifestyle Considerations .......................................................................................... 39 
5.3.1. Contraception .............................................................................................. 39 
5.3.2. Controlled sodium diet ................................................................................ 39 
5.4. Screen Failures ......................................................................................................... 40 


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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ...................................................................................... 40 
6. STUDY INTERVENTION ................................................................................................. 40 
6.1. Study Intervention(s) Administered ........................................................................ 40 
6.1.1. Administration ............................................................................................ 41 
6.1.1.1. CAZ-AVI Treatment Arm ........................................................ 41 
6.1.1.2. Comparator Treatment Arm- Best Available Treatment .......... 42 
6.1.1.3. Optional Gram positive Antibiotics .......................................... 42 
6.1.1.4. Optional Aminoglycosides ........................................................ 43 
6.2. Preparation/Handling/Storage/Accountability ......................................................... 43 
6.2.1. Preparation and Dispensing ........................................................................ 44 
6.3. Measures to Minimize Bias: Randomization and Blinding .................................... 44 
6.3.1. Allocation to Study Intervention ................................................................ 44 
6.3.2. Breaking the Blind ..................................................................................... 45 
6.4. Study Intervention Compliance .............................................................................. 45 
6.5. Concomitant Therapy ............................................................................................. 45 
6.6. Dose Modification .................................................................................................. 49 
6.7. Intervention After the End of the Study ................................................................. 49 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 49 
7.1. Discontinuation of Study Intervention .................................................................... 49 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 51 
7.2.1. Withdrawal of Consent .............................................................................. 51 
7.3. Lost to Follow-up ................................................................................................... 52 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................. 52 
8.1. Efficacy Assessments ............................................................................................. 53 
8.1.1. Clinical Response Assessment ................................................................... 53 
8.1.2. Microbiological Response ......................................................................... 54 
8.1.3. All-cause mortality at Day 28 .................................................................... 57 
8.2. Safety Assessments ................................................................................................. 57 
8.2.1. Physical Examinations ............................................................................... 57 
8.2.2. Vital Signs .................................................................................................. 58 


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8.2.3. Clinical Safety Laboratory Assessments ..................................................... 58 
8.2.4. Pregnancy Testing ....................................................................................... 59 
8.3. Adverse Events and Serious Adverse Events .......................................................... 59 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ....... 60 
8.3.1.1. Reporting SAEs to Pfizer Safety ............................................... 60 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 60 
8.3.2. Method of Detecting AEs and SAEs ........................................................... 61 
8.3.3. Follow-up of AEs and SAEs ....................................................................... 61 
8.3.4. Regulatory Reporting Requirements for SAEs ........................................... 61 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ........................................................................................................... 61 
8.3.5.1. Exposure During Pregnancy ...................................................... 62 
8.3.5.2. Exposure During Breastfeeding ................................................. 63 
8.3.5.3. Occupational Exposure .............................................................. 64 
8.3.6. Cardiovascular and Death Events (Not applicable) ..................................... 64 
8.3.7. Disease -Related Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 64 
8.3.8. Adverse Events of Special Interest ............................................................. 65 
8.3.8.1. Lack of Efficacy ......................................................................... 65 
8.3.9. Medical Device Deficiencies ...................................................................... 65 
8.3.10. Medication Errors ...................................................................................... 65 
8.4. Treatment of Overdose ............................................................................................ 66 
8.5. Pharmacokinetics ..................................................................................................... 66 
8.6. Pharmacodynamics .................................................................................................. 66 
8.7. Genetics ................................................................................................................... 66 
8.8. Biomarkers ............................................................................................................... 66 
8.9. Immunogenicity Assessments ................................................................................. 66 
8.10. Health Economics .................................................................................................. 66 
9. STATISTICAL CONSIDERATIONS ................................................................................. 67 
9.1. Estimands and Statistical Hypotheses ..................................................................... 67 
9.1.1. Estimands .................................................................................................... 67 
9.1.2. Hypothesis ................................................................................................... 68 


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9.2. Sample Size Determination .................................................................................... 68 
9.3. Analysis Sets ........................................................................................................... 69 
9.4. Statistical Analyses ................................................................................................. 70 
9.4.1. General Considerations .............................................................................. 70 
9.4.2. Primary Endpoint(s) ................................................................................... 70 
9.4.3. Secondary Endpoint(s) ............................................................................... 71 
9.4.4. Other Safety Analyses ................................................................................ 71 
9.4.5. Other Analyse(s) (Not applicable) ............................................................. 72 
9.5. Interim Analyses ..................................................................................................... 72 
9.6. Data Monitoring Committee or Other Independent Oversight Committee ............ 72 
9.6.1. Independent Adjudication Committee: ...................................................... 72 
9.6.2. Internal Review Committee: ...................................................................... 72 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.......................................................................................................... 73 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 73 
10.1.1. Regulatory and Ethical Considerations .................................................... 73 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 73 
10.1.2. Financial Disclosure ................................................................................. 74 
10.1.3. Informed Consent Process ....................................................................... 74 
10.1.4. Data Protection ......................................................................................... 75 
10.1.5. Dissemination of Clinical Study Data ...................................................... 75 
10.1.6. Data Quality Assurance ............................................................................ 76 
10.1.7. Source Documents ................................................................................... 78 
10.1.8. Study and Site Start and Closure .............................................................. 78 
10.1.9. Publication Policy .................................................................................... 79 
10.1.10. Sponsor’s Qualified Medical Personnel ................................................. 79 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 81 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................... 82 
10.3.1. Definition of AE ....................................................................................... 82 
10.3.2. Definition of SAE .................................................................................... 83 


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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs ....................... 84 
10.3.4. Reporting of SAEs .................................................................................... 87 
10.4. Appendix 4: Contraceptive Guidance .................................................................... 89 
10.4.1. Male Participant Reproductive Inclusion Criteria .................................... 89 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................. 89 
10.4.3. Woman of Childbearing Potential ............................................................. 90 
10.4.4. Contraception Methods ............................................................................. 91 
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......... 93 
10.6. Appendix 6: APACHE II Classification System ................................................... 95 
10.7. Appendix 7: Calculation of Estimated Creatinine Clearance ................................ 97 
10.8. Appendix 8: Microbiological Assessments ........................................................... 98 
10.9. Appendix 9: Abbreviations .................................................................................. 101 
11. REFERENCES ................................................................................................................. 105 


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LIST OF TABLES 
Table 1. 
Comparison of ceftazidime and avibactam exposure and target 
attainment in Phase 3 participants stratified across different races .......... 32 
Table 2. 
Additional Inclusion Criteria ................................................................... 34 
Table 3. 
Additional Exclusion Criteria .................................................................. 38 
Table 4. 
Recommended intravenous doses for participants with estimated 
CrCL ≤50 mL/mina .......................................................................................................................... 41 
Table 5. 
Allowed Concomitant Medication ........................................................... 46 
Table 6. 
Restricted Concomitant Medications ....................................................... 48 
Table 7. 
Prohibited Concomitant Medications ....................................................... 48 
Table 8. 
Definition of Clinical Response Categories at the EOT and TOC 
Visits ........................................................................................................ 53 
Table 9. 
Definition of Microbiological Response Categories at the EOT and 
TOC Visits, for Each Pathogen Identified at Initial/Pre Study 
(Study Qualifying) Culture ...................................................................... 55 
Table 10. 
Definition of Emergent Infection Categories ........................................... 57 
Table 11. 
Protocol-Required Safety Laboratory Assessments ................................. 81 
 
 
LIST OF FIGURES 
Figure 1. 
Study Outline ........................................................................................... 16 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: The Efficacy and Safety of Ceftazidime-Avibactam (CAZ-AVI) Versus Best 
Available Treatment (BAT) in the Treatment of Infections due to 
Carbapenem-resistant Gram-negative Pathogens in Chinese Adults 
Rationale 
In China, the prevalence of carbapenem-resistant (CR) pathogens has been showing an 
increasing trend in many national surveillance studies and observational studies. Infections 
due to CR pathogens are associated with high risk of death. 
CAZ-AVI was approved by the National Medical Products Administration (NMPA) on 
21 May 2019 for the indications of complicated intra-abdominal infection (cIAI), 
hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP), and infection 
due to aerobic Gram-negative organisms with limited treatment options (LTO) in adults. 
This study is designed to address the request from the Centre of Drug Evaluation (CDE) 
regarding further evaluation of effectiveness and safety of CAZ-AVI in Chinese patients with 
infections due to carbapenem resistant Gram-negative pathogens, which can represent the 
population with limited treatment options. 
Objectives, Estimands, and Endpoints 
 
Objectives 
Estimands 
Endpoints 
Primary: 
Primary: 
Primary: 
• To estimate the 
efficacy of 
CAZ-AVI and best 
available treatment 
(BAT) in patients 
with infections due 
to Carbapenem- 
resistant 
Gram-negative 
pathogens. 
• Estimand E1: The trial will estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the 
difference in clinical response of cure in patients with 
infections due to carbapenem-resistant Gram-negative 
pathogens. A composite estimand strategy will be 
used to account for intercurrent events that are part of 
the definition of clinical response. Intercurrent events 
of death after receiving <48 hours of study treatment, 
or inadequate infection source control at time of 
initial surgical procedure (for cIAI participants) will 
be regarded as indeterminate clinical response. 
Intercurrent events of death after receiving at least 48 
hours of study treatment, or receiving treatment with 
further antibiotics for the index infection will be 
regarded as a failure clinical response. 
• Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
TOC visit 
Secondary: 
Secondary: 
Secondary: 
• To estimate the 
efficacy of 
CAZ-AVI and BAT 
in patients with 
infections due to CR 
• Estimand E1 will be the esimand for this objective. 
• Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
TOC visit 


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Objectives 
Estimands 
Endpoints 
gram-negative 
pathogens and who 
are 
microbiologically 
evaluable. 
• To estimate the 
clinical response to 
CAZ-AVI and BAT 
at the end of 
treatment. 
• Estimand E1 will be the esimand for this objective. 
• Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
EOT visit 
• To estimate the 
microbiological 
response to 
CAZ-AVI and 
BAT. 
• Estimand E2: The trail will estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the 
difference of favorable microbiological response in 
patients with infections due to carbapenem-resistant 
Gram-negative pathogens. A composite estimand 
strategy will be used to account for intercurrent 
events that are part of the definition of 
microbiological response. Intercurrent events of death 
after receiving <48 hours of study treatment, or 
inadequate infection source control at time of initial 
surgical procedure (for cIAI participants) will be 
regarded as indeterminate microbiological response. 
Intercurrent events that result in repeat culture of 
specimen not performed/clinically indicated (specific 
to cIAI and HAP/VAP participants) will be regarded 
as a presumed eradication if a clinical cure is 
assessed, and a presumed persistence microbiological 
response if a clinical failure is assessed. 
• Microbiological 
response (defined by 
favorable, 
unfavorable, or 
indeterminate) at 
EOT and TOC visits 
• To estimate the 
all-cause mortality 
for CAZ-AVI and 
BAT. 
• Estimand E3: Using a treatment-policy estimand 
strategy in patients with infections due to 
carbapenem-resistant Gram-negative pathogens to 
estimate the treatment effect of CAZ-AVI relative to 
BAT in terms of the difference of all-cause mortality 
at Day 28 of the study. Any death that occurred after 
first dose of study drug through Day 28 will be 
included. A participant with the last known survival 
status is before Day 28 or missing will be reported as 
an unknown status. 
• All-cause mortality 
at Day 28 
• To evaluate the 
safety and 
tolerability of CAZ- 
AVI. 
• N/A 
• Assessment of 
TEAEs, 
discontinuation due 
to AEs, 
safety-related 
clinical laboratory 
tests. 


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Overall Design 
This is an open-label, randomized, multi-center, interventional, active-controlled Phase 4 
study to evaluate the efficacy and safety of CAZ-AVI versus BAT in the treatment of 
infected participants with selected infection types (Hospital Acquired Pneumonia [HAP] 
(including Ventilator-Associated Pneumonia [VAP]); Complicated Urinary-Tract Infection 
[cUTI]; Complicated Intra-Abdominal Infection [cIAI]; and Bloodstream Infection [(BSI]) 
due to carbapenem-resistant Gram-negative pathogens in China. Carbapenem-resistant is 
defined as resistant to carbapenems (imipenem, meropenem), including resistant and 
intermediate. 
The study will consist of a Screening visit, a Baseline visit on Day 1 of the study treatment, 
ongoing treatment visits (Days 2-14), an End of Treatment visit within 24 hours after the last 
infusion, a Test of Cure (TOC) visit (7-10 days after EOT visit), and a Late Follow-Up 
(LFU) visit (28-32 days after the last dose of study intervention). 
The study is open-label due to the complicated dosing regimens and choice of appropriate 
best available treatment. The investigators, site personnel, and participants will not be 
blinded in this open-label study. An independent adjudication committee will be blinded with 
the aim of unbiased adjudication of the primary objective measure. 
Number of Participants 
The study will randomize approximately 60 participants in a 1:1 ratio into 2 treatment groups 
(CAZ-AVI or BAT). Randomization will be stratified by the infection sites: HAP (including 
VAP); cUTI; cIAI; BSI (including primary BSI, catheter related BSI [CR BSI], and BSI 
related to HAP [including VAP], cUTI, and cIAI). Among the 4 strata, the first 3 infection 
sites will not include participants with BSI complications. 
Intervention Groups and Duration 
Treatment arms in the study: 
• Study intervention: CAZ-AVI, participants randomized to the CAZ-AVI treatment arm 
will receive CAZ-AVI 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered IV as a 
2-hour infusion every 8 hours (q8h). Dose adjustments are available for participants with 
CrCL ≤50 mL/min. 
• Best Available Treatment (BAT), based on investigative site practice and local 
epidemiology and guideline (main treatment expected to be used as either monotherapy 
or in combination are colistin, tigecycline, fosfomycin, amikacin, and meropenem). 
The duration of treatment is 5 days up to 14 days for cUTI, cIAI and BSI, and 7 days up to 
14 days for HAP/VAP, which can be extended to 21 days depending on the participant’s 
condition and investigator’s judgement as clinical practice required. 


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Independent Adjudication Committee: 
This is an open-label study. An independent adjudication committee consisting of at least 
3 clinical experts will be convened at regular intervals during the study. 
A charter will be in place for the adjudication committee. The adjudication committee will be 
blinded to study treatment and investigator’s assessment of clinical response. The committee 
will review the clinical data points, reports and results of the diagnostic tests used to classify 
the clinical response. In case of a discrepancy with the investigator’s assignment of clinical 
response, the adjudication committee’s assessment will prevail for the analysis. 
Internal Review Committee 
An Internal Review Committee (IRC) will be established with an IRC charter for this study 
and will independently review the data in an unblinded fashion approximately every 
6 months to ensure that the safety of participants is not compromised. 
The IRC will be responsible for ongoing monitoring of the safety of participants in the study 
according to the charter and may propose changes to the protocol as needed to ensure 
participant safety. The IRC will also review results of any interim analysis as planned in the 
study. 
Statistical Methods 
This study will be an estimation study. The statistical inference will be based on point 
estimate and confidence interval. 
Efficacy analyses: 
In general, for continuous variables, N, mean, standard deviation, median, minimum, and 
maximum will be provided, and for categorical variables, numbers and percentages of 
participants from each category will be provided. In particular, the point estimate and 95% 
confidence interval will be calculated for each individual treatment group, as well as the 
difference between treatment groups in clinical cure rate and per-participant favorable 
microbiological response (if data permit). Individual treatment group confidence interval will 
be computed using Jeffrey’s method. Confidence interval for difference between treatment 
group will be computed using Miettinen & Nurminen method stratified by infection site. If 
number of participants in a particular stratum is small, then the unstratified Miettinen & 
Nurminen method will be used. Subgroup analyses will be performed for infection type if 
data permit. 
Safety analyses: 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively. All treatment-emergent AEs, relationship with treatment, discontinuations due 
to AEs, and laboratory data abnormalities will be summarized using percentages. Change 


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from baseline for selected laboratory tests and vital signs will be summarized with 
descriptive statistics. 
A Statistical Analysis Plan (SAP) will be developed that defines all analysis populations, and 
methods to summarize the efficacy and safety data. 


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1.2. Schema 
Figure 1. 
Study Outline 
 


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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
 
Activity 
Abbreviations used in this table 
may be found in Appendix 9 
Prescreening Eligibility/ 
Screeninga 
Treatment duration 
EOT 
TOC 
LFU 
Visit Window/ 
Study Day 
Within 5 
days prior to 
Screening 
Screening 
Visit 1 
Day -1 
Visit 2 
Day 1 
(Baseline)b 
Visits 3-15 
Days 2-14c 
Visit 16 
within 24 hours of end 
of last infusion 
Visit 17 
Day 21 to Day 24 
Visit 18 
28-32 days after 
the last dose of 
study intervention 
Study Procedure 
Abbreviated informed 
consent to CAZ-AVI 
sensitivity test of isolatesd 
X 
Informed consent 
X 
Inclusion and exclusion 
criteria 
X 
X 
Demographics 
X 
Medical history 
X 
APACHE II score (see 
Appendix 6)e 
X 
Review prior and 
concomitant medications 
(including prior antibiotic 
treatment) 
X 
X 
Daily 
X 
X 
X 
Randomization 
X 
Medical Procedures 
Complete physical 
examination 
X 
X 
X 
Weight and height 
X 


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Activity 
Abbreviations used in this table 
may be found in Appendix 9 
Prescreening Eligibility/ 
Screeninga 
Treatment duration 
EOT 
TOC 
LFU 
Visit Window/ 
Study Day 
Within 5 
days prior to 
Screening 
Screening 
Visit 1 
Day -1 
Visit 2 
Day 1 
(Baseline)b 
Visits 3-15 
Days 2-14c 
Visit 16 
within 24 hours of end 
of last infusion 
Visit 17 
Day 21 to Day 24 
Visit 18 
28-32 days after 
the last dose of 
study intervention 
Perform focused physical 
examination 
X 
X 
Daily 
X 
X 
Xf 
Vital sign measurementsg 
X 
X 
Daily 
X 
X 
Ventilator status (HAP/VAP 
only) 
X 
X 
Daily 
X 
X 
Urinary device status (cUTI 
participants only) 
X 
X 
Daily 
X 
X 
Chest X ray or computed 
tomography scan (for 
HAP/VAP participants only) 
Xh 
As clinically 
indicated 
As clinically 
indicated 
As clinically indicated 
As clinically 
indicated 
Collection of imaging and 
surgical report (for cIAI 
participants only) 
X 
As clinically 
indicated 
As clinically 
indicated 
As clinically indicated 
As clinically 
indicated 
Laboratory assessmentsi 
Hematology 
X 
X 
Day 2. Then 
every 3 days 
X 
X 
Blood chemistry 
X 
X 
Day 2. Then 
every 3 daysj 
X 
X 
Coagulation 
X 
X 
Day 2. Then 
every 3 days 
X 
X 
Pregnancy testk 
X 
X 
X 
Estimate CrCLl 
X 
X 
Day 2. Then 
every 3 daysj 
As clinically indicated 
Contraception check 
X 
X 
X 
X 
X 
Urine sample for microscopic 
WBC (cUTI participants 
only)m 
X 
X 
As clinically 
indicated 
X 
X 
Collection of arterial blood 
gases 
Xn 
As clinically 
indicated 
As clinically 
indicated 
As clinically indicated 


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Activity 
Abbreviations used in this table 
may be found in Appendix 9 
Prescreening Eligibility/ 
Screeninga 
Treatment duration 
EOT 
TOC 
LFU 
Visit Window/ 
Study Day 
Within 5 
days prior to 
Screening 
Screening 
Visit 1 
Day -1 
Visit 2 
Day 1 
(Baseline)b 
Visits 3-15 
Days 2-14c 
Visit 16 
within 24 hours of end 
of last infusion 
Visit 17 
Day 21 to Day 24 
Visit 18 
28-32 days after 
the last dose of 
study intervention 
Identify isolate from study 
qualifying cultureo and send 
to central laboratoryp 
X 
Quantitative urine culture 
(cUTI participants only)q 
X 
As clinically 
indicated 
X 
X 
Blood cultures 
Xr 
If blood cultures are positive, repeat at least every 3 days until 
negative or EOT. Blood cultures should also be performed as 
clinically indicated. 
Culture of abdominal site 
infection (for cIAI 
participants only)s 
As clinically 
indicated 
As clinically 
indicated 
As clinically indicated 
As clinically 
indicated 
Appropriate respiratory 
specimen for Gram 
stain/culture (for HAP/VAP 
participants only) 
Xt 
As clinically 
indicated 
Xu 
X 
Study intervention 
Determination and 
documentation of Best 
Available Treatment prior to 
randomization 
X 
Study intervention 
administration 
X 
Daily 
Control treatment 
administration 
X 
Daily 
Clinical assessment 
Assess infection related signs 
and symptoms 
X 
X 
Daily 
X 
X 
Clinical Response 
X 
X 
Safety assessmentv 


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Activity 
Abbreviations used in this table 
may be found in Appendix 9 
Prescreening Eligibility/ 
Screeninga 
Treatment duration 
EOT 
TOC 
LFU 
Visit Window/ 
Study Day 
Within 5 
days prior to 
Screening 
Screening 
Visit 1 
Day -1 
Visit 2 
Day 1 
(Baseline)b 
Visits 3-15 
Days 2-14c 
Visit 16 
within 24 hours of end 
of last infusion 
Visit 17 
Day 21 to Day 24 
Visit 18 
28-32 days after 
the last dose of 
study intervention 
Mortalityw 
X 
→ 
→ 
→ 
X 
Serious and nonserious 
adverse event monitoring 
X 
→ 
→ 
→ 
→ 
→ 
Concomitant treatment(s)x 
X 
X 
→ 
→ 
→ 
X 
a. 
Study treatment should be started as soon as possible (within 24 hours) after a participant’s eligibility has been confirmed and the participant has been 
randomized. Consequently, Day -1 and Day 1 may be the same calendar day, ie, all procedures scheduled for Day -1 and Day 1 could happen on the same 
day. 
b. All procedures at Visit 2 are to be done before first dose of study intervention. Repeat safety lab samples (including local lab for eligibility criteria 
confirmation) and CrCL assessment are only required if Visit 1 and Visit 2 are separated by surgery OR are >24 hours apart. Administration of the first dose 
of IV study treatment marks the beginning of study treatment Day 1 (Visit 2). 
c. 
Treatment duration can be extended to 21 days depending on the participant’s condition and investigator’s judgement as clinical practice required. The 
investigator should continue to perform the assessments for visit 3-visit 15. 
d. The abbreviated informed consent to sensitivity test of CR pathogen is only needed if the test is not the standard of care at the sites. 
e. 
Calculate APACHE using most recent local laboratory results available within the previous 24 hours prior to Screening. Arterial blood gases are required for 
ventilated and recommended for non-ventilated HAP/VAP participants, and for cIAI, cUTI and BSI participants as clinically indicated. If an arterial blood 
gas is not clinically indicated, the APACHE score will be calculated using serum bicarbonate instead of arterial pH and assuming normal oxygenation 
(Variable score = 0). 
f. 
If the participant has been discharged from hospital and is unable to return, the physical examination will not be conducted at the LFU visit since the visit 
will be conducted by telephone. 
g. Vital signs should be measured and documented at least once daily, preferably at a similar time each day. However, if any significant excursions occur 
during the study day, those measurements should also be captured. The participant’s body temperature will be evaluated at least twice a day (suggested at 
least 8 hours apart) and the actual time of body temperature collection will be recorded. Fever will be defined as a body temperature ≥38°C. For each 
individual participant, the method of temperature measurement ideally should be consistent for the duration of the study. At the TOC visit only a single body 
temperature measurement is required. The actual time of body temperature collection will be recorded. For participants with HAP/VAP, respiratory rate 
(breath per minute) and peripheral O2 saturation will be collected at Visit 2, at Visit 3, daily while the participant is receiving IV study treatment, at EOT and 
TOC visits. 
h. Chest X-ray or CT scan, only if test has not already been performed with available results within 48 hours prior to randomization. 
i. 
At Screening, the laboratory assessments will be performed in the local laboratory for eligibility determination as defined in Section 5. During treatment 
period, if ALT or AST are >3 × ULN and the participant has not met the liver discontinuation criteria (see Appendix 5), the frequency of liver laboratory 


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Activity 
Abbreviations used in this table 
may be found in Appendix 9 
Prescreening Eligibility/ 
Screeninga 
Treatment duration 
EOT 
TOC 
LFU 
Visit Window/ 
Study Day 
Within 5 
days prior to 
Screening 
Screening 
Visit 1 
Day -1 
Visit 2 
Day 1 
(Baseline)b 
Visits 3-15 
Days 2-14c 
Visit 16 
within 24 hours of end 
of last infusion 
Visit 17 
Day 21 to Day 24 
Visit 18 
28-32 days after 
the last dose of 
study intervention 
testing collection, and INR, should be increased to daily monitoring (using local laboratory data and recorded as unscheduled visits) until the liver function 
tests recover to ≤3 × ULN. Refer to Appendix 2 for details on collection of the required laboratory variables. Protocol-specified safety laboratory tests may 
be performed at a local hospital if the study participant is unable to visit the study site due to COVID-19 pandemic, where allowable by law or local 
guidance. Local laboratory reference ranges need to be documented. 
j. 
In CAZ-AVI arm, for participants with changing renal function, monitor CrCL at least daily and adjust the dosage of CAZ-AVI accordingly. In BAT arm, 
when colistin is administered, the CrCL should be measured daily and dose adjusted appropriately. The blood chemistry test should be performed also as 
clinically indicated. 
k. Serum or urine β-hCG for pregnancy test in female participants of childbearing potential will performed in local laboratory for eligibility determination. 
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. 
l. 
Participants must be frequently and closely monitored for rapidly changing CrCL through local laboratory measurement of serum creatinine (See 
Appendix 7). In case that renal function recovers or deteriorates during the treatment period, the dose of study treatment should be adjusted by the 
investigator to meet the appropriate dose regimen, based on the latest CrCL value and in line with Section 6.1.1.1. 
m. Obtain a urine sample for microscopic WBC count to assess for presence of persisting pyuria (cUTI participants only). 
n. For HAP/VAP participants – obtaining arterial blood sample for ABG (required for ventilated participants, recommended for non-ventilated participants); 
for cIAI, cUTI and BSI participants obtaining arterial blood sample for ABG as clinically indicated. 
o. The appropriate culture for study qualifying microbiological isolate obtained within 5 days prior to screening will be detailed in the study microbiology 
manual (see Appendix 8). For cIAI, adequate abdominal specimen (such as tissue or aspirate suitable for isolation of both aerobic and anaerobic bacteria) 
must be obtained for culture at the initial qualifying procedure. For HAP/VAP, appropriate respiratory specimen including endotracheal aspirate, 
expectorated or induced sputum bronchoalveolar lavage (BAL), mini-BAL or protected-specimen brush (PSB) sampling should be collected for culture. For 
cUTI participants, a quantitative culture of urine is required. For BSI, 2 sets of blood cultures (1 anaerobic and 1 aerobic bottle in each set) should be 
collected. 
p. Study qualifying microbiological isolate is a CR Gram-negative bacteria and culture-confirmed susceptibility to CAZ-AVI (see Inclusion Criteria in 
Section 5.1) that was isolated from an appropriate specimen obtained within 5 days prior to screening. And the isolate must be sent to the central 
microbiology laboratory vendor for confirmation. 
q. A culture from urine must be obtained at Baseline and prior to the first dose of study therapy and/or change of the antibacterial therapy for participants with 
cUTI only. 
r. 
All participants must have had 2 sets of blood cultures obtained prior to randomization. Repeat samples for blood cultures are not required at baseline if 
available within 48 hours prior to randomization. Blood should be taken prior to the first dose of study treatment if not available within 48 hours prior to 
randomization. When obtaining samples for blood culture, blood should be collected from 2 sites (see Appendix 8). All participants require 2 sets of blood 


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Activity 
Abbreviations used in this table 
may be found in Appendix 9 
Prescreening Eligibility/ 
Screeninga 
Treatment duration 
EOT 
TOC 
LFU 
Visit Window/ 
Study Day 
Within 5 
days prior to 
Screening 
Screening 
Visit 1 
Day -1 
Visit 2 
Day 1 
(Baseline)b 
Visits 3-15 
Days 2-14c 
Visit 16 
within 24 hours of end 
of last infusion 
Visit 17 
Day 21 to Day 24 
Visit 18 
28-32 days after 
the last dose of 
study intervention 
cultures (1 anaerobic and 1 aerobic bottle from each site, ie, 4 bottles in total). For participants who are found to be bacteremic any time during the study, 
repeat blood cultures should be taken at least every 3 days, until clearance of bacteremia is documented or EOT visit. Blood cultures should also be obtained 
as clinically indicated. See Appendix 8 for details of sample collection. 
s. 
For cIAI participants with surgical specimens collected on or after the Baseline visit, both aerobic and anaerobic cultures should be performed on specimens 
collected from the site of abdominal infection and on specimens collected from other clinically relevant intra-abdominal sites (see Appendix 8). 
t. 
Repeat respiratory specimen cultures are not required, unless a study-qualifying sample prior to screening was obtained from a non-ventilated participant 
and the participant is subsequently ventilated (or the participant had a bronchoscopy). In this case, an appropriate respiratory specimen should be obtained 
prior to the first dose of study treatment (see Appendix 8). 
u. If treatment is discontinued early because the participant is failing therapy or other reasons, an appropriate respiratory specimen for Gram stain/culture 
should be obtained, ideally after stopping the initial treatment but before the new treatment is administered. 
v. If participants are unable to visit study sites due to COVID-19 pandemic or local policies, the investigators must continue to collect AEs and perform safety 
reporting responsibilities per protocol via telephone contact or other methods as appropriate. 
w. Investigator should also follow the participants who have died due to any reason up to Day 28 after randomization. 
x. Collection of concomitant treatments will include blood and other blood product transfusions. 


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2. INTRODUCTION 
Ceftazidime is the bactericidal β-lactam component of CAZ-AVI. It is a third-generation 
cephalosporin that is approved for the treatment of several bacterial infections. Its efficacy 
and tolerability profile is well characterized through many years of experience of use in 
clinical practice in numerous countries worldwide. Avibactam is a first-in-class non-β-lactam 
β-lactamase inhibitor of serine β-lactamases with a spectrum of inhibition that includes class 
A extended-spectrum beta-lactamases (ESBLs) and carbapenemases (eg, Klebsiella 
pneumoniae carbapenemase [KPC]), class C β lactamases, and some class D oxacillinases 
and carbapenemases. However, it is not active against class B metallo-β-lactamases, and it is 
not active against Acinetobacter baumannii.1 The addition of avibactam to ceftazidime 
extends the β-lactam’s antibacterial activity against pathogens producing β-lactamases that 
are susceptible to inhibition by avibactam, while retaining ceftazidime’s bactericidal 
activity.2 Avibactam therefore has the potential to restore the utility of ceftazidime in the 
clinical setting. 
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). 
2.1. Study Rationale 
Carbapenems are the drugs of choice for serious infections caused by ESBL-producing 
organisms. Carbapenems are the only reliable β-lactam drugs for the treatment of severe 
Enterobacter spp. infections. Resistance to carbapenems is rare but occurs in strains that 
produce serine-carbapenemases (KPC enzymes) and Metallo-β-lactamases (MBLs). Over the 
past decade, a group of serine carbapenemases termed “KPC” has been increasingly reported 
from around the world.3 
Data from China multicenter bacterial resistance networks (ie, China surveillance network 
for bacterial resistance [CHINET], 2004-20154 and Chinese antimicrobial resistance 
surveillance of nosocomial infection [CARES], 20165) showed that the isolation rate for 
various organisms among various specimens (blood, urine, sputum, etc.) was: 
1. Carbapenem-resistant A baumannii (CRAB) up to 60%-70% 
2. Carbapenem-resistant Pseudomonas aeruginosa (CRPA) was 20% ~ 40% 
3. ESBL-producing K pneumoniae was 25% ~ 35% 
4. ESBL-producing Escherichia coli was 45% ~ 60% 
5. CRE among various specimens (blood, urine, sputum) was 5% ~ 18% 
In 2016, CHINET reported the resistance rates of P aeruginosa to imipenem and meropenem 
were 28. 7% and 25. 3%, respectively.6 


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The INFORM Global Surveillance Project tested 4411 isolates of nosocomial infections from 
a total of 10 medical centers in China from 2014-2016. The resistance rates of K pneumoniae 
to imipenem and meropenem were 12.2% and 12.1%, respectively and the resistance rates of 
P aeruginosa to imipenem and meropenem were 38.3% and 25.8%, respectively. 
Currently the options for the treatment of Gram-negative infections, especially multidrug 
resistant strains including ESBL- and carbapenemase- producers, are extremely limited. 
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), hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia 
(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 address the request from the Centre of Drug Evaluation (CDE) to 
further evaluate the effectiveness and safety of CAZ-AVI in Chinese adult patients with 
infections caused by carbapenem resistant Gram-negative pathogens. 
2.2. Background 
2.2.1. Clinical Urgent clinical needs /Treatment status 
In the light of rising resistance to carbapenems, clinicians are increasingly forced to turn to 
drugs that had previously fallen out of favor due to associated toxicity or lack of supportive 
data to guide dosing.7 Thus, therapy options are limited for patients with infections caused by 
β-lactam resistant pathogens, particularly those that are resistant to carbapenems, and there 
are significant limitations to the few existing alternatives to carbapenems. 
According to the surveillance results of China Antimicrobial Surveillance Network 
(CHINET), the resistance rate of K pneumoniae to imipenem and meropenem has increased 
at an alarming rate from 3.0% and 2.9% in 2005 to 20.9% and 24.0% in 2017, respectively.8,9 
Studies have found that the risk of death in patients infected with carbapenem antibiotic- 
resistant isolates is more than doubled compared with patients infected with non- 
carbapenem-resistant isolates (RR: 2.05, 95% CI: 1.56-2.69).10 In China, the report from 
CRE network have shown that the mortality rate of bloodstream infections caused by 
carbapenem-resistant Enterobacteriales (CRE) is 43.1% (22/51), the highest among all types 
of CRE infection (33.5%, 222/662), followed by lower respiratory tract infection, the 
mortality rate is 34.8% (148/425), the mortality of urinary tract infection and intra-abdominal 
infection are 30.3% and 26%, respectively.11 
There is no single treatment option for all patients with infections caused by a carbapenem- 
resistant (CR) pathogen, as there are limited efficacy data available for many of these 
therapies in the treatment of CR pathogen infections. Therapies for use in the multidrug 
resistant (MDR) setting (which could include CRE) include colistin, tigecycline, and 
fosfomycin.12 In the case of colistin (or polymyxin B), a lack of proof of efficacy from 
prospective trials, coupled with the potential for nephrotoxicity are significant issues, as are 
increasing resistance and uncertainty over the optimum dosing regimen in critically ill 


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patients.13 For tigecycline, low blood levels and failures in cases of bacteremia and HAP, 
poor penetration into the urinary tract for cUTIs, and a connection with increased rates of 
mortality are major concerns. 
Infections due to CRE are associated with high risk of death; therefore effective and safe 
drugs are urgently needed for treatment. Since CAZ-AVI was approved in the United States 
and EU, multiple studies have been published by independent authors, providing real world 
evidence supporting the efficacy of ceftazidime-avibactam for the treatment of a wide variety 
of infections caused by resistant pathogens and for which other treatment options are limited 
or unavailable, including bacteremia, urinary tract infections, HAP including VAP and other 
infections caused by carbapenem resistant and multi-drug resistant Enterobacteriales and 
Pseudomonas spp. 
2.2.2. Clinical Overview 
The global adult CAZ-AVI clinical development program has been completed. Briefly, the 
program comprises a package of 17 completed Phase 1 clinical pharmacology 
studies, 2 completed Phase 2 studies (1 in complicated urinary tract infection [cUTI] and 
1 in cIAI), and the following 5 Phase 3 clinical studies: 
• A randomized, double-blind Phase 3 study in participants with nosocomial pneumonia 
(NP) including VAP: REPROVE 
• Two randomized, double-blind Phase 3 studies in participants with cIAI: RECLAIM 3 
and RECLAIM 
• A randomized, double-blind Phase 3 study in participants with cUTI: RECAPTURE 
• A randomized, open-label Phase 3 study in participants with cIAI or cUTI infections 
caused by CAZ-resistant pathogens: REPRISE 
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 s 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 SRSD for this study. The SRSD for the comparator agent is the LPD for the selected 
BAT. 


 
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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 
• 
Hepatotoxicity 
Development of resistance 
• 
Superinfection (bacterial or fungal) 
The potential risks are based on product 
prescribing information for CAZ-AVI and risk 
management plan. 
This potential risk has been reported with 
ceftazidime when the dose has not been reduced 
in patients with renal impairment. 
There were 6 CAZ-AVI ± MTZ participants with 
superinfection identified in microbiological 
samples across the programme to date, but none 
of the cases found could be considered to 
represent clinical cases of superinfection. 
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. 
Eligibility criteria have been selected to ensure 
that only appropriate participants are included in 
the study (see Section 5). 
For participants with hepatic impairment, 
investigator will closely monitor hepatic function. 
The duration of treatment has been selected based 
on the approved LPD. 
Investigator will closely follow the signs and 
symptoms during the study. If superinfection is 
identified, treating the underlying cause is the best 
way to prevent bacterial overgrowth. 
Study Procedures (Not applicable) 
Other (Not applicable) 
 
 
 
 
 
 
 
 
 
 
 
PFIZER CONFIDENTIAL 
 
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2.3.2. Benefit Assessment 
Participants enrolled into this clinical study will have cIAIs requiring surgical intervention 
(including open laparotomy, percutaneous drainage of an abscess and laparoscopic surgery) 
HAP including VAP, cUTI, or BSI that are of sufficient severity to require hospitalization 
and treatment with IV antibiotics. The potential benefit to participants in this study is that 
they will receive effective antibiotic treatment for their infection. And in this study, they will 
receive close medical monitoring including physical examinations and laboratory tests and 
intensive disease management. The potential benefit of the study, in general, is to further 
characterize the efficacy and safety of a novel antibiotic in the treatment of Chinese adult 
patients with CR Gram-negative bacteria infection in the face of the changing pattern of 
antibiotic resistance. 
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 life threatening serious 
infections caused by CR Gram-negative whom only limited alternative treatment options are 
available. 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
The trial will compare CAZ-AVI with BAT in patients infected with carbapenem-resistant 
Gram-negative pathogens. The primary trial objective is to estimate the range of the 
treatment effect of CAZ-AVI compared to BAT via the proportion of participants with 
clinical response defined as a composite endpoint that includes the intercurrent events of 
death and need for additional antibiotic rescue. 
 
Objectives 
Estimands 
Endpoints 
Primary: 
Primary: 
Primary: 
• To estimate the 
efficacy of 
CAZ-AVI and best 
available treatment 
(BAT) in patients 
with infections due 
to Carbapenem- 
resistant 
Gram-negative 
pathogens. 
• Estimand E1: The trial will estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the 
difference in clinical response of cure in patients 
with infections due to carbapenem-resistant 
Gram-negative pathogens. A composite estimand 
strategy will be used to account for intercurrent 
events that are part of the definition of clinical 
response. Intercurrent events of death after receiving 
<48 hours of study treatment, or inadequate infection 
source control at time of initial surgical procedure 
(for cIAI participants) will be regarded as 
indeterminate clinical response. Intercurrent events 
of death after receiving at least 48 hours of study 
treatment, or receiving treatment with further 
antibiotics for the index infection will be regarded as 
a failure clinical response. 
• Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
TOC visit 


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Objectives 
Estimands 
Endpoints 
Secondary: 
Secondary: 
Secondary: 
• To estimate the 
efficacy of 
CAZ-AVI and BAT 
in patients with 
infections due to 
CR gram-negative 
pathogens and who 
are 
microbiologically 
evaluable. 
• Estimand E1 will be the esimand for this objective. 
• Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
TOC visit 
• To estimate the 
clinical response to 
CAZ-AVI and BAT 
at the end of 
treatment. 
• Estimand E1 will be the esimand for this objective. 
• Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
EOT visit 
• To estimate the 
microbiological 
response to 
CAZ-AVI and 
BAT. 
• Estimand E2: The trail will estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the 
difference of favorable microbiological response in 
patients with infections due to carbapenem-resistant 
Gram-negative pathogens. A composite estimand 
strategy will be used to account for intercurrent 
events that are part of the definition of 
microbiological response. Intercurrent events of 
death after receiving <48 hours of study treatment, or 
inadequate infection source control at time of initial 
surgical procedure (for cIAI participants) will be 
regarded as indeterminate microbiological response. 
Intercurrent events that result in repeat culture of 
specimen not performed/clinically indicated (specific 
to cIAI and HAP/VAP participants) will be regarded 
as a presumed eradication if a clinical cure is 
assessed, and a presumed persistence microbiological 
response if a clinical failure is assessed. 
• Microbiological 
response (defined 
by favorable, 
unfavorable, or 
indeterminate) at 
EOT and TOC 
visits 
• To estimate the 
all-cause mortality 
for CAZ-AVI and 
BAT. 
• Estimand E3: Using a treatment-policy estimand 
strategy in patients with infections due to 
carbapenem-resistant Gram-negative pathogens to 
estimate the treatment effect of CAZ-AVI relative to 
BAT in terms of the difference of all-cause mortality 
at Day 28 of the study. Any death that occurred after 
first dose of study drug through Day 28 will be 
included. A participant with the last known survival 
status is before Day 28 or missing will be reported as 
an unknown status. 
• All-cause mortality 
at Day 28 
• To evaluate the 
safety and 
tolerability of CAZ- 
AVI. 
• N/A 
• Assessment of 
TEAEs, 
discontinuation due 
to AEs, safety- 
related clinical 
laboratory tests. 


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This protocol will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related efficacy endpoints, 
using predefined endpoint criteria. 
For those AEs that are handled as disease-related efficacy endpoints (which may include 
death), a IRC will conduct unblinded reviews on a regular basis throughout the trial (see 
Section 9.6). 
Any AE that is adjudicated by the endpoint adjudication committee NOT to meet endpoint 
criteria will be reported back to the investigator site of incidence. Refer to Section 8.3.7 for 
instructions on how to report any such AE that meets the criteria for seriousness to Pfizer 
Safety. 
4. STUDY DESIGN 
4.1. Overall Design 
This is an open-label, randomized, multi-center, interventional, active-controlled Phase 4 
study to evaluate the efficacy and safety of CAZ-AVI versus BAT in the treatment of 
infected participants with selected infection types (Hospital Acquired Pneumonia [HAP] 
(including Ventilator-Associated Pneumonia [VAP]); Complicated Urinary-Tract Infection 
[cUTI]; Complicated Intra-Abdominal Infection [cIAI]; Bloodstream Infection [BSI]) due to 
carbapenem-resistant Gram-negative pathogens in China. Carbapenem-resistant is defined as 
resistant to carbapenems (imipenem or meropenem), including resistant and intermediate. 
Approximately 60 participants with confirmed carbapenem-resistant Gram-negative 
pathogens infection (with CAZ-AVI and BAT susceptibility) will be randomized in a 
1:1 ratio to the 2 groups in the study, with approximately 30 participants in CAZ-AVI group 
and approximately 30 participants in BAT group. Randomization will be stratified by the 
infection sites: HAP (including VAP); cUTI; cIAI; BSI (including primary BSI, catheter 
related BSI [CR BSI], and BSI related to HAP [including VAP], cUTI, and cIAI). Among the 
4 strata, the first 3 infection sites will not include participants with BSI complications. 
Treatment arms in the study: 
• Study intervention: CAZ-AVI, participants randomized to the CAZ-AVI treatment arm 
will receive CAZ-AVI 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered IV as a 
2-hour infusion every 8 hours (q8h). Dose adjustments for participants with CrCL 
≤50 mL/min will be applied based on the LPD (Section 6.1). 
• Best Available Treatment (BAT), based on investigative site practice and local 
epidemiology and guideline (main treatments: monotherapy or combination of colistin, 
tigecycline, fosfomycin, amikacin and meropenem). Details for dose and frequency of 
administration of BAT will be based on China LPD or standard of care according to local 
guideline. 
Duration of treatment: 


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The study will consist of a Screening visit, a Baseline visit on Day 1 of the study treatment, 
ongoing treatment visits (Days 2-14), an End of Treatment visit within 24 hours after the last 
infusion, a Test of Cure (TOC) visit (7-10 days after EOT visit), and a Late Follow-Up 
(LFU) visit (28-32 days after the last dose of study intervention). The duration of treatment is 
5 days up to 14 days for cUTI, cIAI and BSI, and 7 days up to 14 days for HAP/VAP, which 
can be extended to 21 days depending on the participant’s condition and investigator’s 
judgement as clinical practice required (Figure 1). 
The study is open-label due to the complicated dosing regimens and choice of appropriate 
best available treatment. The investigators, site personnel, and participants will not be 
blinded in this open-label study. An independent adjudication committee will be blinded with 
the aim of unbiased adjudication of the primary objective measure. 
4.2. Scientific Rationale for Study Design 
Ceftazidime is the bactericidal β-lactam component of CAZ-AVI. It is a third generation 
cephalosporin that is approved for the treatment of several bacterial infections. Its efficacy 
and tolerability profile is well characterized through many years of experience of use in 
clinical practice in numerous countries worldwide. Avibactam is a first-in-class non-β-lactam 
β-lactamase inhibitor of serine β-lactamases with a spectrum of inhibition that includes class 
A extended-spectrum beta-lactamases (ESBLs) and carbapenemases (eg, KPC), class C 
β-lactamases, and some class D oxacillinases and carbapenemases. It is not active against 
class B metallo-β-lactamases, and it is not active against A baumannii. The addition of 
avibactam to ceftazidime extends the β-lactam’s antibacterial activity against pathogens 
possessing β-lactamases that are susceptible to inhibition by avibactam, while retaining 
ceftazidime’s bactericidal activity. Avibactam therefore has the potential to restore the utility 
of ceftazidime in the clinical setting.2 
CAZ-AVI was approved by the National Medical Products Administration (NMPA) on 21 
May 21 2019 for the indications of cIAI, HAP including VAP, LTO in adults. The basis of 
the Limited Treatment Options (LTO) indication is pharmacokinetic/pharmacodynamic 
(PK/PD) extrapolation and the ceftazidime existing approvals. Ceftazidime is approved for 
the treatment of infections in a broad range of body sites beyond the standard indications 
(cIAI, cUTI, HAP). The established efficacy of ceftazidime in these additional indications 
(eg, complicated skin and skin structure infections [cSSTIs]) indicates that ceftazidime 
achieves adequate tissue penetration and exposure across body sites. The key physico- 
chemical properties and PK characteristics (eg, protein binding, distribution, excretion) of 
ceftazidime and avibactam are similar and therefore both compounds will partition across 
body sites in a similar fashion. Since the mechanism of action of antibiotics, including 
CAZ-AVI, is based on direct action on the bacteria causing an infection rather than action on 
the human body. It supports CAZ-AVI to be used in the treatment of other infection site. 
Since CAZ-AVI approved in the United States and EU, multiple studies have been published 
by independent authors, providing real world evidence supporting the efficacy of 
ceftazidime-avibactam for the treatment of a wide variety of infections caused by resistant 
pathogens and for which other treatment options are limited or unavailable, including 


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bacteremia, urinary tract infections, HAP including VAP and other infections caused by 
carbapenem resistant and multi-drug resistant Enterobacteriales and Pseudomonas spp. 
This study is designed to address the request from the Centre of Drug Evaluation (CDE) to 
further evaluate the effectiveness and safety of CAZ-AVI in Chinese patients with 
carbapenem resistant Gram-negative pathogens infections. 
There is no single treatment option for all patients with infections caused by a 
carbapenem-resistant (CR) pathogen, as there are limited efficacy data available for many of 
these therapies in the treatment of CR pathogen infections. Therapies for use in the 
multi-drug resistant (MDR) setting (which could include CRE) include colistin, tigecycline, 
and fosfomycin.7 Therefore, the BAT is selected and will be administered per current 
treatment guidelines, investigative site practice and local epidemiology, and may include 
colistin, tigecycline, fosfomycin, amikacin and meropenem, as monotherapy or in 
combination. Details for dose and frequency of administration of BAT will be based on 
China LPD or standard of care according to local guideline. 
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. However, the use of a 
highly effective method of contraception is required (see Appendix 4). 
4.3. Justification for Dose 
The CAZ-AVI dose for treatment of patients with cIAI, cUTI and HAP has been confirmed 
by clinical efficacy demonstrated in the controlled, Phase 3 studies of participants with cIAI 
(RECLAIM, RECLAIM3 and REPRISE), cUTI (RECAPTURE and REPRISE), and NP, 
including VAP (REPROVE). These studies confirm that avibactam plasma exposures 
achieved with the studied dose are adequate to protect ceftazidime and result in efficacy 
against CAZ-resistant pathogens that is comparable to efficacy against CAZ-susceptible 
pathogens. 
The PK samples collected from participants participating in the Phase 3 studies were used to 
calculate individual plasma profiles, from which exposure and PK/PD target attainment were 
calculated. Joint target attainment was achieved in >98% of participants across the Phase 3 
studies in cIAI, cUTI and HAP; and the joint target attainment rate was 98.9% in the 262 
Chinese and Taiwanese participants for whom PK samples were available from the Phase 3 
studies (Table 1). 


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Table 1. 
Comparison of ceftazidime and avibactam exposure and target attainment 
in Phase 3 participants stratified across different races 
 
Covariate 
Category: 
Race 
n 
CAZ 
Css,max 
(µg/mL) 
CAZ 
AUCss,0-24 
(µg.h/mL) 
AVI 
Css,max 
(µg/mL) 
AVI 
AUCss,0-24 
(µg.h/mL) 
Target attainment 
(%) 
Chinese & 
Taiwanese 
262a 
77.6 (112.5) 
884 (120.5) 
14.7 (154.9) 
151 (155.1) 
98.9 (97.6, 100.0) 
Caucasian/ 
Other 
1209 
68.6 (112.9) 
848 (125.0) 
12 (159.4) 
135 (161.3) 
98.3 (97.6, 99.1) 
Asian 
non-Chinese/ 
non- 
Japanese 
248 
82.2 (118.4) 
968 (121.9) 
14.9 (166.5) 
166 (170.8) 
99.6 (98.8, 100.0) 
Japanese 
45 
90.4 (82.6) 
1021 (94.8) 
16.1 (134.3) 
164 (130.9) 
100.0 (N/A) 
a.  Comprising 250 participants from mainland China and 12 participants from Taiwan. 
 
Note: Geometric mean (%CV) are reported for Css,max and AUCss,0-24. Target attainment rates are reported as 
the observed percent (95% CI) of participants who achieved the joint target of 50% fT>CAZ-AVI MIC of 
8 mg/L for ceftazidime and 50% fT >1.0 mg/L for avibactam. 
 
The population PK models for ceftazidime and avibactam (CAZ-MS-09) including Phase 3 
data were used to conduct Monte Carlo simulations in order to calculate the probability of 
target attainment (PTA) to confirm that the dose selected for the treatment of participants 
with cIAI, cUTI, and NP achieved sufficient exposure to exceed the joint PK/PD target in 
>90% of the population (joint PK/PD target of 50% fT>CAZ AVI MIC of 8 mg/L for 
ceftazidime and 50% fT>CT of 1 mg/L for avibactam). The simulation settings took into 
account the demographic distribution for each indication from Phase 3 studies conducted. 
Ceftazidime and avibactam concentration time courses were simulated from 5000 theoretical 
participants (all races) with cIAI, cUTI, and NP (including VAP and non-VAP). From these 
simulated profiles, the exposure in terms of AUCss,0-24 and Css,max were calculated and found 
to be comparable across each indication and in line with the exposure data that are available 
from each of these participant types. 
The overall PTA analysis for each indication demonstrated that the proposed dosing regimen 
used for CAZ-AVI in Phase 3 (2000 mg ceftazidime + 500 mg avibactam given as a 
120 minute IV infusion, q8h, in patients with normal renal function) is predicted to achieve 
sufficient exposure to exceed the joint PK/PD target (MIC of 8 mg/L) in ≥94.9% of the 
simulated patient population (across indications). The approved dose level in the China LPD 
was based on the data from competed pivotal studies and the PK study in Chinese. 
For participants with changing renal function, doses of CAZ-AVI will be modified as needed 
in accordance with the approved LPD. 
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 follow-up visit. The end of the study is defined as the date of the 
last visit of the last participant in the study. 


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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. 
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 >18 years of age, inclusive, 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. Participant must have a diagnosis of an infection (HAP/VAP, cUTI, cIAI, BSI) due to 
confirmed carbapenem-resistant aerobic Gram-negative pathogens, requiring 
administration of IV antibacterial therapy (See additional inclusion criteria for each 
indication). 
Culture-confirmed susceptibility to CAZ-AVI and each components of the chosen 
BAT (except carbapenems) based on evidence from culture or other phenotypic or 
molecular testing within 5 days prior to screening for any cultured Gram-negative 
pathogen according to the local microbiology laboratory testing (the central 
laboratory testing will be as a confirmatory data). 
Note: If a participant is found to have a Gram-negative species not expected to 
respond to CAZ-AVI and/or BAT (eg, A baumanii, Stenotrophomonas species) in 
addition to the causative Gram-negative CR pathogen, the participant may be enrolled 
in the study if the investigator considers that this species is a colonizer and does not 
warrant specific treatment. 
3. Participant who had received appropriate prior empiric antibacterial therapy for a 
carbapenem-resistant pathogen must meet at least 1 of the following criteria: 
a) No or no more than 24 hours of appropriate antibacterial therapy was 
administered for the current infection. OR 


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b) Worsening of objective symptoms or signs of infection (includes white blood cell 
count in hematology or urine test) after at least 48 hours of appropriate 
antibacterial therapy. OR 
c) No change of objective symptoms or signs of infection (includes white blood cell 
count in hematology or urine test) after at least 72 hours of appropriate 
antibacterial therapy. 
(Note: Therapy will be considered appropriate if microbiological susceptibility test 
results show that all carbapenem-resistant pathogens are susceptible to at least 1 of 
the antibacterial[s] received) 
Informed Consent: 
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol. 
5.1.1. Additional Inclusion Criteria 
Table 2. 
Additional Inclusion Criteria 
 
Inclusion Criteria 
cUTI 
1. Expectation, in the judgment of the Investigator, that any indwelling urinary catheter, 
nephrostomy tube, indwelling ureteric stent will be removed or replaced (if removal 
is not clinically acceptable) before or as soon as possible, but not longer than 
12 hours, after randomization. 
2. Participant had pyuria in the 5 days prior to study entry as determined by a 
midstream clean catch or catheterized urine specimen with ≥10 white blood cells 
(WBCs) per high-power field on standard examination of urine sediment 
or ≥10 WBCs/mm3 in unspun urine. 
3. At least two of the following signs or symptoms: 
Chills or rigors or warmth associated with fever (eg, oral temperature 
≥38 degrees Celsius) 
Flank pain (pyelonephritis) or pelvic pain (cUTI) 
Nausea or vomiting 
Dysuria, urinary frequency, or urinary urgency 
Costo-vertebral angle tenderness on physical examination 
4.  Complicating factors: participant must have at least 1 of the following complicating 
factors: 
• 
Documented history of urinary retention (male participants); 


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Inclusion Criteria 
• 
Functional or anatomical abnormality of the urogenital tract, including anatomic 
malformations or neurogenic bladder, or with a postvoid residual urine volume 
of at least 100 mL; 
• 
Use of intermittent bladder catheterization or presence of an indwelling bladder 
catheter for at least 48 hours prior to obtainment of study-qualifying culture; 
• 
Urogenital procedure (such as cystoscopy or urogenital surgery) within the 
7 days before study entry prior to obtainment of study qualifying-culture 
HAP/ 
VAP 
1. Onset of symptoms >48 hours after admission or <7 days after discharge from an 
inpatient care facility (for which the duration of admission was >3 days). 
2. New or worsening infiltrate on chest X-ray (or computed tomography [CT] scan) 
obtained within 48 hours prior to randomization. 
3. At least 1 of the following: 
• 
Documented fever (temperature ≥38°C) or hypothermia (rectal/core temperature 
≤35°C); 
• 
WBC ≥10,000 cells/mm3, leukopenia with total WBC ≤4500 cells/mm3, or 
>15% immature neutrophils (bands) noted on peripheral blood smear. 
At least 2 of the following: 
• 
A new cough (or worsening of cough at Baseline); 
• 
Production of purulent sputum or purulent endotracheal secretions; 
• 
Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, 
rales, rhonchi, bronchial breath sounds, dullness on percussion, egophony); 
• 
Dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths per minute, or 
hypoxemia (O2 saturation <90% or partial pressure of O2 [pO2]<60 mmHg while 
breathing room air); 
• 
Need for acute changes in the ventilator support status/system to enhance 
oxygenation, as determined by worsening oxygenation (arterial blood gas 
[ABG] or pO2 in arterial blood [PaO2]/fraction of inspired O2 [FiO2]) or needed 
changes in the amount of positive end-expiratory pressure. 
4. For known carbapenem-resistant Gram-negative pathogens infections, the respiratory 
specimen includes a culture either of expectorated sputum or a specimen of 
respiratory secretions obtained by endotracheal aspiration in intubated participants, 
or by bronchoscopy with bronchoalveolar lavage (BAL), mini-BAL or 
protected-specimen brush (PSB) sampling (BAL, mini-BAL or PSB only for 


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Inclusion Criteria 
participants undergoing bronchoscopy as part of their clinical management during 
the time). 
BSI 
1. Participant has a confirmed diagnosis of primary BSI or catheter related BSI (CR 
BSI) or the indication of BSI related to HAP (including VAP), cUTI, cIAI. 
2. At least 1 positive blood culture within 5 days prior to study entry indicating 
presence of carbapenem-resistant Gram-negative pathogens. Participants with 
polymicrobial including CR Gram-negative pathogens blood infections may be 
included in the study. 
3. Signs and symptoms of systemic infection are characterized by at least one of the 
following: 
• 
Chills, rigors, fever (temperature of ≥38.0°C or ≥100.4°F) or 
hypothermia(temperature <35°C [<95°F]); 
• 
Elevated white blood cell count (≥10,000/mm3) or left shift (>15% immature 
polymorphonuclear leukocytes [PMNs]). 
• 
Hypotension, systolic <90 mmHg 
cIAI 
1. Participant must have a study-qualifying specimen obtained from an abdominal 
source during a surgical intervention within the 5 days prior to study entry. Surgical 
intervention includes open laparotomy, percutaneous drainage of an abscess, or 
laparoscopic surgery. 
2. The participant has at least 1 of the following diagnosed during the surgical 
intervention: 
• 
Cholecystitis with gangrenous rupture or perforation or progression of the 
infection beyond the gallbladder wall 
• 
Diverticular disease with perforation or abscess 
• 
Appendiceal perforation or periappendiceal abscess 
• 
Acute gastric or duodenal perforations, only if operated on >24 hours after 
diagnosis 
• 
Traumatic perforation of the intestines, only if operated on >12 hours after 
diagnosis 
• 
Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis 
associated with cirrhosis or chronic ascites) 
• 
Intra-abdominal abscess (including of liver or spleen provided that there was 
extension beyond the organ with evidence of intraperitoneal involvement) 


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Inclusion Criteria 
3. 
One or more systemic signs or symptoms that accompany cIAI, such as fever, 
hypotension, abdominal pain, nausea/vomiting, abdominal mass on clinical 
examination, altered mental status. 
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. Any allergy to cephalosporins regardless of seriousness of that reaction. Severe 
hypersensitivity to any other betalactams (eg, penicillins, monobactams or 
carbapenems). 
3. Participant is expected to require more than 21 days of treatment per the 
investigator’s judgment. 
4. Participants who need more than 3 systemic antibiotics as part of best available 
treatment (BAT) for the treatment of the Gram-negative infection. 
5. Participant has a concurrent bacterial infection such as endocarditis, osteomyelitis, 
central nervous system (CNS) infection, prosthetic joint infection, C difficile diarrhea 
OR non-bacterial infection such as active tuberculosis, or pulmonary disease such as 
cystic fibrosis. 
6. Participants receiving hemofiltration or peritoneal dialysis. 
7. Participant is pregnant or breastfeeding. 
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. 


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Prior/Concurrent Clinical Study Experience: 
9. 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: 
10. Participant has an Acute Physiology and Chronic Health Evaluation (APACHE) II 
score >30. 
Other Exclusions: 
11. 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. 
5.2.1. Additional Exclusion Criteria 
Table 3. 
Additional Exclusion Criteria 
 
Exclusion Criteria 
cUTI 
1. Participants with suspected or confirmed complete obstruction of any portion of 
the urinary tract, perinephric or intrarenal abscess, or prostatitis, or history of any 
illness that, in the opinion of the investigator, may confound the results of the 
study or pose additional risk in administering the study therapy to the participant. 
2. Participants with renal transplantation. 
3. Participants with a permanent urinary diversion (eg, with ileal loops, cutaneous 
ureterostomy or vesicoureteral reflux). 
4. Participants who are likely to receive ongoing antibacterial drug prophylaxis 
after treatment of cUTI (eg, recurrent UTIs). 
5. Any recent history of trauma to the pelvis or urinary tract. 
6. Participants with uncomplicated lower urinary tract infections (generally female 
participants with urinary frequency, urgency, or pain or discomfort without 
systemic symptoms or signs of infection). 
HAP/ 
VAP 
1. Pulmonary disease that precludes evaluation of therapeutic response (eg, lung 
cancer, active tuberculosis, cystic fibrosis, granulomatous disease, fungal 
pulmonary infection, or recent pulmonary embolism). 
2. Participants with lung abscess, pleural empyema, or post-obstructive pneumonia. 
3. Participants with uncompensated heart failure. 


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Table 3. 
Additional Exclusion Criteria 
 
Exclusion Criteria 
4. Participant is a recipient of a lung or heart transplant. 
5. Participants with myasthenia gravis. 
BSI 
1. Participant has a prosthetic cardiac valve or synthetic endovascular graft. 
2. Participant has a suspected or documented medical condition with well-defined 
requirement for prolonged antibiotic treatment (eg, infectious endocarditis, 
osteomyelitis/septic arthritis, undrainable/undrained abscess, 
unremovable/unremoved prosthetic associated infection, non-removable or 
implantable device or line). 
cIAI 
1. Participant has infections limited to the hollow viscous, such as simple 
cholecystitis, gangrenous cholecystitis without rupture, and simple appendicitis, 
or has acute suppurative cholangitis, infected necrotizing pancreatitis, or 
pancreatic abscess. 
2. Participant has abdominal wall abscess or small-bowel obstruction without 
perforation or ischemic bowel without perforation. 
3. Participant has a cIAI managed by staged abdominal repair (STAR), or “open 
abdomen” technique, or marsupialization. This criterion is intended to exclude 
participants in whom the abdomen is left open, particularly those for whom 
re-operation is planned. 
4. Participant who has prior liver, pancreas or small bowel transplant. 
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 approximately 146 mg sodium, which is equivalent to 7.3% of the 
maximum daily sodium intake recommended by WHO. The maximum daily dose of this 


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product is equivalent to 22% of the maximum daily sodium intake recommended by 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 randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
The participants 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. 
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention. 
6.1. Study Intervention(s) Administered 
 
Intervention Name 
Zavicefta 
(ceftazidime/avibactam 
or CAZ-AVI) 
Best Available 
Treatment (BAT) 
Metronidazole 
ARM Name 
CAZ-AVI treatment arm 
BAT treatment arm 
CAZ-AVI arm and 
optional for BAT arm 
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Powder for injections 
Vial 
Solution for injections 
Unit Dose Strength(s) 
CAZ-AVI 2.5 g (2 g 
ceftazidime + 0.5 g 
avibactam) 
N/A 
500 mg / 100 ml 
Dosage Level(s) 
CAZ-AVI 2.5 g 
administered IV as a 
2-hour infusion every 8 
hours (q8h). 
N/A 
MTZ 500 mg IV q8h (by 
IV infusion over 60 
minutes) 
Route of 
Administration 
Infusion 
Infusion 
Infusion 
Use 
Experimental 
Active comparator 
other 
IMP or NIMP 
IMP 
IMP 
IMP 
Sourcinga 
Provided centrally by the 
sponsor. 
Refer to the IP manual. 
Provided centrally by 
the sponsor. 
Refer to the IP manual. 
Provided centrally by the 
sponsor. 
Refer to the IP manual. 


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Intervention Name 
Zavicefta 
(ceftazidime/avibactam 
or CAZ-AVI) 
Best Available 
Treatment (BAT) 
Metronidazole 
Packaging and 
Labeling 
Zavicefta will be 
provided in a sealed vial 
within a carton and is 
labeled in a way that is 
consistent with the study 
design and with the 
regulatory requirement 
for each country. 
Study intervention will 
be provided in 
container. Each 
container will be 
labeled as required per 
country requirement. 
Refer to the IP manual. 
Study intervention will 
be provided in container. 
Each container will be 
labeled as required per 
country requirement. 
Refer to the IP manual. 
Refer to the IP manual. 
Current/Former 
Name(s) or Alias(es) 
Zavicefta 
N/A 
Metronidazole Injection 
a. If the sponsor cannot provide study drugs centrally due to COVID-19 pandemic, and the investigator 
assesses that the participant should receive study drugs continuously, study drugs can be provided with local 
sourcing. 
 
6.1.1. Administration 
The duration of treatment is 5 days up to 14 days for cUTI, cIAI and BSI, and 7 days up to 
14 days for HAP/VAP, which can be extended to 21 days depending on the participant’s 
condition and investigator’s judgement as clinical practice required. 
6.1.1.1. CAZ-AVI Treatment Arm 
Participants randomized to the CAZ-AVI treatment arm will receive CAZ-AVI 2.5 g (2 g 
ceftazidime + 0.5 g avibactam) administered IV as a 2-hour infusion every 8 hours (q8h). 
No dosage adjustment is required in participants with estimated CrCL ≥ 51 - ≤ 80 mL/min. 
Table 4 shows the recommended dose adjustments for participants with estimated 
CrCL ≤ 50 mL/min. For participants with changing renal function, monitor CrCL at least 
daily and adjust the dosage of Zavicefta accordingly. 
 
Table 4. 
Recommended intravenous doses for participants with estimated CrCL ≤ 
50 mL/mina 
 
Estimated CrCL 
(mL/min) 
Dose regimenb 
Frequency 
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 
≤5c 
0.94 g (0.75 g/0.19 g) 
Every 48 hours 
2 hours 
a. 
CrCL estimated using the Cockcroft-Gault formula. 
b. Dose recommendations are based on pharmacokinetic modelling. 
c. 
Ceftazidime and avibactam are removed by haemodialysis. Dosing of CAZ-AVI on haemodialysis days 
should occur after completion of haemodialysis. 


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6.1.1.2. Comparator Treatment Arm- Best Available Treatment 
The comparator treatments in this study are to be the best available treatment (BAT) based 
upon site practice and local epidemiology. The choice of BAT for each participant must be 
recorded prior to randomization. Acceptable BAT may include but not limit to the following 
(which can be used as monotherapy or in combination): 
• Aminoglycoside; 
• Colistin (or polymyxin B if colistin is not available or readily accessible); 
• Fosfomycin; 
• Meropenem; 
• Tigecycline. 
Participants randomized to this BAT group, may receive combination therapy for 
Gram-negative coverage (such as with an aminoglycoside) as per the investigator’s standard 
of care. All components of combination therapy must be selected and documented prior to 
randomization. If randomized to BAT, all components must be initiated at the start of study 
therapy. 
The BAT must not consist solely of the original failed therapy. Switching therapy within the 
carbapenem class should be considered carefully by investigators as this may not represent 
best clinical practice. 
Details for dose and frequency of administration of BAT (as well as any warnings, 
precautions, and contraindications) will be based on China LPD or standard of care according 
to local guideline.16 
The warnings, precautions, and contraindications found in the local LPD for the specific 
BAT antibacterial chosen by the investigator must be closely reviewed. If a participant has 
contraindications for a particular BAT option, that antibiotic should not be used, but other 
BAT options to which the participant has no contraindications may be considered. 
The investigator should follow dose adjustments for participants with renal impairment as 
established by the China LPD and locally accepted standard of care according to local 
guideline. 
6.1.1.3. Optional Gram positive Antibiotics 
Participants may receive optional vancomycin or linezolid at the investigators discretion to 
provide antibiotic cover for a Gram positive infection. The need for an adjunctive Gram 
positive antibiotic should be reevaluated once culture and susceptibility results are available 
and the Gram positive agent should be discontinued if a Gram positive species is not isolated 
or is no longer suspected. 


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6.1.1.4. Optional Aminoglycosides 
In CAZ-AVI arm, participants with HAP/VAP and proven or suspected coinfection with 
P aeruginosa may receive an optional IV aminoglycoside (eg, amikacin, gentamicin or 
tobramycin, based upon local practice and epidemiology) at the investigators discretion to 
allow coverage for suspected or proven P aeruginosa infection. The need for adjunctive 
aminoglycoside therapy should be re-evaluated once culture and susceptibility results are 
available and the aminoglycoside should be discontinued if P aeruginosa is not isolated or is 
no longer suspected. The need for continued dosing with an aminoglycoside should be 
reviewed at least after 72 hours to mitigate potential nephrotoxic effect. 
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. 
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 or other specified location. 
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. 
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 


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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. 
6.2.1. Preparation and Dispensing 
See the IP manual or LPD 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 
This is an open-label study. The study will randomize approximately 60 participants in a 1:1 
ratio into 2 treatment groups (CAZ-AVI and BAT). Randomization will be stratified by the 
infection type: HAP (including VAP); cUTI; cIAI; BSI. 
6.3.1. Allocation to Study Intervention 
This is an open label study; however, the specific study intervention dispensed to the 
participant will be assigned using an IRT. The site will contact the IRT prior to the start of 
study intervention administration for each participant. The site will record the study 
intervention assignment on the applicable CRF, if required. Potential bias will be reduced by 
central randomization and involving a central blinded adjudication committee to review the 
clinical response data. 
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 re-dispensed to the participants. 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system. 


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6.3.2. Breaking the Blind 
Not applicable. This is an open-label study. The investigators, site personnel, and participants 
will not be blinded in this open-label study; however, reasonable attempts by investigators 
and site personnel should be made to minimize bias wherever possible. Programming and 
statistical personnel separate from the Sponsor study team will be responsible for producing 
the data outputs and will help limit access by the study team to individual participant and 
group treatment assignment until database lock has occurred. 
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. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
Participant compliance with dosing administration will be verified by accounting doses 
administered. The participant dosing compliance should be within the range of 80% and 
120% of expected doses during treatment period. Participant noncompliance cases should be 
discussed with medical monitors. 
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 blood and other blood product 
transfusions, herbal products, being taken by the participant from signed informed consent 
prior to registration (considered prior medications) and from registration through the LFU 
visit (considered concomitant medications) must be documented on the appropriate pages of 
the eCRF. Systemic antibiotics should be documented for the entire duration of the study 
(from 2 weeks prior to study entry through the LFU visit). 
The use of probenecid or chloramphenicol is not permitted from informed consent to end of 
IV study treatment. 
Concomitant medications which are allowed per protocol, restricted and prohibited are 
detailed in Table 5, Table 6, and Table 7, respectively: 


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Allowed Procedure/ 
Medication/ Class of 
Drug: 
Participants 
with cIAI: 
Participants 
with cUTI: 
Participants 
with BSI: 
Participants 
with HAP/VAP: 
MTZ 
Participants in 
the CAZ-AVI 
arm will all 
receive MTZ as 
part of study 
therapy (see 
Section 6.1.1.1). 
Participants in 
the BAT arm 
may receive 
MTZ if the 
chosen BAT 
does not provide 
adequate 
anaerobic 
coverage. 
N/A 
N/A 
N/A 
Vancomycin or linezolid 
If a 
Gram-positive 
pathogen is 
suspected then 
vancomycin or 
linezolid may be 
added to the 
study regimen 
according to the 
usual practice of 
the investigator. 
If a 
Gram-positive 
pathogen is not 
isolated, then the 
Gram-positive 
agent should be 
stopped, at the 
investigator’s 
discretion, and 
participants 
should continue 
in the study. 
If a 
Gram-positive 
pathogen is 
suspected then 
vancomycin or 
linezolid may be 
added to the 
study regimen 
according to the 
usual practice of 
the investigator. 
If a 
Gram-positive 
pathogen is not 
isolated, then the 
Gram-positive 
agent should be 
stopped, at the 
investigator’s 
discretion, and 
participants 
should continue 
in the study. 
If a 
Gram-positive 
pathogen is 
suspected then 
vancomycin or 
linezolid may be 
added to the 
study regimen 
according to the 
usual practice of 
the investigator. 
If a 
Gram-positive 
pathogen is not 
isolated, then the 
Gram-positive 
agent should be 
stopped, at the 
investigator’s 
discretion, and 
participants 
should continue 
in the study. 
If a 
Gram-positive 
pathogen is 
suspected then 
vancomycin or 
linezolid may be 
added to the 
study regimen 
according to the 
usual practice of 
the investigator. 
If a 
Gram-positive 
pathogen is not 
isolated, then the 
Gram-positive 
agent should be 
stopped, at the 
investigator’s 
discretion, and 
participants 
should continue 
in the study. 


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Allowed Procedure/ 
Medication/ Class of 
Drug: 
Participants 
with cIAI: 
Participants 
with cUTI: 
Participants 
with BSI: 
Participants 
with HAP/VAP: 
IV aminoglycoside (eg, 
amikacin, gentamicin or 
tobramycin based upon 
local practice and 
epidemiology) 
N/A 
N/A 
N/A 
In the CAZ-AVI 
arm, an IV 
aminoglycoside 
may be added if 
P aeruginosa is 
suspected. If 
aminoglycoside 
is started, and if 
P aeruginosa is 
NOT 
subsequently 
isolated, then 
aminoglycoside 
should be 
discontinued. 
The need for 
continued dosing 
with an 
aminoglycoside 
should be 
reviewed after 
72 hours to 
mitigate potential 
nephrotoxic 
effects. 
Peritoneal lavage with 
saline or other 
non-antibacterial-containing 
solution. 
Permitted (note 
that antibiotic 
peritoneal lavage 
is not allowed). 
N/A 
N/A 
N/A 
Topical antibacterial and 
antifungals (or any oral 
antibiotic that has very poor 
absorption systemically, eg, 
oral vancomycin). 
Permitted except 
that they may not 
be applied to the 
surgical site. 
Permitted 
Permitted 
Permitted 


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Table 6. 
Restricted Concomitant Medications 
 
Restricted Procedure/Medication/Class of Drug: 
Participants with cIAI, HAP/VAP, cUTI or BSI: 
Systemic antibiotics 
Concomitant systemic antibiotics are not allowed 
(except those specified as allowed per the protocol), 
unless the participant is considered to have failed 
study treatment and requires additional antibiotics to 
treat their infection. 
OR 
The participant develops a new infection at a remote 
site and the investigator considers addition of 
non-study antibiotics essential for the safety and 
well-being of the participant. 
Systemic antifungals 
Antifungal treatment to treat the cIAI, HAP/VAP, 
cUTI or BSI should be avoided unless clinically 
indicated. For other infection that are not the primary 
diagnosis, a systemic antifungals may be added. 
 
 
Table 7. 
Prohibited Concomitant Medications 
 
Prohibited 
Procedure/Medication/Class of 
drug: 
Participants with cIAI, cUTI or 
BSI: 
Participants with HAP/VAP 
Probenecid or chloramphenicol 
Not permitted from informed consent to end of IV study treatment 
Antibiotic peritoneal lavage 
Not permitted (note that peritoneal 
lavage with saline or other 
non-antibacterial-containing 
solution is allowed). 
N/A. 
Inhaled antibiotics 
N/A. 
Should be avoided from the start 
to the end of IV study treatment 
for participants in either treatment 
arm. 
 
The use of other systemic antimicrobials not specified by this protocol is not permitted 
during the study. However, if a new infection develops at a remote site (ie, outside of the 
abdomen for cIAI participants or outside of the urine tract for cUTI or outside of the lung for 
HAP/VAP participants) between the date and time of the first dose of study treatment and the 
LFU visit, and the investigator considers addition of non-study antibiotics essential to the 
safety and well being of the participant, additional antibiotics may be added. If possible, the 
investigator should first discuss this with the Medical Monitor and attempt to choose 
antibiotics (guided by local microbiology and sensitivity testing) that will not have 
antibacterial activity against the participant’s baseline pathogens to avoid confounding the 
assessment of the effect of study therapy. 
Information on contraindications, special warnings and precautions and interactions with 
other medicinal products and other forms of interaction for protocol allowed antibiotics are 
available in the respective LPD for these products and investigators are recommended to 
refer to these for further prescribing information. 


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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 therapy, the investigator should contact the Pfizer physician before 
initiating therapy. Continued receipt of study therapy 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 an unplanned surgical 
procedure during the study, the reason for the surgery must be documented as an AE in the 
eCRF. 
6.6. Dose Modification 
In case a dose reduction is necessary, please refer to Section 6.1.1. 
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 
Participants may be discontinued from study intervention in the following situations: 
• Condition under investigation resolved prior to minimum treatment period; 
• Participant decision. The participant is at any time free to discontinue treatment, 
without prejudice to further treatment; 
• Occurrence of an AE or any other condition posing a risk to a participant or 
jeopardizing a safe continuation of the study treatment for the respective participant 
(as judged by the investigator, and/or the national coordinators, and/or the Medical 
Monitor and the Study Sponsor); 
• Positive pregnancy test at any time during the treatment period. 
• In the absence of any alternative explanation for the 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 TBili >2 × ULN or international normalized 
ratio (INR) >1.5; 


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• ALT or AST >3 × ULN and with appearance of symptoms and signs 
suggestive of new or progressive liver disease (eg, new or worsening 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia [eosinophils >2 × ULN]); 
• A participant meeting Hy’s Law criteria (see Appendix 5). 
• Treatment failure (refer to Table 8); 
• In the opinion of the investigator, it is not in the best interest of the participant to 
continue the study treatment or at the request of the sponsor or delegates that the 
participant stops participation in the study; 
• Severe non-compliance with the CSP. 
Investigators should not discontinue a participant from study therapy 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 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 therapy or at the request of Pfizer that the participant 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. 


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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, post-treatment 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; 
Lost to follow-up; 
Death; 
Study terminated by sponsor; 
At the time of discontinuing from the study, if possible, an early discontinuation visit (EOT 
visit) should be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
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 


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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. 
The following actions must be taken if a participant fails to return to the clinic 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 


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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 
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 
142 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 Assessment 
Clinical response will be determined at the EOT and TOC visits as either cure, failure or 
indeterminate. The clinical response at each visit will be assessed by the investigator, and 
subsequently by an independent adjudication committee that will be blinded to study 
treatment (see Section 9.6). In case of a discrepancy with the investigator’s assignment of 
clinical response, the adjudication committee’s assessment will prevail for the analysis. 
Reason for failure will be indicated according to the clinical response definitions as follows 
(Table 8): 
 
Table 8. 
Definition of Clinical Response Categories at the EOT and TOC Visits 
 
Clinical Response 
Definition 
Cure 
Baseline signs and symptoms have improved such that after study 
treatment, no further antimicrobial treatment for the index infection 
(ie, cIAI, cUTI, HAP/VAP or BSI) is required.a 
In addition, none of the failure criteria listed below should be met. 
Additionally for cIAI participants: 
No unplanned drainage or surgical intervention is necessary since 
the initial procedure. 


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CCI 
Table 8. 
Definition of Clinical Response Categories at the EOT and TOC Visits 
 
Clinical Response 
Definition 
Failure 
Participants who meet any of the following criteria will be 
considered a treatment failure: 
• Death (after receiving at least 48 hours of study treatment). 
• Participant who received treatment with further antibiotics 
for the index infection.a This includes participants 
prematurely discontinued from study treatment due to an AE 
who require further antibiotics for the index infection. 
Additionally for cIAI participants: 
• Persisting or recurrent infection within the abdomen 
documented by the findings at re-intervention either 
percutaneously or operatively in situation of adequate 
infection source control at time of initial surgical procedure. 
• Postsurgical wound infections (eg, signs of local infection 
such as purulent exudates, erythema, or warmth that requires 
additional antibiotics and/or non-routine wound care). 
Indeterminate 
• Death (after receiving less than 48 hours of study treatment). 
• Participant lost to follow-up. 
Additionally for cIAI participants: 
• Inadequate infection source control at time of initial surgical 
procedure. 
a. 
Further antibiotics for the index infection should only be initiated for ongoing or worsening signs and 
symptoms of the infection. 
 
If a participant is assessed as a clinical failure at the EOT visit, this assessment will be 
carried forward to the TOC visit. 
 
8.1.2. Microbiological Response 
For each pathogen identified, microbiological outcome at EOT and TOC will be determined 
as shown in Table 9. 


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Table 9. 
Definition of Microbiological Response Categories at the EOT and TOC 
Visits, for Each Pathogen Identified at Initial/Pre Study (Study 
Qualifying) Culture 
 
Microbiological 
Response 
Definition 
Eradication 
Absence (or urine quantification <103 CFU/mL for cUTI participants) 
of causative pathogen from an appropriately obtained specimena at the 
site of infection. 
Presumed 
eradication 
Repeat culture of specimens were not performed/clinically indicated 
in a participant who had a clinical response of cure (specific to cIAI 
and HAP/VAP participants). 
Persistence 
-Persistence with 
increasing MIC 
Causative organism is still present from an appropriately obtained 
specimen at the site of infection (for cUTI, the urine culture taken at 
study intervention completion grows >103 CFU/mL of the original 
pathogen identified at trial entry). 
If the causative organism displays ≥4-fold higher MIC to study 
therapy after treatment with IV study therapy, the response will also 
be categorized as "Persistence with increasing MIC”. 
Presumed 
persistence 
Participant was assessed as a clinical failure and repeat culture of 
specimens were not performed/clinically indicated (specific to cIAI 
and HAP/VAP participants). 
Indeterminate 
microbiological 
response 
Death (after receiving less than 48 hours of study treatment). 
Participant lost to follow-up such that a determination of 
microbiological response cannot be made on the basis of clinical 
status. 
Additionally for cIAI participants: 
Inadequate infection source control at time of initial surgical 
procedure. 
a. 
A definition of an appropriately obtained specimen for each infection site will be included in the study 
microbiology manual (see Appendix 8). For participants with cIAI, an appropriately obtained specimen 
for determination of microbiological response is defined as a specimen obtained using an adequate 
technique (eg, surgical procedure [laparotomy or laparoscopy], percutaneous drainage (where in place 
for less than 24 hours) or wounds where the participant has a superficial or deep surgical wound reported 
at any point during the follow up period). From expectorated or induced sputum, an adequate sample is 
one with ≤10 squamous epithelial cells and >25 polymorphonuclear neutrophils per Low Power Field 
(LPF) upon a Gram stain; throat secretions are considered to be inadequate; other specimens such as 
endotracheal aspirate, BAL, mini BAL, and PSB are considered to be adequate. For participants with 
cUTI, preferred methods of collection of urine for culture include straight catheterization using sterile 
technique (preferred for female participants), midstream clean catch and suprapubic specimen collection 
using sterile technique. For blood specimens for culture, 2 sets of blood cultures should be collected (ie, 
4 bottles) from 2 different sites for aerobic and anaerobic incubation. One set of blood cultures must be 
obtained through a venipuncture. Collect samples, ideally over a period of 2 hours at least 10 to 20 
minutes apart from separate sites. 


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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. 
8.1.2.1 Microbiological Response Assessment 
The per-participant and per-pathogen microbiological response at the EOT and TOC visits 
will be assessed based on the pathogen(s) isolated from the study qualifying baseline and 
post-baseline cultures per the definitions outlined below. It is based on outcome per-pathogen 
isolated from the study-qualifying culture and on the isolation of pathogens during the course 
of treatment or the post-treatment period. 
Per-pathogen Microbiological Assessments after Completion of All Follow Up Visits 
Microbiological response will be assessed separately for each pathogen after completion of 
all follow-up visits using the definitions listed in Table 9. 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.” Participants with a microbiological response 
assessment of “indeterminate” will be considered to be non-evaluable for the micro-ITT and 
ME analysis sets. Classifications such as “superinfection” and “new infection” will be 
considered separately (see “emergent infections” below). 
Per-participant (Overall) Microbiological Response Assessments 
Overall microbiological response will also be assessed as “favorable” or “unfavorable” for 
each participant. Participants will be determined to have a favorable microbiological 
response if all baseline pathogens for that participant have a favorable outcome (eradicated or 
presumed eradicated) at the appropriate time point (EOT, TOC). If the outcome for any 
pathogen is unfavorable (persistence, persistence with increasing MIC, or presumed 
persistence), the participant will be considered to have an unfavorable microbiological 
response. 
Emergent Infections 
New pathogens that appear after Baseline are categorized in Table 10 and will be 
summarized separately. 


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Table 10. Definition of Emergent Infection Categories 
 
Emergent 
Infection 
Definition 
Superinfection 
cIAI/HAP/VAP/Bacteraemia: Emergence of a new pathogen(s) 
associated with emergence or worsening of signs and symptoms of 
infection and a requirement for additional antibiotics during the period 
up to and including the EOT visit. 
cUTI: Isolation of a new pathogen(s) at ≥105 CFU/mL from a urine 
culture associated with emergence or worsening of signs and symptoms 
of infection and a requirement for additional antibiotics during the 
period up to and including the EOT visit. 
New infection 
cIAI/HAP/VAP/Bacteraemia: Emergence of new pathogen(s) 
associated with emergence or worsening of signs and symptoms of 
infection and a requirement for additional antibiotics in the time period 
after the EOT visit. 
cUTI: Isolation of a new pathogen(s) at ≥105 CFU/mL from a urine 
culture associated with emergence or worsening of signs and symptoms 
of infection and a requirement for additional antibiotics in the time 
period after the EOT visit. 
 
8.1.3. All-cause mortality at Day 28 
The proportion of participants who have died due to any reason up to the TOC and up to Day 
28 will be measured. The denominator for the calculation of the proportion will include all 
participants irrespective of the status (dead, alive and unknown). 
The number of participants who died up to Day 28 of the study will be calculated as the 
number of participants with a date of death on or before the end of Day 28; participants who 
have died after Day 28 will be assumed to be alive at Day 28. If there is no record of a 
participant’s death and the participant attended the LFU visit, or if the participant is known to 
be alive after Day 28, then the survival status will be considered as alive at Day 28. 
Participants who withdraw from the study before Day 28 will be considered to have 
“unknown” mortality status, unless further information is available (eg, date of death). 
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 


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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. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
The following infection-related focused physical examinations will be conducted: 
For HAP/VAP participants, a pulmonary assessment, which includes auscultation, will be 
performed. 
For cIAI participants, abdominal signs and symptoms will be assessed and postoperative 
abdominal and wound examinations will be performed. Surgical wound examination should 
occur daily even if inspection is limited by the presence of a negative pressure wound 
therapy device. A thorough wound evaluation should occur when a full dressing change is 
performed. 
For cUTI participants, focused physical examination will include an assessment for 
suprapubic pain and costovertebral angle tenderness. And investigator should assess the 
catheter and nephrostomy tube status if present. 
For BSI participants, focused physical examination will include general appearance, vital 
signs, and focal signs of source infection. 
8.2.2. Vital Signs 
Tympanic or axillary temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed. 
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 measurement. 
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 


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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 negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the IP. 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. 
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. 


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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 
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. 


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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. 
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. 


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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, ingestion or skin 
contact. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation, ingestion 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 
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 


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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, ingestion or skin contact. 
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. 


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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 DREs are common in participants with CR pathogens infection and can be 
serious/life threatening: 
• Death 
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. 
OR 
• The investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
Death will be adjudicated by an independent adjudication committee. Any SAE that is 
adjudicated by the endpoint adjudication committee NOT to meet endpoint criteria is 
reported back to the investigator site of incidence. The investigator must report the SAE to 
Pfizer Safety within 24 hours of being made aware that the SAE did not meet endpoint 


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criteria. The investigator’s SAE awareness date is the date on which the investigator site of 
incidence receives the SAE back from the endpoint adjudication committee. 
8.3.8. Adverse Events of Special Interest 
Not applicable. 
8.3.8.1. Lack of Efficacy 
This section is not applicable because lack of efficacy is captured as an efficacy outcome 
(Table 8). 
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. 
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 parameters are not evaluated in this study. 
8.6. Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 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 
This study will be an estimation study. For the primary efficacy objective and the secondary 
efficacy objectives except for estimating all-cause mortality, composite estimand strategy 
will be used; for the secondary efficacy objective of estimating all-cause mortality at Day 28, 
a treatment-policy estimand strategy will be used. 
Primary Efficacy Estimand: 
Estimand E1 -- A composite estimand strategy will be used to estimate the treatment effect of 
CAZ-AVI relative to BAT in terms of clinical response rate in patients with infections due to 
carbapenem-resistant Gram-negative pathogens. Clinical response will be categorized as 
cure, failure, and indeterminate per investigator’s assessment and adjudicated by independent 
adjudication committee. Intercurrent events will be part of the definition of clinical response. 
Intercurrent events of death after receiving <48 hours of study treatment, or inadequate 
infection source control at time of initial surgical procedure (for cIAI participants) will be 
regarded as indeterminate clinical response. Intercurrent events of death after receiving at 
least 48 hours of study treatment, or receiving treatment with further antibiotics for the index 
infection will be regarded as failure clinical response. The difference in the proportion of 
participants with clinical cure rate between treatment groups will be summarized. 
Secondary Efficacy Estimands: 
• To estimate the efficacy of CAZ-AVI and BAT in patients with infections due to CR 
Gram-negative pathogens and who are microbiologically evaluable: 
Estimand E1 will be the estimand for this secondary objective. 
• To estimate the clinical response to CAZ-AVI and BAT at end of treatment: 
Estimand E1 will be the estimand for this secondary objective. 
• To estimate the microbiological response to CAZ-AVI and BAT: 
Estimand E2 -- A composite estimand strategy will be used to estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the microbiological response rate in 
patients with infections due to carbapenem-resistant Gram-negative pathogens. 
Microbiological response will be categorized as favorable (ie. eradication, or presumed 


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eradication), unfavorable (persistence, persistence with increasing MIC, or presumed 
persistence), and indeterminate. Intercurrent events will be part of the definition of 
microbiological response. Intercurrent events of death after receiving <48 hours of study 
treatment, or inadequate infection source control at time of initial surgical procedure (for 
cIAI participants) will be regarded as indeterminate microbiological response. 
Intercurrent events that result in repeat culture of specimen not performed/clinically 
indicated (specific to cIAI and HAP/VAP participants) will be regarded as a presumed 
eradication if a clinical cure is assessed, and a presumed persistence microbiological 
response if a clinical failure is assessed. Participants with intercurrent events that result in 
an indeterminate assessment will be excluded from the evaluable population. The 
difference in the proportion of participants with favorable microbiological response 
between treatment groups will be summarized. 
• To estimate the all-cause mortality for CAZ-AVI and BAT: 
Estimand E3 -- A treatment-policy estimand strategy will be used in patients with 
infections due to carbapenem-resistant Gram-negative pathogens to estimate the 
treatment effect of CAZ-AVI relative to BAT in terms of the all-cause mortality at Day 
28 of the study. Any death that occurred after first dose of study intervention through Day 
28 will be included. A participant with the last known survival status is before Day 28 or 
missing will be reported as an unknown status. The difference in the mortality rate 
between treatment groups will be summarized. 
9.1.2. Hypothesis 
There are no formal hypothesis tests planned for this study. Statistical inference will be based 
on point estimate and confidence interval. 
9.2. Sample Size Determination 
The study will randomize approximately 60 participants in a 1:1 ratio to CAZ-AVI and BAT 
treatment groups. Through literature review and meta-analysis, the clinical cure rate of 
CAZ-AVI in the target carbapenem-resistant population was approximately estimated to be 
57%. 
Due to the life-threatening nature of CRE infections, the scarcity of participants for LTO 
indication and the large variation associated with limited sample size, a non-inferiority study 
design is not feasible for the current study. The sample size is based on feasibility 
assessment, literature review with meta-analysis, and simulation. Approximately 30 
participants per arm (60 total sample size) is considered sufficient to quantitate the clinical 
cure rates in each treatment group, and the difference between treatment groups. The small 
numbers of participants will be reflected in the precision of the estimate of individual 
treatment group and treatment difference. 


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9.3. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant 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. 
Intent-to-Treat (ITT) 
Analysis Set 
It will include all participants randomly assigned to study 
intervention and who take at least one dose of study 
intervention. 
microbiologically 
Modified ITT (mMITT) 
Analysis Set 
It is a subset of the ITT analysis set, and will include 
participants who: 
 meet minimum disease requirements and received any 
amount of study therapy. 
 have at least 1 carbapenem-resistant Gram-negative 
pathogens in an adequate initial/pre-study culture. Participants 
with inherently resistant pathogens (monomicrobial infections 
due to any Acinetobacter spp.) will be excluded from the 
mMITT analysis set. 
Microbiologically 
Evaluable (ME) Analysis 
Set 
It is a subset of the mMITT analysis set, and will include 
participants who: 
 received at least 3 days of study intervention (CAZ-AVI or 
BAT), or received study intervention treatment for ≥ 48 hours 
with ≥80% compliance, or received study intervention 
treatment for <48 hours before discontinuing treatment due to 
an AE. 
 did not receive concomitant antibiotic therapy with potential 
activity against any baseline carbapenem-resistant Gram- 
negative pathogens between the time of randomization and the 
time of TOC. This does not include those participants who 
have failed study therapy and require additional antibiotics to 
treat their infection. 


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Participant Analysis Set 
Description 
 had the baseline entry organism(s) genetically confirmed by 
central microbiological testing. 
 did not have a clinical outcome of indeterminate for the 
respective analysis at EOT or TOC visits. 
 had no important protocol deviations that may affect the 
assessment of efficacy. 
Safety Analysis Set 
(SAS) 
All participants who take any study intervention. Participants 
will be analyzed according to the product they actually 
received 
 
The above analyses sets will be used for different endpoints according to the objectives and 
estimands: 
For the primary objective and estimand, the mMITT analysis set will be used to 
analyze the clinical cure rate at TOC visit. 
For the secondary objectives and estimands, clinical cure rate at TOC visit will be 
analyzed in the ME analysis set; clinical cure rate at EOT visit will be analyzed in the 
mMITT and ME analysis sets; favorable microbiological response at EOT and TOC 
visits will be analyzed in the ME analysis set; and all-cause mortality at Day 28 will 
be analyzed in the ITT analysis set. 
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 
The treatment effect will be evaluated based on the point estimate and its corresponding 95% 
confidence interval (CI) for CAZ-AVI and BAT treatment individually and for the difference 
between the 2 treatments. No adjustment for multiple comparisons will be made. 
9.4.2. Primary Endpoint(s) 
The number and percent of participants having clinical cure, failure, and indeterminate at 
TOC visit in the mMITT analysis population will be summarized by treatment group. 
Responses missing at the analysis visit such as due to intercurrent events, loss to follow up, 
early discontinuation will follow the details stated in Table 9 and Table 10 in Section 8.1. 
The point estimate and 95% confidence interval will be calculated for each individual 


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treatment group, as well as the difference between CAZ-AVI and BAT treatments in clinical 
cure rate. Individual teatment group confidence interval will be omputed using Jeffrey's 
method. The confidence interval for difference between CAZ-AVI and BAT treatments will 
be derived using Miettinen & Nurminen method stratified by infection site. If the number of 
participants in a particular stratum is small, then the unstratified Miettinen & Nurminen 
method will be used. 
Subgroup analyses will be performed for infection type (cIAI, HAP including VAP, cUTI, 
and other) and whether participants having BSI (Yes/No) if data permit. 
9.4.3. Secondary Endpoint(s) 
Same analysis method as that for primary endpoint will be applied. 
Clinical response will be tabulated showing the number and percentage of participants at the 
TOC visit in the ME analysis population, and at the EOT visit in the mMITT and ME 
analysis populations. Microbiological response will be tabulated at the EOT and TOC visits 
in the mMITT and ME analysis populations. The number and percentage of participants who 
have died due to any cause by Day 28 will be summarized for the ITT population. For 
summaries in the ME analysis population, participants with indeterminate clinical and 
microbiological responses will be excluded by definition. 
For all-cause mortality at Day 28 in the ITT analysis population, the number and percentage 
of participants defined as died, alive and unknown will be summarized by treatment group. 
The analysis for the proportion of participants with death due to any cause (all-cause 
mortality) will be presented by providing the difference in the proportions between the 
treatment groups and its 95% CI. If the proportion of participants with unknown status is 
unbalanced between the treatment groups, then a sensitivity analysis will be considered for 
all-cause mortality. 
9.4.4. Other 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 treatment-emergent AEs , relationship with treatment, 
discontinuations due to AEs, and laboratory data abnormalities will be summarized by 
treatment group using percentages. Change from baseline for selected laboratory tests and 
vital signs will be summarized with descriptive statistics. 
For continuous variables, absolute and change from baseline values in selected laboratory 
tests, and vital signs will be summarized with N, mean, standard deviation, median, 
minimum, and maximum. Number and percentages of participants from each category 
meeting the categorical criteria of laboratory abnormality will be presented. 


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9.4.5. Other Analyse(s) (Not applicable) 
9.5. Interim Analyses 
The study is anticipated to have a long recruitment duration, and therefore an interim analysis 
may be performed prior to the CAZ-AVI license renewal application in China when a 
complete study report is not yet accomplished. The analysis methods in the interim report 
will follow the methods planned for the full study and will be based on communication with 
China agency. 
9.6. Data Monitoring Committee or Other Independent Oversight Committee 
9.6.1. Independent Adjudication Committee: 
This is an open-label study. An independent adjudication committee consisting of at least 
3 clinical experts will be convened at regular intervals during the study. 
A charter will be in place for the adjudication committee. The adjudication committee will be 
blinded to study treatment and investigator’s assessment of clinical response. The committee 
will review the clinical data points, reports and results of the diagnostic tests used to classify 
the clinical response. In case of a discrepancy with the investigator’s assignment of clinical 
response, the adjudication committee’s assessment will prevail for the analysis. 
In addition, for cIAI participants classified as a clinical failure, and all cIAI participants 
classified as a cure who undergo another procedure (eg, another surgical procedure) 
subsequent to randomization, the adjudication committee will review the adequacy of the 
surgical source control. All cIAI participants assessed by the adjudication committee as 
having inadequate initial infection source control (ie, the cIAI procedure performed was not 
considered to be adequate to control the source of infection) will be reclassified as having an 
indeterminate clinical response and will be excluded from the Microbiologically Evaluable 
(ME) analysis set. 
9.6.2. Internal Review Committee: 
An internal review committee (IRC) will be established with a IRC charter for this study and 
will independently review the data in an unblinded fashion approximately every 6 months to 
ensure that the safety of participants is not compromised. 
The IRC will be responsible for ongoing monitoring of the safety of participants in the study 
according to the charter and may propose changes to the protocol as needed to ensure 
participant safety. The IRC will also review results of any interim analysis as described in 
Section 9.5. The recommendations made by the IRC to alter the conduct of the study will be 
forwarded to the appropriate Pfizer management for final decision. The Pfizer management 
will forward such decisions, which may include summaries of aggregate analyses of safety 
data, to regulatory authorities, as appropriate. 


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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 or their legally authorized representative 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 or their legally authorized representative 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 or their legally authorized representative 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 or their legally authorized representative must be reconsented to the most current 
version of the ICD(s) during their participation in the study. 


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A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative. 
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. 


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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. 
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. 


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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. 
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. 


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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. 
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 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. 


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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. 
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 


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should be used only in the event that the established communication pathways between the 
investigator site and the study team are not available. It is therefore intended to augment, but 
not replace, the established communication pathways between the investigator site and the 
study team for advice on medical questions or problems that may arise during the study. The 
contact number is not intended for use by the 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 11. Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Coagulation 
Arterial blood 
gasa 
Urine test 
Other 
Hemoglobin, 
Hematocrit, 
RBC count, 
MCV, 
MCH, 
MCHC, 
Platelet count, 
WBC count, 
Total 
neutrophils 
(Abs), 
Eosinophils 
(Abs), 
Monocytes 
(Abs), 
Basophils 
(Abs), 
Lymphocytes 
(Abs) 
BUN/Urea, 
Creatinine, 
Glucose (fasting), 
Calcium, 
Sodium, 
Potassium, 
Chloride, 
AST, 
ALT, 
Total bilirubin, 
Alkaline 
phosphatase, 
Uric acid, 
Albumin, 
Total protein, 
Bicarbonate 
(HCO3)/ CO2CP 
Partial 
thromboplastin 
time, 
Prothrombin 
time, 
International 
normalized 
ratio (INR) 
Partial pressure 
of oxygen 
(PaO2), 
Partial pressure 
of carbon 
dioxide (PaCO2), 
pH, 
Oxygen 
saturation 
Bicarbonate 
Microscopic 
examinationb: 
red blood cells, 
white blood 
cells, 
casts, 
crystals, 
bacteria, 
yeast cells or 
parasites 
Culture 
At screening 
only: 
FSHc, 
Pregnancy 
test 
(β-hCG)d 
a. 
For HAP/VAP participants, arterial blood gases are required for ventilated participants, recommended 
for non-ventilated participants at Screening visit to calculate APACHE II score; for cIAI, cUTI and BSI 
participants, arterial blood gases are only collected as clinically indicated to calculate APACHE II score 
at Screening visit. For all participants, arterial blood gases are collected as clinically indicated at 
Baseline, during treatment period and at EOT. 
b. For cUTI participants, a microscopic analysis is performed to confirm the presence of pyuria at Screening 
and Baseline, as clinically indicated during treatment period and at EOT and TOC. 
c. 
For confirmation of postmenopausal status only. 
d. Serum or urine β-hCG for female participants of childbearing potential 
 
Investigators must document their review of each laboratory safety report. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE: 
• Is associated with accompanying symptoms. 
• Requires additional diagnostic testing or medical/surgical intervention. 
• Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
• Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 


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Events NOT Meeting the AE Definition 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.3.2. Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a.  Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 


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Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e.  Is a congenital anomaly/birth defect 
f. Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are 
considered synonymous. These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel. Such cases are also 
considered for reporting as product defects, if appropriate. 
 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs 
 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety. 
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 


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events (AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
The investigator will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page. 
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure 
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding 
Occupational exposure is 
not recorded. 
All (and EDP supplemental 
form for EDP) 
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure. 


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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 


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The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements. 
 
 
Follow-up of AEs and SAEs 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool 
The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool. 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
The site will enter the SAE data into the electronic system as soon as the data 
become available. 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 


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If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone. 
 
 
SAE Reporting to Pfizer Safety via CT SAE Report Form 
Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service. 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames. 


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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. 


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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. 
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. 


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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; 
• 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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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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Glasgow Coma Scale 
(Circle appropriate response) 
B Age 
Points 
C 
Chronic Health Points 
Apache-Ⅱ Score (sum of 
A+B+C) 
Eyes open 
verbal – nonintubated 
Age 
Points 
If any of the 5 CHE 
categories is answered 
yes give +5 points for 
non-operative or 
emergency 
postoperative patient 
A APS points 
+B Age points 
+C Chronic Health Points 
Apache Ⅱ 
4 – spontaneously 
5 - oriented 
≤44 
0 
3 – to speech 
4 – confused 
45-54 
2 
2 – to pain 
3 – inappropriate words 
55-64 
3 
1 – no response 
2 – incomprehensible sounds 
65-74 
5 
1 – no response 
≥75 
6 
Liver 
Motor response 
Age points = 
CV 
Class Ⅳ angina or at rest or 
with minimal self-care 
activities 
6 – to verbal command 
verbal – intubated 
5 – localizes to pain 
5 – seem able to talk 
Pulmonary 
Chronic hypoxemia or 
hypercapnia or polycythemia 
of PHT > 40 mm Hg 
4 – withdraw to pain 
3 – questionable ability to talk 
3 – flexion to pain 
1 – generally unresponsive 
Kidney 
Chronic peritoneal or 
hemodialysis 
2 – extension to pain 
Immune 
Immune compromised host 
1 – no response 
Chronic Health Points = 


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10.7. Appendix 7: Calculation of Estimated Creatinine Clearance 
Estimated creatinine clearance will be calculated using the following Cockcroft-Gault 
formula.14 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 
therapy to be administered, the participant’s estimated creatinine clearance must be 
calculated using the most recent serum creatinine value that was obtained at the local 
laboratory, the participant’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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10.8. Appendix 8: Microbiological Assessments 
All microbiological assessments will be initiated at the local laboratory for specimen 
collection, shipment of isolates, and analysis of isolates according to the sections below and 
as outlined in more detail in the microbiology laboratory manual. All microbiological isolates 
(except anaerobic bacterial pathogens isolated from participants with respiratory infections 
and urine tract infections) must be shipped to the central reference laboratory for 
confirmation of microbiological assessments. An unstained Gram stain slide of each 
respiratory specimen from induced sputum and expectorated sputums must also be sent to the 
central reference laboratory. 
All specimens should be processed according to recognized methods that culture for both 
aerobic and anaerobic organisms15 following the standard operating procedures of the clinical 
microbiology laboratory at each study center. All cultured isolates should be kept by the local 
laboratory at –20°C or colder (preferably at 70°C) until the end of the study or when 
contacted by the central reference laboratory (except for screening visit). 
Specimen collection: 
a. Intra-abdominal specimens: An adequate abdominal specimen (such as tissue or aspirate 
suitable for isolation of both aerobic and anaerobic bacteria) should be obtained from all 
participants and sent to the local laboratory for culture, identification, and in vitro 
susceptibility testing. If treatment is discontinued early because the participant is failing 
therapy and the participant requires a second surgery, an appropriate specimen for culture 
should be obtained, ideally after stopping the initial treatment but before the new 
treatment is administered. The CRF should indicate whether or not a sample was 
obtained. 
b. Respiratory specimens: An adequate and appropriate respiratory specimen should be sent 
to the local laboratory for Gram stain (expectorated and induced sputum only), culture, 
identification, and in vitro susceptibility testing. 
Appropriate specimens from ventilated participants include: 
• endotracheal aspirate; 
• BAL; 
• mini BAL; 
• PSB sample. 
Appropriate specimens from nonventilated participants include: 
• expectorated or induced sputum; 
• BAL; 


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• mini BAL; 
• PSB sample. 
Note that there may be nonventilated participants who develop HAP and subsequently 
require intubation and mechanical ventilation. If such participants require ventilation prior to 
the first dose of study treatment, 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 the first dose of study treatment should 
provide a respiratory specimen during the procedure even if a sputum sample or endotracheal 
aspirate has already been obtained. 
To be adequate, respiratory specimen from expectorated or induced sputum must show 
<10 squamous epithelial cells and >25 polymorphonuclear neutrophils per Low Power Field 
(LPF) 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 laboratory. 
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 CRF should indicate 
whether or not a sample was obtained. 
c. Blood specimen: Blood cultures should be obtained prior to the first dose of study 
treatment (if blood cultures are not available within 48 hours prior to randomization) and 
thereafter as clinically indicated. When obtaining samples for blood culture, 2 sets of 
blood cultures should be collected (ie, 4 bottles) from 2 different sites for aerobic and 
anaerobic incubation. 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 must be obtained through a 
venipuncture. Collect samples, ideally over a period of 2 hours at least 10 to 20 minutes 
apart from separate sites. If a participant is on antibiotics, blood cultures should ideally be 
taken immediately before the next dose. Organisms isolated in the blood within 48 hours 
prior to randomization or at Baseline will be assigned a microbiologic response similar to 
those given for pathogens isolated from abdominal, urine or respiratory specimens (see 
Table 9 for list of response categories). Details concerning the collection of blood 
cultures are provided in the laboratory manual. 
d. Urine specimen: Urine samples specimens should not be obtained from urinary catheter 
bags. Preferred methods of collection of urine for culture include: 
• Straight catheterization using sterile technique (preferred for female participants); 


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• Midstream clean catch; 
• Suprapubic specimen collection using sterile technique. 
Urine specimens must not be obtained from indwelling catheter bags. When necessary, urine 
specimens in participants with indwelling bladder catheters may be obtained by sterile 
aspiration through the catheter port . The urine specimen should be plated for culture within 
2 hours from the collection time, if the specimen is kept at room temperature. Alternatively, 
this test may be performed within 24 hours of collection if the specimen is stored at 2°C to 
8°C before processing. The specimen for microscopic evaluation (eg, evidence of persisting 
pyuria) and culture obtained at Baseline should be collected before randomization and 
administration of study therapy. 


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10.9. Appendix 9: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
%CV 
% coefficient of variation 
%fT 
percentage of time over the dosing interval that free drug 
concentrations exceed the threshold concentration or minimum 
inhibitory concentration 
A-aDO2 
alveolar-arterial oxygen difference 
ABG 
arterial blood gas 
Abs 
absolute 
AE 
adverse event 
ALT 
alanine aminotransferase 
APACHE 
acute physiology and chronic health evaluation 
APS 
acute physiology score 
AST 
aspartate aminotransferase 
AUCss,0-24 
steady-state total daily area under the plasma concentration-time 
curve 
BAL 
bronchoalveolar lavage 
BAT 
best available treatment 
-hCG 
beta-human chorionic gonadotropin 
BSI 
bloodstream infection 
BUN 
blood urea nitrogen 
CARES 
chinese antimicrobial resistance surveillance 
CAZ-AVI 
ceftazidime-avibactam 
CDE 
Centre of Drug Evaluation 
CFR 
Code of Federal Regulations 
CFU 
colony-forming unit 
CHINET 
china antimicrobial surveillance network 
CHP 
chronic health points 
CI 
confidence interval 
cIAI 
complicated intra-abdominal infection 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CNS 
central nervous system 
CO2 
carbon dioxide (bicarbonate) 
CO2CP 
carbon dioxide combining power 
CONSORT 
Consolidated Standards of Reporting Trials 
Covid-19 
coronavirus disease of 2019 
CR 
carbapenem-resistant 
CRAB 
carbapenem-resistant Acinetobacter baumannii 
CrCL 
creatinine clearance 
CRE 
carbapenem-resistant Enterobacteriaceae 


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Abbreviation 
Term 
CRF 
case report form 
CRO 
contract research organization 
CRPA 
carbapenem-resistant pseudomonas aeruginosa 
CSP 
clinical study protocol 
CSR 
clinical study report 
Css,max 
maximum steady-state drug concentration in plasma during a dosing 
interval 
cSSTI 
complicated skin and skin structure infection 
CT 
clinical trial; computed tomography 
cUTI 
complicated urinary-tract infection 
CV 
coefficient of variation 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DRE 
disease-related event 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
IRC 
Internal Review Committee 
EDP 
exposure during pregnancy 
EMA 
European Medicines Agency 
EOT 
end of treatment 
ESBL 
extended-spectrum beta-lactamase 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FiO2 
fraction of inspired O2 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCS 
glasgow coma scale/score 
GGT 
gamma-glutamyl transferase 
HAP 
hospital-acquired pneumonia 
HCO3 
Hydrogencarbonate or bicarbonate 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
investigational product 
IP manual 
investigational product manual 
IPAL 
Investigational Product Accountability Log 


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Abbreviation 
Term 
IRB 
Institutional Review Board 
IRC 
internal review committee 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous/ly 
KPC 
Klebsiella pneumoniae carbapenemase 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LFU 
late follow up 
LPD 
local product document 
LPF 
low power field 
LTO 
limited treatment options 
MBL 
metallo-β-lactamase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDR 
multidrug resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
ME 
microbiologically evaluable 
MIC 
minimum inhibitory concentration 
mMITT 
microbiologically modified intent-to-treat 
MTZ 
metronidazole 
N 
number 
N/A 
not applicable 
NIMP 
noninvestigational medicinal product 
NMPA 
National Medical Products Administration 
NP 
nosocomial pneumonia 
O2 
oxygen 
PACL 
Protocol Administrative Change Letter 
PaO2 
pressure of O2 in arterial blood 
PD 
pharmacodynamic(s) 
pH 
potential of hydrogen 
PHT 
pulmonary hypertension 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PMN 
polymorphonuclear leukocyte 
pO2 
partial pressure of O2 
PSB 
protected-specimen brush 
PT 
prothrombin time 
PTA 
probability of target attainment 
q8h 
every 8 hours 
RBC 
red blood cell 


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Abbreviation 
Term 
RR 
resistance rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
safety analysis set 
SCr 
serum creatinine 
SoA 
schedule of activities 
SOP 
standard operating procedure 
spp 
plural of species 
SRSD 
single reference safety document 
STAR 
staged abdominal repair 
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 
UTI 
urinary-tract infection 
VAP 
ventilator-associated pneumonia 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 


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11. REFERENCES 
1. 
Drawz SM, Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors: a therapeutic 
renaissance in an MDR world. Antimicrob Agents Chemother. 2014;58(4):1835-46. 
2. 
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. Antimicrob Agents Chemother. 
2014;58:5297-305. 
3. 
Hirsch EB, Tam VH. Detection and treatment options for Klebsiella pneumonia 
carbapenemases (KPCs): an emerging cause of multidrug-resistant infection. J 
Antimicrob Chemother. 2010;65(6):1119-25. 
4. 
Hu FP, Guo Y, Zhu DM, et al. Resistance trends among clinical isolates in China 
reported from CHINET surveillance of bacterial resistance, 2005-2014. Clin Microbiol 
Infect. 2016;22:S9-S14. 
5. 
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. (available upon request) 
6. 
Hu Fupin, Guo Y, Zhu DM, et al. CHINET surveillance of bacterial resistance across 
China: report of the results in 2016. Chin J Infect Chemother 2017; 17:481–91. 
7. 
Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An 
update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1-12. 
8. 
Hu F, Zhu D, Wang F, et al. Current status and trends of antibacterial resistance in 
China. Clin Infect Dis. 2018;67(Suppl 2):S128-34. 
9. 
Hu Fupin, Guo Y, Zhu DM, et al. Antimicrobial resistance profile of clinical isolates in 
hospitals across China: report from the CHINET Surveillance Program, 2017. Chin J 
Infect Chemother. 2018;18(3):241-9. 
10. Falagas ME, Tensarli GS, Karageorgopoulos DE, et al. Deaths attributable to 
carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis. 
2014;20(7)(Jul):1170-5. 
11. Zhang Y, Wang Q, Yin Y, et al. Epidemiology of carbapenem-resistant 
Enterobacteriaceae infections: report from the China CRE Network. Antimicrob Agents 
Chemother. 2018;62(2):e01882-17. 
12. Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram- 
negative pathogens: current and emerging therapeutic approaches. Exp Opin 
Pharmacother 2014;15(10):1351-70. 


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13. Rigatto MH, Behle TF, Falci DR, et al. Risk factors for acute kidney injury (AKI) in 
patients treated with polymyxin B and influence of AKI on mortality: a multicentre 
prospective cohort study. J Antimicrob Chemother. 2015; 70(5):1552-7. 
14. Cockcroft DW, Gault HM. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
15. 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. 
16. Expert consensus writing group on the diagnosis, treatment and prevention of 
carbapenem-resistant Enterobacteriaceae bacterial infections in China, Professional 
Committee on Infectious Diseases of China Medical Education Association, and 
Professional Committee on Prevention and Control of Bacterial Infection and Drug 
Resistance of Chinese Medical Association. Expert consensus on diagnosis, treatment 
and prevention of carbapenem-resistant Enterobacteriaceae infections in China. Chinese 
Medical Journal, 2021, 101(36): 2850-2860. DOI: 10.3760/cma. j.cn112137-20210219- 
00438. 

SAP_001.pdf: 
Protocol C3591033 (Ceftazidime - Avibactam) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C3591033 
 
 
 
 
AN OPEN-LABEL, RANDOMIZED, MULTI-CENTER, ACTIVE-CONTROLLED 
STUDY TO ESTIMATE THE EFFICACY AND SAFETY OF CEFTAZIDIME- 
AVIBACTAM (CAZ-AVI) VERSUS BEST AVAILABLE TREATMENT (BAT) IN 
THE TREATMENT OF INFECTIONS DUE TO CARBAPENEM-RESISTANT 
GRAM-NEGATIVE PATHOGENS IN CHINESE ADULTS 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
Version: 
2 
Date: 
29 Jan 2023 


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TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 4 
LIST OF FIGURES ................................................................................................................... 4 
1. VERSION HISTORY ........................................................................................................... 5 
2. INTRODUCTION ................................................................................................................. 5 
2.1. Study Objectives, Endpoints, and Estimands ........................................................... 6 
2.1.1. Primary Estimand (E1) ................................................................................. 7 
2.1.2. Secondary Estimand(s) ................................................................................. 8 
2.1.2.1. Estimand for Clinical Response (E1) .......................................... 8 
2.1.2.2. Estimand for Microbiological Response (E2) ............................ 8 
2.1.2.3. Estimand for All-cause Mortality (E3) ....................................... 9 
2.1.3. Additional Estimand(s) ................................................................................ 9 
2.2. Study Design ............................................................................................................. 9 
2.3. Methods for Ensuring Blinding .............................................................................. 10 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................ 11 
3.1. Primary Endpoint(s) ................................................................................................ 11 
3.1.1. Clinical response ........................................................................................ 11 
3.2. Secondary Endpoint(s) ............................................................................................ 12 
3.2.1. Microbiological Response ......................................................................... 13 
3.2.2. All-cause Mortality at Day 28 .................................................................... 15 
CCI 
 
3.4. Baseline Variables ................................................................................................... 16 
3.4.1. Baseline Clinical Laboratory and Vital Signs ............................................. 16 
3.4.2. Baseline Microbiology ................................................................................ 16 
3.4.3. Stratification Variables ................................................................................ 16 
3.4.4. Other Baseline Variables ............................................................................. 16 
3.5. Safety Endpoints ...................................................................................................... 17 
3.5.1. Adverse Events ........................................................................................... 18 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).................................................... 18 
5. GENERAL METHODOLOGY AND CONVENTIONS .................................................... 22 


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5.1. Hypotheses and Decision Rules .............................................................................. 22 
5.2. General Methods ...................................................................................................... 22 
5.3. Impact Assessment of COVID-19 and Remote TOC Visits ................................... 23 
5.4. Methods to Manage Missing Data ........................................................................... 24 
6. ANALYSES AND SUMMARIES ...................................................................................... 24 
6.1. Primary Endpoint(s) ................................................................................................. 24 
6.1.1. Clinical Response at TOC visit ................................................................... 24 
6.1.2. Sensitivity Analyses .................................................................................... 25 
6.2. Secondary Endpoint(s) ............................................................................................. 25 
6.2.1. Clinical Response at TOC and EOT visit ................................................... 25 
6.2.2. Microbiological Response at EOT and TOC visits ..................................... 25 
6.2.3. Emergent Infections .................................................................................... 26 
6.2.4. All-cause Mortality at Day 28 ..................................................................... 26 
6.2.5. Safey Endpoints .......................................................................................... 26 
CCI 
 
6.4. Subset Analyses ....................................................................................................... 27 
6.5. Baseline and Other Summaries and Analyses .......................................................... 27 
6.5.1. Baseline Summaries .................................................................................... 27 
6.5.2. Study Conduct and Participant Disposition ................................................ 27 
6.5.3. Concomitant Medications ........................................................................... 27 
6.6. Safety Summaries and Analyses .............................................................................. 28 
6.6.1. Adverse Events ........................................................................................... 28 
6.6.2. Laboratory Data .......................................................................................... 29 
6.6.3. Vital Signs ................................................................................................... 29 
6.6.4. Physical Examination .................................................................................. 30 
6.6.5. Extent of Exposure and Compliance ........................................................... 30 
6.7. COVID-19 related analyses ..................................................................................... 31 
7. INTERIM ANALYSES ....................................................................................................... 31 
7.1. Introduction .............................................................................................................. 31 
7.2. Interim Analyses and Summaries ............................................................................ 31 
8. REFERENCES ..................................................................................................................... 31 


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9. APPENDICES ...................................................................................................................... 33 
9.1. Appendix 1. Summary of Efficacy Analyses .......................................................... 33 
CCI 
 
9.3. Appendix 3. Criteria for Potentially Clinically Significant Lab Results ................. 36 
9.5. Appendix 5. List of Abbreviations........................................................................... 39 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ................................................................................. 5 
Table 2. 
Definition of Clinical Response Categories at the EOT and TOC 
Visits ........................................................................................................ 12 
Table 3. 
Definition of Microbiological Response Categories at the EOT and 
TOC Visits, for Each Pathogen Identified at Initial/Pre Study 
(Study Qualifying) Culture ...................................................................... 13 
Table 4. 
Definition of Emergent Infection Categories ........................................... 15 
CCI 
 
Table 7. 
HEMATOLOGY ...................................................................................... 36 
Table 8. 
CHEMISTRY............................................................................................ 37 
LIST OF FIGURES 
Figure 1. 
Study Outline ............................................................................................ 10 
CCI 


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1. VERSION HISTORY 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
19 Feb 2021 
Original 
22 Dec 2020 
N/A 
N/A 
2 
29 Jan 2023 
Amendment 
1 
02 Jun 2022 
Add impact 
assessment of 
COVID-19 
and remote 
TOC visits 
and related 
sensitivity 
analysis. Add 
specifications 
on interim 
analysis. Add 
COVID-19 
related 
analyses. 
Made some 
clarifications 
on mMITT 
analysis set, 
baseline 
definitions and 
compliance 
calculation. 
• Section 2.3, added descriptions of 
independent team for the interim 
analysis. 
• Section 3.2.1: added definitions of 
baseline pathogens. 
• Section 4: made clarifications on the 
minimum disease requirements for 
mMITT analysis set. 
• Section 5.3: added a section on the 
impact assessment of COVID-19 and 
remote TOC visits per DMB02- 
GSOP-SD-GL01. 
• Section 5.4: made clarifications for 
missing data. 
• Section 6.1.2: added sensitivity 
analysis on primary endpoint to reflect 
the impact of remote TOC visits. 
• Section 6.6.5: made clarifications on 
the treatment compliance calculation. 
• Section 6.7: added COVID-19 related 
analysis. 
• Section 7.2: added some specifications 
on interim analysis. 
• Section 9.4: added example SAS code. 
 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3591033. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment. 


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2.1. Study Objectives, Endpoints, and Estimands 
 
Objectives 
Estimands 
Endpoints 
Primary: 
Primary: 
Primary: 
• 
To estimate the 
efficacy of 
CAZ-AVI and best 
available treatment 
(BAT) in patients 
with infections due 
to Carbapenem- 
resistant (CR) 
Gram-negative 
pathogens. 
• Estimand E1: The trial will estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the 
difference in clinical response of cure in patients with 
infections due to carbapenem-resistant Gram- 
negative pathogens. A composite estimand strategy 
will be used to account for intercurrent events that are 
part of the definition of clinical response. Intercurrent 
events of death after receiving <48 hours of study 
treatment, or inadequate infection source control at 
time of initial surgical procedure (for cIAI 
participants) will be regarded as indeterminate 
clinical response. Intercurrent events of death after 
receiving at least 48 hours of study treatment, or 
receiving treatment with further antibiotics for the 
index infection will be regarded as a failure clinical 
response. 
• 
Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
Test of Cure (TOC) 
visit 
Secondary: 
Secondary: 
Secondary: 
• 
To estimate the 
efficacy of 
CAZ-AVI and BAT 
in patients with 
infections due to 
CR gram-negative 
pathogens and who 
are 
microbiologically 
evaluable. 
• Estimand E1 will be the esimand for this objective. 
• 
Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
TOC visit 
• 
To estimate the 
clinical response to 
CAZ-AVI and BAT 
at the end of 
treatment (EOT). 
• Estimand E1 will be the esimand for this objective. 
• 
Clinical response 
(defined by cure, 
failure, or 
indeterminate) at 
EOT visit 
• 
To estimate the 
microbiological 
response to 
CAZ-AVI and 
BAT. 
• Estimand E2: The trail will estimate the treatment 
effect of CAZ-AVI relative to BAT in terms of the 
difference of favorable microbiological response in 
patients with infections due to carbapenem-resistant 
Gram-negative pathogens. A composite estimand 
strategy will be used to account for intercurrent 
events that are part of the definition of 
microbiological response. Intercurrent events of 
death after receiving <48 hours of study treatment, or 
inadequate infection source control at time of initial 
surgical procedure (for cIAI participants) will be 
regarded as indeterminate microbiological response. 
Intercurrent events that result in repeat culture of 
specimen not performed/clinically indicated (specific 
• 
Microbiological 
response (defined 
by favorable, 
unfavorable, or 
indeterminate) at 
EOT and TOC visits 


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Objectives 
Estimands 
Endpoints 
to cIAI and HAP/VAP participants) will be regarded 
as a presumed eradication if a clinical cure is 
assessed, and a presumed persistence microbiological 
response if a clinical failure is assessed. 
• To estimate the 
all-cause mortality 
for CAZ-AVI and 
BAT. 
• Estimand E3: Using a treatment-policy estimand 
strategy in patients with infections due to 
carbapenem-resistant Gram-negative pathogens to 
estimate the treatment effect of CAZ-AVI relative to 
BAT in terms of the difference of all-cause mortality 
at Day 28 of the study. Any death that occurred after 
first dose of study drug through Day 28 will be 
included. A participant with the last known survival 
status is before Day 28 or missing will be reported as 
an unknown status. 
• 
All-cause mortality 
at Day 28 
• 
To evaluate the 
safety and 
tolerability of CAZ- 
AVI. 
N/A 
• 
Assessment of 
TEAEs, 
discontinuation due 
to AEs, safety- 
related clinical 
laboratory tests. 
 
2.1.1. Primary Estimand (E1) 
The primary estimand of this study will use the composite strategy to estimate the treatment 
effect of CAZ-AVI relative to BAT accounting for both treatment adherence and response. 
The estimand is defined according to the primary objective and in alignment with the primary 
endpoint. It includes the following 4 attributes: 
• Population: Patients with infections due to Carbapenem-resistant Gram negative 
pathogens; 
• Variable: Clinical response per investigator’s assessment and adjudicated by 
independent adjudication committee at the TOC visit. Clinical response will be 
categorized as cure, failure, and indeterminate. Intercurrent events of death after 
receiving <48 hours of study treatment, or inadequate infection source control at time 
of initial surgical procedure (for cIAI participants) will be regarded as indeterminate 
clinical response. Intercurrent events of death after receiving at least 48 hours of 
study treatment, or receiving treatment with further antibiotics for the index infection 
will be regarded as failure clinical response; 
• Intercurrent event: The intercurrent events are captured through the variable 
definition; 
• Population-level summary: Difference of the clinical cure rate between CAZ-AVI 
and BAT. 


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2.1.2. Secondary Estimand(s) 
2.1.2.1. Estimand for Clinical Response (E1) 
For the secondary objectives related to clinical response, same estimand (E1) as the primary 
estimand will be used. 
• To estimate the efficacy of CAZ-AVI and BAT in patients with infections due to CR 
Gram-negative pathogens and who are microbiologically evaluable: 
The primary estimand E1 will be used. 
• To estimate the clinical response to CAZ-AVI and BAT at end of treatment: 
The primary estimand E1 will be used. Clinical response per investigator’s assessment 
and adjudicated by independent adjudication committee at the EOT visit will be the 
analysis variables. 
2.1.2.2. Estimand for Microbiological Response (E2) 
The secondary estimand for microbiologic response will use the composite strategy to 
estimate the microbiological response of CAZ-AVI relative to BAT accounting for both 
treatment adherence and response. The estimand is defined according to the secondary 
objective and in alignment with the secondary endpoint. It includes the following 4 
attributes: 
• Population: Patients with infections due to Carbapenem-resistant Gram negative 
pathogens; 
• Variable: The per-participant 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 after receiving 
<48 hours of study treatment, or inadequate infection source control at time of initial 
surgical procedure (for cIAI participants) will be regarded as indeterminate 
microbiological response. Intercurrent events that result in repeat culture of specimen 
not performed/clinically indicated (specific to cIAI and HAP/VAP participants) will 
be regarded as a presumed eradication if a clinical cure is assessed, and a presumed 
persistence microbiological response if a clinical failure is assessed; 
• Intercurrent event: The intercurrent events are captured through the variable 
definition; 
• Population-level summary: Difference in the proportion of participants with 
favorable microbiological response between CAZ-AVI and BAT. 


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2.1.2.3. Estimand for All-cause Mortality (E3) 
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 with infections due to Carbapenem-resistant Gram negative 
pathogens; 
• Variable: Death due to any cause at Day 28; 
• Intercurrent event: Any death that occurred after first dose of study drug through Day 
28 will be included. A participant with the last known survival status is before Day 28 
or missing will be reported as an unknown status. 
• Population-level summary: Difference of the mortality rate between CAZ-AVI and 
BAT. 
2.1.3. Additional Estimand(s) 
There is no defined estimand for other endpoints. 
2.2. Study Design 
This is an open-label, randomized, multi-center, interventional, active-controlled Phase 4 
study to evaluate the efficacy and safety of CAZ-AVI versus BAT in the treatment of 
infected participants with selected infection types (Hospital Acquired Pneumonia [HAP] 
(including Ventilator-Associated Pneumonia [VAP]); Complicated Urinary-Tract Infection 
[cUTI]; Complicated Intra-Abdominal Infection [cIAI]; and Bloodstream Infection [(BSI]) 
due to carbapenem-resistant Gram-negative pathogens in China. Carbapenem-resistant is 
defined as resistant to carbapenems (imipenem, meropenem), including resistant and 
intermediate. 
The study will randomize approximately 60 participants in a 1:1 ratio into 2 treatment groups 
(CAZ-AVI or BAT). Randomization will be stratified by infection site: HAP (including 
VAP); cUTI; cIAI; BSI (including primary BSI, catheter related BSI [CR BSI], and BSI 
related to HAP [including VAP], cUTI, and cIAI) that is identified prior to conducting 
treatment randomization. Among the 4 strata, the first 3 infection sites will not include 
participants with BSI. 
The study will consist of a Screening visit, a Baseline visit on Day 1 of the study treatment, 
ongoing treatment visits (Days 2-14), an End of Treatment visit within 24 hours after the last 
infusion, a Test of Cure (TOC) visit (7-10 days after EOT visit), and a Late Follow-Up 
(LFU) visit (28-32 days after the last dose of study intervention)(Figure 1). 


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The duration of treatment is 5 days up to 14 days for cUTI, cIAI and BSI, and 7 days up to 
14 days for HAP/VAP, which can be extended to 21 days depending on the participant’s 
condition and investigator’s judgement as clinical practice requires. 
Figure 1. 
Study Outline 
 
2.3. Methods for Ensuring Blinding 
The study is open-label. The investigators, site personnel, and participants will not be blinded 
in this open-label study. However, reasonable attempts by investigators and site personnel 
should be made to minimize bias wherever possible. Programmer(s) and statistician 
personnel who are unblinded will be responsible for producing the unblinded data outputs for 
the IRC review and for interim analysis prior to the CAZ-AVI license renewal application in 
China to help limit the access to individual participant treatment assignment until database 
lock has occurred. 
An independent adjudication committee will be blinded with the aim of unbiased 
adjudication of the primary objective measure. A charter will be in place for the adjudication 
committee. The adjudication committee will be blinded to study treatment and investigator’s 
assessment of clinical response. The committee will review the clinical data points, reports 
and results of the diagnostic tests used to classify the clinical response. In case of a 
discrepancy with the investigator’s assignment of clinical response, the adjudication 
committee’s assessment will prevail for the analysis. 
An Internal Review Committee (IRC) will be established with an IRC charter for this study 
and will independently review the safety data in an unblinded fashion approximately at least 


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every 6 months or as needed to ensure that the safety of participants is not compromised. In 
addition, the committee will receive SAE reports approximately every 3 months. Details 
about IRC review process and frequencies are described in IRC charter. 
The IRC will be responsible for ongoing monitoring of the safety of participants in the study 
according to the charter and may propose changes to the protocol as needed to ensure 
participant’s safety. The IRC will also review the interim analysis outputs. 
An independent team will be identified for the interim analysis (IA) and interim CSR 
development to maintain the study team as blinded to the summary report when study is 
ongoing. Anyone who will work on the IA related work and unblind to the summary report 
will be added to an independent team roster which mainly includes members from applicable 
functional lines, IRC committee members, IA CSR reviewers and IA CSR approvers. 
Anyone who is added to the independent team will not be involved in the routine study team 
work. The operation process for IA is included in the IRC charter. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
• Clinical response (defined by cure, failure, or indeterminate) at the TOC visit; 
3.1.1. Clinical response 
Clinical response will be determined at the EOT and TOC visits as either cure, failure or 
indeterminate. The clinical response at each visit will be assessed by the investigator, and 
subsequently by an independent adjudication committee which is blinded to study treatment. 
In case of a discrepancy with the investigator’s assignment of clinical response, the 
adjudication committee’s assessment will prevail for the analysis. 
The clinical response categories will be indicated according to the clinical response 
definitions as follows (Table 2): 
If a participant is assessed as a clinical failure at the EOT visit, this assessment will be 
carried forward to the TOC visit. 


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Table 2. 
Definition of Clinical Response Categories at the EOT and TOC Visits 
 
Clinical Response 
Definition 
Cure 
Baseline signs and symptoms have improved such that after study 
treatment, no further antimicrobial treatment for the index infection 
(ie, cIAI, cUTI, HAP/VAP or BSI) is required.a 
In addition, none of the failure criteria listed below should be met. 
Additionally for cIAI participants: 
No unplanned drainage or surgical intervention is necessary since 
the initial procedure. 
Failure 
Participants who meet any of the following criteria will be 
considered a treatment failure: 
• Death (after receiving at least 48 hours of study treatment). 
• Participant who received treatment with further antibiotics 
for the index infection.a This includes participants 
prematurely discontinued from study treatment due to an AE 
who require further antibiotics for the index infection. 
Additionally for cIAI participants: 
• Persisting or recurrent infection within the abdomen 
documented by the findings at re-intervention either 
percutaneously or operatively in situation of adequate 
infection source control at time of initial surgical procedure. 
• Postsurgical wound infections (eg, signs of local infection 
such as purulent exudates, erythema, or warmth that requires 
additional antibiotics and/or non-routine wound care). 
Indeterminate 
• Death (after receiving less than 48 hours of study treatment). 
• Participant lost to follow-up. 
Additionally for cIAI participants: 
• Inadequate infection source control at time of initial surgical 
procedure. 
a. 
Further antibiotics for the index infection should only be initiated for ongoing or worsening signs and 
symptoms of the infection. 
 
 
3.2. Secondary Endpoint(s) 
• Clinical response (defined by cure, failure, or indeterminate) at TOC visit in the 
microbiologically evaluable (ME) analysis set as defined in Section 4; 
• Clinical response (defined by cure, failure, or indeterminate) at EOT visit; 
• Microbiological response (defined by favorable, unfavorable, or indeterminate) at EOT 
and TOC visits; 


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• All-cause mortality at Day 28; 
• Assessment of TEAEs, discontinuation due to AEs, safety-related clinical laboratory 
tests. 
3.2.1. Microbiological Response 
For each pathogen identified at baseline, microbiological outcome at EOT and TOC will be 
determined as shown in Table 3. Baseline pathogens are defined as all the pathogens 
identified in both screening and Day 1 visits prior to the first dose. Unplanned assessments 
prior to the first dose will be considered as baseline only if microbiology tests were not done 
in screening and Day 1 visits. 
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 if there 
are inconsistencies between local and central lab. Data from local lab will be used only if the 
microbiology tests were not done in the central lab. 
Baseline microbiology susceptibility is defined as the most recent data prior to first dose. 
 
Table 3. 
Definition of Microbiological Response Categories at the EOT and TOC 
Visits, for Each Pathogen Identified at Initial/Pre Study (Study 
Qualifying) Culture 
 
Microbiological 
Response 
Definition 
Eradication 
Absence (or urine quantification <103 CFU/mL for cUTI participants) 
of causative pathogen from an appropriately obtained specimena at the 
site of infection. 
Presumed 
eradication 
Repeat culture of specimens were not performed/clinically indicated 
in a participant who had a clinical response of cure (specific to cIAI 
and HAP/VAP participants). 
Persistence 
-Persistence with 
increasing MIC 
Causative organism is still present from an appropriately obtained 
specimen at the site of infection (for cUTI, the urine culture taken at 
study intervention completion grows >103 CFU/mL of the original 
pathogen identified at trial entry). 
If the causative organism displays ≥4-fold higher MIC to study 
therapy after treatment with IV study therapy, the response will also 
be categorized as "Persistence with increasing MIC”. 
Presumed 
persistence 
Participant was assessed as a clinical failure and repeat culture of 
specimens were not performed/clinically indicated (specific to cIAI 
and HAP/VAP participants). 


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Table 3. 
Definition of Microbiological Response Categories at the EOT and TOC 
Visits, for Each Pathogen Identified at Initial/Pre Study (Study 
Qualifying) Culture 
 
Microbiological 
Response 
Definition 
Indeterminate 
microbiological 
response 
Death (after receiving less than 48 hours of study treatment). 
Participant lost to follow-up such that a determination of 
microbiological response cannot be made on the basis of clinical 
status. 
Additionally for cIAI participants: 
Inadequate infection source control at time of initial surgical 
procedure. 
a. 
A definition of an appropriately obtained specimen for each infection site will be included in the study 
microbiology manual. For participants with cIAI, an appropriately obtained specimen for determination 
of microbiological response is defined as a specimen obtained using an adequate technique (eg, surgical 
procedure [laparotomy or laparoscopy], percutaneous drainage (where in place for less than 24 hours) or 
wounds where the participant has a superficial or deep surgical wound reported at any point during the 
follow up period). From expectorated or induced sputum, an adequate sample is one with ≤10 squamous 
epithelial cells and >25 polymorphonuclear neutrophils per Low Power Field (LPF) upon a Gram stain; 
throat secretions are considered to be inadequate; other specimens such as endotracheal aspirate, BAL, 
mini BAL, and PSB are considered to be adequate. For participants with cUTI, preferred methods of 
collection of urine for culture include straight catheterization using sterile technique (preferred for 
female participants), midstream clean catch and suprapubic specimen collection using sterile technique. 
For blood specimens for culture, 2 sets of blood cultures should be collected (ie, 4 bottles) from 2 
different sites for aerobic and anaerobic incubation. One set of blood cultures must be obtained through a 
venipuncture. Collect samples, ideally over a period of 2 hours at least 10 to 20 minutes apart from 
separate sites. 
 
 
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. 
Microbiological response will be assessed separately for each pathogen after completion of 
all follow-up visits using the definitions listed in Table 3. 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.” 
Per-participant microbiological response will be assessed as “favorable”, “unfavorable” or 
“indeterminate” for each participant. Participants will be determined to have a favorable 
microbiological response if all baseline pathogens for that participant have a favorable 
outcome (eradicated or presumed eradicated) at the appropriate time point (EOT, TOC). If 
the outcome for any pathogen is unfavorable (persistence, persistence with increasing MIC, 
or presumed persistence), the participant will be considered to have an unfavorable 
microbiological response. Participants will be assessed as a indeterminate microbiological 


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CCI 
response if all baseline pathogens for that participant have a indeterminate outcome at the 
appropriate time point (EOT, TOC). 
New pathogens that appear after Baseline are categorized in Table 4 and will be summarized 
separately. 
 
Table 4. 
Definition of Emergent Infection Categories 
 
Emergent 
Infection 
Definition 
Superinfection 
cIAI/HAP/VAP/Bacteraemia: Emergence of a new pathogen(s) 
associated with emergence or worsening of signs and symptoms of 
infection and a requirement for additional antibiotics during the period 
up to and including the EOT visit. 
cUTI: Isolation of a new pathogen(s) at ≥105 CFU/mL from a urine 
culture associated with emergence or worsening of signs and symptoms 
of infection and a requirement for additional antibiotics during the 
period up to and including the EOT visit. 
New infection 
cIAI/HAP/VAP/Bacteraemia: Emergence of new pathogen(s) 
associated with emergence or worsening of signs and symptoms of 
infection and a requirement for additional antibiotics in the time period 
after the EOT visit. 
cUTI: Isolation of a new pathogen(s) at ≥105 CFU/mL from a urine 
culture associated with emergence or worsening of signs and symptoms 
of infection and a requirement for additional antibiotics in the time 
period after the EOT visit. 
 
3.2.2. All-cause Mortality at Day 28 
The proportion of participants who have died due to any reason up to and including Day 28 
will be measured. The denominator for the calculation of the proportion will include all 
participants irrespective of the status (dead, alive and unknown). 
The number of participants who died up to Day 28 of the study will be calculated as the 
number of participants with a date of death on or before the end of Day 28; participants who 
have died after Day 28 will be assumed to be alive at Day 28. If there is no record of a 
participant’s death and the participant attended the LFU visit, or if the participant is known to 
be alive after Day 28, then the survival status will be considered as alive at Day 28. 
Participants who withdraw from the study before Day 28 will be considered to have 
“unknown” mortality status, unless further information is available (eg, date of death). 
 
 
 


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3.4. Baseline Variables 
3.4.1. Baseline Clinical Laboratory and Vital Signs 
Baseline clinical laboratory (Hematology, Chemistry, etc.) and vital signs values will be 
defined as the last non-missing value observed before treatment begins. 
3.4.2. Baseline Microbiology 
Study qualifying microbiological isolate is a CR Gram negative bacteria and culture- 
confirmed susceptibility to CAZ-AVI that was isolated from an appropriate specimen 
obtained within 5 days prior to screening. Culture, identification, and in vitro susceptibility 
testing, isolated from adequate specimens, is performed at the local laboratory. And the 
isolate (including all pathogens that may or may not be carbapenem resistant) must be sent to 
the central microbiology laboratory vendor for confirmation. 
For cIAI, adequate abdominal specimen (such as tissue or aspirate suitable for isolation) must 
be obtained for culture at the initial qualifying procedure. For HAP/VAP, appropriate 
respiratory specimen including endotracheal aspirate, expectorated or induced sputum 
bronchoalveolar lavage (BAL), mini BAL or protected specimen brush (PSB) sampling 
should be collected for culture. For cUTI participants, a quantitative culture of urine is 
required. For BSI, 2 sets of blood cultures (1 anaerobic and 1 aerobic bottle in each set) 
should be collected. Details about the specimen collection is included in the study 
microbiology manual. 
3.4.3. Stratification Variables 
Randomization will be stratified based on infectious site (HAP (including VAP), cUTI, cIAI 
and BSI). BSI will include primary BSI, catheter related BSI [CR BSI], and BSI related to 
HAP [including VAP], cUTI, and cIAI that is identified prior to conducting treatment 
randomization. Among the 4 strata, the first 3 infection sites will not include participants 
with BSI. 
3.4.4. Other Baseline Variables 
Demographic and baseline characteristics include the following: 
• Age (years); 
• Gender (male, female) 
• Height (cm); 
• Weight (kg); 
CCI 


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• Medical history; 
• APACHE II score; 
• Prior systemic antibiotic use (yes [subcategories of ≤24h / >24h] / No); 
• Failure of prior antibiotics use (Yes / No); 
Note: Based on protocol inclusion criteria #3, a participant is allowed to enter this 
study if one of the following 3 items is met： 
a) No - or no more than 24 hours of appropriate antibacterial therapy was 
administered for the current infection [this defines failure of prior antibiotic use 
as ‘no’]. 
The following two items will define failure of prior antibiotics use as ‘yes’: 
b) Worsening of objective symptoms or signs of infection after at least 48 hours of 
appropriate antibacterial therapy. OR 
c) No change of objective symptoms or signs of infection after at least 72 hours of 
appropriate antibacterial therapy. 
(Note: Therapy will be considered appropriate if microbiological susceptibility 
test results show that all carbapenem-resistant pathogens are susceptible to at 
least 1 of the antibacterial[s] received) 
If a patient incorrectly enter the study and do not meet the above criteria, then the 
patient will be assigned as ‘Other’. (In other words, “failure of prior antibiotic = yes” 
indicates participants who failed therapy that had no potential activity against the 
baseline pathogens.) 
• Estimated creatinine clearance (CrCl) [mL/min]; 
• Primary diagnosis, complicating factors for cUTI, mechanical ventilation status (for 
HAP/VAP); 
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. 
3.5. Safety Endpoints 
The safety endpoints of this study are: 
• Incidence of treatment-emergent adverse events and discontinuation due to adverse 
events; 
• 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; 


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• Measurements and change from baseline in vital sign measures by scheduled visit. 
• Incidence of abnormalities in the complete physical examination 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 infusion 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. 
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 the database lock and classifications will be 
documented per standard operating procedures. 
 
Participant 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. 
Intent-to-Treat (ITT) 
Analysis Set 
It will include all participants randomly assigned to study 
intervention and who take at least one dose of study 
intervention. 
microbiologically 
Modified ITT (mMITT) 
Analysis Set 
It is a subset of the ITT analysis set, and will include 
participants who: 
• meet minimum disease requirementsa and received any 
amount of study therapy. 
• have at least 1 carbapenem-resistant Gram-negative pathogen 
in an adequate initial/pre-study culture. Participants with 
inherently resistant pathogens (monomicrobial infections due 
to any Acinetobacter spp.) will be excluded from the mMITT 
analysis set. 


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Participant Analysis Set 
Description 
Microbiologically 
Evaluable (ME) Analysis 
Set 
It is a subset of the mMITT analysis set, and will include 
participants who: 
• received at least 3 days of study intervention (CAZ-AVI or 
BAT), or received study intervention treatment for ≥ 48 hours 
with ≥80% compliance, or received study intervention 
treatment for <48 hours before discontinuing treatment due to 
an AE. 
• did not receive concomitant antibiotic therapy with potential 
activity against any baseline carbapenem-resistant Gram- 
negative pathogens between the time of first dose and the time 
of TOC. This does not include those participants who have 
failed study therapy and require additional antibiotics to treat 
their infection. 
• had the baseline entry organism(s) genetically confirmed by 
central microbiological testing. 
• did not have a clinical outcome of indeterminate for the 
respective analysis at EOT or TOC visits. 
• had no important protocol deviations that may affect the 
assessment of efficacy. 
Safety Analysis Set 
(SAS) 
All participants who take any study intervention. Participants 
will be analyzed according to the product they actually 
received. 
See Section 9.1 Appendix 1 for a detailed list of analysis sets used for different estimand, 
endpoint and timepoint. 
a. Minimum disease requirements for each infection site are defined based on the 
following inclusion criteria as below: 
Inclusion Criteria 2: 
Participant must have a diagnosis of an infection (HAP/VAP, cUTI, cIAI, BSI) due to 
confirmed carbapenem-resistant aerobic Gram-negative pathogens, requiring administration 
of IV antibacterial therapy (See additional inclusion criteria for each indication). 
Additional minimum disease criteria for HAP/VAP (See Protocol Table 2 for details): 
Additional Inclusion Criteria 1: 


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Onset of symptoms >48 hours after admission or <7 days after discharge from an inpatient 
care facility (for which the duration of admission was >3 days). 
Additional Inclusion Criteria 2: 
New or worsening infiltrate on chest X-ray (or computed tomography [CT] scan) obtained 
within 48 hours prior to randomization. 
Additional Inclusion Criteria 3: 
At least 1 of the following: 
• Documented fever (temperature ≥38°C) or hypothermia (rectal/core temperature ≤ 
35°C); 
• WBC ≥10,000 cells/mm3, leukopenia with total WBC ≤4500 cells/mm3, or >15% 
immature neutrophils (bands) noted on peripheral blood smear. 
At least 2 of the following: 
• A new cough (or worsening of cough at Baseline); 
• Production of purulent sputum or purulent endotracheal secretions; 
• Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, rales, 
rhonchi, bronchial breath sounds, dullness on percussion, egophony); 
• Dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths per minute, or 
hypoxemia (O2 saturation <90% or partial pressure of O2 [pO2]<60 mmHg while 
breathing room air); 
• Need for acute changes in the ventilator support status/system to enhance 
oxygenation, as determined by worsening oxygenation (arterial blood gas [ABG] or 
pO2 in arterial blood [PaO2]/fraction of inspired O2 [FiO2]) or needed changes in the 
amount of positive end-expiratory pressure. 
Additional minimum disease criteria for cUTI: 
Additional Inclusion Criteria 2: 
Participant had pyuria in the 5 days prior to study entry as determined by a midstream clean 
catch or catheterized urine specimen with ≥10 white blood cells (WBCs) per high-power 
field on standard examination of urine sediment or ≥10 WBCs/mm3 in unspun urine. 
Additional Inclusion Criteria 3: 
At least two of the following signs or symptoms: 


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• Chills or rigors or warmth associated with fever (eg, oral temperature ≥38 degrees 
Celsius) 
• Flank pain (pyelonephritis) or pelvic pain (cUTI) 
• Nausea or vomiting 
• Dysuria, urinary frequency, or urinary urgency 
• Costo-vertebral angle tenderness on physical examination 
Additional Inclusion Criteria 4: 
Complicating factors: participant must have at least 1 of the following complicating factors: 
• Documented history of urinary retention (male participants); 
• Functional or anatomical abnormality of the urogenital tract, including anatomic 
malformations or neurogenic bladder, or with a postvoid residual urine volume of at 
least 100 mL; 
• Use of intermittent bladder catheterization or presence of an indwelling bladder 
catheter for at least 48 hours prior to obtainment of study-qualifying culture; 
• Urogenital procedure (such as cystoscopy or urogenital surgery) within the 7 days 
before study entry prior to obtainment of study qualifying-culture. 
Additional minimum disease criteria for cIAI: 
Additional Inclusion Criteria 2: 
The participant has at least 1 of the following diagnosed during the surgical intervention: 
• Cholecystitis with gangrenous rupture or perforation or progression of the infection 
beyond the gallbladder wall 
• Diverticular disease with perforation or abscess 
• Appendiceal perforation or periappendiceal abscess 
• Acute gastric or duodenal perforations, only if operated on >24 hours after diagnosis 
• Traumatic perforation of the intestines, only if operated on >12 hours after Diagnosis 
• Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis associated 
with cirrhosis or chronic ascites) 


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• Intra-abdominal abscess (including of liver or spleen provided that there was 
extension beyond the organ with evidence of intraperitoneal involvement) 
Additional Inclusion Criteria 3: 
One or more systemic signs or symptoms that accompany cIAI, such as fever, hypotension, 
abdominal pain, nausea/vomiting, abdominal mass on clinical examination, altered mental 
status. 
Additional minimum disease criteria for BSI: 
Additional Inclusion Criteria 3: 
Signs and symptoms of systemic infection are characterized by at least one of the following: 
• Chills, rigors, fever (temperature of ≥38.0°C or ≥100.4°F) or 
hypothermia(temperature <35°C [<95°F]); 
• Elevated white blood cell count (≥10,000/mm3) or left shift (>15% immature 
polymorphonuclear leukocytes [PMNs]). 
• Hypotension, systolic <90 mmHg 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
This study will be an estimation study. There are no formal hypothesis tests planned for this 
study. Statistical inference will be based on point estimate and confidence interval. 
5.2. General Methods 
All data will be presented by treatment arm (CAZ-AVI, BAT, and Total). 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 confidence interval (CI) for the response rates for each treatment 
group will be calculated using Jeffrey’s method (Brown et al. 2001; Cai 2005)1,2. The CI for 
response rate difference between treatment arms will be derived using Miettinen & Nurminen 
(1985)3 method stratified by infection site. If the number of participants in a particular 
stratum is small (less than 3 participants per each treatment group), then the unstratified 
Miettinen & Nurminen method will be used. Listings of individual participant data will also 
be produced. 
Categorical and qualitative variable summaries for safety will include n and percentage of 
participants who are in the particular category and have evaluable data collected. In general, 
the denominator for the percentage calculation will be based upon the total number of 
participants with evaluable data collected in the corresponding analysis population. 


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5.3. Impact Assessment of COVID-19 and Remote TOC Visits 
For reducing risk to participants, alternative measures were allowed in protocol amendment 1 
(dated 02 Jun 2022) about participant remote safety monitoring due to COVID-19 impact. If 
participants are unable to visit study sites due to COVID-19 pandemic or local policies, the 
investigators must continue to collect AEs and perform safety reporting responsibilities per 
protocol via telephone contact or other methods as appropriate. 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 reported with consistent wording starting 
with “Remote TOC visit…”, 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 
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). 


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5.4. Methods to Manage Missing Data 
For clinical response and microbiological response, 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 TOC visit 
• Estimand strategy: Composite strategy estimand E1 (Section 2.1.1). 
• Analysis set: mMITT population (Section 4). 
• Analysis methodology: Jeffrey’s method will be used to calculate the 95% CIs for the 
response rate for each treatment arm and Miettinen & Nurminen method will be used to 
calculate the 95% CI for the response rate difference between CAZ-AVI and BAT 
treatment arms (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 mMITT analysis population will be summarized by treatment group. 
The point estimate and 95% confidence interval will be calculated for each individual 
treatment group, as well as the difference between CAZ-AVI and BAT treatments in 
clinical cure rate. 
• Subgroup analyses will be performed for infection site (cIAI, HAP including VAP, 
cUTI, and BSI) that is identified prior to conducting treatment randomization (see 
Section 3.4.3) and whether participants having BSI (Yes/No) if data permit. 


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6.1.2. Sensitivity Analyses 
A sensitivity analysis based on the Investigator’s assessment of clinical response in the mMITT 
analysis set at the TOC visit will be performed using the same methodology specified in Section 
6.1.1. 
A second sensitivity analysis based on the adjudication assessment of clinical response 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. 
Another sensitivity analysis for the adjudication assessment of clinical response will be 
performed by removing participants with remote TOC visit 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 TOC and EOT visit 
• Estimand strategy: Composite strategy estimand E1 (Section 2.1.1, Section 2.1.2.1). 
• Analysis set: mMITT population and the ME population (Section 4). 
• Analysis methodology: Jeffrey’s method will be used to calculate the 95% CIs for the 
response rate for each treatment arm and Miettinen & Nurminen method will be used to 
calculate the 95% CI for the response rate difference between CAZ-AVI and BAT 
treatment arms (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 ME analysis population and at EOT visit in the mMITT and ME 
analysis population will be summarized by treatment group. The point estimate and 95% 
confidence interval will be calculated for each individual treatment group, as well as the 
difference between CAZ-AVI and BAT treatments in clinical cure rate. 
6.2.2. Microbiological Response at EOT and TOC visits 
• Estimand strategy: Composite strategy estimand E2 (Section 2.1.2.2). 
• Analysis set: mMITT population and the ME population (Section 4). 
• Analysis methodology: Jeffrey’s method will be used to calculate the 95% CIs for the 
per-participant microbiological response rate for each treatment arm and Miettinen & 
Nurminen method will be used to calculate the 95% CI for the response rate difference 
between CAZ-AVI and BAT treatment arms (Section 5.2). 


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• 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 per-participant microbiological response at TOC visit in the mMITT and 
ME analysis population will be summarized by treatment group. The point estimate and 
95% confidence interval will be calculated for each individual treatment group, as well 
as the difference between CAZ-AVI and BAT treatments in per-participant favorable 
microbiological response rate. 
6.2.3. 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. 
6.2.4. All-cause Mortality at Day 28 
• Estimand strategy: Treatment policy strategy estimand E3 (Section 2.1.2.3). 
• Analysis set: ITT population (Section 4). 
• Analysis methodology: Jeffrey’s method will be used to calculate the 95% CIs for the 
all-cause mortality for each treatment arm and Miettinen & Nurminen method will be 
used to calculate the 95% CI for the mortality difference between CAZ-AVI and BAT 
treatment arms (Section 5.2). 
• Intercurrent events and missing data: These have been accounted for in the estimand 
(Section 2.1.2.3). 
• The number and percent of participants defined as died, alive and unknown will be 
summarized by treatment group. The point estimate and 95% confidence interval will be 
calculated for each individual treatment group, as well as the difference between CAZ- 
AVI and BAT treatments in all cause mortality. 
• If the proportion of participants with unknown status is unbalanced between the treatment 
groups, then a sensitivity analysis will be considered for all-cause mortality. 
6.2.5. Safey Endpoints 
The details of safety analyses are described in the Section 6.6. 
 
 
 


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6.4. Subset Analyses 
Subgroup analyses will be performed for infection site (cIAI, HAP including VAP, cUTI, 
and BSI) that is identified prior to conducting treatment randomization (Section 3.4.3), and 
whether participants having BSI (Yes/No) if data permit. 
The analysis described for the primary efficacy endpoint clinical response at TOC visit in 
Section 6.1.1 will be done for each infection site (or combined infection sites). The 
summaries broken down by infection site (or combined infection sites) will only present 
counts and percentages for individual treatment arm and difference between treatment arms 
due to small sample size. 
Similarly, the analyses for secondary and other efficacy endpoints will be presented for each 
infection site (or combined infection sites). 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
Baseline variables are defined as outlined in Section 3.4. 
Demographic and baseline characteristics will be summarized by treatment arm and infection 
site in the safety analysis set. Baseline disease characteristics will also be summarized for the 
mMITT analysis set. 
Baseline microbiology will be summarized by treatment arm and infection site (or combined 
infection sites). Pathogens at baseline will be summarized overall and by infection site. 
Pathogens will be summarized by individual baseline pathogen and by pathogen type (Gram- 
negative/positive pathogens, carbapenem-resistant/or not resistant).The susceptibility profile 
and MIC frequency distributions of study treatment for all baseline pathogens will also be 
summarized. Microbiological culture results will be listed. 
6.5.2. Study Conduct and Participant Disposition 
The number of participants who are enrolled, who are randomized, who are randomized but 
are never treated, who complete the study up to the EOT visit, TOC visit, who complete the 
study up to the LFU visit, who are withdrawn from the study treatment, and who are 
withdrawn from the study, including reason for withdrawal, will be summarized by treatment 
arm for all participants. 
The number of participants in each of the analysis sets (ie, ITT, mMITT, SAS) will be 
summarized by treatment arm and infection site (or combined infection sites). 
6.5.3. Concomitant Medications 
All prior and concomitant medications will be summarized. Systemic antibiotic medications 
will be summarized and listed separately. 


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6.6. Safety Summaries and Analyses 
In general, safety analyses will be performed by treatment group and infection site (or 
combined infection sites) 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, serious adverse events, death, SAEs with an outcome 
of death, lab parameters (hematology, blood chemistry etc.), vital signs, discontinuations 
from study, discontinuations from treatment, and treatment duration. Safety analyses will be 
primarily presented by treatment group with all infection sites combined; high-level 
summary of TEAE, summaries of discontinuations from study and treatment, summary of 
discontinuation from treatment due to treatment, summaries of death and SAE, and summary 
of potentially clinically significant laboratory results will be presented by treatment group 
and infection site (or combined infection sites). 
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 
TEAEs will be summarized by number and percent by system organ class (SOC) and 
preferred term (PT). 
The following high-level TEAE summaries 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 by as 
following： 
• Summary of TEAEs by system organ class and preferred term 
• Summary of TEAEs by system organ class and preferred term, categorised 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 
• Summary of SAEs with an outcome of death 
• Summary of all cause death 
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 and other satefy laboratory tests 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 Section 9.3. 
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. For urinalysis, shifts from negative (or normal), trace and positive will be 
tabulated. Arterial Blood Gas (ABG) results, where available, will be summarized and listed. 
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 LFU visit: The AST, ALT, total 
bilirubin and ALP elevations can occur at any time in the specific review period and do not 
need to occur simultaneously. 
A listing of participants with elevations in any one of the AST, ALT, Total bilirubin 
parameters will be also presented. ie, Participants with a value of ≥3xULN (upper limit of 
normal range) 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 participant 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 by treatment group. 
Vital signs for all participants will be listed. 


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6.6.4. Physical Examination 
The numbers and percentage of subjects with an abnormal complete physical exam 
assessment for each body system will be displayed by scheduled visit. All the physical 
examination data will be listed. 
6.6.5. Extent of Exposure and Compliance 
Exposure (in days) to study drug during the treatment period will be summarized by 
treatment group for the safety analysis set. 
Compliance over the whole treatment period for each drug 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 participant 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. For the BAT treatment, the compliance can 
be calculated for each drug separately using above method. In the combination therapy of 
BAT treatment, any of the drug in the combination that meet <80% or >120% criteria will be 
considered non-compliance of that participant. 
Considering there are multiple drugs in BAT, the compliance of each participant will be 
categorized as 4 categories, <80%, ≥ 80% to 120%, >120% and “both <80% and >120%”. 
Each drug from a combination therapy meeting <80%, ≥ 80% to 120%, or >120% will be 
categorized first for a participant. If one drug of the combination therapy has compliance 
<80%, in the meantime, another drug has compliance >120%, then the participant will be 
categorized to “both <80% and >120%”. Only when compliance for all drugs of the 
combination therapy meet “≥ 80% to 120%”, a participant will be categorized into this 
category. 
The compliance will be summarized in the following four categories by the number and 
percentage of participants in each treatment group: 
• <80% (i.e. <80% in CAZ-AVI group, <80% for any drug of the combination therapy 
in BAT group) 
• ≥ 80% to 120% (i.e. ≥ 80% to 120% in CAZ-AVI group, ≥ 80% to 120% for all 
drugs of the combination therapy in BAT group) 
• >120% (i.e. >120% in CAZ-AVI group, >120% for any drug of the combination 
therapy in BAT group) 


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• both <80% and >120% (i.e. both <80% and >120% non-compliant issues occurred for 
different drugs of the combination therapy in BAT group) 
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 
7.1. Introduction 
The study is anticipated to have a long recruitment duration, and therefore an interim analysis 
will be performed prior to the CAZ-AVI license renewal application in China. The analysis 
methods in the interim report will follow the methods planned for the full study and will be 
based on communication with China agency. 
7.2. Interim Analyses and Summaries 
For development of the interim analysis report, the study database will be cleaned and a 
snapshot of the database will be created. Final unblinded tables, figures and listings (TFLs), 
and interim report will be produced using snapshot data by unblinded statistician and 
programmer(s). 
Considering the small number of participants included in the interim analysis, in addition to 
the general analyses planned in above sections, more specifications are described below. 
For the subgroup efficacy summaries by infection site, the response rate will be presented by 
treatment and the difference between the treatments, but the corresponding CIs will not be 
included due to the small number of participants in each infection site. 
The efficacy summaries that will be generated based on the ME analysis set will only be 
displayed for the overall participants without broken down by infection site since the ME 
analysis set will contain fewer participants than the primary mMITT analysis set. 
Considering the data for per-pathogen microbiological response will be very sparse, the 
interim analysis for per-pathogen microbiological response will only be summarized with 
overall participants using the mMITT analysis set. 
8. REFERENCES 
1. Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. Statistical 
Science 2001, 16 (2):101-117. 


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2. Cai TT. One-sided confidence intervals in discrete distributions. J Stat Plan Inference 
2005;131(1):63-68. 
3. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4: 213-226. 


 
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9. APPENDICES 
9.1. Appendix 1. Summary of Efficacy Analyses 
 
Endpoint/Variable 
Analysis Set 
Statistical Method 
Timepoint 
Objective 
Estimand 
Clinical Cure 
(adjudicated) 
mMITT 
Summary of Proportion 
95% CI for Response Rate 
Difference and 95% CI 
between Treatment Arms 
TOC 
Primary Endpoint 
E1 
Clinical Cure (per 
investigator’s 
assessment) 
mMITT 
Summary of Proportion 
95% CI for Response Rate 
Difference and 95% CI 
between Treatment Arms 
TOC 
Sensitivity 
Analysis to 
Primary Endpoint 
E1 
Clinical Cure 
(adjudicated) 
ME 
Summary of Proportion 
95% CI for Response Rate 
Difference and 95% CI 
between Treatment Arms 
TOC 
Secondary 
Endpoint 
E1 
Clinical Cure 
(adjudicated) 
mMITT and 
ME 
Summary of Proportion 
95% CI for Response Rate 
Difference and 95% CI 
between Treatment Arms 
EOT 
Secondary 
Endpoint 
E1 
Per-participant 
Microbiologic 
Response 
mMITT and 
ME 
Summary of Proportion 
95% CI for Response Rate 
Difference and 95% CI 
between Treatment Arms 
EOT and TOC 
Secondary 
Endpoint 
E2 
All-cause mortality 
ITT 
Summary of Proportion 
95% CI for mortality 
Difference and 95% CI 
between Treatment Arms 
TOC and Day 
28 
Secondary 
Endpoint 
E3 
 
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9.3. Appendix 3. Criteria for Potentially Clinically Significant Lab Results 
Table 7. 
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 8. 
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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9.5. Appendix 5. List of Abbreviations 
 
Abbreviation 
Term 
ABG 
arterial blood gas 
AE 
adverse event 
ALP 
llkaline phosphatase 
ALT 
alanine aminotransferase 
APACHE 
Acute Physiology and Chronic Health Evaluation 
AST 
aspartate aminotransferase 
BAL 
bronchalveoloar lavage 
BAT 
best available treatment 
BSI 
bloodstream infection 
BUN 
blood urea nitrogen 
CAZ-AVI 
ceftazidime-avibactam 
CDARS 
Clinical Data Analysis and Reporting System 
CFB 
change from baseline 
CFU 
colony-forming unit 
CI 
confidence interval 
cIAI 
complicated intra-abdominal infection 
CR 
carbapenem-resistant 
CR BSI 
catheter related BSI 
CrCl 
creatinine clearance 
cUTI 
complicated urinary-tract infection 
EOT 
end of treatment 
HAP 
hospital-acquired pneumonia 
HLGT 
High-Level Group Terms 
HLT 
High-Level Terms 
IRC 
internal review committee 
ITT 
intent-to-treat 
IV 
intravenously 
LFU 
late follow up 
LLN 
lower limit of normal range 
LPF 
low power field 
ME 
microbiologically evaluable 
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 
PCS 
Potentially clinically significant 
PSB 
protected-specimen brush 
PT 
Preferred Term 
RBC 
red blood cell 
SAE 
serious adverse event 


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Abbreviation 
Term 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SD 
Standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, listings 
TOC 
test of cure 
ULN 
upper limit of normal range 
VAP 
ventilator-associated pneumonia 
WBC 
white blood cell