Conditions: Serious Bacterial Infection
Keywords: Serious bacterial infection cIAI HAP/(VAP cUTI BSI MBL
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
Phase 3 study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.

Detailed description:
This is a prospective, randomized, multicenter, open-label, parallel group, comparative study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.

The study will randomize approximately 60 subjects in a 2:1 randomization scheme (ATM-AVI: BAT) with infections due to MBL-producing Gram-negative bacteria. Molecular testing at the central microbiology laboratory will be performed to confirm the MBL status of the organism upon study completion or at pre-designated intervals.

The study will consist of a Screening Visit (Visit 1), a Baseline visit (Visit 2) on Day 1 of the study treatment, ongoing treatment visits (Visits 3 to 15) from Day 2 to Day 14, an End of Treatment (EOT) visit (Visit 16) within 24 hours after the last infusion, a Test of Cure (TOC) visit (Visit 17) on Day 28 (±3 days) and a Late Follow Up (LFU) visit (Visit 18) on Day 45 (±3 days).

Subjects will be stratified at randomization based on infection type (cIAI, HAP/VAP, cUTI or BSI). The number of subjects with cUTI will be no more than approximately 75% of the study population.

After obtaining written informed consent and confirming eligibility, subjects will be randomized in a 2:1 ratio to the ATM AVI treatment arm or the BAT treatment arm according to a central randomization schedule (approximately 40 (ATM AVI) and approximately 20 (BAT) subjects per group).

The duration of treatment is 5 to 14 days for cIAI, cUTI and BSI and 7 to 14 days for HAP/VAP. Each subject is expected to complete the study, including the LFU visit. The precise duration of treatment will be determined by the investigator based on the subject's severity of infection and subsequent response to treatment.

For subjects randomized to ATM AVI treatment arm, sparse blood samples will be collected for population pharmacokinetic (PK) assessments and PK/pharmacodynamic (PD) relationships will be evaluated in subjects where plasma samples and microbiological response data have been collected.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: ATM-AVI intervention 2: BAT
Intervention descriptions: intervention 1: ATM-AVI doses (loading, extended loading and maintenance) and the dosing frequency of the maintenance dose are dependent on renal function. Subjects will be given a loading dose of 500 mg ATM plus 167 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 30 minutes. This treatment will immediately be followed by an extended loading dose of 1500 mg ATM plus 500 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 3 hours. Then there will be a 3 hour or 5 hour gap. Subjects will receive a maintenance dose of 1500 mg ATM plus 500 mg AVI every 6 hours or 750 mg ATM plus 250 mg AVI every 6 hours, or 675 mg ATM plus 225 mg AVI every 8 hours. Subjects with cIAI will also receive Metronidazole (MTZ) 500 mg IV q8h over 60 minutes. The first dose of MTZ will be started immediately after the extended loading dose of ATM-AVI has completed and treatment will be continued until the end of the treatment period. intervention 2: The comparator treatment in this study is best available therapy (BAT) based upon site practice and local epidemiology. The choice of BAT (monotherapy or combination) for each subject must be recorded prior to randomization. If the chosen BAT does not provide adequate anaerobic coverage for cIAI subjects MTZ is to be administered as a co therapy. BAT dose, frequency, dose adjustments with renal impairment will be based on per local package inserts.

Protocol document:
Prot_000.pdf: 
ATM-AVI 
C3601009 
Final Protocol Amendment 2, 23 May 2022 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
A PROSPECTIVE, RANDOMIZED, OPEN-LABEL, COMPARATIVE STUDY TO 
ASSESS THE EFFICACY, SAFETY AND TOLERABILITY OF 
AZTREONAM-AVIBACTAM (ATM-AVI) AND BEST AVAILABLE THERAPY 
FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO MULTI-DRUG 
RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING 
METALLO-Β-LACTAMASE (MBL) 
 
 
Investigational Product Number: 
PF-06947387 
Investigational Product Name: 
Aztreonam-Avibactam 
United States (US) Investigational New 
Drug (IND) Number: 
European Clinical Trials Database 
(EudraCT) Number: 
CCI  
 
2017-004544-38 
Protocol Number: 
C3601009 
Phase: 
3 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


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Document History 
 
Document 
Version Date 
Amendment 2.0 
23 May 2022 
Amendment 1.0 
05 July 2018 
Original Protocol 
13 November 2017 


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This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs) and any protocol administrative change letter. 
Protocol Amendment Summary of Changes Table 
Amendment 2.0 (23 May 2022) 
Overall Rationale for the Amendment: Updates to Study Eligibility Criteria to better 
reflect the target patient population in clinical practice. Updates consistent with the current 
Pfizer protocol template and PACLs have also been made. 
Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Section 4: Study 
Eligibility Criteria 
Updates to Study 
Eligibility Criteria to 
better reflect the target 
patient population in 
clinical practice. 
The objective of the study 
is to generate efficacy and 
safety data that is 
representative and 
generalizable to the target 
patient population in 
clinical practice, therefore 
consistent with the US 
FDA 2020 Guidance on 
‘Enhancing the Diversity of 
Clinical Trial Populations - 
Eligibility Criteria, 
Enrollment Practices, and 
Trial Designs Guidance for 
Industry’26, the rationale 
for this protocol 
amendment is to streamline 
the study eligibility criteria 
to enhance the 
generalizability of the study 
population to the target 
patient population whilst 
continuing to maintain an 
acceptable benefit-risk 
assessment for each 
patient’s participation in 
the study. As the safety 
experience with ATM-AVI 
across the development 
program has increased 
since the start of study 
C3601009 and no clinically 
meaningful safety concerns 
have been 
observed/reported, it is 
appropriate and necessary 
to broaden the study 
eligibility criteria to better 
reflect the target patient 
population and enhance the 
Substantial 


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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
ability to better understand 
the benefit-risk profile of 
ATM-AVI across the 
patient population likely to 
be treated with ATM-AVI 
in clinical practice. 
Protocol Summary 
(Comparator 
Treatment Arm - Best 
Available Therapy 
and Comparators-Best 
Available Treatment 
Arms) 
Removal of examples of 
acceptable best available 
therapy as the list is not 
exclusive and was not 
intended to be 
prescriptive. 
Updated as per PACL 
dated 15-Jan-2021. 
Nonsubstantial 
Protocol Summary 
(Table 1: Schedule of 
Activities) 
Updated timeframe for 
microbiology sample 
collection and 
requirements for 
collection of blood culture 
samples. 
To reflect operational 
feasibility in clinical 
practice. 
Substantial 
Section 1.5: Single 
Reference Safety 
Document 
Updated Single Reference 
Safety Document. 
Updated as per PACL 
dated 03-Sep-2019. 
Nonsubstantial 
Section 1.6: 
Benefits/Risk and 
Ethical Assessment 
Updated risk/benefit 
language to replace “Drug 
induced liver injury” with 
“Increased liver 
transaminases” to be 
consistent with 
Investigator Brochure. 
Updated as per PACL 
dated 09-Nov-2021. 
Nonsubstantial 
Section 5.1: 
Allocation to 
Treatment 
Clarification to the 
instructions for allocation 
to study treatment. 
Updated as per PACL 
dated 15-Jan-2021. 
Nonsubstantial 
Section 5.4.1: Dosage 
Forms and Packaging 
Clarification to the study 
drug characteristics and 
removal of examples of 
acceptable best available 
therapy as the list is not 
exclusive and was not 
intended to be 
prescriptive. 
Updated as per PACL 
dated 15-Jan-2021. 
Nonsubstantial 
Section 5.5.2: 
Comparator 
Treatment Arm - Best 
Available Therapy 
Clarification to the study 
drug characteristics and 
removal of examples of 
acceptable best available 
therapy as the list is not 
exclusive and was not 
intended to be 
prescriptive. 
Updated as per PACL 
dated 15-Jan-2021. 
Nonsubstantial 


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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Section 6.1: 
Prescreening on 
MBL-positive 
Gram-negative 
Pathogens (within 
7 Days prior to 
screening) 
Updated timeframe for 
microbiology sample 
collection and 
requirements for 
collection of blood culture 
samples. 
To reflect operational 
feasibility in clinical 
practice. 
Substantial 
Section 7.1.2: 
Microbiological 
Response 
Updated microbiology 
sample collection 
requirements. 
To reflect operational 
feasibility in clinical 
practice. 
Substantial 
Section 7.4: 
Microbiology 
Updated timeframe for 
microbiology sample 
collection and 
requirements for 
collection of blood culture 
samples. 
To reflect operational 
feasibility in clinical 
practice and enhance the 
generalizability of the study 
data to the target patient 
population. 
Substantial 
Section 7.2.3: ECG 
Clarification on when 
ECG should be performed 
for both treatment arms 
Updated as per PACL 
dated 05-Aug-2020. 
Nonsubstantial 
Section 7.4: 
Microbiology 
Updated timeframe for 
microbiology sample 
collection and 
requirements. 
To reflect operational 
feasibility in clinical 
practice and enhance the 
generalizability of the study 
data to the target patient 
population. 
Substantial 
Section 7.6: 
Biological Samples 
Updated volume for 
microbiology blood 
sample collection and 
total blood collection. 
To reflect a reduction in 
microbiology blood sample 
and total blood volume. 
Substantial 
Section 11.1: Case 
Report 
Forms/Electronic 
Data Record 
Added a statement on 
deletion of data in line 
with the current Pfizer 
Protocol template. 
To be consistent with the 
current Pfizer Protocol 
template. 
Nonsubstantial 
Section 11.3: Data 
Protection 
Added a new section on 
Data Protection from the 
current Pfizer Protocol 
template. 
To be consistent with the 
current Pfizer Protocol 
template. 
Nonsubstantial 
Sections 12.1: 
Regulatory and 
Ethical 
Considerations 
Updated language based 
on the current Pfizer 
Protocol template. 
To be consistent with the 
current Pfizer Protocol 
template. 
Nonsubstantial 
Sections 12.1.1: 
Reporting of Safety 
Issues and Serious 
Breaches of the 
Protocol or ICH GCP 
Updated language based 
on the current Pfizer 
Protocol template. 
To be consistent with the 
current Pfizer Protocol 
template. 
Nonsubstantial 
Section 16: 
References 
Updated Reference list. 
To reflect current and 
additional sources of study 
drugs/comparators and a 
Nonsubstantial 


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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
reference to support the 
rationale for the changes to 
the study eligibility criteria. 
Appendix 6: 
Microbiological 
Assessments 
Updated microbiology 
sample collection 
requirements. 
To reflect operational 
feasibility in clinical 
practice. 
Substantial 
Appendix 7: 
Summary of Protocol 
Amendment 1 
New appendix added. 
To provide a Summary of 
Protocol Amendment 1 
Nonsubstantial 


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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................... 13 
LIST OF FIGURES .................................................................................................................. 13 
APPENDICES .......................................................................................................................... 13 
PROTOCOL SUMMARY ....................................................................................................... 15 
1. INTRODUCTION ................................................................................................................ 32 
1.1. Background .............................................................................................................. 32 
1.2. Mechanism of Action/Indication ............................................................................. 33 
1.3. Rationale for Conducting This Study ...................................................................... 33 
1.4. Rationale for Study Design, Doses and Control Groups ......................................... 34 
1.4.1. Study Design and Control Group ................................................................ 34 
1.4.2. Dose Selection for ATM-AVI ..................................................................... 36 
1.4.3. Dose Selection for Metronidazole ............................................................... 38 
1.4.4. Dose Selection for Comparator Arms - Best Available Therapy ................ 38 
1.5. Single Reference Safety Document ......................................................................... 39 
1.6. Benefits/Risk and Ethical Assessment ..................................................................... 39 
2. STUDY OBJECTIVES AND ENDPOINTS ....................................................................... 42 
3. STUDY DESIGN ................................................................................................................. 44 
4. SUBJECT ELIGIBILITY CRITERIA ................................................................................. 48 
4.1. Inclusion Criteria ..................................................................................................... 48 
4.1.1. All Subjects ................................................................................................. 48 
4.1.2. Additional Inclusion Criteria - cIAI Subjects ............................................. 49 
4.1.3. Additional Inclusion Criteria – HAP/VAP Subjects ................................... 51 
4.1.4. Additional Inclusion Criteria – cUTI Subjects ........................................... 52 
4.1.5. Additional Inclusion Criteria – BSI Subjects .............................................. 53 
4.2. Exclusion Criteria .................................................................................................... 53 
4.2.1. All Subjects ................................................................................................. 54 
4.2.2. Additional Exclusion Criteria – cIAI Subjects ........................................... 55 
4.2.3. Additional exclusion criteria – cUTI Subjects ............................................ 55 
4.2.4. Additional exclusion criteria – BSI Subjects............................................... 55 
4.3. Randomization Criteria............................................................................................ 55 
4.3.1. Subject Enrollment and Randomization ...................................................... 55 


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4.3.2. Procedures for Handling Incorrectly Enrolled or Randomized 
Subjects ............................................................................................................56 
4.4. Lifestyle Requirements ............................................................................................56 
4.4.1. Contraception ..............................................................................................56 
4.5. Sponsor’s Qualified Medical Personnel ...................................................................57 
5. STUDY TREATMENTS .....................................................................................................58 
5.1. Allocation to Treatment ...........................................................................................58 
5.2. Methods for Ensuring Blinding ...............................................................................58 
5.2.1. Methods for Unblinding ..............................................................................59 
5.3. Subject Compliance .................................................................................................59 
5.4. Investigational Product Supplies .............................................................................59 
5.4.1. Dosage Forms and Packaging .....................................................................59 
5.4.2. Labelling .....................................................................................................60 
5.4.3. Preparation and Dispensing .........................................................................61 
5.5. Administration (Dose and Treatment Regimen) .....................................................61 
5.5.1. ATM-AVI Treatment Arm ..........................................................................61 
5.5.2. Comparator Treatment Arm - Best Available Therapy ...............................62 
5.5.3. Optional Gram-positive Antibiotics ............................................................62 
5.5.4. Optional Aminoglycosides ..........................................................................62 
5.5.5. Changes in Renal Function during Study Treatment ..................................62 
5.6. Investigational Product Storage ...............................................................................63 
5.7. Investigational Product Accountability ...................................................................64 
5.7.1. Destruction of Investigational Product Supplies .........................................65 
5.8. Post Study Access to Study Treatment ....................................................................65 
5.9. Concomitant Treatment(s) .......................................................................................65 
5.9.1. Other Concomitant Treatment .....................................................................70 
5.10. Drug-drug Interaction ............................................................................................71 
5.10.1. Aztreonam-avibactam................................................................................71 
5.10.2. Coagulation and Concomitant Use of Anticoagulants ..............................72 
5.10.3. Other Investigational Products ..................................................................72 
6. STUDY PROCEDURES ......................................................................................................72 
6.1. Prescreening on MBL-positive Gram-negative Pathogens (within 7 Days 
prior to screening) ......................................................................................................72 


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6.2. Screening and Enrollment ........................................................................................72 
6.2.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1) ..............................73 
6.3. Study Period ............................................................................................................74 
6.3.1. Visit 2: Baseline Procedures and Day 1 of Treatment (Day 1) ...................74 
6.3.2. Visit 3 to 15: Ongoing Treatment (Days 2 to 14) .......................................76 
6.3.3. Post-Treatment Period ................................................................................78 
6.3.3.1. Visit 16: End of Treatment (Within 24 Hours after Last 
Infusion) .............................................................................................78 
6.3.3.2. Visit 17: Test of Cure (Day 28±3 days) .....................................80 
6.3.3.3. Visit 18: Late Follow-up (Day 45±3 days) ................................81 
6.4. Discontinuation of Investigational Product ..............................................................81 
6.4.1. Procedures for Discontinuation of a Subject from Investigational 
Product .............................................................................................................82 
6.5. Subject Withdrawal .................................................................................................83 
6.5.1. Screen Failures ............................................................................................83 
6.5.2. Withdrawal of Consent ...............................................................................83 
6.5.3. Lost to Follow-up ........................................................................................84 
7. ASSESSMENTS ..................................................................................................................84 
7.1. Efficacy Assessments ..............................................................................................85 
7.1.1. Clinical Response Assessment ....................................................................85 
7.1.2. Microbiological Response ..........................................................................86 
7.1.2.1. Microbiological Response Assessment .....................................87 
7.2. Safety Assessments ..................................................................................................88 
7.2.1. Laboratory Safety Assessments ..................................................................89 
7.2.2. Physical Examination ..................................................................................91 
7.2.3. ECG .............................................................................................................91 
7.2.4. Vital Signs ...................................................................................................92 
7.2.4.1. Pulse and Blood Pressure ..........................................................92 
7.2.4.2. Body Temperature .....................................................................92 
7.2.5. Pregnancy Testing .......................................................................................92 
7.2.6. Other Safety Assessments ...........................................................................93 
7.2.6.1. Chest X-ray/ CT Scan ................................................................93 
7.2.6.2. Acute Physiology and Chronic Health Evaluation ....................93 


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7.3. Pharmacokinetics ..................................................................................................... 93 
7.3.1. Collection of Plasma Samples for Analysis of Aztreonam-Avibactam ...... 93 
7.3.2. Determination of Drug Concentration ........................................................ 97 
7.3.3. Storage and Destruction of Pharmacokinetic Samples ............................... 97 
7.4. Microbiology ........................................................................................................... 97 
CCI 
 
7.6. Biological Samples ................................................................................................ 100 
7.6.1. Storage, Re-use and Destruction of Biological Samples........................... 101 
7.6.2. Labelling and Shipment of Biological Samples ........................................ 101 
7.6.3. Chain of Custody of Biological Samples .................................................. 102 
8. ADVERSE EVENT REPORTING .................................................................................... 102 
8.1. Requirements ......................................................................................................... 102 
8.1.1. Additional Details on Recording Adverse Events on the CRF ................. 104 
8.1.2. Eliciting Adverse Event Information ........................................................ 104 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal Section) .......................................................................... 104 
8.1.4. Time Period for Collecting AE/SAE Information .................................... 104 
8.1.4.1. Reporting SAEs to Pfizer Safety ............................................. 104 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ................ 105 
8.1.5. Causality Assessment ................................................................................ 105 
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................. 105 
8.2. Definitions ............................................................................................................. 105 
8.2.1. Adverse Events ......................................................................................... 105 
8.2.2. Abnormal Test Findings ............................................................................ 106 
8.2.3. Serious Adverse Events............................................................................. 107 
8.2.4. Hospitalization .......................................................................................... 107 
8.3. Severity Assessment .............................................................................................. 108 
8.4. Special Situations .................................................................................................. 109 
8.4.1. Protocol-Specified Serious Adverse Events ............................................. 109 
8.4.2. Adverse Events Based on Signs and Symptoms ....................................... 109 
8.4.3. Adverse Events Based on Examinations and Tests................................... 109 
8.4.4. Exceptions from Standard Adverse Events Collection .............................109 


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8.4.4.1. Lack of Effect ..........................................................................110 
8.4.4.2. Disease Progression .................................................................110 
8.4.5. Potential Cases of Drug-Induced Liver Injury ..........................................110 
8.4.6. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure ...................................................112 
8.4.6.1. Exposure During Pregnancy ....................................................112 
8.4.6.2. Exposure During Breastfeeding ...............................................113 
8.4.6.3. Occupational Exposure ............................................................113 
8.4.7. Medication Errors ......................................................................................113 
8.4.7.1. Overdose ..................................................................................114 
8.5. Management of Laboratory Safety ........................................................................115 
8.5.1. Renal Function ..........................................................................................115 
8.5.2. Monitoring of Liver-related Laboratory Parameters .................................115 
9. DATA ANALYSIS/STATISTICAL METHODS .............................................................116 
9.1. Sample Size Determination ...................................................................................116 
9.2. Definitions of Analysis Sets ..................................................................................117 
9.2.1. Efficacy Analysis Set ................................................................................117 
9.2.1.1. Intent-To-Treat (ITT) Analysis Set ..........................................117 
9.2.1.2. Microbiological Intent-To-Treat (micro-ITT) Analysis Set .....117 
9.2.1.3. Microbiologically Evaluable (ME) Analysis Set .....................117 
9.2.2. Safety Analysis Set....................................................................................117 
9.2.3. Population Pharmacokinetic (pop PK) Analysis Set .................................117 
9.2.4. Other Analysis Sets ...................................................................................118 
9.2.4.1. All Subjects Analysis Set ........................................................118 
9.3. Endpoints ...............................................................................................................118 
9.3.1. Primary Endpoint ......................................................................................118 
9.3.2. Secondary Endpoints .................................................................................118 
9.3.3. Exploratory Endpoints ..............................................................................118 
9.4. Methods for Statistical Analysis ............................................................................119 
9.4.1. Analysis of the Primary Endpoint .............................................................120 
9.4.2. Analysis of the Secondary Endpoints .......................................................120 
9.4.3. Subgroup Analysis .................................................................................... 121 
9.4.4. Interim Analysis ........................................................................................ 121 


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9.4.5. Supportive Analyses ................................................................................. 121 
9.4.6. Exploratory Analysis ................................................................................. 121 
9.5. Data Monitoring Committee .................................................................................. 121 
9.6. Independent Clinical Hepatologist Review of Potential Hy’s Law Cases ............ 122 
9.7. Independent Adjudication Committee ................................................................... 122 
10. QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 122 
11. DATA HANDLING AND RECORD KEEPING ............................................................ 123 
11.1. Case Report Forms/Electronic Data Record ........................................................ 123 
11.2. Record Retention ................................................................................................. 123 
11.3. Data Protection .................................................................................................... 124 
12. ETHICS ............................................................................................................................ 124 
12.1. Regulatory and Ethical Considerations ................................................................ 124 
12.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ........................................................................................................ 125 
12.2. Subject Information and Consent ........................................................................ 125 
12.3. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .......................................................................................................................... 126 
13. DEFINITION OF END OF TRIAL ................................................................................. 127 
13.1. End of Trial in a Member State ........................................................................... 127 
13.2. End of Trial in All Other Participating Countries ................................................ 127 
14. SPONSOR DISCONTINUATION CRITERIA............................................................... 127 
15. PUBLICATION OF STUDY RESULTS ........................................................................ 127 
15.1. Communication of Results by Pfizer ................................................................... 127 
15.2. Publications by Investigators ............................................................................... 128 
16. REFERENCES ................................................................................................................. 130 


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LIST OF TABLES 
Table 1. 
Schedule of Activities ...............................................................................25 
Table 2. 
Objectives and Endpoints ..........................................................................42 
Table 3. 
Identity of Investigational Product ............................................................59 
Table 4. 
ATM-AVI Doses in Relationship to CrCL ...............................................61 
Table 5. 
Allowed Concomitant Medication ............................................................67 
Table 6. 
Restricted Concomitant Medications ........................................................69 
Table 7. 
Prohibited Concomitant Medications ........................................................69 
Table 8. 
Definition of Clinical Response Categories at the EOT and TOC 
Visits .........................................................................................................85 
Table 9. 
Definition of Microbiological Response Categories at the EOT and 
TOC Visits, for Each Pathogen Identified at Initial/Pre Study 
(Study Qualifying) Culture .......................................................................86 
Table 10. 
Definition of Emergent Infection Categories ............................................88 
Table 11. 
Laboratory Safety Variables .....................................................................90 
Table 12. 
Pharmacokinetic ATM-AVI Sample Collection Time Points ..................94 
Table 13. 
Volume of Blood to Be Drawn from Each Subject ................................101 
 
 
LIST OF FIGURES 
Figure 1. 
Study Outline ............................................................................................46 
Figure 2. 
Study Treatment ........................................................................................47 
Figure 3. 
ATM-AVI Pharmacokinetic Sample Collection Time-Points for 
Subjects with CrCL >30mL/min (Q6h Maintenance Dose) .....................95 
Figure 4. 
ATM-AVI Pharmacokinetic Sample Collection Time-Points for 
Subjects with CrCL > 15 to ≤ 30 mL/min (Q8h Maintenance Dose) .......96 
 
APPENDICES 
Appendix 1. Abbreviations .....................................................................................................135 
Appendix 2. International Airline Transportation Association (IATA) 6.2 Guidance 
Document ................................................................................................140 
Appendix 3. Calculation of Estimated Creatinine Clearance .................................................141 
Appendix 4. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ..........................................................................142 
Appendix 5. Acute Physiology and Chronic Health Evaluation - APACHE II Score ...........148 


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Appendix 6. Microbiological Assessments ............................................................................ 154 
Appendix 7. Summary of Protocol Amendment 1 ................................................................. 157 


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PROTOCOL SUMMARY 
Background and Rationale 
The prevalence of multidmg resistant (MDR) bacteria is increasing worldwide. This has 
become a significant public health threat as there are fewer, or even sometimes no, effective 
antimicrobial agents available for infections caused by MDR bacteria. In paiiicular, ongoing 
surveillance studies have demonstrated an increasing frequency of antibiotic resistance 
among MDR Gram-negative bacteria. Of paiiiculai·concern is the spread of 
metallo- -lactamase (MBL) producing isolates, which are often MDR. The combination 
product azti·eonam-avibactam (ATM-AVI) is being developed for inti·avenous (IV) ti·eatment 
of serious infections caused by Gram-negative pathogens producing MBL in addition to other 
-lactamases. 
Study Sites and Number of Subjects Planned 
The study is planned to be perfonned in approximately 44 sites across about 14 counti·ies in 
the Americas, Europe, and Asia, in regions with emerging and/or elevated incidence of 
carbapenem resistance, including resistance caused by MBLs. 
Approximately 60 subjects hospitalized with an infection due to a MBL- producing 
Gram-negative bacteria will be randomized in this study, including approximately 
40 randomized in the aztreonam-avibactam (ATM-AVI) treatment ann and approximately 
20 in the best available therapy (BAT) ti·eatment ann. 
Objectives and Endpoints 
Objectives 
Primary Objective: 
Primary Endpoint: 
To evaluate the efficacy of 
azti·eonam-avibactam (ATM-AVI) and 
best available therapy (BAT) at the Test of 
Cure (TOC) visit in the microbiological 
Intent-To-Treat (micro-ITT) population 
for the ti·eatment of selected serious 
infections that are due to MBL-producing 
Gram-negative bacteria. 
Propo1iion of subjects with clinical cure at 
the TOC visit in the micro-ITT analysis set. 
Secondary Objectives: 
Secondary Endpoints: 
To evaluate the efficacy of ATM-AVI and 
BAT at the TOC in the Microbiologically 
Evaluable (ME) population, and at the End 
of Treatment (EOT) visit in the micro-ITT 
and ME populations. 
• Propo1iion of subjects with clinical cure 
at the TOC visit in the ME analysis set; 
• Propo1iion of subjects with clinical cure 
at the EOT visit in the micro-ITT and 
ME analysis sets. 


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To assess the microbiological response to 
ATM-AVI at the EOT and TOC visits in 
the micro-ITT and ME populations. 
• Propo1iion of subjects with a favorable 
(defined as eradication or presumed 
eradication) per-subject microbiological 
response at the EOT and TOC visits in 
the micro-ITT and ME analysis sets; 
• Propo1iion of subjects with a favorable 
per-pathogen microbiological response 
at the EOT and TOC visits in the 
micro-ITT and ME analysis sets. 
To assess 28-day all cause mo1iality. 
Propo1iion of subjects who died on or 
before 28 days from randomization in the 
Intent-To-Treat (ITT) and micro-ITT 
analysis sets. 
To evaluate the safety and tolerability 
profile of ATM-AVI and BAT. 
Safety and tolerability as assessed by 
adverse events, physical examination, vital 
signs, electrocardiograms, and laborato1y 
assessments in the safety analysis set. 
Exploratory Objectives: 
Exploratory Endpoints: 
To evaluate the phannacokinetics (PK) of 
ATM and AVI in subjects with serious 
infections and to attempt to characterize 
the relationship between exposure and 
clinical and microbiological response for 
ATM-AVI. 
•  PK of aztreonam and avibactam in 
subjects in the population PK analysis 
set. 
• PK/phannacodynamic (PD) relationship 
between exposure and clinical and 
microbiological response for ATM-AVI 
in the population PK analysis set. 
To assess 14-day all-cause mo1iality. 
Propo1iion of subjects who died on or 
before 14 days from randomization in ITT 
and micro-ITTanalvsis sets. 


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To collect data to allow an explorato1y 
evaluation of health utilization (to be 
• 
Length of hospital stay, including any 
readmissions up to TOC (days); 
repo1ied outside of the CSR). 
• 
Length of study treatment (days); 
• 
Length of intensive care unit stays 
(days); 
• 
Transfe1Ted to the intensive care unit 
(Yes/No); 
• 
Mechanical ventilation (Yes/No) for 
hospital-acquired 
pneumonia/ventilator-associated 
pneumonia subjects; 
• 
Length of mechanical ventilation (days) 
for hospital-acquired 
pneumonia/ventilator-associated 
pneumonia subjects; 
• 
Subsequent unplanned surgical 
intervention after treatment success 
versus failure (up to the TOC visit) for 
complicated intra-abdominal infection 
subjects. 
I 
 
Study Design 
This is a prospective, randoinized, multicenter, open-label, parallel group, comparative study 
to detennine the efficacy, safety, and tolerability of ATM-AVI versus best available therapy 
(BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections 
(cIAI), nosocoinial pneumonia (NP) including hospital-acquired pneumonia (HAP) and 
ventilator associated pneumonia (VAP), complicated urinaiy tract infections (cUTI), or 
bloodstream infections (BSI) due to MBL-producing Gram-negative bacteria. 


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Final Protocol Amendment 2, 23 May 2022 
The study will randomize approximately 60 subjects in a 2:1 randomization scheme 
(ATM-AVI: BAT) with infections due to MBL-producing Gram-negative bacteria. 
Molecular testing at the central microbiology laboratory will be performed to confirm the 
MBL status of the organism upon study completion or at pre-designated intervals. 
The study will consist of a Screening Visit (Visit 1), a Baseline visit (Visit 2) on Day 1 of the 
study treatment, ongoing treatment visits (Visits 3 to 15) from Day 2 to Day 14, an End of 
Treatment (EOT) visit (Visit 16) within 24 hours after the last infusion, a Test of Cure (TOC) 
visit (Visit 17) on Day 28 (±3 days) and a Late Follow Up (LFU) visit (Visit 18) on 
Day 45 (±3 days). 
Subjects will be stratified at randomization based on infection type (cIAI, HAP/VAP, cUTI 
or BSI). The number of subjects with cUTI will be no more than approximately 75% of the 
study population. 
After obtaining written informed consent and confirming eligibility, subjects will be 
randomized in a 2:1 ratio to the ATM-AVI treatment arm or the BAT treatment arm 
according to a central randomization schedule (approximately 40 (ATM-AVI) and 
approximately 20 (BAT) subjects per group). Please refer to Section 5.4 and 
Section 5.5 Investigational product, dosage and mode of administration and duration of 
treatment for more details with regard to treatment arms. 
For subjects randomized to ATM-AVI treatment arm, sparse blood samples will be collected 
for population pharmacokinetic (PK) assessments and PK/pharmacodynamic (PD) 
relationships will be evaluated in subjects where plasma samples and microbiological 
response data have been collected. 
Each subject is expected to complete the study, including the LFU visit. Subjects will 
receive their study therapy by study center personnel while in the hospital. 
Target Subject Population 
Adult hospitalized subjects with a confirmed diagnosis of cIAI, HAP/VAP, cUTI or BSI due 
to MBL-producing Gram-negative bacteria will be enrolled in this study. The study will 
randomize approximately 60 subjects and will be conducted in countries that have reported 
the emergence of MBL-producing Gram-negative bacteria as a cause of serious infection. 
Study Treatments 
Duration of Treatment 
The recommended minimal duration of planned study treatment is 5 days for all infections 
with the exception of HAP/VAP, where the recommended minimal treatment duration is 
7 days. The duration of therapy may be extended up to a maximum of 14 days by the 
investigator. 


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Investigational Product, Dosage Form and Strength 
 
Investi2ational Product 
Dosa2e Form and Stren2th 
Test Product 
Aztreonam 
Aztreonam 2 g powder concentrate for 
infusion2. 
Avibactam 
Avibactam 600 mg powder concentrnte for 
infusion. 
Comparator-Best Available Therapy 
<BAT) 
Based on investigative site practice and local epidemiolo!ZV. 
Co-therapy dru2 
Metronidazole• 
Metronidazole 500 mg/100 mL solution for 
infusion. 
a.  Subjects with clAI assigned to ATM-AVI treatment are to receive Metronidazole (MTZ) co-therapy. 
Subjects with clAI assigned to BAT treatment may receive MTZ if the BAT does not provide adequate 
anaerobic coverage. 
Note: Co-administered dmg is supplied centrally via the sponsor. 
Note: Aztreonam and Metronidazole are commercial products over-labeled with the study clinical label. 
Note: Comparator drug is sourced locally under local regulato1y conditions. 
 
 
All investigational products will be administered by intravenous infusion. Aztreonam and 
avibactam will be supplied as vials for reconstitution. The investigational ATM-AVI will be 
prepared for co-administrntion in saline using standard aseptic intrnvenous infusion technique 
(see Investigational Product Manual (IP Manual)). 
ATM-AVI Treatment Arm: 
Subjects will be given a loading dose and then an extended loading dose before commencing 
on a maintenance dose. The loading dose and extended loading dose are only given once on 
Day 1 at the start of study ti·eatment. All doses (loading, extended loading and maintenance), 
and the dosing frequency of the maintenance dose are dependent on renal function as per the 
table below and also Section 5.5.1. All ti·eatments are given by intravenous (IV) infusion 
over the times specified below. 


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Creatinine 
ATM-AVI 
ATM-AVI 
ATM-AVI 
ATM-AVI 
ATM-AVI 
Clearance 
(mL/min)* 
Loading 
Dose (LD) 
Extended 
Loading Dose 
Time 
Interval 
Maintenance 
Dose (3 hr IV 
Frequency 
of 
(30 min 
(ELD) 
between 
infusion) 
maintenance 
IV 
infusion) 
Immediately 
following LD 
(3 hr IV infusion) 
ELD and 
Start of first 
Maintenance 
dosing 
Dose 
>50 
500mg 
1500 mg 
3 hours 
1500 mg 
Eve1y 
azt:reonam aztreonam plus 
aztreonam plus 
6 hours 
plus 
500 mg avibactam 
500mg 
167 mg 
avibactam 
avibactam 
>30 to 50 
500mg 
aztreonam 
plus 
167 mg 
avibactam 
1500 mg 
aztreonam plus 
500 mg avibactam 
3 hours 
750mg 
aztreonam plus 
250mg 
avibactam 
Eve1y 
6 hours 
>15to30 
675mg 
675 mg aztreonam 5 hours 
675 mg 
Eve1y 
aztreonam 
plus 225 mg 
aztreonam plus 
8 hours 
plus 
avibactam 
225 mg 
225mg 
avibactam 
avibactam 
Abbreviations: ATM-AVI= aztreonam-avibactam; ELD= extended loading dose; IV=intravenous(ly); 
LD=loading dose. 
*Estimated creatinine clearance using Cockcroft-Gault fo1mula rounded to the nearest whole number (see 
Appendix 3). 
 
 
Creatinine clearance should be monitored daily through the local laborato1y from Day 1 to 
Day 4 (and Day 3 or 5 by the central laborato1y, if PK samples are to be collected on 
Days 3 or 5) and then as clinically indicated. In the case that renal impai1ment recovers or 
deteriorates during the treatment period, the dose of ATM-AVI should be adjusted by the 
investigator to meet the applicable dose regimen, based on the latest creatinine clearance 
value. If subsequent to randomization and while still on intravenous study treatment, a 
subject's estimated creatinine clearance falls below the threshold for study inclusion (ie, 
estimated creatinine clearance :Sl 5 mL/min) and there is a requirement to sta1t renal 
replacement therapy, the investigator should discontinue ATM-AVI therapy. 
In addition to ATM-AVI, subjects with complicated intra-abdominal infection in this 
treatment aim will also receive intravenous metronidazole (MTZ) 500 mg eve1y 8 hours (by 
intravenous infusion over 60 minutes), staiting after the extended loading dose of ATM-AVI 
has completed and maintained until the end of the intravenous study treatment period. The 
Summaiy of Product Characteristics (Baxter Healthcare Ltd.)37 does not indicate a dose 
reduction for MTZ in subjects with renal impai1ment. 


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Comparators – Best Available Treatment Arms: 
The comparator treatment in this study is Best Available Therapy (BAT) based upon site 
practice and local epidemiology. The choice of BAT (monotherapy or combination) for each 
subject must be recorded prior to randomization. 
Optional Gram -positive Antibiotics: 
Subjects with HAP/VAP and cUTI may receive optional vancomycin or linezolid and 
subjects with cIAI and BSI may receive optional vancomycin, linezolid or daptomycin at the 
investigators discretion to provide antibiotic coverage for a Gram-positive infection. The 
need for an adjunctive Gram-positive antibiotic should be re-evaluated 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. 
Optional Aminoglycosides: 
Subjects with hospital-acquired pneumonia/ventilator-associated pneumonia and proven or 
suspected co-infection with Pseudomonas aeruginosa may receive adjunctive therapy with 
an IV aminoglycoside (eg, amikacin, gentamicin or tobramycin, based upon local practice 
and epidemiology) at the investigator's discretion. The need for adjunctive aminoglycoside 
therapy should be re-evaluated once culture and susceptibility results are available and the 
aminoglycoside should be discontinued if not needed. 
Statistical Methods 
The study will randomize approximately 60 subjects (40 ATM-AVI, 20 BAT) with serious 
infections caused by MBL-producing Gram-negative bacteria. As no formal hypothesis 
testing will be performed for this study, no power calculation was carried out to assess the 
number of subjects required for each treatment arm. The total number of 60 subjects 
(approximately 40 in ATM -AVI group and approximately 20 in BAT group) is considered 
sufficient to estimate the overall clinical cure rates in each arm. The smaller numbers of 
subjects in these groups will be reflected in the precision of the estimate of clinical cure rate. 
Definition of analysis sets 
The Intent-To-Treat (ITT) population includes all randomized subjects. The microbiological 
Intent-To-Treat (micro-ITT) analysis set is a subset of the ITT analysis set and includes all 
subjects who have at least 1 MBL-positive Gram-negative pathogen in an adequate 
initial/prestudy culture. 
The Microbiologically Evaluable (ME) analysis set includes all subjects who: 
1. Meet the definition of the micro-ITT analysis set. 
2. Received at least 48 hours of study therapy (ATM-AVI or BAT) or received 
<48 hours of study therapy before discontinuing study drug due to an adverse event 
(AE). 


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3. Did not receive concomitant antibiotic therapy with potential activity against any 
baseline MBL-positive pathogens between the time of first dose of study treatment 
and the time of TOC. This does not include those subjects who have failed study 
therapy and require additional antibiotics to treat their infection. 
4. Had the baseline entry organism(s) genetically confirmed by central microbiological 
testing. 
5. Did not have a clinical outcome of indeterminate at TOC. 
The population PK analysis set includes all subjects who have at least 1 plasma concentration 
data assessment available for ATM and AVI and will be used to report all PK data. The 
safety analysis set includes all subjects who received any amount of IV study treatment and 
will be used for reporting safety data. 
Methods for statistical analysis 
All data will be presented by treatment arm. Descriptive statistics (number, mean, standard 
deviation, median, minimum, and maximum) will be provided for continuous variables, and 
counts and percentages will be presented for categorical variables. 
No formal hypothesis testing will be performed for this study; any comparisons between 
treatment arms will only be assessed as evidence of an effect, no formal statistical 
comparisons between treatment arms will be made. Methodology for dealing with missing 
data will be specified in the Statistical Analysis Plan. 
Descriptive statistical analyses will be performed. For the primary objective, the number and 
proportion of subjects with clinical cure in each treatment group at TOC will be tabulated for 
the micro-ITT analysis set. 95% confidence intervals for the clinical cure rate in each 
treatment arm will be computed using Jeffrey’s method (Brown et al 2001; Cai 2005).4,5 
The primary analysis will be conducted using the clinical response assessment determined by 
an independent adjudication committee. The independent adjudication committee is the 
central blinded assessor. A charter will be in place for the adjudication committee. The 
adjudication committee will be blinded to study treatment and will review the clinical 
response assessments at each visit. In case of a discrepancy with the investigator’s 
assignment of clinical response, the adjudication committee’s assessment will prevail for the 
analysis. 
Clinical response summaries will be presented for the overall population, and also split by 
infection type (cIAI, HAP/VAP, cUTI or BSI) and by resistance group (eg, drug resistance 
group and β-lactamase content). 
Secondary efficacy outcome measures will be presented using the same methods as the 
primary outcome measures. For descriptive secondary outcome measures, number and 
percentage in each treatment arm will be tabulated. 


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Regarding secondary safety variables, adverse events will be summarized by means of counts 
summaries by Medical Dictionary for Regulatory Activities System Organ Class and 
preferred term separately for the study periods (treatment period [from first dose to EOT] 
[treatment emergent adverse events], from EOT to LFU, and for the full study period [from 
first dose to LFU]). All adverse events and treatment emergent adverse events will be listed 
(including prior to first dose). Deaths, adverse events leading to discontinuation, and serious 
adverse events will be summarized. 
Laboratory data for hematology and clinical chemistry will be summarized. The frequency 
of changes with respect to normal ranges between baseline and each post treatment time 
point will be tabulated. Frequencies of clinically noteworthy values (defined in the Statistical 
Analysis Plan) occurring during the clinical study will also be given. Shifts from normal to 
abnormal between baseline and each post baseline time point will be evaluated for all 
laboratory parameters. 
The incidence of markedly abnormal values and changes from baseline in the 
electrocardiogram parameters will be summarized by treatment arm. 
Exploratory health outcome measures will be presented using the same methods as the 
primary outcome measures. For descriptive exploratory outcome measures, number and 
percentage in each treatment arm will be tabulated. 
The final PK data will be pooled with data from other studies to conduct a population PK 
analysis (using Nonlinear Mixed Effects Modelling). Using these parameter estimates (mean 
PK parameters including inter individual variance estimates), Monte-Carlo simulation will be 
undertaken and potential PK/PD relationships will be explored. Aztreonam and avibactam 
plasma concentrations versus time will be depicted graphically in the Clinical Study Report 
(CSR). Full details of the PK and PK/PD analysis will be given in the PK Modeling Analysis 
Plan. These results will be reported separately. 


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Page 24 
 
 
For exploratory safety variables, the proportion of subjects who died on or before 14 days 
after randomization will be presented by treatment arm. Further details on the analysis 
methods for CCI 
 
evaluation of health resource utilization will be detailed in the Statistical Analysis Plan. 
Subgroup analyses, which may include infection type and resistance type, may be performed. 
More details on the subgroup analyses will be provided in the Statistical Analysis Plan. 
Additional descriptive analyses of the primary endpoint (clinical cure rate) will be performed 
for the effect of protocol-allowed additional antibiotics (eg, Gram-positive antibiotics, 
aminoglycosides). 


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SCHEDULE OF ACTIVITIES 
The schedule of activities table provides an overview of the protocol visits and procedures. Please refer to Section 6 (Study 
Procedures) and Section 7 (Assessments) of the protocol for detailed info1mation on each procedure and assessment required for 
compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject. 
 
Table 1. 
Schedule of Activities 
 
Visit Name 
Prescreening 
Eligibility/ 
Screenin2a 
Treatment Period 
EOT 
TOC 
LFU 
Visit 
Visit 1 
Visit 2 
Visits 3 to 
15 
Visit 16 
Visit 17 
Visit 
18 
Visit Day and Window 
Within 
7 Days prior 
to Screening 
Day-1 to 
1 
Dayl 
(Baseline)b 
Days 2 to 14 
Within 
24 hours 
after 
last 
infusion 
Day28 
±3 days 
Day45 
±3 days 
Study Procedure 
Abbreviated info1med consent to test 
MBL status of isolatesc 
X 
Infonned consent 
X 
Inclusion and exclusion criteria 
X 
X 
Demographics 
X 
Medical history 
X 
APACHE II score (see Appendix 5)d 
X 
Review prior and concomitant 
medications (including prior antibiotic 
treatment) 
X 
X 
Daily 
X 
X 
X 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Prescreening 
Eligibility/ 
Screenin2a 
Treatment Period 
EOT 
TOC 
LFU 
Visit 
Visit 1 
Visit 2 
Visits 3 to 
15 
Visit 16 
Visit 17 
Visit 
18 
Visit Day and Window 
Within 
7 Days prior 
to Screening 
Day-1 to 
1 
Dayl 
(Baseline)b 
Days 2 to 14 
Within 
24 hours 
after 
last 
infusion 
Day28 
±3 days 
Day45 
±3 days 
Medical Procedures 
Complete physical examination 
X 
X 
X 
Height and body wei!mt 
X 
Perfo1m focused physical examination 
X 
X 
Daily 
X 
X 
xe 
Vital sign measurementsf 
X 
X 
Daily 
X 
X 
12-lead digital triplicate ECG 
X 
Day3 
Ventilator status (HAPN AP onlv) 
X 
X 
Dailv 
X 
X 
Urina1y device status (cUTI subjects 
only) 
X 
X 
Daily 
X 
X 
Chest X-ray or computed tomography 
scan (for HAPN AP subjects only) 
xg 
As 
clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 
As 
clinically 
indicated 
Collection of imaging and surgical 
report (for cIAI subjects only) 
X 
As 
clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 
As 
clinically 
indicated 
Clinical Assessments 
Assess infection-related signs and 
symptoms 
X 
X 
Daily 
X 
X 
Clinical response assessment 
X 
X 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Prescreening 
Eligibility/ 
Screenin2a 
Treatment Period 
EOT 
TOC 
LFU 
Visit 
Visit 1 
Visit 2 
Visits 3 to 
15 
Visit 16 
Visit 17 
Visit 
18 
Visit Day and Window 
Within 
7 Days prior 
to Screening 
Day-1 to 
1 
Dayl 
(Baseline)b 
Days 2 to 14 
Within 
24 hours 
after 
last 
infusion 
Day28 
±3 days 
Day45 
±3 days 
Laborato1y Assessments 
Safety laboratories (chemistiy, 
hematology, urinalysisl 
X 
Xb 
Cenu-al lab 
samples: 
Eve1y 
3 days, 
staiiing on 
Day4; 
Local lab 
senun 
creatinine: 
Day2 to 
Day 4, and 
as clinically 
indicated 
X 
X 
Estimate CrCV 
X 
Xb 
Daily from 
Day2 to 
Day4 and as 
clinically 
indicated 
As 
clinically 
indicated 
As 
clinically 
indicated 
Sernm or urine P-hCG for women of 
childbearing potentialj 
X 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Prescreening 
Eligibility/ 
Screenin2a 
Treatment Period 
EOT 
TOC 
LFU 
Visit 
Visit 1 
Visit 2 
Visits 3 to 
15 
Visit 16 
Visit 17 
Visit 
18 
Visit Day and Window 
Within 
7 Days prior 
to Screening 
Day-1 to 
1 
Dayl 
(Baseline)b 
Days 2 to 14 
Within 
24 hours 
after 
last 
infusion 
Day28 
±3 days 
Day45 
±3 days 
Urine sample for microscopic WBC 
(cUTI subjects only)k 
X 
As clinically 
indicated 
X 
X 
Collection of a1terial blood gases 
xi 
As 
clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 
Identify isolate from study-qualifying 
culturemand send to centrnl 
laboratorv11 
X 
Quantitative urine culture (cUTI 
subiects onlv)0 
X 
As clinically 
indicated 
X 
X 
Blood culturesP 
xP 
If blood cultures are positive, repeat 
at least eve1y 3 days until negative. 
Blood cultures should also be 
perfo1med as clinically indicated. 
Culture of abdominal site infection 
(for cIAI subjects only)q 
As 
clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 
As 
clinically 
indicated 
Appropriate respirato1y specimen for 
-
Gram- stain/culture (for HAPN AP 
subjects only) 
xr 
As clinically 
indicated 
xs 
X 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Prescreening Eligibility/ 
Screenin23 
Treatment Period 
EOT 
TOC 
LFU 
Visit 
Visit 1 
Visit 2 
Visits 3 to 
15 
Visit 16 
Visit 17 
Visit 
18 
Visit Day and Window 
Within 
7 Days prior 
to Screening 
Day-1 to 
1 
Dayl 
(Baseline)b 
Days 2 to 14 
Within 
24 hours 
after 
last 
infusion 
Day28 
±3 days 
Day45 
±3 days 
Phannacokinetic 
Blood for PK analvsisw 
xx 
Dav4±1dar 
Trial Treatment 
Detennination and documentation of 
Best Available Therapy prior to 
randomization 
X 
Randomization 
X 
Administer study treatment 
X 
Daily 
Safety 
Serious and non-serious adverse event 
monitoring 
X 
X 
Daily 
X 
X 
X 
Mortality assessment 
X 
Daily 
X 
X 
Contraception check 
X 
X 
Daily 
X 
X 
Abbreviations: ABG=a1terial blood gas; ALP= alkaline phosphatase; ALT=alanine aminotransferase; APACHE=Acute Physiology and Chronic Health 
Evaluation; AST=aspa1tate aminotransferase; ATM-AVI=aztreonam-avibactam; BAL=bronchoalveolar lavage; P-hCG= P-human chorionic gonadotropin; 
clAI=complicated intra-abdominal infections; cUTI=complication urinaiy tract infection; CrCL=creatinine clearance; ECG=electrocardiogram; EOT=end of 
treatment; HAP=hospital-acquired pneumonia; LFU=late follow-up; PSB=protected-specimen bmsh; PK=pharmacokinetics; TBili = total bilimbin; TOC=test of 
cure; ULN=upper limit of no1mal; VAP=ventilator-associated pneumonia; WBC=White blood cell. 
 
 
a. Study treatment should be sta1ted as soon as possible (within 24 hours) after a subject's eligibility has been confumed and the subject 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. 


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Final Protocol Amendment 2, 23 May 2022 
 
b. All procedures at Visit 2 are to be done before first dose of study therapy except for PK sampling. 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 >12 hours apart (see 
Section 6.3.1). Administration of the first dose of IV study therapy marks the beginning of study treatment Day 1. 
c. The abbreviated informed consent to test MBL status of isolates is only needed if test on MBL status is not the standard of care at the sites. 
d. 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 subjects, and for cIAI, cUTI and BSI subjects as clinically indicated. Use of temperature 
obtained rectally in determining the APACHE II score is preferred but not mandatory. See Appendix 5. 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). 
e. If the subject 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. 
f. 
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. Body temperature will be measured using an automated thermometer. The subject’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 subject, 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 subjects with HAP/VAP, respiratory rate (breath per minute) and peripheral O2 saturation will be collected at Visit 1, at Visit 2, daily while 
the subject is receiving IV study treatment, at EOT and TOC visits. 
g. Performing a chest X-ray or CT scan (if not available within 48 hours prior to randomization) in subjects with HAP/VAP. 
h. At Screening, the following assessments will be performed in the local laboratory for eligibility determination: serum creatinine (including calculation of 
CrCL), AST, ALT, ALP, TBili, and hematology as defined in Section 4.2.1. In addition, safety laboratory samples must be sent to the central reference 
laboratory for testing. During treatment period, if ALT or AST are >3 x ULN and the subject has not met the liver discontinuation criteria (see 
Section 8.4.5), the frequency of liver laboratory 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 x ULN. 
i. 
Subjects must be frequently and closely monitored for rapidly changing CrCL through local laboratory measurement of serum creatinine (See Appendix 3). 
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 5.5.5. In addition, to coincide with PK sample collection for subjects 
randomized to the ATM-AVI treatment arm, CrCL will be estimated using central laboratory measurement of serum creatinine. PK samples should be 
collected on Day 4, but can be collected on Day 3 or Day 5. CrCL will therefore also be estimated on Day 3 or Day 5 if PK blood samples are collected on 
Day 3 or Day 5. In this case, a blood sample for measurement of serum creatinine will also be collected on Day 3 or Day 5 and sent to the central laboratory 
for estimation of CrCL. 
j. 
Serum or urine β-hCG for pregnancy test will performed in local laboratory for eligibility determination. 
k. Obtain a urine sample for microscopic WBC count to assess for presence of persisting pyuria (cUTI subjects only). A urine sample must also be submitted 
to the central laboratory. 
l. 
For HAP/VAP subjects – obtaining arterial blood sample for ABG (required for ventilated subjects, recommended for non-ventilated subjects); for cIAI, 
cUTI and BSI subjects obtaining arterial blood sample for ABG as clinically indicated. 


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m. The appropriate culture for study qualifying microbiological isolate obtained within 7 days prior to screening will be detailed in the study microbiology 
manual (see Appendix 6). For clAI, 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 HAPN AP, appropriate respiratory specimen including endotracheal aspirate, 
expectorated or induced sputum bronchoalveolar lavage (BAL), mini-BAL or protected-specimen bmsh (PSB) sampling should be collected for culture. For 
cUTI subjects, a quantitative culture of urine is required. For BSI, a set of blood cultures (1 anaerobic and 1 aerobic bottle in each set) should be collected. 
n. Study qualifying microbiological isolate is an MEL-positive Gram-negative bacteria (see Inclusion Criteria in Section 4.1.1) that was isolated from an 
appropriate specimen obtained within 7 days prior to screening. Submission of this isolate to the central microbiology laborato1y vendor is critical for study 
objectives: thus, the isolate must be sent to the central microbiology laborato1y vendor for confirmation of identification and MBL resistance and analysis of 
additional genotypic and phenotypic characteristics. 
o.  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 subjects with 
cUTI only. 
p.  All subjects must have had a set of blood cultures obtained prior to randomization. Repeat samples for blood cultures are not required at Screening 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. All subjects require a set of blood cultures (1 anaerobic and 1 aerobic bottle from each site, ie, 2 bottles in total). For subjects who are found 
to be bacteremic any time during the study, repeat blood cultures should be taken at least eve1y 3 days, until clearance ofbacteremia is documented. Blood 
cultures should also be obtained as clinically indicated. See Section 7.4 and Appendix 6 for details of sample collection. 
q.  For clAI subjects with surgical specimens collected on or after the Baseline Visit, both aerobic and anaerobic cultures should be perfonned on specimens 
collected from the site of abdominal infection and on specimens collected from other clinically relevant intra-abdominal sites (see Appendix 6). 
r.  Repeat respirato1y specimen cultures are not required, unless a study-qualifying sample prior to screening was obtained from a non-ventilated subject and the 
subject is subsequently ventilated (or the subject had a bronchoscopy). In this case, an appropriate respirato1y specimen should be obtained prior to the first 
dose of study treatment (see Appendix 6). 
s. If treatment is discontinued early because the subject is failing therapy or other reasons, an appropriate respirato1y specimen for culture should be obtained, 
ideally after stopping the initial treatment but before the new treatment is administered. 
I' 
I 
w. PK sampling is only relevant for subject randomized to ATM-AVI. 
x. 3 samples have to be taken. See Table 12 and Figure 3 and Figure 4 for detailed guidance on schedule. 


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1. INTRODUCTION 
1.1. Background 
The prevalence of multidrug resistant (MDR) bacteria is increasing worldwide. This has 
become a significant public health threat as there are fewer, or even sometimes no, effective 
antimicrobial agents available for infections caused by MDR bacteria (Lucasti et al. 2013; 
Magiorakos et al. 2012).33,38 In particular, ongoing surveillance studies have demonstrated 
an increasing frequency of antibiotic resistance among MDR Gram-negative bacteria. New 
antibiotics or combinations of existing antibiotics with resistance enzyme inhibitors are 
urgently needed to provide treatment options for patients with infections known or suspected 
to be caused by MDR Gram-negative pathogens (IMI; IMI 2015).28 
One of the most common resistance mechanisms in Gram-negative pathogens is the 
production of extended-spectrum β-lactamase (ESBL) (Lucasti et al. 2013).33 Infections due 
to ESBL-producing organisms present a major therapeutic dilemma especially as isolates are 
also increasingly expressing resistance to other first line agents such as fluoroquinolones or 
aminoglycosides, leaving few available options for treatment. ESBL are found in a 
significant percentage of Enterobacteriaceae (including Escherichia coli, Klebsiella 
pneumoniae, Enterobacter spp., Citrobacter spp., Proteus spp., Morganella morganii, 
Serratia marcescens, and Shigella dysenteriae). They can also be found in Pseudomonas 
aeruginosa although they do not contribute significantly to resistance in this organism. 
Carbapenems are the preferred treatment option for serious infections due to such MDR 
Gram-negative pathogens, but carbapenemases have steadily accumulated in the 
Enterobacteriaceae with the epidemiology of carbapenem-resistant Enterobacteriaceae 
characterized by large heterogeneity in genotypes (with >20 reported resistance gene 
families, such as New Delhi Metallo-β-lactamase (NDM), Klebsiella pneumonia 
carbapenemase (KPC), Verona Integron encoded metallo-β-lactamase (VIM), and 
Oxacillinase (OXA)-48 (Nordmann and Poirel 2013).44 The expression of 
metallo-β-lactamases (MBLs) such as VIM and NDM-1, in addition to other resistance 
mechanisms, is of increasing concern as the treatment options are extremely limited. 
A particular threat is posed by a family of MBLs known as NDM. NDM-1-producing 
pathogens have already been reported in a number of countries outside of the regions where 
the first producing strains were identified in 2009 (India, Pakistan, Sweden, United Kingdom 
[UK]), including Australia, Singapore, Taiwan, and the United States (US). The recent 
emergence of NDM-1 has caused particular concern in the international infection 
community, as the genetic element encoding NDM-1 is able to rapidly spread amongst 
bacteria in both community and hospital settings (Johnson and Woodford 2013; Moellering 
2010).30,40 
The spread of resistance leading to multi-drug resistant pathogens due to the ESBL 
cefotaximase -M (CTX-M) may provide a useful model for the spread of NDM-1 as the 
blaNDM-1 gene is found on the same promiscuous ST131 clone as CTX-M. In particular, 
organisms that produce NDM-1 have spread geographically and are now seen in 
community-acquired infections, similar to the spread of CTX-M, which has reached endemic 


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levels in much of Asia, Europe, and South America. These pathogens have become endemic 
in the Indian subcontinent, where they have been detected in the environment (Walsh et al. 
2011).52 
1.2. Mechanism of Action/Indication 
With more than 30 years of use worldwide, aztreonam (ATM) is an established injectable 
antibiotic indicated for the treatment of various infections caused by Gram-negative bacteria 
(see Summary of Product Characteristics [SmPC] of ATM and ATM prescribing 
information). It has a unique monocyclic β-lactam nucleus that makes it structurally different 
from other β-lactam antibiotics (including penicillins and cephalosporins), as well as several 
chemical side groups that interfere with degradation by MBLs. Activity against MBL 
(Class B) producing pathogens is possible, although potential inactivation by Class A, C, or 
D β-lactamases remains problematic. 
Avibactam (AVI) is a novel, non β-lactam, β-lactamase inhibitor of a broad spectrum of 
enzymes, including Ambler Class A ESBLs, Class A KPC, and Class C (ampicillinase 
Class C [AmpC]) enzymes, and some Class D enzymes, notably OXA-48, a problematic 
carbapenemase in the European Union (EU) and Middle East. The inhibition of β-lactamase 
by AVI occurs through formation of a covalent bond between AVI and the enzyme. Alone, 
AVI has no meaningful antibacterial activity; rather, its beneficial effect in combination with 
ATM occurs by rendering inactive those enzymes that inactivate ATM. 
Together, ATM and AVI have the potential to address the unmet need for safe and effective 
agents to combat MBLs and other problematic β-lactamases, such as ESBLs and KPCs, 
which may be co-expressed with MBLs and contribute to a MDR phenotype. 
1.3. Rationale for Conducting This Study 
The combination product referred to as ATM-AVI in this Clinical Study Protocol (CSP) is 
being developed for the treatment of serious infections caused by MDR, Gram-negative 
MBL-producing pathogens for which there are limited or no treatment options. These 
include infections caused by MBL-producing pathogens that can also co-produce ESBLs, 
KPC and/or AmpC β-lactamases. The MBL-producing Enterobacteriacea infections 
selected to evaluate the safety and effectiveness of ATM-AVI therapy in this study are: BSI, 
cIAI, cUTI, and HAP/VAP. This study will also evaluate the safety and effectiveness of the 
best available treatments for MDR, Gram- negative MBL-producing pathogens. 
Relevant to the clinical development of the study treatment is the fact that ATM-AVI has 
shown excellent activity in pre-clinical studies against a broad range of Gram-negative 
pathogens thereby restoring ATM activity against ATM-resistant pathogens, including 
several of the most problematic MDR pathogens, but excluding A. baumannii as listed above 
(see Investigator’s Brochure (IB) for further details). 
To date, 92 healthy volunteers have been dosed with the investigational product (IP) 
(ie, ATM-AVI, placebo or ATM/AVI separately), in a single Phase 1 study (Please 
see Section 1.4 for further details). Additional details can be found in the ATM-AVI IB. 


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A prospective, open-label, multicenter Phase 2a study to determine the pharmacokinetics 
(PK), safety and tolerability of ATM-AVI for the treatment of cIAI in hospitalized adults, 
and to provide dose confirmation for Phase 3 clinical studies has completed enrollment and 
the CSR is pending. The PK/pharmacodynamic (PD) data generated will contribute to a 
robust package of data, supported by prior experience with ATM and AVI, and will be 
validated by qualitative data for the combination from the ATM-AVI phase 3 program. 
1.4. Rationale for Study Design, Doses and Control Groups 
Among the Gram-negative pathogens, coliform (Escherichia species (spp.,), Klebsiella spp., 
Enterobacter spp., Serratia spp., and Citrobacter spp.) and Proteus bacilli currently cause 
29% of nosocomial infections in the United States. This group of nosocomial pathogens is 
responsible for 46% of urinary tract infections (UTIs), 24% of surgical site infections, 
17% of bacteremia cases, and 30% of pneumonia cases (Guentzel 1996).20 
In patients with complicated intra-abdominal infections (cIAI), hospital-acquired 
pneumonia/ventilator-associated pneumonia (HAP/VAP), complicated urinary tract infection 
(cUTI) and bloodstream infection (BSI), Gram-negative bacteria, including those producing 
ESBLs, KPC and AmpC β-lactamases, are important causative pathogens. 
Most intra-abdominal infections are polymicrobial and caused by organisms residing in the 
gastrointestinal tract, including aerobes and facultative and obligate anaerobes. In patients 
with cIAI, MTZ will be added to ATM-AVI to provide coverage for anaerobic organisms 
such as the Bacteroides fragilis group. The spectrum of activity of ATM-AVI when 
combined with MTZ is well suited to treatment of pathogens commonly responsible for 
cIAIs. In patients with HAP/VAP, cUTI and BSI, anaerobic organisms are not common 
causative pathogens; therefore ATM-AVI is considered to provide efficient coverage for the 
pathogens causing HAP/VAP, cUTI and BSI. 
The rationale for the study design is that it provides comparative data in an open setting. The 
approved agents considered the BATs for the treatment of selected infections due to 
MBL-producing Gram-negative bacteria, are permitted within the comparator arm in this 
study. Efficacy and safety data for ATM-AVI and BAT from this study will be used to 
further evaluate the benefit and risk of ATM-AVI potential therapy. 
The study is open-label due to the complicated dosing regimens of the investigational 
product. Due the serious nature of infections due to MBL-producing Gram-negative bacteria, 
use of a placebo group was not an option. 
1.4.1. Study Design and Control Group 
This is a Phase 3 prospective, randomized, open-label, parallel group, multicenter 
comparative study to determine the efficacy, safety and tolerability of ATM-AVI versus the 
best available therapy (BAT) in the treatment of serious infections due to Gram-negative, 
MBL-producing MDR pathogens for which there are limited or no treatment options. 


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The comparative, study design is sufficient to provide descriptive estimates of efficacy, 
safety and tolerability for ATM-AVI and comparators in the treatment of patients with cIAI, 
cUTI, HAP/VAP, cUTIs or BSI. The study is open-label due to the complicated dosing 
regimens of the investigational product. The investigators, site personnel, and patients will 
not be blinded in this open-label study. The independent adjudication committee (central 
assessor) will be blinded with the aim of unbiased adjudication of the primary objective 
measure. The 2:1 ratio for randomization (to ATM-AVI versus BAT, respectively) is chosen 
in order to enrich the safety and efficacy data for patients treated with ATM-AVI. Due to the 
excessive fluid burden that would be expected in the case of a double-blinded study, for 
patients with different infection types (cIAI, HAP/VAP, cUTIs or BSI) and for a range of 
renal functions, it was not considered feasible to use placebo infusions to create a 
double-blinded study. Volume overload is associated with the development of serious 
medical complications and increased mortality; a recent study in 3147 patients in the Sepsis 
Occurrence in Acutely Ill Patients (SOAP) study in 24 European countries found that a 1 L 
positive fluid balance per 24 hours was associated with an approximate 20% increase in 
mortality risk (Payen et al. 2008).45 Instead, a study design with a blinded central 
adjudication committee is considered to be most appropriate for the proposed ATM-AVI 
study in order to reduce risk to patients and reduce the risk for bias. 
Clinical efficacy for the study population will be estimated using a clinical response endpoint 
applicable to all patients. Secondary endpoints include microbiological response in 
microbiological analysis sets, safety and tolerability and 28 day mortality. 
The duration of study drug treatment (5 to 14 days for cIAI, cUTIs and BSI and 7 to 14 days 
for HAP/VAP) takes into account the current US Food and Drug Administration (FDA) 
recommendations for the development of drugs for treatment of cIAI (FDA 2015).25 The 
study is approximately 45 days in duration. It will consist of a Screening Visit (Visit 1), a 
Baseline Visit (Visit 2) on Day 1 of the study treatment, ongoing treatment visits 
(Visits 3 to 15) from Day 2 to Day 14, an End of Treatment (EOT) visit (Visit 16) within 
24 hours after the last infusion, a Test of Cure (TOC) visit (Visit 17) on Day 28 (±3 days) 
and a Late Follow Up (LFU) visit (Visit 18) on Day 45 (±3 days). 
The study is planned to be performed in approximately 44 sites across about 14 countries in 
the Americas, Europe, and Asia, in regions that have reported the emergence and/or elevated 
incidence of MBL-producing Gram-negative bacteria as the cause of serious infection. The 
chosen study design as described below takes into account the joint scientific advice received 
from the European Medicines Agency (EMA) and the FDA in October 2012 and 
April 2015 and further scientific advice from the FDA in December 2016 alongside the 
current regulatory guidelines, ie, the EMA “Guideline on the evaluation of medicinal 
products indicated for treatment of bacterial infections” (EMA 2011),12 EMA “Addendum to 
the guideline on the evaluation of medicinal products indicated for treatment of bacterial 
infections” (EMA 2013),13 the US FDA Guidance for Industry “Antibacterial Therapies for 
Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases” 
(FDA 2017),25 the US FDA Guidance for Industry “Complicated Intra-Abdominal Infections: 
Developing Drugs for Treatment” (FDA 2015a)23, the US FDA Guidance for Industry 
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Developing Dmgs for Treatment" (FDA 2014)22, and the US FDA Guidance for Industry 
"Complicated Urinaiy Tract Infections: Developing Dmgs for Treatment" (FDA 2015b).24 
 
1.4.2. Dose Selection for ATM-AVI 
The intention for ATM-AVI is that it will be active against clinically isolated Gram-negative 
bacteria for which there are limited or no tr·eatment options. The ATM-AVI doses for this 
Phase 3 study have been selected based on pre-clinical and clinical data on ATM-AVI, using 
PK data for ATM, AVI and ATM-AVI and including covariate info1mation collected in 
healthy volunteers and patients to construct a robust population PK model. Fmihe1more, 
AVI PK and safety data together with PK/PD modelling results obtained dming development 
of the new ceftazidime-avibactam (CAZ-AVI) combination product Avycaz™ in the US 
(Zavicefta® in Em-ope) have been taken into account (FDA prescribing info1mation: 
AVYCAZ 2017; Emopean Commission: Product info1mation Zavicefta 2016).17,24 
Subjects will be monitored frequently and closely for rapidly changing creatinine clearance 
(CrCL), and the investigator will adjust the study diug dose promptly if needed (See 
Appendix 3). 
Dose selection (ATM-A VI) for patients with n01mal renal function or inild renal impainnent 
(CrCL >50 mL/min). 
For patients with serious bacterial infections where there are limited or no tr·eatment options, 
it is recommended fo-rlactams torapidly achieve target attainment and steady state 
concentr·ations while prolonging time above the minimum inhibito1y concenti-ation (MIC) 
with extended infusion time and sho1ier dosing intervals. The rationale for the selected dose 
regimen is based on the objective of obtaining optimal exposme to achieve a 
>90% probability of target attainment (PTA) against PK/PD targets for both ATM and AVI 
which have been identified from non-clinical data.. The PK/PD tai·gets are: 
 
• 
Maintain unbound ATM concentr·ations above an MIC for 60% of the dosing interval; 


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• Maintain unbound AVI concentrations above a threshold concentration (CT) of 
2.5 mg/L for 50% of the dosing interval. 
The dose has been selected to achieve >90% PTA at an ATM-AVI MIC of 8 mg/L. 
Population PK models have been constructed using the following data: ATM PK data from 
the literature, ATM and AVI PK data from the Phase 1 study (C3601005) of the ATM-AVI 
development program, and AVI PK data from the Zavicefta development program (AVI in 
combination with ceftazidime [CAZ]) which included a substantial amount of PK data in 
patients. Most recently, the PK model was updated using PK and covariate data from 
patients with cIAI in the Phase 2a study. The PK models were used in Monte Carlo 
simulations of 5000 patients to select a dosing regimen which achieves a >90% joint PTA for 
ATM and AVI. 
In Cohort 1 of the Phase 2a study in patients with cIAI (and CrCL >50 mL/min) the dosing 
regimen was selected based on the Phase 1 safety data and PK/PD modeling above, ie, a 
loading dose (500 mg ATM plus 137 mg AVI by IV infusion) over a 30 minute period, was 
immediately followed by a maintenance infusion of 1500 mg ATM plus 410 mg AVI over a 
3 hour period [q6h]). Patients also receive 500 mg MTZ infused over 1 hour every 8 hours 
(q8h), starting after the first ATM-AVI maintenance infusion. 
The safety and PK data from 10 patients in Cohort 1 (who completed all safety and PK 
assessments) was reviewed by a Scientific Advisory Committee (SAC). Based on 
assessment of the safety and PK data in Cohort 1, Cohort 2 was subsequently initiated using 
a higher AVI dose (a loading dose of 500 mg ATM plus 167 mg AVI by IV infusion over a 
30 minute period, immediately followed by a dose of 1500 mg ATM plus 500 mg AVI by 
IV infusion over a 3 hour period q6h [maintenance infusion]). Following the review of PK 
and safety data from 10 patients in Cohort 2 by the SAC, the higher AVI dose was continued 
in Cohort 3. The higher AVI dose was selected as it provides a higher PTA for AVI using 
the PK/PD targets as described above compared to the lower AVI dose. 
In this Phase 3 study, the dosing regimen is the same as that administered in Cohorts 2 and 
3 of the Phase 2a study. The loading dose for patients with normal renal function or mild 
renal impairment (CrCL >50 mL/min) is 500 mg ATM plus 167 mg AVI infused over a 
30 minute period, immediately followed by an extending loading dose of 1500 mg ATM plus 
500 mg AVI over a three hour period. Three hours after the extended loading dose is 
completed, a maintenance dose of 1500 mg ATM and 500 mg AVI is infused over 3 hours 
and administered (q6h). The targeted total daily dose on Day 1 is 6500 mg 
ATM/2167 mg AVI. From Day 2 onwards, this will be 6000 mg ATM/2000 mg AVI. 
Dose selection (ATM-AVI) for patients with moderate renal impairment (CrCL >30 mL/min 
to ≤50 mL/min) and severe renal impairment (CrCL >15 mL/min to ≤30 mL/min). 
As both ATM and AVI are eliminated primarily as unchanged substances by the kidney, 
dosing regimens for patients with moderate to severe renal impairment (CrCL >15 mL/min to 
≤50 mL/min) require adjustment. Doses are based on PK modeling and simulation. 


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The review and approval of data from the Phase 2a Cohort 1 by the SAC also led to the 
approval that Cohort 2 could recruit patients with moderate renal impairment (CrCL 
>30 mL/min to ≤50 mL/min). The population PK models for both ATM and AVI included 
data from patients with renal impairment which allowed the use of modeling and simulation 
for dose selection in Phase 2a and 3. The dose selection for patients with moderate renal 
impairment was based on the following criteria: matching the predicted ATM steady state 
area under the curve between time zero and 24 hours after dose (AUC(0-24,ss)) in patients with 
moderate renal impairment, to the predicted AUC(0-24,ss) in patients with normal renal 
function (CrCL >80 mL/min) receiving ATM 1500 mg/AVI 500 mg; maintaining the same 
dosing ratio between ATM and AVI; and maintaining >90% PTA. Furthermore, since the 
dosing ratio between ATM and AVI is fixed, and given the differential impact of renal 
impairment on the clearance of ATM and AVI, it was accepted that matching an area under 
the plasma concentration versus time curve (AUC) target for ATM would result in exceeding 
the exposure targets for AVI in patients with normal renal function, but should not 
appreciably exceed the exposure in patients with mild renal impairment with the standard 
dose. As patients can have fluctuating renal function, in order to ensure sufficient exposure 
on the first day of dosing, the loading and first maintenance dose for patients with moderate 
renal impairment (CrCL >30 to 50 mL/min) will be the same as for patients with normal 
renal function. Thus in this Phase 3 study, the dose for patients with moderate renal 
impairment is a loading dose of 500 mg ATM plus 167 mg AVI by IV infusion over a 
30 minute period, immediately followed by an extended loading dose of 1500 mg ATM plus 
500 mg AVI by IV infusion over a 3 hour period, and then following a 3 hour gap, a reduced 
maintenance doses of 750 mg ATM plus 250 mg AVI by infusion over a 3 hour period q6h. 
In this Phase 3 study, the dose for patients with severe renal impairment (CrCL >15 mL/min 
to ≤30 mL/min) has been selected on a similar basis using modeling and simulation and is a 
loading dose of 675 mg ATM plus 225 mg AVI by IV infusion over a 30 minute period, 
immediately followed by an extended loading dose of 675 mg ATM plus 225 mg AVI by 
IV infusion over a 3 hour period, then following a 5 hour gap, maintenance dose of 
675 mg ATM plus 225 mg AVI by IV infusion over 3 hours q8h. 
1.4.3. Dose Selection for Metronidazole 
MTZ will be co-administered with ATM-AVI in patients with cIAI for the entire duration of 
study drug treatment (5 to 14 days) to provide coverage for anaerobic pathogens. The dose 
to be administered (500 mg MTZ IV over 1 hour q8h starting after the extended loading dose 
[second dose] of ATM-AVI) was chosen based on the current Guidelines of the Infectious 
Diseases Society of America for management of cIAI (Solomkin et al. 2010).48 This dose 
selection for MTZ is also in line with nationally approved SmPCs in Europe (Baxter 
Healthcare Ltd.)37 which do not indicate a need for dose adjustments in renal impairment. 
1.4.4. Dose Selection for Comparator Arms - Best Available Therapy 
The dose selection for BAT will be based on the investigator’s standard of care and the local 
label recommendation. 


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1.5. Single Reference Safety Document 
Additional information for ATM-AVI may be found in the single reference safety document 
(SRSD), which for this study is the ATM-AVI Investigator Brochure (IB). 
The SRSD for co- administered drug MTZ is MTZ United Kingdom (UK) SmPC (Baxter 
Healthcare Ltd.).37 The SRSD for BAT is per local label for the selected BAT. 
1.6. Benefits/Risk and Ethical Assessment 
Patients enrolled into this clinical study will have cIAIs requiring surgical intervention 
(including open laparotomy, percutaneous drainage of an abscess and laparoscopic surgery) 
nosocomial pneumonia (NP) including HAP and VAP, cUTI, or BSI that are of sufficient 
severity to require hospitalization and treatment with IV antibiotics. 
The potential benefit to patients participating in this study is that they will receive effective 
antibiotic treatment for their infection. ATM-AVI is covering Gram-negative pathogens in 
cIAI, cUTI, HAP/VAP or BSI patients, and other suspected pathogens are covered by the 
administration of allowed concomitant antibiotics while MTZ will be covering anaerobic 
pathogens in cIAI, see details in Section 5.9. Microbiology data reported for ATM-AVI to 
date shows it has potent in vitro activity against Enterobacteriaceae, including activity 
against MDR isolates that carry MBLs (see IB for further details). In addition, AVI has been 
shown to restore the effectiveness of ceftazidime in clinical studies in patients with cIAI, 
HAP/VAP and cUTI (see IB of ATM-AVI), and restoration of activity of aztreonam is also 
expected when combined with AVI. Thus ATM-AVI warrants further study in difficult to 
treat, serious infections where MDR Enterobacteriaceae may occur. The potential benefit of 
the study, in general, is the identification of a novel antibiotic combination product that is an 
effective treatment for a representative serious bacterial infection, in the face of the changing 
pattern and increasing frequency of antibiotic resistance which results in limited or no current 
treatment options (see Section 1.1). It is possible that ATM-AVI will not prove to be as 
effective as the BAT regimens which represent current standard of care for a cIAI, NP, cUTI, 
and/or BSI. In order to mitigate this risk, the study patients will be closely monitored and 
managed with appropriate therapies as determined by the investigator who is providing 
treatment, based on the clinical response of the patient. In addition, protocol-allowed 
specified concomitant antibiotics to cover non-susceptible pathogens, are permitted 
according to local microbiological results (see Section 5.9). 
ATM-AVI is not approved for marketing in any country. However, ATM has been marketed 
for over 30 years and has an established safety profile. Extensive data in over 2000 patients 
from the CAZ-AVI program indicates that AVI does not alter the established safety profile of 
its β-lactam partner in the combination, thus the same could be reasonably expected for ATM 
in combination with AVI. 
All adverse drug reactions (ADRs) expected for the ATM monoproduct are considered ADRs 
for ATM-AVI, and to date no unique risks have been identified for the combination of 
ATM-AVI compared with ATM alone. 


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ATM solution for injection (Azactam™) was first approved by the US FDA in 1986 and is 
indicated for intra-abdominal infections. The most frequent ADR for ATM comprise 
gastrointestinal disorders (diarrhea, nausea, vomiting: common according to Council for 
International Organizations of Medical Science (CIOMS) Working Group III standard 
categories; see IB). Further relevant ADRs are Clostridium difficile colitis, anaphylactic 
reactions and ventricular extrasystoles (uncommon). For further information regarding the 
risks attributable to ATM see IB and SmPC (ER Squibb & Sons Ltd. 2014).16 
Human experience with AVI includes studies of all phases in which AVI was administered 
either as a single agent or in combination with other antibiotics (CAZ or ceftaroline). As part 
of the CAZ-AVI development program and in a Phase I study for the ATM-AVI 
development, the safety and PK of AVI have been investigated in more than 10 clinical 
pharmacology studies after IV administration of AVI alone or in combination with 
ceftaroline, CAZ or ATM. CAZ-AVI was approved by the FDA on 
25 February 2015 (Trademark: Avycaz) and by the EMA on 28 April 2016 (Trademark: 
Zavicefta). No ADRs are currently expected for the AVI monoproduct. More than 
2000 patients across the indications of cIAI, complicated urinary tract infections, and 
HAP/VAP have been exposed to CAZ-AVI and no significant differences in the safety 
profile for CAZ-AVI were found compared to ceftazidime (CAZ) only. 
To date on the ATM-AVI clinical development program, data are available from 1 completed 
Phase I study in healthy volunteers (Study C3601005), and an ongoing Phase 2a study in 
patients with cIAI (Study C3601001). In completed Study C3601005, the most common 
adverse events (AEs) reported in the ATM-AVI treatment arms were headache, liver function 
test abnormal, diarrhoea and infusion/cannula site pain/reaction, which are expected events 
for the ATM monoproduct (ER Squibb & Sons Limited 2014).16 
Increases in transaminase levels are expected for ATM-AVI on the basis of the ATM 
labelling and are listed in Section 4.8 (“Undesirable effects”) of the UK ATM SmPC where 
they are considered to be “usually reversing during therapy and without overt signs or 
symptoms of hepatobiliary dysfunction” (ER Squibb & Sons Limited 2014).16 Although data 
are limited at this stage of development, the transaminase elevations observed in the 
completed ATM-AVI Study C3601005 and preliminary unvalidated data from ongoing Study 
C3601001 show a similar pattern to that expected with ATM monotherapy, ie, generally 
asymptomatic, mild and reversible. Preliminary post-hoc exposure-response analyses for 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations in study 
C3601005 suggest that AVI does not contribute to the expected effect of ATM on AST and 
ALT (in-house data). Increased liver transaminases are considered an important potential 
risk for ATM-AVI (see IB for further details). Liver related AEs and increases in serum 
transaminases will continue to be kept under close surveillance in ATM-AVI clinical studies 
and managed appropriately, including the use of individual patient liver specific withdrawal 
criteria in line with guidance from the Regulatory Agencies. 


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Data from the Phase I study did not show evidence of a drug-drug interaction (DDI) between 
ATM and AVI after single doses. Based on current knowledge, also the potential for DDIs 
between ATM-AVI and other drugs is low. Both ATM and AVI show linear (approximately 
dose proportional) PK, undergo limited metabolism and are eliminated primarily as 
unchanged substances by the kidney. In addition, neither shows significant inhibition or 
induction of cytochrome P450 (CYP) enzymes in vitro and/or in vivo. Both ATM and AVI 
have low binding to human plasma proteins (ATM: approximately 43% [Colomycin SmPC 
2016; Crandon and Nicolau 2013; Vinks et al. 2007];7,8,51 AVI: 5.7% to 8.2% [FDA 
prescribing information: AVYCAZ 2017]).24 Furthermore, data from the Phase I study 
suggest that there is no clinically relevant influence of sex or age on the PK of AVI (Tarral 
and Merdjan).49 As only renal function influences PK of ATM and AVI, reduced doses in 
the regimens for moderate and severe renal impairment patients were included in this study. 
In addition to the identified and potential risks for ATM-AVI described above, there are also 
general study related risks that encompass puncture of a vein and/or placement of indwelling 
catheters for blood sampling, which may cause pain and occasionally results in thrombosis or 
thrombophlebitis and/or peripheral nerve damage (numbness). The total volume of blood to 
be drawn from each patient is expected to range – depending on clinical response – from 
107 to 171.5 mL; 18 mL thereof will be used for PK analysis (see Table 13). The results of 
safety laboratory sampling (clinical chemistry, hematology) will be made available to the 
investigators. Similarly, the results of specimen cultures obtained for study purposes will be 
made available to the investigators without delay and may yield clinically important 
additional information. Discomfort may be caused by any further study procedure such as 
study-related examinations, microbiological sampling, and recording of electrocardiograms 
(ECGs). These procedures however are not considered as risks for the patients that would 
affect the benefit-risk assessment. 
In summary, the known and potential risks of receiving ATM-AVI are expected to be similar 
to those seen with ATM. To date, no unique risks have been identified for the AVI 
component or the combination of ATM and AVI. Thus, the benefit/risk of ATM-AVI 
remains acceptable in this population of patients with life-threatening serious infections 
caused by Gram-negative pathogens producing MBLs and other β-lactamases implicated in 
the development of MDR for whom only limited alternative treatment options are available. 
The potential risks and discomforts to the individual patients in this study are well balanced 
by providing best practice medical monitoring and clinical care for each patient. Under the 
conditions of the study as described in the present protocol, the investigators and the sponsor 
consider the benefit/risk relation to be positive (ie, medically and ethically justified). 
Detailed information on identified and important risks for ATM-AVI is located in the 
ATM-AVI IB. 


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2. STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and conesponding endpoints are provided in Table 2. 
 
Table 2. 
Objectives and Endpoints 
 
Primary Objective: 
Primary Endpoint: 
To evaluate the efficacy of 
aztreonam-avibactam (ATM-AVI) and best 
available therapy (BAT) at the Test of Cure 
(TOC) visit in the microbiological 
Intent- To-Treat (micro-ITT) population for 
the treatment of selected serious infections 
that are due to MBL-producing 
Gram-negative bacteria. 
Propo1iion of subjects with clinical cure at the 
TOC visit in the micro-ITT analysis set. 
Secondary Objectives: 
Secondary Endpoints: 
To evaluate the efficacy of ATM-AVI and 
BAT at the TOC in the Microbiologically 
Evaluable (ME) population, and at the End 
of Treatment (EOT) visit in the micro-ITT 
and ME populations. 
• Propo1iion of subjects with clinical cure at 
the TOC visit in the ME analysis set; 
• Propo1iion of subjects with clinical cure at 
the EOT visit in the micro-ITT and ME 
analysis sets. 
To assess the microbiological response to 
ATM-AVI at the EOT and TOC visits in the 
micro-ITT and ME populations. 
• Propo1iion of subjects with a favorable 
(defined as eradication or presumed 
eradication) per-subject microbiological 
response at the EOT and TOC visits in the 
micro-ITT and ME analysis sets; 
• Propo1iion of subjects with a favorable 
per-pathogen microbiological response at 
the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 
To assess 28-day all cause mortality. 
Propo1iion of subjects who died on or before 
28 days from randomization in the 
Intent-To-Treat (ITT) and micro-ITT analysis 
sets. 
To evaluate the safety and tolerability 
profile of ATM-AVI and BAT. 
Safety and tolerability as assessed by adverse 
events, physical examination, vital signs, 
electrocardiograms, and laborato1y 
assessments in the safety analysis set. 


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Table 2. 
Objectives and Endpoints 
 
Exploratory Objectives: 
Exploratory Endpoints: 
To evaluate the phaimacokinetics (PK) of 
ATM and AVI in subjects with serious 
infections and to attempt to characterize the 
relationship between exposure and clinical 
and microbiological response for 
ATM-AVI. 
• PK of azti·eonam and avibactam in subjects 
in the population PK analysis set; 
• PK/phannacodynamic (PD) relationship 
between exposure and clinical and 
microbiological response for ATM-AVI in 
the population PK analysis set. 
To assess 14-day all-cause mo11ality. 
Propo11ion of subjects who died on or before 
14 days from randomization in the ITT and 
micro-ITT analysis sets. 
To collect data to allow an explorato1y 
evaluation of health utilization (to be 
repo11ed outside of the CSR). 
• Length of hospital stay, including any 
readmissions up to TOC (days); 
• Length of study ti·eatinent (days); 
• Length of intensive cai·e unit stays (days); 
• Transfe1Ted to the intensive care unit 
(Yes/No); 
• Mechanical ventilation (Yes/No) for 
hospital-acquired 
pneumonia/ventilator-associated 
pneumonia subjects; 
• Length of mechanical ventilation (days) for 
hospital-acquired 
pneumonia/ventilator-associated 
pneumonia subjects; 
• Subsequent unplanned surgical 
intervention after ti·eatinent success versus 
failure (up to the TOC visit) for 
complicated inti·a-abdominal infection 
subjects. 


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This protocol will use an independent adjudication committee (central blinded assessor) to 
detennine whether ce11ain investigator-repo11ed events meet the definition of disease-related 
efficacy endpoints, using predefined endpoint criteria (see Section 9.7). 
3. STUDY DESIGN 
This is a prospective, randomized, multicenter, open-label, parallel group, comparative study 
to detennine the efficacy, safety, and tolerability of ATM-AVI versus BAT in the treatment 
of hospitalized adults with cIAI, NP including HAP and VAP, cUTI, or BSI due to 
MBL-producing Gram-negative bacteria. 
The study outline is provided in Figure 1, the study treatments are provided in Figure 2. 
Adult hospitalized subjects with a confomed diagnosis of cIAI, HAPNAP, cUTI or BSI due 
to MBL producing Gram-negative pathogens requiring administration of intravenous 
antibacterial treatment will be emolled in this study. 
The study will randomize approximately 60 subjects in a 2:1 randomization scheme 
(ATM-AVI: BAT) with infections due to MBL-producing Gram-negative bacteria. 
Molecular testing at the central microbiology laborato1y will be perfo1med to confmn the 
MBL status of the organism upon study completion or at pre-designated intervals. 
The study will consist of a Screening Visit (Visit 1), a Baseline Visit (Visit 2) on Day 1 of 
the study treatment, ongoing treatment visits (Visits 3 to 15) from Day 2 to Day 14, an EOT 
visit (Visit 16) within 24 hours after the last infusion, a TOC visit (Visit 17) on 
Day 28 (±3 days) and a LFU visit (Visit 18) on Day 45 (±3 days). 
Subjects will be stratified at randomization based on infectious disease type (cIAI, 
HAPN AP, cUTI and BSI). The number of subjects with cUTI will be no more than 
approximately 75% of the study population. 
After obtaining written info1med consent and confoming eligibility, subjects will be 
randomized in a 2:1 ratio to the ATM-AVI treatment group or the BAT treatment group 
according to a central randomization schedule (approximately 40 (ATM-AVI) subjects and 
approximately 20 (BAT) subjects per group). Please refer to Section 5.5 for more details 
with regard to treatment aims, dosage and mode of administration and duration of treatment. 
Subjects will be stratified at randomization based on infectious disease type (cIAI, 
HAPN AP, cUTI and BSI). 
 


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The recommended minimal duration of treatment is 5 days for cIAI, cUTI and BSI and 
7 days for HAP/VAP. The maximal duration of treatment is 14 days. 
For subjects randomized to ATM-AVI, sparse blood samples will be collected for PK 
assessments by population pharmacokinetic (pop PK) analysis, and PK/PD relationships will 
be evaluated in subjects where plasma samples and microbiological response data have been 
collected. 
Each subject is expected to complete the study, including the Late Follow-Up (LFU) visit. 
Subjects will receive their study therapy by study center personnel while in the hospital. 


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Figure 1. Study Outline 
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Visit 1 
Day-1 to 1 
 
Eligibility! 
Screening 
Visit 2 
Day 1 
 
Baseline 
Visits 3 to 15 
Days 2 to 14 
Duration IV of 
Treatment: 
', 5 to 14 days for 
cIAI, cUTI or 
BSI 
', 7 to 14 days for 
HAPNAP 
Visit 16 
 
 
Within 24 hom·s 
of end oflast 
infosion 
EOT 
Visit 17 
Day 28 ± 3 days 
TOC 
Visit 18 
Day 45 ± 3 days 
LFU 
 
 
 
 
Abbreviations: ATM-AVI=aztreonam-avibactam; BAT=best available therapy; BSI=bloodstream infection; clAI=complicated intra-abdominal infections; 
cUTI=complicated urina1y tract infections; EOT=end of treatment; HAPN AP=hospital-acquired pneumonia/ ventilator-associated pneumonia; IU=intemational 
units; IV=intravenous(ly); LFU=late follow-up; MTZ= metronidazole: TOC=test of cure. 
 
Note: Administration of the first dose of IV study therapy marks the beginning of study treatment Day 1. 


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Figure 2. Study Treatment 
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ATM-AVI 
 
 
ATM-AVI 
arm 
 
 
BAT 
 
 
ATM-AVI 
 
 
 
IV aminoglycoside 
 
 
  
 
 
IV aminoglycoside 
 
cIAI, cUTI 
 
 
BAT 
arm 
 
ATM-AVI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I 
I 
D 
=mandatory 
= ootional 
 
Abbreviations: ATM-AVI=aztreonam-avibactam; BAT=Best Available Therapy; BSI=Bloodstream Infection; clAI=complicated intra-abdominal infections; 
cUTI=complicated mina1y tract infections; HAPN AP=hospital-acquired pneumonia/ ventilator-associated pneumonia; IV=intravenous(ly); 
MTZ=metronidazole. 
* = MTZ for clAI only; t = Daptomycin for clAI and BSI only. 
For details of study ti·eatment see Section 5.5, and for details of allowed concomitant medication see Section 5.9. 
 
 
 


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4. SUBJECT ELIGIBILITY CRITERIA 
This study can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol. 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
The target population is hospitalized subjects with a diagnosis of cIAI, cUTI, HAP/VAP or 
BSI due to MBL-producing Gram-negative bacteria. Subjects must have an MBL- positive 
Gram-negative bacteria that was isolated from an appropriate specimen obtained within 
7 days prior to screening. 
The exact clinical diagnoses and brief descriptions that define the population of subjects with 
cIAI eligible for this study are given in Section 4.1.1 and Section 4.1.2, for subjects with 
HAP/VAP in Sections 4.1.1 and Section 4.1.3, for subjects with cUTI in Section 4.1.1 and 
Section 4.1.4 for BSI in Sections 4.1.1 and Section 4.1.5. 
The inclusion and exclusion criteria will be assessed by a site investigator before enrollment 
of the subject to the study. Clinically indicated antibiotic treatment must not be delayed 
because subject is being considered for clinical study participation. 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for 
this study. Under no circumstances can there be exceptions to this rule. 
4.1. Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
4.1.1. All Subjects 
1. Subject must be ≥18 years of age. 
2. Evidence of a personally signed and dated informed consent document indicating that 
the subject or a legally acceptable representative has been informed of all pertinent 
aspects of the study. If a subject is unable to consent for themselves at Screening, the 
subject’s legally acceptable representative may provide written consent, in 
accordance with the country-specific regulations. Those subjects who are 
unconscious or considered by the investigator clinically unable to consent at 
Screening and who are entered into the study by the consent of a legally acceptable 
representative should provide their own written informed consent for continuing to 
participate in the study as soon as possible on recovery, as applicable in accordance 
with local regulations. 


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3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically 
cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy 
(see additional Inclusion Criteria on HAP/VAP, cIAI, cUTI, or BSI for minimum 
disease criteria). 
4. Subjects must have an MBL- positive Gram-negative bacteria (an Enterobacteriaceae 
and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is 
≥4 µg/mL), that was isolated from an appropriate specimen obtained within 7 days 
prior to screening (the study qualifying pathogen, which was determined to be the 
causative agent of entry infection and which is available to be sent to the central 
laboratory). Prior to screening, genotypic confirmation of an MBL-positive pathogen 
at the local laboratory is required. If this is not possible then selected phenotypic tests 
may be acceptable with prior approval of the sponsor. In the case of mixed infection, 
the subject is allowed to participate in the study if the species are deemed susceptible 
to ATM-AVI or the investigator considers that the additional species are colonizers 
which do not warrant specific treatment. 
5. Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria: 
a. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and status may be confirmed with a serum 
follicle-stimulating hormone (FSH) level confirming the postmenopausal state; 
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c. Have medically confirmed ovarian failure. 
Note: All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
6. Female subject of childbearing potential must have a negative serum or urine 
pregnancy test, with sensitivity of at least 25 mIU/mL. 
7. Subjects who have received more than 48 hours of an appropriate prior systemic 
antibiotic[s] for a carbapenem non-susceptible pathogen may be enrolled if they 
demonstrate worsening or lack of improvement of objective symptoms or signs of 
infection (Note: antibiotic[s] is considered appropriate if microbiological 
susceptibility test results show that all carbapenem non-susceptible pathogens are 
susceptible to the systemic antibiotic[s] received). 
4.1.2. Additional Inclusion Criteria - cIAI Subjects 
1. Subject must have a specimen obtained from an abdominal source during a surgical 
intervention within 7 days prior to screening from which a study-qualifying pathogen 


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was isolated upon culture. Surgical intervention includes open laparotomy, 
percutaneous drainage of an abscess, or laparoscopic surgery. 
2. The subject 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 peri-appendiceal 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 the liver and spleen provided that there is 
extension beyond the organ with evidence of intra-peritoneal involvement). 
3. Subject has at least 1 of the following signs/symptoms from each of the following 
2 groups: 
• Group A: Evidence of systemic inflammatory response: 
• Documented fever (defined as body temperature ≥38°C) or hypothermia (with 
a rectal core body temperature ≤35°C); 
• Elevated white blood cells (WBC) (>12000 cells/μL); 
• Systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP) 
<70 mmHg, or a SBP decrease of >40 mmHg; 
• Increased heart rate ( >90 beats per minute [bpm]) and respiratory rate 
(>20 breaths/min); 
• Hypoxemia (defined as oxygen [O2] saturation <95% by pulse oximetry); 
• Altered mental status. 
• Group B: Physical findings consistent with intra-abdominal infection, such as: 
• Abdominal pain and/or tenderness, with or without rebound; 


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• Localized or diffuse abdominal wall rigidity; 
• Abdominal mass. 
4.1.3. Additional Inclusion Criteria – HAP/VAP Subjects 
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 computerized 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. 
4. 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, 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. 


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5. Subjects must have a respiratory specimen obtained within 7 days prior to screening 
for Gram-stain and culture from which a study-qualifying pathogen was isolated upon 
culture. This includes culture of either an expectorated sputum or a specimen of 
respiratory secretions obtained by endotracheal aspiration in intubated subjects, or by 
bronchoscopy with bronchoalveolar lavage (BAL), mini-BAL or protected-specimen 
brush (PSB) sampling. See Appendix 6 for details on appropriate specimen 
collection for ventilated and non-ventilated subjects. 
4.1.4. Additional Inclusion Criteria – cUTI Subjects 
1. Subject had urine within 7 days prior to screening that cultured positive; containing 
≥105 colony-forming unit (CFU)/mL of at least 1 carbapenem-non-susceptible, 
MBL-positive Gram-negative bacteria, ie, the isolate from the study-qualifying 
culture. 
2. Subject had pyuria in the 7 days prior to screening as determined by a midstream 
clean catch or catheterized urine specimen with ≥10 white blood cells (WBCs) per 
HighPower Field (HPF) on standard examination of urine sediment 
or ≥10 WBCs/mm3 in unspun urine. 
3. Subject demonstrates either acute pyelonephritis or complicated lower UTI without 
pyelonephritis as defined by the following criteria: 
a. Acute pyelonephritis indicated by flank pain (which must have onset or worsened 
within 7 days of enrollment) or costovertebral angle tenderness on examination 
and at least 1 of the following: 
i)  Fever, defined as body temperature ≥38°C (with or without patient symptoms 
of rigor, chills, or warmth); 
ii) Nausea and/or vomiting. 
OR 
b. Complicated lower UTI, as indicated by qualifying symptoms plus at least 
1 complicating factor as follows: 
i)  Qualifying symptoms: subject must have at least 2 of the following symptoms 
with at least 1 symptom from Group A: 
• Group A symptoms include dysuria, urgency, frequency, and or 
suprapubic pain; 
• Group B symptoms include fever (defined as body temperature 
≥38°C with or without patient symptoms of rigor, chills, warmth), nausea, 
and/or vomiting. 


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ii) Complicating factors: subject must have at least 1 of the following 
complicating factors: 
• Documented history of urinary retention (male subjects); 
• Obstructive uropathy that is scheduled to be medically or surgically 
relieved during study therapy and before the EOT; 
• 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 prior to obtainment of the specimen used for the study-qualifying 
culture. 
4.1.5. Additional Inclusion Criteria – BSI Subjects 
1. Subject has a confirmed diagnosis of primary BSI or catheter-related BSI (CR-BSI). 
2. Signs and symptoms of systemic infection characterised by at least one of the 
following: 
a. Chills, rigors, or fever (temperature of ≥38.0°C or ≥100.4°F); 
b. Elevated white blood cell count (≥10,000/mm3) or left shift (>15% immature 
polymorphonuclear leukocytes (PMNs)). 
4.2. Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the 
study: 


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4.2.1. All Subjects 
1. Subject has a history of serious allergy such as anaphylaxis, angioedema and 
bronchospasm, hypersensitivity or any serious reactions to any systemic antibacterial 
which is allowed per protocol including ATM, carbapenem, monobactam or other 
β-lactam antibiotics, AVI, colistimethate or polymyxin B, nitroimidazoles or MTZ, 
vancomycin, linezolid, daptomycin, aminoglycosides (eg, amikacin, gentamicin, 
tobramycin), or any of the excipients of the respective (investigational) medicinal 
products to be administered during the study. 
2. Subject has a concurrent infection that may interfere with the evaluation of response 
to the study antibiotics 
3. Subject has a need for effective concomitant systemic antibacterials in addition to 
those allowed per protocol for the diagnoses under study. 
4. Subject has an estimated CrCL ≤ 15 mL/min by Cockcroft-Gault formula (Cockcroft 
and Gault 1976), receiving or requirement for peritoneal dialysis, haemodialysis or 
hemofiltration. 
5. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study treatment and for at least 7 days after the last infusion of investigational product 
(see Section 4.4.1). 
6. Subject is participating in or has participated in other studies involving investigational 
drug(s) within the last 30 days (or five times the half-life of the previously 
administered investigational compound, whichever is longer) prior to screening 
and/or during study participation. 
7. Subject has other acute or chronic medical or psychiatric condition including recent 
(within the past year) or active suicidal ideation or behavior or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of study results and, in 
the judgment of the investigator, would make the subject inappropriate for entry into 
this study (eg, in HAP/VAP subjects with pulmonary disease such as lung cancer, 
active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary disease 
or recent pulmonary embolism). 
8. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study. 


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4.2.2. Additional Exclusion Criteria – cIAI Subjects 
1. Subject 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. Subject has abdominal wall abscess or small-bowel obstruction without perforation or 
ischemic bowel without perforation. 
3. Subject has a cIAI managed by staged abdominal repair (STAR), or “open abdomen” 
technique, or marsupialization. This criterion is intended to exclude subjects in 
whom the abdomen is left open, particularly those for whom re-operation is planned. 
4.2.3. Additional exclusion criteria – cUTI Subjects 
1. Subjects 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 subject. 
2. Any recent history of trauma to the pelvis or urinary tract. 
4.2.4. Additional exclusion criteria – BSI Subjects 
1. Subject has a prosthetic cardiac valve or synthetic endovascular graft. 
2. Subject has a suspected or documented medical condition with well-defined 
requirement for prolonged antibiotic treatment (eg, infectious endocarditis, 
osteomyelitis/septic arthritis, undrainable/undrained abscess, 
unremoveable/unremoved prosthetic associated infection). 
For procedures for withdrawal of incorrectly enrolled subjects see Section 4.3.2. 
4.3. Randomization Criteria 
All subjects being enrolled and fulfilling all eligibility criteria will be randomized in a 
2:1 ratio to receive either the ATM-AVI treatment arm or the BAT treatment arm. 
4.3.1. Subject Enrollment and Randomization 
Investigator(s) should keep a record, the subject screening log, of subjects who entered 
screening. 
The investigator will: 
1. Obtain signed informed consent from the potential subject or their legally acceptable 
representative before any study specific procedures are performed. The subject is 
considered enrolled when the ICF is signed at the Screening Visit and the enrollment 
call is done in the interactive response technology (IRT) system. 


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2. IRT system will assign the subject with a unique enrollment number ie, subject 
identifier (ID) at the Screening Visit (sites will have to enter the subject ID into the 
IRT system to retrieve subject data). 
3. Determine subject eligibility. See Section 4.1 and Section 4.2. 
4. At Baseline, the investigator will confirm that all eligibility criteria still are fulfilled 
and will then perform the randomization transaction in the IRT system. 
5. At randomization the IRT system will assign eligible subjects a unique randomization 
code and IP kit number(s). 
If a subject withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused. 
Randomization codes will be assigned strictly sequentially as subjects become eligible for 
randomization. 
4.3.2. Procedures for Handling Incorrectly Enrolled or Randomized Subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. There can be no exceptions to this rule. Subjects 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the Medical Monitor 
immediately, and a discussion should occur between the Medical Monitor and the 
investigator regarding whether to continue or discontinue the subject from treatment. The 
Medical Monitor must ensure all decisions are appropriately documented. 
4.4. Lifestyle Requirements 
4.4.1. Contraception 
All fertile male subjects and female subjects who are of childbearing potential who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 7 days after the last dose of 
investigational product. The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and his or her partner from the permitted list of contraception methods 
(see below) and will confirm that the subject has been instructed in its consistent and correct 
use. At time points indicated in the Schedule of Activities, the investigator or designee will 
inform the subject of the need to use highly effective contraception consistently and correctly 
and document the conversation and the subject’s affirmation in the subject’s chart (subject 
needs 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 subject to call 


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immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the subject or the partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following: 
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom used WITH a separate spermicide product (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate. 
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label). 
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject, or as necessitated by the clinical status of the subject during the 
period of hospitalization, eg, unconscious/ventilated. 
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 7 days after the last 
dose of investigational product. 
4.5. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 


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only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site. 
5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational products are test product ATM-AVI, co-administered drug 
Metronidazole (MTZ) and comparator BAT. 
5.1. Allocation to Treatment 
All subjects being enrolled and fulfilling all eligibility criteria will be randomized. 
Randomization will be performed using an IRT system. Specific information concerning the 
use of the IRT system will be provided in a separate user manual. 
Block randomization using an IRT system will be used to randomize subjects in a 2:1 ratio to 
receive IV dosing regimens of either the ATM-AVI treatment arm or BAT treatment arm. 
The randomization scheme for this study will be generated using the sponsor randomization 
system. 
Subjects will be stratified at randomization based on infectious disease type (cIAI, 
HAP/VAP, cUTI or BSI). The number of subjects with cUTI will be no more than 
approximately 75% of the study population. 
The study treatment (ATM-AVI or BAT) should, if possible, be administered as soon as 
possible after randomization and (where applicable) the IP kit number is assigned. 
5.2. Methods for Ensuring Blinding 
This is an open-label study. The investigators, site personnel, and subjects 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. 
Clinical response outcome recorded at scheduled visits will be assessed by an independent 
adjudication committee (central assessor) in a blinded fashion with the aim of unbiased 
adjudication of the primary objective measure. Data will be provided relating to the subject’s 
clinical response (eg, death status, disease progression, AEs, surgical procedures) without 


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disclosing ti·eatment aim. Details on the centi·al independent adjudication committee will be 
provided in a separate cha1ter. 
No interim analysis is planned, and no analysis of data according to ti·eatment ann 
assignment will be made prior to database lock, except for interim external data monitoring 
committee (E-DMC) reviews (See Section 9.5). 
Prograinming 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 subject and group ti·eatment assignment until database lock has occmTed. 
5.2.1. Methods for Unblinding 
Only the independent adjudication committee will be blinded during the study. They will not 
require unblinding. 
5.3. Subject Compliance 
The administi·ation of all study diugs (including IPs) should be recorded in the appropriate 
sections of the Case Repo1t Fo1m (CRF). 
Qualified study center personnel will administer the IV study ti·eatment and assure ti·eatment 
compliance. At a minimum the dose, date, and exact stait and stop time of adminisu-ation of 
the IV study ti·eatment will be recorded in the appropriate sections of the CRF and checked 
by the monitor at monitoring visits. The deviation from study ti·eatment will be repo1ted and 
documented. 
Subject compliance with dosing administi·ation will be verified by accounting doses 
administered. The subject dosing compliance should be within the range of 80% and 
120% of expected doses during ti·eatment period. Subject noncompliance cases should be 
discussed with medical monitors. 
5.4. Investigational Product Supplies 
5.4.1. Dosage Forms and Packaging 
The identity of the IP is provided in Table 3. 
 
Table 3. 
Identity of Investigational Product 
 
Investh?:ational Products 
Dosa2e Form and Stren2th 
Test Product 
Aztreonam 
Aztreonam 2 g powder concentrate for 
infusion2. 
Avibactam 
Avibactam 600 mg powder concentrate for 
infusion. 
Comparator - Best Available Therapy 
Based on investigative site practice and local epidemiology. 
Co-theraov Drue 


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Metronidazolea 
Metronidazole 500 mg/100 mL solution for 
infusion. 
a. 
Subjects with cIAI in the ATM-AVI arm will all receive MTZ co-therapy. Subjects with cIAI in the 
BAT arm may receive MTZ if BAT does not provide adequate anaerobic coverage. 
Note: Co-administered drug is supplied centrally via the sponsor. 
Note: Aztreonam and Metronidazole are commercial products over-labeled with the study clinical label. 
Note: Comparator drug is sourced locally under local regulatory conditions. 
 
Central supply or locally obtained commercial supplies of these drugs will be used in 
accordance with local regulations. 
All IPs will be administered by IV infusion. Aztreonam and AVI will be supplied as vials for 
reconstitution. The IP ATM-AVI will be prepared for co-administration in saline using 
standard aseptic IV infusion technique (see Investigational Product Manual (IP Manual)). 
5.4.2. Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling 
(European Commission GMP Guideline 2010).17 Label text will be translated into local 
language. 
Labels will be provided as either a single panel label or as multi-language booklet labels. 


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5.4.3. Preparation and Dispensing 
See the IP manual and package inse1i for instmctions on how to prepare the investigational 
product for administration. Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician's assistant, nurse practitioner, phannacy assistant/technician, or phaimacist) as 
allowed by local, state, and institutional guidance. 
5.5. Administration (Dose and Treatment Regimen) 
The recommended minimal duration of treatment with IV study treatment is 5 days for cIAI, 
cUTI or BSI and 7 days for HAPN AP. The maximal duration of treatment is 14 days. 
5.5.1. ATM-AVI Treatment Arm 
ATM-AVI: Subjects will be given a loading dose and then an extended loading dose before 
commencing on a maintenance dose. All doses (loading, extended loading and 
maintenance), and the dosing frequency of the maintenance dose are dependent on renal 
function according to Table 4 below. 
 
Table 4. 
ATM-AVI Doses in Relationship to CrCL 
 
Creatinine 
Clearance 
(mL/min)* 
ATM-AVI 
Loading Dose 
(LD) 
(30 min IV 
infusion) 
ATM-AVI 
Extended 
Loading Dose 
(ELD) 
Immediately 
followingLD 
(3 hr IV 
infusion) 
ATM-AVI 
Time Interval 
between ELD 
and Start of 
first 
Maintenance 
Dose 
ATM-AVI 
Maintenance 
Dose (3 hr IV 
infusion) 
ATM-AVI 
Frequency 
of 
maintenance 
dosing 
>50 
500mg 
azt:reonam 
plus 167 mg 
avibactam 
1500 mg 
aztreonam 
plus 500 mg 
avibactam 
3 hours 
1500 mg 
aztreonam 
plus 500 mg 
avibactam 
q6h 
>30 to 50 
500mg 
aztreonam 
plus 167 mg 
avibactam 
1500 mg 
aztreonam 
plus 500 mg 
avibactam 
3 hours 
750mg 
aztreonam 
plus 250 mg 
avibactam 
q6h 
>15to30 
675mg 
aztreonam 
plus 225 mg 
avibactam 
675mg 
aztreonam 
plus 225 mg 
avibactam 
5 hours 
675 mg 
aztreonam 
plus 225 mg 
avibactam 
q8h 
Abbreviations: ATM-AVI= aztreonam-avibactam; CrCL=creatinine clearance; ELD=extended loading dose; 
IV=intravenous(ly); LD=loading dose; q6h=eve1y 6 hours; q8h=every 8 hours. 
*Estimated crea.tinine clearance using Cockcroft-Ga.ult fo1mula rounded to the nearest whole number (see 
Appendix 3). 


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MTZ: Subjects with cIAI will also receive MTZ 500 mg IV q8h (by IV infusion over 
60 minutes). The first dose of MTZ will be started immediately after the extended loading 
dose of ATM-AVI has completed and treatment will be continued until the end of the 
treatment period. The SmPC (Baxter Healthcare Ltd.)37 does not indicate a dose reduction 
for MTZ in subjects with renal impairment. However, a dose reduction may be necessary in 
end stage renal disease (ESRD) subjects (see Section 5.5.5). 
5.5.2. Comparator Treatment Arm - Best Available Therapy 
The comparator treatment in this study is best available therapy (BAT) based upon site 
practice and local epidemiology. The choice of BAT (monotherapy or combination) for each 
subject must be recorded prior to randomization. 
5.5.3. Optional Gram-positive Antibiotics 
Subjects with HAP/VAP and cUTI may receive optional vancomycin or linezolid and 
subjects with cIAI and BSI may receive optional vancomycin, linezolid or daptomycin at the 
investigators discretion to provide antibiotic cover for a Gram-positive infection. The need 
for an adjunctive Gram-positive antibiotic should be re-evaluated 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. 
5.5.4. Optional Aminoglycosides 
Subjects with HAP/VAP and proven or suspected co-infection with Pseudomonas 
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 Pseudomonas 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 Pseudomonas 
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. 
5.5.5. Changes in Renal Function during Study Treatment 
In some subjects, the CrCL estimated from serum creatinine can rapidly recover (or 
deteriorate), especially early in the course of treatment for the infection. There is potential 
for accumulation of MTZ metabolites in ESRD subjects, and therefore enhanced monitoring 
for MTZ associated AEs is recommended, and a dose reduction may be necessary. Renal 
function should therefore be closely monitored throughout the treatment period (as clinically 
indicated) and the dose of study treatment adjusted by the investigator according to the CrCL 
value calculated by the Cockcroft-Gault formula (Appendix 3). 
Creatinine clearance should be monitored daily through the local laboratory from Day 1 to 
Day 4 (and Day 3 or Day 5 by the central laboratory, if PK samples are to be collected on 
Day 3 or Day 5) and then as clinically indicated. If subsequent to randomization and while 


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still on IV study treatment, a subject’s estimated CrCL falls below the threshold for study 
inclusion (ie, estimated CrCL ≤15 mL/min) and/or there is a requirement to start renal 
replacement therapy, the investigator should discontinue ATM-AVI or BAT investigational 
therapies. 
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products including any comparator and/or marketed products are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements. 
Investigational products should be stored in their original containers and in accordance with 
the labels. 
See the IP manual for storage conditions of the product once reconstituted for ATM-AVI. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products). This should 
be captured from the time of investigational product receipt throughout the study. Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available. The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations. The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product. It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site. 


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5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. All investigational products will be 
accounted for using a drug accountability form/record. 
The study treatment provided for this study will be used only as directed in the study 
protocol. 
The study personnel at the investigational site will account for all drugs supplied, purchased, 
dispensed and returned for appropriate destruction. Certificates of delivery, destruction and 
return must be signed. 
Study site personnel will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction. Certificates of delivery, destruction and return should be 
signed. 
IV study treatment will be dispensed to the investigator or medically qualified personnel by 
the study center pharmacist. IV study treatment will only be prepared/administered to 
subjects by qualified pharmacy personnel/medically qualified personnel who have been 
appropriately trained to prepare/administer IV study treatment. Written authorization of 
study personnel to administer IP must be documented on the Delegation of Authority Log in 
one of 2 ways: 
• All study staff trained and authorized by the investigator to prepare/administer IV 
study treatment are listed on the Delegation of Authority Log; 
OR 
• The nurse manager(s)/supervisor(s) and study pharmacists authorized by the 
investigator are listed on the Delegation of Authority Log as the person(s) responsible 
for ensuring that the nursing/pharmacy staff are appropriately trained on IV study 
treatment preparation/administration prior to preparing/administering it, and for 
maintaining current and complete training documentation at all times. 
Written documentation of training of IV study treatment administration and pharmacy study 
center personnel will be kept current throughout the study, and ongoing training will be 
provided by study center personnel as assigned by the investigator on the Delegation of 
Authority Log. It is the investigator’s responsibility to ensure that all documentation remains 
current and complete throughout the study. The investigator will document how he or she 
will ensure staff are adequately trained before they perform the infusion, and he or she will 
ensure that there is a system in place that will guarantee supervision of the study treatment 
administration process and subject safety (eg, study treatment will only be administered to 
subjects under supervision of an investigator). Source documentation should clearly indicate 
who administered the infusion. Records of IV study treatment usage should include the 
identification of the subject to whom the IV study treatment was administered, the quantity 
and date of administration, and a record of unused IV study treatment. The 


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investigator/pharmacist is responsible for maintaining accurate IV study treatment 
accountability records throughout the study on the relevant forms provided by Pfizer. Each 
administration of IV study treatment will be documented in the CRF. 
It is the investigator’s responsibility to establish a system for handling study treatments, 
including IPs, to ensure that: 
• Deliveries of such products are correctly received by a responsible person (eg, 
pharmacist); 
• Deliveries are recorded; 
• IV study treatment is handled and stored safely and properly; 
• IV study treatment provided for this study is used only as directed in the study 
protocol; 
• Study center personnel account for all study drugs received at the study center, 
dispensed for the subject, and returned to the pharmacy. Any discrepancies should be 
documented, investigated, and appropriately resolved; 
• The monitor performs complete IV study treatment accountability during each 
monitoring visit, including verifying documentation of receipt, dispensing, return, and 
destruction of IV study treatment and consistency of this documentation with physical 
inventory. 
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented. 
5.8. Post Study Access to Study Treatment 
At the end of the study, the sponsor will not continue to supply study drug to subjects or 
investigators unless the sponsor chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study. 
5.9. Concomitant Treatment(s) 
All prescription and over the counter medications being taken by the subject for the 2 weeks 
prior to the first dose of investigational product (considered prior treatment) and from the 
first dose of study medication through the LFU visit (considered concomitant treatments) 
must be documented on the appropriate pages of the CRF. Systemic antibiotics should be 
documented for the entire duration of the study (from 2 weeks prior to the first dose of study 
medication through the LFU visit). Application of topical antibacterial and antifungal agents, 


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and peritoneal lavage for cIAI subjects, also need to be recorded in the CRF. All actions 
related to the administration of concomitant antibiotics should be documented in the CRF. 
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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Table 5. 
Allowed Concomitant Medication 
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Allowed Procedure/ 
Medication/ Class of 
Drug: 
Subjects with 
cIAI: 
Subjects with 
cUTI: 
Subjects with 
BSI: 
Subjects with 
HAP/VAP: 
MTZ 
Subjects in 
the ATM-AVI 
arm will all 
receive MTZ 
as part of 
study therapy 
(see 
Section 5.5.1). 
Subjects in 
the BAT arm 
may receive 
MTZ if the 
chosen BAT 
does not 
provide 
adequate 
anaerobic 
coverage. 
N/A 
NA 
N/A 
Vancomycin, linezolid or 
daptomycin 
If a 
Gram-positive 
pathogen is 
suspected 
then 
vancomycin, 
linezolid or 
daptomycin 
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 subjects 
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 
subjects should 
continue in the 
study. 
If a 
Gram-positive 
pathogen is 
suspected then 
vancomycin, 
linezolid or 
daptomycin 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 
subjects 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 
subjects should 
continue in the 
study. 


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Table 5. 
Allowed Concomitant Medication 
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Allowed Procedure/ 
Medication/ Class of 
Drug: 
Subjects with 
cIAI: 
Subjects with 
cUTI: 
Subjects with 
BSI: 
Subjects with 
HAP/VAP: 
IV aminoglycoside (eg, 
amikacin, gentamicin or 
tobramycin based upon 
local practice and 
epidemiology) 
N/A 
N/A 
N/A 
In the ATM-AVI 
or BAT arm, an 
IV 
aminoglycoside 
may be added if 
Pseudomonas 
aeruginosa is 
suspected. If 
aminoglycoside is 
started, and if 
Pseudomonas 
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 
Abbreviations: ATM-AVI=aztreonam avibactam; BAT=Best Available Therapy; BSI=Bloodstream Infection; 
cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; 
HAP/VAP=hospital-acquired pneumonia/ventilator-associated pneumonia; IV=intravenous (ly); 
MTZ=metronidazole; N/A=not applicable. 


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Table 6. 
Restricted Concomitant Medications 
 
Restricted 
Procedure/Medicatio 
n/Class of Drug: 
Subjects 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 subject is 
considered to have failed study treatment and requires 
additional antibiotics to treat their infection. 
OR 
The subject 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 subject. 
Systemic antifungals 
Antifungal treatment to treat the cIAI, HAP/VAP, cUTI or BSI 
should be avoided unless clinically indicated. 
Abbreviations: BSI=bloodstream infection; cIAI=complicated intra-abdominal infection; cUTI=complicated 
urinary tract infection; HAP/VAP=hospital-acquired pneumonia/ventilator-associated pneumonia. 
 
 
Table 7. 
Prohibited Concomitant Medications 
 
Prohibited 
Procedure/Medicatio 
n/Class of drug: 
Subjects with cIAI, cUTI or 
BSI: 
Subjects with HAP/VAP 
Probenecid 
To be avoided 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 subjects in 
either treatment arm. 
Abbreviations: BSI=Bloodstream infections; cIAI=complicated intra-abdominal infection; cUTI=complicated 
urinary tract infections; HAP/VAP=hospital-acquired pneumonia/ventilator-associated pneumonia; 
IV=intravenous(ly); N/A=not applicable. 
 
 
Both ATM (Mattie 1994)39 and AVI (see IB) are predominantly eliminated by the kidney, 
partly by active tubular excretion. In vitro studies have shown probenecid and furosemide 
interfere with the active tubular excretion, resulting in increased plasma concentrations of the 
study drugs, however, these increases are considered to be clinically insignificant (ER Squibb 
& Sons Ltd. 2014).16 Concomitant administration of probenecid should be avoided during 
IV study treatment. Furosemide should be used with caution in the setting of potentially 
nephrotoxic drugs, eg, aminoglycosides and colistin. Based on current knowledge, further 


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relevant DDIs with regard to ATM-AVI administration in this study are not to be expected 
(see Section 5.10.1). 
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 subjects or outside of the urine tract for cUTI or outside of the lung for 
HAP/VAP subjects) 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 subject, 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 subject’s baseline pathogens to avoid confounding the 
assessment of the effect of study therapy. 
It is anticipated that in instances of suspected clinical failure, alternative or additional 
antibiotic treatment to treat the index infection (cIAI, HAP/VAP, cUTI or BSI) may be 
required, and where rescue antibiotic treatment is provided the subject should be assessed as 
a clinical failure. An appropriate antibiotic should be selected, taking into account results of 
sensitivity testing. If possible, the investigator should first discuss this with the Medical 
Monitor. 
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 SmPCs for these products and investigators are recommended to 
refer to these for further prescribing information. For ATM-AVI drug-drug Interaction 
(DDI) see Section 5.10.1. 
Other medication, which is considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
CRF. If analgesic medications are needed for pain, the use of analgesic medication without 
antipyretic properties is preferred. Should a subject require a biologic immunosuppressive 
agent or chemotherapy treatment after randomization, the investigator should contact the 
Medical Monitor before initiating treatment. Continued subject study participation will be 
determined based upon assessment of the safety risk to the subject if he or she were to 
continue on study treatment. Subjects who have already completed the IV study treatment 
should remain in the study until LFU assessment as they are not actively on study treatment 
but being followed up for outcomes. 
5.9.1. Other Concomitant Treatment 
Concomitant medication other than that described above, which is considered necessary for 
the subject’s safety and well-being, may be given at the discretion of the investigator and 
recorded in the appropriate sections of the CRF. 


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5.10. Drug-drug Interaction 
5.10.1. Aztreonam-avibactam 
Drug-drug interactions with AVI are unlikely. The binding of AVI to human plasma proteins 
is very low and concentration-independent. AVI had negligible or no direct inhibitory effect 
on CYP isoenzymes in vitro; the negligible inhibition observed was at high concentration of 
AVI that exceed any clinically relevant exposure. AVI showed no potential for in vitro 
induction of CYP1A2, 2B6, 2C9 and 3A4 isoenzymes in human hepatocytes. Against 
CYP2E1, AVI showed a slight induction potential at very high concentrations (1326 μg/mL) 
that exceed any clinically relevant exposure. Neither AVI nor ATM is an inhibitor of any 
major renal or hepatic transporters in the clinically relevant exposure range. In vitro, AVI is 
a potential substrate of human organic anion transporter (OAT)1 and OAT3 renal 
transporters and ATM dose-dependently inhibited the OAT1-mediated uptake of AVI, with 
maximum inhibition of 78% at 1000 µM. However, considering the in vitro half maximal 
inhibitory concentration (IC50) values (~ 700 µM for OAT1 and > 1000 µM for OAT2) 
relative to the maximum likely clinical plasma concentrations (187 µM) suggests that any 
interaction would probably be minimal. 
The lack of an interaction between ATM and AVI was confirmed clinically. The PK and 
statistical comparison results indicated no DDI between ATM (2000 mg) and AVI (600 mg) 
when each drug was administered alone or in combination as a single 1-hour IV infusion in 
healthy young subjects. In addition, following 10 days multiple dosing of the combination, 
PK parameters at steady state for both ATM and AVI were comparable to Day 1. 
Concomitant administration of probenecid or furosemide and ATM cause clinically 
insignificant increases in the serum levels of ATM. 
Due to the induction of β lactamases, certain antibiotics (eg, cefoxitin, imipenem) have been 
found to cause antagonism with many β-lactams, including ATM, for certain Gram-negative 
aerobes, such as Enterobacter species and Pseudomonas species. 
Prolongation of prothrombin time has been reported rarely in subjects receiving ATM. In 
addition, numerous cases of increased activity of oral anticoagulants have been reported in 
subjects receiving antibiotics, including β-lactams. Severe infection or inflammation, and the 
age and general condition of the subject appear to be risk factors. 
Single-dose PK studies have not shown any significant interaction between ATM and 
gentamicin, cephradine, clindamycin or MTZ. 
Unlike broad spectrum antibiotics, ATM produces no effects on the normal anaerobic 
intestinal flora. No disulfiram-like reactions with alcohol ingestion have been reported. 


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5.10.2. Coagulation and Concomitant Use of Anticoagulants 
Appropriate monitoring (according to applicable medical guidelines and institutional 
standard of care) should be undertaken when anticoagulants are prescribed concomitantly 
with antibiotics. Adjustments in the dose of oral anticoagulants may be necessary to 
maintain the desired level of anticoagulation. 
5.10.3. Other Investigational Products 
Information on DDIs with other medicinal products and other forms of interaction for 
protocol allowed antibiotics are available in the respective SmPCs for these products and 
investigators are recommended to refer to these for further prescribing information. 
6. STUDY PROCEDURES 
Study periods are defined in Figure 1. Details of the study plan and timing of procedures are 
provided in Schedule of Activities (Table 1). 
Every effort should be made to collect all the data, blood samples, and cultures and to 
complete all assessments required for each visit as detailed in the Schedule of Activities 
(Table 1) detailing the procedures and discussed by visit in the following sections. 
6.1. Prescreening on MBL-positive Gram-negative Pathogens (within 7 Days prior to 
screening) 
Where identification of genotype of pathogens does not constitute local standard of care, 
consent specifically to test MBL status of isolates must be obtained from the subjects (or 
their legally acceptable representative if applicable) prior to screening. If the test on MBL 
status of isolates is the standard of care at the sites, this consent is not necessary. However, 
the source documents must indicate “identification of genotype of pathogens including MBL 
is the standard of care”. 
The following procedures will be performed within 7 days prior to screening: 
• Obtaining abbreviated informed consent to test MBL status of isolates (only needed if 
test on MBL status is not the standard of care at the sites). 
For all subjects, sufficient documentation on the sample collection and identification of 
MBL- positive Gram-negative pathogens should be filed in the source documents. Only 
subjects with MBL-positive Gram-negative pathogens that were isolated from an appropriate 
specimen obtained within 7 days prior to screening will be invited to participate in the trial 
and will proceed with the full Informed Consent process prior to Screening. 
6.2. Screening and Enrollment 
Prior to any study specific procedures, subjects (or their legally acceptable representative if 
applicable) must provide written informed consent. Enrollment/Screening procedures will be 
performed according to the Schedule of Activities (Table 1). At Screening, subjects will be 
assessed regarding eligibility criteria. Subjects who do not meet all of these criteria must not 
be enrolled in the study (see Section 4.3). 


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6.2.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1) 
At Eligibility/Screening (Day -1 to 1), each potential subject (or his/her legally acceptable 
representative) will provide written informed consent prior to starting any study-specific 
procedures. 
Each subject will undergo Screening assessment procedures less than 24 hours prior to 
randomization (except for chest X-ray/CT scan for HAP/VAP subjects which are valid if 
collected within 48 hours prior to randomization). Local laboratory test results will be used 
to qualify subjects for inclusion. To this end, the following assessments need to be 
performed in the local laboratory and entered in the CRF: serum creatinine (including 
calculation of CrCL), serum or urine β-human chorionic gonadotropin (β-hCG) for 
pregnancy test, AST, ALT, alkaline phosphatase (ALP), total bilirubin (TBili), and 
hematology as listed in Section 4.2.1. For eligibility assessment, CrCL needs to be 
calculated at the study site, based on the creatinine value determined at local laboratory (see 
Appendix 3). In addition, safety laboratory samples must be sent to the central reference 
laboratory for testing (see Section 7.2.1). 
Eligibility/Screening assessments will consist of: 
1. Obtaining informed consent. 
2. Reviewing of the inclusion and exclusion criteria. 
3. Collecting demographics. 
4. Collecting medical history. 
5. Completing the APACHE II score (Appendix 5). 
6. Reviewing and recording prior medications (including prior antibiotic treatment). 
7. Performing complete physical examination as defined in Section 7.2.2. 
8. Determine height and body weight. 
9. Performing focused physical examination (see Section 7.2.2). 
10. Measuring vital signs including blood pressure (BP), heart rate and body temperature 
as defined in Section 7.2.4. For subjects with HAP/VAP, collecting respiratory rate 
(breath per minute) and peripheral O2 saturation. 
11. Completing the ventilation device status in subjects with HAP/VAP. 
12. Assessing urinary device status in subjects with cUTI. 
13. Performing a chest X-ray or CT scan (if not available within 48 hours prior to 
randomization) in subjects with HAP/VAP. 


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14. Collecting imaging and surgical report in subjects with cIAI. 
15. Assessing infection-related signs and symptoms. 
16. Obtaining blood and urine samples for safety analysis and sending to local laboratory 
(for testing laboratory eligibility criteria as listed in Section 4.2.1) and central 
laboratory. 
17. Estimating CrCL using the serum creatinine results from the local laboratory. See 
Appendix 3 for CrCL calculation. 
18. Obtaining blood or urine sample for serum β-hCG for women of childbearing 
potential (local laboratory reference laboratory). 
19. Collection of ABGs (ABGs are required for ventilated and recommended for 
non-ventilated HAP/VAP subjects, and for cIAI, cUTI and BSI subjects as clinically 
indicated). 
20. Identifying isolate from study-qualifying culture, and sending isolates to central 
laboratory. The isolate should produce an MBL to qualify the subject for the study. 
21. Collecting AEs. 
22. Confirming highly effective contraception is being used. 
6.3. Study Period 
6.3.1. Visit 2: Baseline Procedures and Day 1 of Treatment (Day 1) 
Local laboratory test results obtained at Visit 1 will be used to qualify subjects for inclusion 
(see Section 6.2.1). At Visit 2, blood and urine samples for safety analysis (including local 
lab for eligibility criteria confirmation) (and further assessments as listed in points 11 to 
12 of this section) are only required if Visit 1 and Visit 2 are separated by surgery or are 
more than 12 hours apart. Blood cultures (as listed in point 16 of this section) are required if 
blood cultures are not available within 48 hours prior to randomization. If safety lab samples 
and blood cultures are required, they should be collected prior to dosing. The safety lab 
samples and isolate of blood cultures must be sent to the central reference laboratory for 
testing. 
Study treatment should be started as soon as possible (within 24 hours) after a subject’s 
eligibility has been confirmed and the subject 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. All procedures at Visit 2 are to be done before first 
dose of study therapy except for PK sampling. 


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The following assessments should be performed for all subjects at Visit 2: 
1. Reviewing of the inclusion and exclusion criteria. 
2. Reviewing and recording prior and concomitant medications (including prior 
antibiotic treatment). 
3. Performing focused physical examination (see Section 7.2.2). 
4. Measuring vital signs including BP, heart rate and body temperature as defined in 
Section 7.2.4. For subjects with HAP/VAP, collecting respiratory rate (breath per 
minute) and peripheral O2 saturation. 
5. Performing a 12-lead digital triplicate ECG. The subject should be resting in a supine 
position for at least 10 minutes prior to the evaluation (see Section 7.2.3). 
6. Completing the ventilation device status in subjects with HAP/VAP. 
7. Assessing urinary device status in subjects with cUTI. 
8. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
9. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
10. Assessing infection-related signs and symptoms. 
11. Obtaining blood and urine samples for safety analysis and sending to local laboratory 
(for eligibility criteria confirmation) and central laboratory. 
12. Estimating CrCL using the serum creatinine results from the local laboratory. See 
Appendix 3 for CrCL calculation. 
13. Obtaining urine sample and sending to local laboratory for microscopic white blood 
cell count to assess for the presence of persisting pyruria in subjects with cUTI only. 
A urine sample must also be submitted to the central laboratory. 
14. Collection of ABGs as clinically indicated. 
15. Obtaining urine samples and sending to local laboratory for quantitative culture and 
sending isolates to central laboratory (for cUTI subjects only) (see Appendix 6). 
16. Obtaining blood samples and sending to local laboratory for microbiological culture, 
and sending isolates to central laboratory (see Appendix 6). Repeat blood cultures do 
not need to be performed at Baseline if available within 48 hours prior to 
randomization. 


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17. Collecting specimen as clinically indicated of abdominal site infection and sending to 
local laborato1y for microbiology culture, and sending isolates to central laborato1y 
(for subjects with cIAI only) (see Appendix 6). 
18.  For subjects who were not ventilated at the time when a study qualifying sample was 
obtained but were intubated subsequently (or subjects who had a bronchoscopy 
perfo1med): obtaining an appropriate respirato1y specimen for Gram- stain and 
culture. Specimens will be sent to local laborato1y for microbiological culture and 
isolates and unstained Gram-stain slides (for induced sputum and expectorated 
sputums only) will be sent to central laborato1y (for subjects with HAPN AP only) 
(see Appendix 6) 
19. 
 
I 
 
I 
 
 
20. Detennine and document of BAT prior to randomization. 
21. Randomization. 
22. Commence dosing according to the randomization schedule. 
23.  Following the initiation of the IV infusion of study treatment, blood samples for 
PK analysis will be obtained for subjects randomized to ATM-AVI as according to 
Table 12 and Figure 3 and Figure 4. 
24. Collecting new AEs and reviewing ongoing AEs. 
25. Collecting mo1iality assessment. 
26. Confoming highly effective contraception is being used. 
6.3.2. Visit 3 to 15: Ongoing Treatment (Days 2 to 14) 
The recommended minimal duration of treatment will be 5 days for subjects with cIAI, cUTI 
and BSI and 7 days for subjects with HAPNAP. The maximal duration of treatment will be 
14 days. Subjects, who require continuation of IV study treatment after 5 days (cIAI. cUTI 
and BSI) or 7 days (HAPNAP), will continue to receive their IV study treatment by study 
center personnel in the hospital. 


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The following assessment procedures will be performed during treatment with IV study 
treatment: 
1. Daily reviewing prior and concomitant medications (including prior and concomitant 
antibiotic treatment). 
2. Daily performing focused physical examination (see Section 7.2.2). 
3. Daily measuring vital signs including BP, heart rate and body temperature as defined 
in Section 7.2.4. For subjects with HAP/VAP, daily collecting respiratory rate 
(breath per minute) and peripheral O2 saturation. 
4. Performing a 12-lead digital triplicate ECG on Day 3 immediately following the end 
of the study drug infusion. The subject should be resting in a supine position for at 
least 10 minutes prior to the evaluation (see Section 7.2.3). 
5. Daily completing the ventilation device status in subjects with HAP/VAP. 
6. Daily assessing urinary device status in subjects with cUTI. 
7. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
8. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
9. Daily assessing infection-related signs and symptoms. 
10. Obtaining blood and urine samples every 3 days starting on Day 4 for safety analysis 
and sending to local laboratory (for estimating CrCL on Day 4, and as clinically 
indicated) and central laboratory. Obtaining blood samples on Day 2 and Day 3, and 
as clinically indicated, and sending to local laboratory (for estimating CrCL). If PK 
samples are to be collected on Day 3 or Day 5, collecting a blood sample on Day 3 or 
Day 5 and sending to central laboratory (for estimating CrCL). 
11. Estimating CrCL daily from Day 2 to Day 4, and as clinically indicated, using the 
serum creatinine results from the local laboratory. See Appendix 3 for CrCL 
calculation. 
12. Obtaining urine sample for microscopic white blood cell count as clinically indicated 
to assess for the presence of persisting pyruria in subjects with cUTI only. A urine 
sample must also be submitted to the central laboratory. 
13. Collection of ABGs as clinically indicated. 
14. Obtaining urine samples as clinically indicated and sending to local laboratory for 
quantitative culture, and sending isolates to central laboratory (for cUTI subjects 
only) (see Appendix 6). 


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15. Obtaining blood samples for subjects who are bacteremic at least every 3 days until 
clearance of bacteremia and sending to local laboratory for microbiological culture, 
and sending isolates to central laboratory (see Appendix 6). Blood cultures should 
also be obtained as clinically indicated. 
16. Collecting specimen as clinically indicated of abdominal site infection and sending to 
local laboratory for microbiology culture, and sending isolates to central laboratory 
(for subjects with cIAI only) (see Appendix 6). 
17. Collecting respiratory specimen for Gram-stain/culture as clinically indicated and 
sending to local laboratory for microbiology culture, and sending isolates and 
unstained Gram-stain slides (for induced sputum and expectorated sputums only) to 
central laboratory (for subjects with HAP/VAP only) (see Appendix 6). 
CCI 
 
. 
19. Obtaining blood samples for PK analysis on Day 4 (Subjects randomized to 
ATM-AVI only) (Day 4 PK samples can be collected on Day 4±1 day, see 
Table 12 and Figure 3 and Figure 4 for schedule). 
20. Daily dosing according to the randomization schedule. 
21. Daily collecting new AEs and reviewing ongoing AEs. 
22. Collecting mortality assessment daily. 
23. Confirming daily that highly effective contraception is being used. 
6.3.3. Post-Treatment Period 
6.3.3.1. Visit 16: End of Treatment (Within 24 Hours after Last Infusion) 
The following assessment procedures will be performed within 24 hours after the completion 
of the last infusion of IV study treatment: 
1. Reviewing prior and concomitant medications (including prior and concomitant 
antibiotic treatment). 
2. Performing complete physical examination as defined in Section 7.2.2. 
3. Performing focused physical examination (see Section 7.2.2). 
4. Measuring vital signs including BP, heart rate and body temperature as defined in 
Section 7.2.4. For subjects with HAP/VAP, collecting respiratory rate (breath per 
minute) and peripheral O2 saturation. 
5. Completing the ventilation device status in subjects with HAP/VAP. 


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6. Assessing urinary device status in subjects with cUTI. 
7. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
8. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
9. Assessing infection-related signs and symptoms. 
10. Performing clinical response assessment. 
11. Obtaining blood and urine samples for safety analysis and sending to local laboratory 
(for estimating CrCL as clinically indicated) and central laboratory. 
12. Estimating CrCL as clinically indicated, using the serum creatinine results from the 
local laboratory. See Appendix 3 for CrCL calculation. 
13. Obtaining urine sample for microscopic white blood cell count to assess for the 
presence of persisting pyruria in subjects with cUTI only. 
14. Collection of ABGs as clinically indicated. 
15. Obtaining urine samples and sending to local laboratory for quantitative culture, and 
sending isolates to central laboratory (for cUTI subjects only) (see Appendix 6). 
16. Obtaining blood samples for subjects who are bacteremic as clinically indicated until 
clearance of bacteremia and sending to local laboratory for microbiological culture, 
and sending isolates to central laboratory (see Appendix 6). 
17. Collecting specimen as clinically indicated of abdominal site infection and sending to 
local laboratory for microbiology culture, and sending isolates to central laboratory 
(for subjects with cIAI only) (see Appendix 6). 
18. Collecting respiratory specimen for Gram-stain/culture if at all possible and sending 
to local laboratory for microbiology culture, and sending isolates and unstained 
Gram-stain slides (for induced sputum and expectorated sputums only) to central 
laboratory (for subjects with HAP/VAP only) (see Appendix 6). 
CCI 
 
 
20. Collecting new AEs and reviewing ongoing AEs. 
21. Collecting mortality assessment. 
22. Confirming highly effective contraception is being used. 


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6.3.3.2. Visit 17: Test of Cure (Day 28±3 days) 
If it is not possible to perform the TOC on study Day 28, then the allowed visit window is 
Day 25 to 31. 
The following assessment procedures will be performed at TOC: 
1. Reviewing prior and concomitant medications (including antibiotic treatment). 
2. Performing complete physical examination as defined in Section 7.2.2. 
3. Performing focused physical examination (see Section 7.2.2). 
4. Measuring vital signs including BP, heart rate and body temperature as defined in 
Section 7.2.4. For subjects with HAP/VAP, collecting respiratory rate (breath per 
minute) and peripheral O2 saturation. 
5. Completing the ventilation device status in subjects with HAP/VAP. 
6. Assessing urinary device status in subjects with cUTI. 
7. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
8. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
9. Assessing infection-related signs and symptoms. 
10. Assessing clinical response. 
11. Obtaining blood and urine samples for safety analysis and sending to local laboratory 
(for estimating CrCL as clinically indicated) and central laboratory. 
12. Estimating CrCL as clinically indicated, using the serum creatinine results from the 
local laboratory. See Appendix 3 for CrCL calculation. 
13. Obtaining urine sample for microscopic white blood cell count to assess for the 
presence of persisting pyruria in subjects with cUTI only. 
14. Obtaining urine samples and sending to local laboratory for quantitative culture, and 
sending isolates to central laboratory (for cUTI subjects only) (see Appendix 6). 
15. Obtaining blood samples for subjects who are bacteremic as clinically indicated until 
clearance of bacteremia and sending to local laboratory for microbiological culture, 
and sending isolates to central laboratory (see Appendix 6). 


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16. Collecting specimen as clinically indicated of abdominal site infection and sending to 
local laboratory for microbiology culture, and sending isolates to central laboratory 
(for subjects with cIAI only) (see Appendix 6). 
17. Collecting respiratory specimen for Gram-stain/culture if at all possible and sending 
to local laboratory, and sending isolates and unstained Gram-stain slides (for induced 
sputum and expectorated sputums only) to central laboratory (for subjects with 
HAP/VAP only) (see Appendix 6). 
18. Collecting new AEs and reviewing ongoing AEs. 
19. Collecting mortality assessment. 
20. Confirming highly effective contraception is being used. 
6.3.3.3. Visit 18: Late Follow-up (Day 45±3 days) 
If it is not possible to perform the LFU on study Day 45, then the allowed visit window is 
Day 42 to 48. If the subject has been discharged from hospital and is unable to return, the 
LFU visit can be conducted by telephone (with the permitted omission of the physical 
examination). 
The LFU visit assessment procedures include: 
1. Reviewing prior and concomitant medications (including prior and concomitant 
antibiotic treatment). 
2. Performing focused physical examination. 
3. Collecting new AEs and reviewing ongoing AEs. 
6.4. Discontinuation of Investigational Product 
Subjects may be discontinued from IP in the following situations: 
• Condition under investigation resolved prior to minimum treatment period; 
• Subject decision. The subject 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 subject or jeopardizing 
a safe continuation of the study treatment for the respective subject (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. 


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• In the absence of any alternative explanation for the increase in the following 
abnormalities, individual subjects should be withdrawn if the following criteria are 
met (see also Section 8.5.2): 
• ALT or AST >8 x ULN; 
• ALT or AST >3 x ULN and TBili >2 x ULN or international normalized ratio 
(INR) >1.5; 
• 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 x ULN]); 
• A subject meeting Hy’s Law (HL) criteria (see Section 8.4.5 and Appendix 4). 
• If CrCL falls ≤15 mL/min, or there is a requirement to start renal replacement 
therapy, ATM-AVI should be discontinued. It is at the investigator’s discretion to 
either discontinue BAT therapy or whether an immediate dose change or a short 
period of continued observation is required; 
• Treatment failure (refer to Table 8); 
• In the opinion of the investigator, it is not in the best interest of the subject to 
continue the study treatment or at the request of the sponsor or delegates that the 
subject stops participation in the study; 
• Severe non-compliance with the CSP. 
6.4.1. Procedures for Discontinuation of a Subject from Investigational Product 
At any time, subjects are free to discontinue IP or withdraw from the study (ie, IP and 
assessments – see Section 6.5), without prejudice to further treatment. A subject that decides 
to discontinue IP will always be asked about the reason(s) and the presence of any AEs. If 
possible, they will be seen and assessed by an investigator(s). AEs will be followed up (See 
Section 8). 
The subject should be scheduled for the EOT visit within 24 hours after IV study treatment 
discontinuation. For subjects who discontinue study treatment but wish to continue in the 
study, their follow-up assessments should be collected (EOT, TOC and LFU visits). Data 
from these visits should be captured in the electronic case report form (CRF). 
Adverse events (AEs) and serious adverse events (SAEs) will be followed up as described in 
Section 8.1.4. 
If a subject is withdrawn from study, see Section 6.5. 


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6.5. Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events Section 8.1.3) or behavioral reasons, or 
the inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record. In any circumstance, every effort 
should be made to document subject outcome, if possible. The investigator should inquire 
about the reason for withdrawal, request that the subject return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused. Withdrawn subjects will not be replaced. 
6.5.1. Screen Failures 
Screening failures are subjects who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomized. These subjects should have the reason for study 
withdrawal recorded as ‘Screen failure’ (the potential subject who does not meet one or more 
criteria required for participation in a study, this reason for study withdrawal is only valid for 
not randomized subjects). 
6.5.2. Withdrawal of Consent 
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information. 
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 


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6.5.3. Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records. 
7. ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
The electronic data capture (EDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded on the CRFs as specified in the 
CSP and in accordance with the instructions provided. 
For studies conducted at US (investigational new drug [IND]) sites and non-US (non-IND) 
sites, data from IND and non-IND study sites will be pooled together for analysis. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The investigator will sign the completed CRFs. A copy of the completed CRFs will be 
archived at the study site. 


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7.1. Efficacy Assessments 
7.1.1. 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 validated by an independent adjudication committee that will be blinded to 
study treatment (see Section 9.7). 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 subjects: 
• No unplanned drainage or surgical intervention is necessary 
since the initial procedure. 
Failure 
Subjects who meet any of the following criteria will be considered a 
treatment failure: 
• Death (after receiving at least 48 hours of study treatment). 
• Subject who received treatment with further antibiotics for the 
index infection.a This includes subjects prematurely 
discontinued from study treatment due to an AE who require 
further antibiotics for the index infection. 
Additionally for cIAI subjects: 
• 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). 
• Subject lost to follow-up. 
Additionally for cIAI subjects: 
• 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. 


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Abbreviations: AE=adverse event; BSI=Bloodstream infection; clAI=complicated intra-abdominal infection; 
cUTI=complicated urina1y tract infection; EOT=end of treatment; HAP=hospital-acquiredpneumonia; 
TOC=test of cure; VAP=ventilator-associated pneumonia. 
 
 
If a subject is assessed as a clinical failure at the EOT visit, this assessment will be canied 
fo1ward to the TOC visit. 
 
7.1.2. Microbiological Response 
For each pathogen identified, microbiological outcome at EOT and TOC will be detennined 
as shown in Table 9. 
 
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 <103CFU/mL for cUTI subjects) of 
causative pathogen from an appropriately obtained specimena at the 
site of infection. 
Presumed 
eradication 
Repeat culture of specimens were not perfo1med/clinically indicated 
in a subject who had a clinical response of cure (specific to cIAI and 
HAPN AP subjects). 
Persistence 
Causative organism is still present from an appropriately obtained 
specimen at the site of infection (for cUTI, the urine culture taken at 
study dmg completion grows103 CFU/mL of the original pathogen 
identified at trial entiy). If the causative organism display4s -fold 
higher MIC to study therapy after ti·eatinent with IV study therapy, the 
response will also be categorized as "Persistence with increasing 
MIC". 
Presumed 
persistence 
Subject was assessed as a clinical failure and repeat culture of 
specimens were not perfo1med/clinically indicated (specific to cIAI 
and HAPN AP subjects). 
Indeterminate 
microbiological 
response 
Death (after receiving less than 48 hours of study ti·eatinent). 
Subject lost to follow-up such that a dete1mination of microbiological 
response cannot be made. 
Additionally for cIAI subjects: 
Inadequate infection source conti·ol at time of initial surgical 
procedure. 
Abbreviations: BAL=bronchoalveolar lavage; clAI=complicated intra-abdominal infection; EOT=end of 
treatment; IV=intravenous(ly); MIC=minimum inhibit01y concentration; PSB=protected-specimen brnsh; TOC 
=test of cure. 


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a. 
A definition of an appropriately obtained specimen for each infection site will be included in the study 
microbiology manual (see Appendix 6). For subjects 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 laproscopy), percutaneous drainage (where in place for less than 
24 hours) or wounds where the subject 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 subjects with cUTI, preferred 
methods of collection of urine for culture include straight catheterization using sterile technique (preferred 
for female subjects), midstream clean catch and suprapubic specimen collection using sterile technique. 
For blood specimens for culture, a set of blood cultures should be collected, one for aerobic culturing and 
the other for anaerobic culturing. 
 
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. 
7.1.2.1. Microbiological Response Assessment 
The per-subject 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.” Subjects 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-subject (Overall) Microbiological Response Assessments 
Overall microbiological response will also be assessed as “favorable” or “unfavorable” for 
each subject. Subjects will be determined to have a favorable microbiological response if all 
baseline pathogens for that subject 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 
subject will be considered to have an unfavorable microbiological response. 


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Per-resistance Type Microbiological Response Assessments 
Microbiological response (per subject and per pathogen) will be presented for the subgroup 
of subjects with pathogens belonging to a certain drug resistance group (eg, 
ATM-non-susceptible, MDR), and for subgroups of subjects with pathogens belonging to a 
certain group based on β-lactamase content (eg, MBL only, MBL in combination with 
ESBLs, MBL in combination with serine carbapenemases). For these same groups, 
microbiological response per pathogen will also be presented. 
Emergent Infections 
New pathogens that appear after Baseline are categorized in Table 10 and will be 
summarized separately. 
 
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. 
Abbreviations: cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection; 
EOT=end of treatment; HAP=hospital-acquired pneumonia; VAP=ventilator-associated pneumonia. 
 
7.2. Safety Assessments 
Safety and tolerability assessment will be undertaken on individual subject and cohort basis 
through a determination of SAEs and AEs based on signs and symptoms, examinations and 
laboratory tests. If deterioration in a laboratory value is associated with clinical signs and 
symptoms, the clinical diagnosis (or sign or symptom) will be reported as an AE and the 
associated laboratory result or vital sign will be considered as additional information. For 
details on AE definition and reporting see Section 8. If the findings meet the criteria for an 
SAE, procedures for reporting such events should be followed (refer to Section 8.1.4.1). 


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7.2.1. Laboratory Safety Assessments 
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the Schedule of Activities (see Table 1 and Section 6). 
Blood and urine samples collected for safety analyses will be sent to the central laboratory 
for analysis. The results of safety laboratory sampling will be made available to the 
investigators. Investigators are to review central laboratory results and to confirm and 
document any significant results. The laboratory safety variables to be measured at the 
central laboratory are displayed in Table 11. 
Local laboratory results, including safety parameters will be used for eligibility determination 
(ie, serum creatinine for calculation of CrCL, serum or urine β-hCG for pregnancy test, AST, 
ALT, ALP, TBili, and hematology as defined in Section 4.2.1) and subject management 
throughout the study. Local laboratory test results will be entered in the CRF (see 
Section 6.2.1). 
For HAP/VAP subjects, arterial blood gases are required for ventilated subjects, 
recommended for non-ventilated subjects at Screening Visit to calculate APACHE II score; 
for cIAI, cUTI and BSI subjects, arterial blood gases are to be collected as clinically 
indicated at Screening Visit to calculate APACHE II score. Where ABGs are not available at 
Screening, serum bicarbonate is to be used to calculate APACHE II score as per Appendix 5. 
For all subjects, arterial blood gases are also collected as clinically indicated at Baseline, 
during treatment period and at EOT. 
Liver function tests and CrCL must be closely monitored throughout the study. Further 
details for the monitoring of liver function tests are described in Section 8.5.2. Further 
details regarding the calculation of the CrCL are described in Appendix 3. 
Further safety samples may be collected if clinically indicated at the discretion of the 
investigator and analyzed in the local laboratory of the study site. The date, time of 
collection and results (values, units and reference ranges) will be recorded on the appropriate 
CRF. 
The following safety laboratory variables will be measured: 


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Table 11. Laboratory Safety Variables 
 
Clinical Chemistry 
Hematology 
Arterial Blood Gasesb 
Urinalysis 
Albumin 
Total protein 
ALT 
AST 
ALP 
Bilirubin (total, direct 
and indirect) 
Bicarbonate 
Hematocrit 
Hemoglobin 
INR (at Baseline and as 
clinically indicated) 
Platelet count 
Red blood cell count 
WBC count (total and 
differential) 
Partial pressure of 
oxygen (PaO2) 
Partial pressure of 
carbon dioxide (PaCO2) 
pH 
Oxygen saturation 
Bicarbonate (HCO3) 
Appearance (color, 
clarity) 
Bilirubin 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Blood urea nitrogen 
Calcium, total 
Chloride 
Serum creatininea 
Glucose (nonfasting) 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic 
examination: red 
blood cells, white 
blood cells, casts, 
crystals, bacteria, 
yeast cells or 
parasitesc 
Inorganic phosphorus 
Potassium 
Sodium 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CrCL=creatinine clearance; INR=international normalized ratio; WBC=white blood cells. 
a. 
Following each determination of serum creatinine until TOC (inclusive), also the estimate CrCL will be 
calculated. 
b. For HAP/VAP subjects, arterial blood gases are required for ventilated subjects, recommended for 
non-ventilated subjects at Screening Visit to calculate APACHE II score; for cIAI, cUTI and BSI subjects, 
arterial blood gases are only collected as clinically indicated to calculate APACHE II score at Screening 
Visit. For all subjects, arterial blood gases are collected as clinically indicated at Baseline, during treatment 
period and at EOT. 
c. 
For cUTI subjects, a microscopic analysis is performed to confirm the presence of pyuria at Baseline, as 
clinically indicated during treatment period and at EOT and TOC. 
 
 
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities and criteria for intensified monitoring and/or discontinuation of study 
drug (see Section 6.4 and Section 8.5.2). The laboratory results should be signed and dated 
and retained at center as source data for laboratory variables. For information on how AEs 
based on laboratory tests should be recorded and reported, see Section 8.4.3. 


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7.2.2. Physical Examination 
A complete physical examination will be performed as scheduled in the Schedule of 
Activities (Table 1) and include an assessment of the following: general appearance 
including site of infection, skin, head and throat (head, eyes, ears, nose, and throat), lymph 
nodes, respiratory, cardiovascular (CV), abdomen including wound examination, 
musculoskeletal, and neurological systems. 
If clinically abnormal findings emerge or there is worsening of any condition compared to 
the physical examination at Screening, these findings should be documented as AEs on the 
respective page of the CRF. 
Height and weight will be measured at the Screening Visit, and the body mass index will be 
calculated as the ratio of weight in kg/(height in cm/100)2. If these assessments cannot be 
performed due to the subject’s clinical condition, they may be done later (as soon as 
possible). After the Screening Visit, weight should be measured as clinically indicated. If 
these assessments cannot be performed due to the subject's clinical condition, they may be 
done later (as soon as possible). For the purpose of assessing eligibility, a subject's weight 
obtained during the current or most recent hospitalization may be used if the subject's clinical 
condition at the time of Screening does not allow this assessment to be performed. 
A detailed infection-related focused physical examination will be performed at Screening, at 
Baseline, daily during treatment with IV study treatment, at the EOT, TOC and LFU visits 
(see Table 1). 
The following infection-related focused physical examinations will be conducted: 
• For HAP/VAP subjects, a pulmonary assessment, which includes auscultation, will be 
performed. 
• For cIAI subjects, 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 subjects, focused physical examination will include an assessment for 
suprapubic pain and costovertebral angle tenderness. 
• For BSI subjects, focused physical examination will include general appearance, vital 
signs, and focal signs of source infection. 
7.2.3. ECG 
Standard 12-lead ECGs (triplicates for each recording time point) will be recorded and 
assessed at Baseline and Day 3 during the treatment period (Table 1). The ECG on 
Day 3 should be performed at maximum plasma concentration (Cmax) which is immediately 
(within 30 minutes) after the infusion of study drug is completed. 


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The date of ECG must be recorded in the CRF. 
The ECGs should be standard 12-lead ECGs with a lead II rhythm strip with the subject in 
the supine position after the subject has rested in this position for at least 10 minutes. If 
clinically indicated, additional ECG recordings can be made at the discretion of the 
Investigator as unscheduled assessments. A single independent third party using uniform 
techniques will carry out formal analysis and reporting of ECG data for purposes of the 
study. 
7.2.4. Vital Signs 
Vital sign measurements (including BP, heart rate and body temperature) should be assessed 
at Screening, Baseline, daily (twice daily for body temperature) while the subject is receiving 
IV study treatment, at EOT and TOC visits; for subjects with HAP/VAP, respiratory rate 
(breath per minute) and peripheral O2 saturation will be collected at Screening, Baseline, 
daily while the subject is receiving IV study treatment, at EOT and TOC visits (see Table 1). 
Vital signs should be measured and documented at least once daily, preferably at a similar 
time each day. However, if any significant excursions occur, those measurements should 
also be captured. 
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The results should be signed and dated and retained at study center as 
source data. For information on how AEs based on vital signs should be recorded and 
reported, see Section 8.4.3. 
7.2.4.1. Pulse and Blood Pressure 
Supine BP and heart rate should be measured using a semiautomatic BP recording device 
with an appropriate cuff size or by direct measurement via arterial catheter. The subjects will 
be required to rest in a supine position for at least 10 minutes prior to heart rate and BP 
measurements. 
7.2.4.2. Body Temperature 
Body temperature will be measured using an automated thermometer. The subject’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 subject, 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. 
7.2.5. Pregnancy Testing 
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL for β-hCG will be performed locally at Screening Visit 
(Visit 1). 


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A negative pregnancy test result is required before the subject may receive the investigational 
product. Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected). Pregnancy 
tests may also be repeated if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations. 
Urine pregnancy tests must be sensitive to at least 25 mIU/mL for β-hCG and will be 
conducted with the test kit provided by the central laboratory in accordance with instructions 
provided in its package insert An indeterminate or positive urine pregnancy test will be 
confirmed by a serum pregnancy test performed either locally or by the central laboratory. 
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product but may remain in the study. 
7.2.6. Other Safety Assessments 
7.2.6.1. Chest X-ray/ CT Scan 
For HAP/VAP subjects only, a chest X-ray or a CT scan will be taken at Screening (if not 
available within 48 hours prior to randomization) and as clinically indicated during the study 
(see Table 1). 
7.2.6.2. Acute Physiology and Chronic Health Evaluation 
At Screening, all subjects will be assessed by using the Acute Physiology and Chronic Health 
Evaluation (APACHE) II score (see Appendix 5). ABGs will be collected at Screening to 
calculate APACHE II score (see Table 1) as required for ventilated subjects, recommended 
for non-ventilated subjects with HAP/VAP and as clinically indicated for other subjects. 
Where ABGs are not available at Screening, serum bicarbonate is to be used to calculate 
APACHE II score. 
7.3. Pharmacokinetics 
PK sampling will be employed to achieve further information on the PK of ATM-AVI in the 
subject population. 
7.3.1. Collection of Plasma Samples for Analysis of Aztreonam-Avibactam 
A total of 6 blood samples (2 mL/sample to provide approximately 1.0 mL of plasma) for PK 
and/or PK/PD evaluation should be collected into appropriately labeled tubes containing 
sodium fluoride/potassium oxalate (gray top) from subjects assigned to the ATM-AVI 
treatment arm. Samples will be collected from the subject’s arm opposite to that into which 
study drugs (ATM-AVI) are infused and/or via use of a concurrent multi-lumen central line, 
and will be labelled, stored and shipped as detailed in the Laboratory Manual. Three samples 
should be taken on both Day 1 and Day 4 of study treatment as scheduled in Table 1 and at 
the times presented in Table 12 as well as in Figure 3 and Figure 4 below. Where this 
presents difficulty to the site, priority should be given to collection of sample 2 on Day 1 and 
all 3 samples on Day 4. Where possible, Day 1 samples 1 and/or 3 should also be collected. 
To provide greater flexibility, Day 4 PK samples can be collected on Day 4±1 day [Note: A 


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blood sample (5 mL) for estimation of serum creatinine will also be collected on Days 3 or 
5 and sent to the central laboratory if PK samples are collected on Days 3 or 5]. The time of 
sample collection for sample 3 on both days 1 and 4 is different depending on the CrCL 
value of either >30 mL/min or >15 mL/min to ≤30 mL/min, ie, whether the subject is 
receiving q6h or q8h maintenance dosing (see Table 12). 
 
Table 12. Pharmacokinetic ATM-AVI Sample Collection Time Points 
 
Study Day 
Sample time 
Day 1 
All subjects randomized to ATM-AVI: (3 samples/subject) 
Sample 1: Within 5 minutes before the end of the loading dose infusion 
(25 to 30 min after the start of the loading dose infusion). 
Sample 2: Within 15 minutes before the end of the extended loading 
dose infusion (3.25 to 3.5 hours after the start of the loading 
dose infusion). 
Sample 3: Within 1 hour before the start of the first 
maintenanceinfusion: 
For subjects on q6h dosing: 2 to 3 hours after stopping the 
extended loading dose (5.5 to 6.5 hours after the start of the 
loading dose infusion). 
For subjects on q8h dosing: 4 to 5 hours after stopping the 
extended loading dose (7.5to 8.5 hours after the start of the 
loading dose infusion). 
Day 4 
All subjects randomized to ATM-AVI: (3 samples/subject) 
Sample 1: Within 15 minutes before the end of the IV infusion 
(2.75 to 3 hours after the start of the IV infusion). 
Sample 2: 30 to 90 minutes after stopping the IV infusion (3.5 to 
4.5 hours after the start of the IV infusion). 
Sample 3: Within 1 hour before the start of the next maintenance 
infusion: 
For subjects on q6h dosing: 2 to 3 hours after stopping the 
IV infusion (5 to 6 hours after the start of the IV infusion). 
For subjects on q8h dosing: 4 to 5 hours after stopping the 
IV infusion (7 to 8 hours after the start of the IV infusion). 
Abbreviations: ATM-AVI=aztreonam-avibactam; IV=intravenous(ly); q6h = every 6 hours; q8h = every 
8 hours. 


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Figure 3. ATM-AVI Pharmacokinetic Sample Collection Time-Points for Subjects with CrCL >30mL/min (Q6h 
Maintenance Dose) 
 
Abbreviations: ATM-AVI=aztreonam-avibactam; CrCL = creatinine clearance; IV = intravenous(ly); LD=loading dose; PK=pharmacokinetics; q6h = every 
6 hours. 


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Figure 4.  ATM-AVI Pharmacokinetic Sample Collection Time-Points for Subjects with CrCL > 15 to :5 30 mL/min (Q8h 
Maintenance Dose) 
Dayl 
 ■•• 
(I  
:6ta,f,Pf:ib 9 
• llll 
•
-1 •
0 • •
1 •
2 •3 •4 •
5
 
0.5 
[PK Sample time from start of LDil= 25-30 min 
fJ = 3.25-3.5 hr 
 
 
•
6
 •7
 •8
 
- 
maintenance 
•
9 •
10 •
11 
7.5-8.5 hr 
• 
12 
iii I - 
Day4 
•
0 •
1 •
2 •
3 •
4 •
5 •
6 •
7 •
8 •
9 •
10 • • 
11 
12 
PK Sample time from start of IV infusion 
II=2.75-3 hr 
•= 
3.5-4.5 hr 
PK Sample number 
ATM-AVI Infusion  I 
Hours 
Abbreviations: ATM-AVI=aztreonam-avibactam; CrCL = creatinine clearance; IV= intravenous(ly); LD=loading dose; PK=phannacokinetics; q8h = eve1y 
8 hours. 


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The date, staiiing and stop time of infusion and exact time of sample collection must be 
recorded in the CRF for each sample. If a deviation from the protocol is experienced due to 
technical difficulties, eg, with the administrntion of the infusion or PK sampling, the details 
of the deviation have to be recorded in the CRF. 
The plasma samples will be analyzed, and the resulting data will be used in population PK 
analysis. A PK/PD analysis will be perfonned if adequate microbiological response data are 
collected. PK/PD analyses will be repo1ied sepai·ately. 
7.3.2. Determination of Drug Concentration 
Samples will be analyzed for ATM and AVI using a validated analytical method in 
compliance with Pfizer and vendor standai·d operating procedures (SOPs). 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case by case basis, the sponsor may make a detennination as to whether sample 
integrity has been compromised. Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation. 
 
7.3.3. Storage and Destruction of Pharmacokinetic Samples 
PK samples will be disposed of 12 months after the Bioanalytical Repo1i finalization unless 
requested for future analyses. 
fucmTed sample reproducibility analysis, if any, will be perfonned alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Repo1i. 
7.4. Microbiology 
It is impo1iant that the microbiology laborato1y retains all Gram-negative pathogens from 
subjects for at least 7 days and that the MBL status of the pathogen (positive or negative) is 
determined. The reason is that only subjects with MBL-positive Gram-negative pathogens 
that were isolated from an appropriate specimen within 7 days prior to screening (the 
study-qualifying pathogen) can be emolled in this ti·ial (see Section 4.1.1). Study-qualifying 
pathogens need to be submitted to the cenu-al laborato1y. 
The study-qualifying MBL-producing-isolate is the baseline pathogen. Any other pathogens 
isolated prior to first dose of study ti·eatinent may require use of protocol allowed 
concomitant therapy (Section 5.9). 
 


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Cultures of abdominal site infections (for cIAI subjects only) 
Subject must have a study-qualifying isolate obtained from an abdominal source (such as 
tissue or aspirate suitable for isolation of both aerobic and anaerobic bacteria) during a 
surgical intervention within 7 days prior to screening. Surgical intervention includes open 
laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. 
Additional specimens will be collected, as clinically appropriate at the time of repeat surgical 
procedures or from the wound, during the treatment period, and at EOT and TOC (see 
Table 1), if surgical procedure/intervention permits. All abdominal specimens will be sent to 
the local laboratory for microbiological culture, and isolates will be sent to the central 
laboratory. 
Respiratory specimen for Gram-stain/culture (for HAP/VAP subjects only) 
Subjects must have a respiratory specimen obtained within 7 days prior to screening for 
Gram stain and culture from which a study-qualifying pathogen was isolated. This includes a 
specimen of either an expectorated sputum or a specimen of respiratory secretions obtained 
by endotracheal aspiration in intubated subjects, or by bronchoscopy with bronchoalveolar 
lavage (BAL), mini BAL or protected specimen brush (PSB) sampling. 
Repeat respiratory specimens are not required at Baseline, unless a study-qualifying 
respiratory sample was obtained from a non-ventilated subject and the subject is 
subsequently ventilated (or the subject had a bronchoscopy). In this case, an appropriate 
respiratory specimen should be obtained prior to the first dose of study treatment. 
Respiratory specimens will also be collected during the treatment period if clinically 
indicated and at EOT and TOC (see Table 1) if at all possible. If treatment is discontinued 
early, an attempt to obtain an appropriate respiratory specimen for culture should be made, 
ideally after stopping the study treatment and before the new treatment is administered. 
All respiratory specimens will be sent to the local laboratory for microbiological culture, and 
isolates will be sent to the central laboratory. A Gram-stain needs to be performed and an 
unstained Gram-stain slide (dried glass mount) of each respiratory specimen (expectorated 
and induced sputum only) must also be sent to the central reference laboratory. 
Collection of Urine Specimen for Culture (for cUTI subjects only) 
Subject must have a positive culture from urine collected within 7 days prior to screening, 
containing ≥105 CFU/mL of at least 1 carbapenem- nonsusceptible, MBL-positive 
Gram-negative bacteria, ie, the isolate from the study qualifying culture. A culture of urine 
must be obtained at Baseline prior to the first dose of study therapy. Urine specimens will 
also be collected during the treatment period if clinically indicated and at EOT and TOC (see 
Table 1). 


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For cUTI subjects, any time the antibacterial therapy for the disease under study is changed, 
an appropriate specimen for culture should be obtained after stopping the initial ti·eatment, 
but before the new ti·eatment is administered. This is to ensure accuracy of the database and 
assist with microbiological assessments. For subjects with cUTI, the CRF should indicate 
collection date and time for the urine sample. 
All urine specimens will be sent to the local laborato1y for microbiological culture, and 
isolates will be sent to the centi·al laborato1y. 
Collection of Blood for Culture (for all subjects) 
Subject with BSI must have a blood specimen obtained within 7 days prior to screening that 
contained a study-qualifying pathogen upon culture. 
Blood cultures should be taken at Baseline prior to first dose of study treatment if blood 
cultures are not available within 48 hours prior to randomization. When obtaining samples 
for blood culture, a set of blood cultures should be collected, one for aerobic culturing and 
the other for anaerobic culturing. For subjects who are found to be bacteremic at any time 
during the study, repeat blood cultures should be taken at least eve1y 3 days, until clearance 
of bacteremia is documented. If a negative culture repo1i has not been achieved by the time 
of the EOT visit, blood cultures should be obtained at the TOC visit. Blood cultures should 
also be obtained as clinically indicated (see Table 1). 
All blood specimens will be sent to the local laborato1y for microbiological culture, and 
isolates will be sent to the centi·al laborato1y. 
Fmiher details are provided in Appendix 6. 
 


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Table 13.  Volume of Blood to Be Drawn from Each Subject 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: P-hCG=P-hlllllan chorionic gonadotropin; CrCL = creatinine clearance; EOT=end of treatment; 
TOC=test of cure. 
a.  Number of samples depends on clinical response (duration of treatment: 5 - 14 days). Sampling time 
points: Screening (local lab and central lab), Baseline, study days 4, 7, 10, and 13; EOT, within 24 hours 
after end of last infusion); TOC, Day 28±3 days. In addition samples on clinical chemistiy panel are 
required on Day 2 and Day 3 for sel'Ulll creatinine for estimation of CrCL. 
b. Detennination of urine or sernm P-hCG for women of childbearing potential at Screening (Visit 1). 
c.  If the subject is found to be bacteremic, the total volume required for blood culture will increase by a 
fiuther 60 ml for each follow-up sample being drawn. 
 
 
7.6.2. Labelling and Shipment of Biological Samples 
The principal investigator ensures that samples are labelled and shipped in accordance with 
the Laborato1y Manual and the Biological Substance, Catego1y B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Catego1y A 
criteria), see Appendix 2 'International Airline Transportation Association (I.AT.A) 
6.2 Guidance Document'. 
 
 
Hematology 
 
 
 
Pregnancy testb 
 
 
 
 
 
Minimum 6, 
maximum 9a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with Pfizer and appropriate labelling, 
shipment and containment provisions are approved. 
Samples must be collected, labelled, processed, analyzed, stored and transported to the 
relevant storage site, as indicated in the Laboratory Manual. Tubes will be labelled with the 
study number, sample description and date and time of collection. The date and time of the 
sample collection will be recorded in the source documents and in the appropriate section of 
the CRF. 
An isolate ID number will be allocated to all pathogen isolates obtained. Samples of all 
isolates will be sent to the central reference laboratory (see Section 7.4). PK samples will be 
shipped periodically from the study centers to the responsible (Pfizer-approved) laboratory at 
agreed intervals. 
Samples should be shipped in batches if possible. Logistics should be coordinated between 
involved parties to ensure that samples will arrive during working hours. A requisition sheet 
should accompany the shipment that details the study number, center number, enrollment 
number, date of sample collection, and a unique ID for each of the samples in the shipment. 
7.6.3. Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each center keeps full traceability of collected biological samples from 
the subjects while in storage at the center until shipment or disposal (where appropriate) and 
keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and keeps documentation of receipt of 
arrival. 
Pfizer keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
8. ADVERSE EVENT REPORTING 
8.1. Requirements 
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety. These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 


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Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Non-serious AE 
All 
None 
Exposure to the 
All (regardless of whether 
Exposure during pregnancy, 
investigational product 
associated with an AE), 
exposure via breastfeeding, 
under study during 
except occupational 
occupational exposure 
pregnancy or 
exposure. 
(regardless of whether 
breastfeeding, and 
associated with an AE). 
occupational exposure. 
 
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs. 
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study. In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information. This time frame also applies to additional new (follow-up) information on 
previously forwarded reports. In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event. 
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events Section 8.2.3 below). In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion. 
This information is more detailed than that recorded on the CRF. In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality. Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided. In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety. Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request. 


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.1.1. Additional Details on Recording Adverse Events on the CRF 
All events detailed in the table above will be recorded on the AE page(s) of the CRF. It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information. 
8.1.2. Eliciting Adverse Event Information 
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/legally acceptable representative. In addition, each study 
subject/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner. 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Subject 
Withdrawal Section) 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above. 
8.1.4. Time Period for Collecting AE/SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through the treatment 
period and including the LFU visit. 
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined. 
8.1.4.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form. 


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SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety. 
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment. 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF 
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF. 
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
8.1.5. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable. An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided. If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor. If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements. 
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations. 
8.2. Definitions 
8.2.1. Adverse Events 
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage. Examples of AEs include, but are not limited to: 
• Abnormal test findings; 


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• Clinically significant signs and symptoms; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Drug abuse; 
• Drug dependency. 
Additionally, AEs may include signs and symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse; 
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy (EDP); 
• Exposure via breastfeeding; 
• Medication error; 
• Occupational exposure. 
8.2.2. Abnormal Test Findings 
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or 
• Test result is considered to be an AE by the investigator or sponsor. 


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
recording as an AE. 
8.2.3. Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
Or that is considered to be: 
• An important medical event. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
8.2.4. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance. 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 


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• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE. Examples include: 
• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality); 
• Social admission (eg, subject has no place to sleep); 
• Administrative admission (eg, for yearly physical examination); 
• Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
• Hospitalization for observation without a medical AE; 
• Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE. For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE. 
8.3. Severity Assessment 
 
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE. For purposes 
of consistency, these intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 


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Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
8.4. Special Situations 
8.4.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study personnel: ‘Have you had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and 
recorded in the CRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately. 
8.4.3. Adverse Events Based on Examinations and Tests 
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
CSR. Deterioration as compared to Baseline in protocol-mandated laboratory values, vital 
signs and ECG should therefore only be reported as AEs if they fulfil any of the AE criteria 
or are the reason for discontinuation of treatment with the IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the clinical diagnosis (or sign or symptom) will be reported as an AE and the 
associated laboratory result/vital sign will be considered as additional information. Wherever 
possible the reporting Investigator uses the clinical, rather than the laboratory term (eg, 
anemia versus low hemoglobin value). In the absence of clinical signs or symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, 
should not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE. 
8.4.4. Exceptions from Standard Adverse Events Collection 
Where there is deterioration in the condition for which the IV study treatment is being used, 
there may be uncertainty as to whether this is lack of efficacy, disease progression or 
constitutes an AE. In such cases, unless the Pfizer or reporting physician considers that the 
study treatment contributed to the deterioration or local regulations state to the contrary, the 
deterioration should be compared with the definitions below and considered to be either lack 
of effect (Section 8.4.4.1) or disease progression (Section 8.4.4.2) and not an AE. 


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8.4.4.1. Lack of Effect 
Insufficient therapeutic effect will be captured as an efficacy outcome. Instances of, or 
discontinuation due to insufficient therapeutic effect (ie, lack of efficacy) should not be 
collected as AEs. A clinical failure should not be recorded as an AE. 
8.4.4.2. Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. Expected progression 
of the disease under study and /or expected progression of signs and symptoms of the disease 
under study, unless more severe in intensity or more frequent than expected for the subject’s 
condition should not be reported as an AE. Any event or extended hospitalization that is 
unequivocally due to disease progression must not be reported as an SAE unless it is believed 
that the study drug actively contributed to the progression of the disease (ie, not by way of 
insufficient therapeutic effect). Events, which are unequivocally due to disease progression, 
should not be reported as an AE/SAE during the study unless the outcome is fatal within the 
active collection period. If disease under study has a fatal outcome during the study or 
within the active collection period, then the event leading to death must be recorded as an 
SAE on the AE CRF, and SAE Report Form. 
8.4.5. Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome. These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI). Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.” 
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (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 lab sample). In rare instances, 
by the time TBili elevations are detected, AST/ALT values might have decreased. This 
occurrence is still regarded as a potential DILI. Therefore, abnormal elevations in either 
AST OR ALT in addition to TBili that meet the criteria outlined below are considered 
potential DILI (assessed per Hy’s law criteria) cases and should always be considered 
important medical events, even before all other possible causes of liver injury have been 
excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions. Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values: 


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• Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
• For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or 
ALT values >2 times the baseline values AND >3 × ULN; or >8 × ULN 
(whichever is smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller). 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels. 
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology. A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected. Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the Liver Function Test (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 
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A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 
8.4.6. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 
8.4.6.1. Exposure During Pregnancy 
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if: 
• A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
• An example of environmental exposure would be a case involving direct 
contact with a Pfizer product in a pregnant woman (eg, a nurse reports that she 
is pregnant and has been exposed to chemotherapeutic products). 
• A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred. In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form. This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure. The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 


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If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner. The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.4.6.2. Exposure During Breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form. An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use. However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding. 
8.4.6.3. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE. Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 
8.4.7. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors. 


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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 may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include: 
• Medication errors involving subject exposure to the investigational product; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
In the event of a medication dosing error, the sponsor should be notified immediately. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.4.7.1. Overdose 
Overdose is defined as a dose of study drug administered to a subject in excess of that 
specified in Section 5.5. Overdose does not automatically make an AE/SAE but if the 
consequences of the overdose are accompanied by an AE or serious for example death or 
hospitalization, the event is AE or SAE and should be reported as such. 
Avibactam alone and in combination with another β-lactam partner antibiotic CAZ 
(CAZ-AVI) was studied in healthy volunteers at doses up to 2000 mg of AVI in single and 
multiple dose regimens in Phase 1 clinical pharmacology studies, including a thorough 
QT study, with no safety signals or trends identified for AVI (see IB). 
If an overdose or intoxication on the IV study treatment occurs in the course of the study, 
then the investigator or other site personnel will inform Pfizer immediately when he or she 
becomes aware of it. 


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Overdose should be reported to Pfizer Safety within 24 hours on a CT SAE Report Form 
only when associated with an SAE. 
Recording an overdose will be done according to the following: 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the medication error CRF module. Relevant 
information regarding any corresponding SAE(s) related to the overdose must be 
forwarded to Pfizer safety in CT SAE Report Form for data entry in the safety 
database. 
• An overdose without associated symptoms is only reported on the medication error 
CRF module. 
8.5. Management of Laboratory Safety 
If necessary, ATM may be cleared from the serum by hemodialysis and/or peritoneal 
dialysis. ATM has been shown to be cleared from the serum by continuous arteriovenous 
hemofiltration. AVI may also be cleared from the serum by hemodialysis (55% of the AVI 
dose was removed in 4 hours in a group of subjects with ESRD). 
8.5.1. Renal Function 
CrCL will be monitored at Screening, Baseline, Day 2 through Day 4 (daily) (and Day 5 if 
PK sample collected on Day 5) and as clinically indicated and dose of study drug will be 
adjusted accordingly throughout the study. Determination of creatinine will be part of each 
safety laboratory until TOC inclusive, ie, every 3 days until end of IV study treatment (as 
defined in Table 1), followed by calculation of CrCL at the central laboratory. For eligibility 
assessment at Screening and renal function monitoring for dose adjustment of study drug at 
subsequent visits, CrCL needs to be calculated at the study site, based on the creatinine value 
determined at local laboratory (see Section 6 and Appendix 3). 
If subsequent to randomization and while still on IV study treatment, a subject’s estimated 
CrCL falls below the threshold for study inclusion (ie, estimated CrCL ≤15 mL/min) and/or 
there is a requirement to start renal replacement therapy, the investigator should discontinue 
ATM-AVI or BAT investigational therapies. 
8.5.2. Monitoring of Liver-related Laboratory Parameters 
If a subject reaches an ALT or AST >3 x ULN and has not met the discontinuation criteria, 
the following enhanced monitoring and subject follow-up will be instigated: 
• Collection of clinical and historical information to determine the cause of ALT and/or 
AST elevations in the source documents; 
• Frequency of liver function tests, 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 x ULN. 


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In the absence of any alternative explanation for an increase in the following abnormalities, 
individual subjects of both treatment arms should be discontinued from study treatment if 
any of the following criteria are met (also see Section 8.4.5): 
• ALT or AST >8 x ULN; 
• ALT or AST >3 x ULN and either TBili >2 x ULN or INR > 1.5; 
• 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 x ULN]). 
With regards to any cases of Potential Hy’s Law (PHL) (occurrences of AST or ALT 
>3 x ULN together with TBili >2 x ULN), the Pfizer medical monitor will initially review 
the case (as described in Appendix 4) and then the case will be referred for independent 
clinical hepatologist review. The independent clinical hepatology review will be unblinded 
to study treatment allocation. 
9. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment. 
9.1. Sample Size Determination 
The study will randomize approximately 60 subjects in a 2:1 randomization ratio 
(approximately 40 subjects to ATM-AVI and approximately 20 subjects to BAT with a 
diagnosis of cIAI, HAP/VAP, cUTI or BSI due to MBL-producing Gram-negative bacteria. 
As no formal hypothesis testing will be performed for this study, no power calculation was 
carried out to assess the number of subjects required for each treatment arm. The total 
number of 60 subjects (approximately 40 in ATM-AVI group and approximately 20 in BAT 
group) is considered sufficient to estimate the overall clinical cure rates in each arm. The 
smaller numbers of subjects in these groups will be reflected in the precision of the estimate 
of clinical cure rate. 


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9.2. Definitions of Analysis Sets 
9.2.1. Efficacy Analysis Set 
9.2.1.1. Intent-To-Treat (ITT) Analysis Set 
The ITT analysis set will include all randomized subjects regardless of receipt of study drug. 
Subjects in the ITT analysis set will be analyzed according to the treatment they are 
randomized to. The ITT analysis set will be used to evaluate the secondary and exploratory 
objectives. 
9.2.1.2. Microbiological Intent-To-Treat (micro-ITT) Analysis Set 
The microbiological Intent-To-Treat (micro-ITT) analysis set is a subset of the ITT analysis 
set and includes all subjects who have at least 1 MBL-positive Gram-negative pathogen in an 
adequate initial/prestudy culture. Subjects with inherently resistant pathogens 
(monomicrobial infections due to any Acinetobacter spp.) will be excluded from the 
micro-ITT analysis set. The micro-ITT analysis set will be used to evaluate primary, 
secondary and exploratory objectives. 
9.2.1.3. Microbiologically Evaluable (ME) Analysis Set 
The Microbiologically Evaluable (ME) analysis set includes all subjects who: 
1. Meet the definition of the micro-ITT analysis set. 
2. Received at least 48 hours of study therapy (ATM-AVI or BAT) or received 
<48 hours of study therapy before discontinuing study drug due to an AE. 
3. Did not receive concomitant antibiotic therapy with potential activity against any 
baseline MBL-positive pathogens between the time of the first dose of study 
treatment and the time of TOC. This does not include those subjects who have failed 
study therapy and require additional antibiotics to treat their infection. 
4. Had the baseline entry organism(s) genetically confirmed by central microbiological 
testing. 
5. Did not have a clinical outcome of indeterminate at TOC. 
9.2.2. Safety Analysis Set 
The safety analysis set will be used for reporting safety data and will include all subjects who 
received any amount of IV study treatment. Subjects in the safety analysis sets will be 
analyzed according to the treatment they receive. 
9.2.3. Population Pharmacokinetic (pop PK) Analysis Set 
The population pharmacokinetic (pop PK) analysis set will include all subjects who have at 
least 1 plasma concentration data assessment available for ATM-AVI and will be used to 
report all PK data. 


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9.2.4. Other Analysis Sets 
9.2.4.1. All Subjects Analysis Set 
This analysis set will compromise all subjects enrolled into the study and will be used for 
reporting of disposition. 
9.3. Endpoints 
9.3.1. Primary Endpoint 
The primary endpoint is the proportion of subjects with clinical cure at TOC in the 
micro-ITT analysis set. The proportion of subjects with clinical cure for the micro-ITT 
analysis set is defined as the number of subjects with clinical cure at TOC divided by the 
number of subjects in the micro-ITT analysis set. Details are included in the SAP. 
9.3.2. Secondary Endpoints 
The secondary endpoints are: 
• Proportion of subjects with clinical cure at TOC in the ME analysis set; 
• Proportion of subjects with clinical cure at the EOT in the micro-ITT and ME 
analysis sets; 
• Proportion of subjects with a favorable (defined as eradication or presumed 
eradication) per-subject microbiological response at the EOT and TOC visits in the 
micro-ITT and ME analysis sets; 
• Proportion of subjects with favorable per-pathogen microbiological response at the 
EOT and TOC visits in the micro-ITT and ME analysis sets; 
• Proportion of subjects who died on or before 28 days after randomization in the ITT 
and micro-ITT analysis sets; 
• Safety and tolerability as assessed by adverse events, physical examination, vital 
signs, ECGs, and laboratory assessments. 
9.3.3. Exploratory Endpoints 
The exploratory endpoints are: 
• PK of aztreonam and avibactam in subjects in the population PK analysis set. 
• PK /PD relationship between exposure and clinical and microbiological response for 
ATM-AVI in the population PK analysis set. 
• Proportion of subjects who died on or before 14 days after randomization. 
• For the health utilization objective: 


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• 
Length of hospital stay, including any readmissions up to TOC (days); 
 
• 
Length of intensive care unit (ICU) stay (days); 
 
• 
TransfeITed to the ICU (Yes/No); 
 
• 
Length of study treatment (days); 
• 
Mechanical ventilation (Yes/No) for HAPN AP subjects; 
 
• 
Length of mechanical ventilation (days) for HAPN AP subjects; 
 
• 
Subsequent unplanned surgical intervention after treatment success vs failure 
(up to the TOC visit) for cIAI subjects. 
• 
 
9.4. Methods for Statistical Analysis 
All data will be presented by ti·eatment aim. Descriptive statistics (number, mean, standard 
deviation [SD], median, minimum, and maximum) will be provided for continuous vai·iables, 
and counts and percentages will be presented for categorical vai·iables. 
No fonnal hypothesis testing will be perfo1med for this study. Any compai·isons between 
ti·eatment anns will only be assessed as evidence of an effect, no fo1mal statistical 
compai·isons will be made. 
Methodology for dealing with missing data will be specified in the SAP. 
Impo1iant protocol deviations ai·e defined as any impo1iant variations from the protocol that 
could affect the assessment of efficacy and will be defined in the SAP. An impo1iant 
protocol deviation may include: 
1. Those who entered the study even though they did not satisfy the entiy criteria. 
2.  Those who developed withdrawal criteria from IP or from study or for both during the 
study but were not withdrawn. 
3. Those who received the wrong treatment or dose. 
4. Those who received an excluded concomitant ti·eatment. 
5. Those identified through review of all protocol deviations repo1ied during the study. 


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9.4.1. Analysis of the Primary Endpoint 
The primary descriptive efficacy analysis will be the estimate of the clinical cure rate and 
95% confidence interval (CI) in each treatment arm (ATM-AVI and BAT) in the micro-ITT 
analysis set. Single arm CIs will be computed using Jeffrey’s method (Brown et al. 2001; 
Cai 2005).4,5 The number and percentage of subjects who had a clinical response of clinical 
cure, clinical failure, and indeterminate in each treatment arm will be tabulated for the 
micro-ITT set at the TOC visit. 
The primary descriptive analysis will be conducted using the clinical response assessment 
determined by a blinded independent adjudication committee (see Section 9.7). The 
investigator’s assessment of clinical response will also be summarized in the micro-ITT 
analysis set at the TOC visit. In case of any discrepancy between the investigator’s and 
adjudication committee’s clinical response assessment, the adjudication committee’s 
assessment will prevail for the analysis. 
9.4.2. Analysis of the Secondary Endpoints 
Secondary efficacy outcome measures will be assessed and presented using the same 
methods as described in Section 9.4.1. For descriptive secondary outcome measures, number 
and percentage in each treatment arm will be tabulated. Summaries will be presented for the 
overall population, and also split by infection type (cIAI, HAP/VAP, cUTI or BSI), and by 
resistance group (eg, drug resistance group and β-lactamase content). 
The proportion of subjects who died on or before 28 days after randomization will be 
presented for the overall population, and also split by infection type. 
AEs will be summarized by means of counts summaries by Medical Dictionary for 
Regulatory Activities System Organ Class and preferred term separately for the study periods 
(treatment period [from first dose to EOT], from EOT to LFU, and for the full study period 
[from first dose to LFU].) All AEs and treatment emergent adverse events (TEAEs) will be 
listed (including prior to first dose). Deaths, AEs leading to discontinuation, and SAEs will 
be summarized. 
Laboratory data for hematology and clinical chemistry will be summarized. The frequency 
of changes with respect to normal ranges between Baseline and each post-treatment time 
point will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) 
occurring during the clinical study will also be given. Shifts from normal to abnormal 
between Baseline and each post-baseline time point will be evaluated for all laboratory 
parameters. 
The incidence of markedly abnormal values and changes from Baseline in the ECG 
parameters will be summarized by treatment arm. 
Other safety variables will be summarized as appropriate. Further details will be provided in 
the SAP. 


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9.4.3. Subgroup Analysis 
Subgroup analysis may include infection type and resistance type. More details on the 
subgroup analyses will be provided in the SAP. 
9.4.4. Interim Analysis 
No fonnal interim analysis will be conducted for this study. However, as this is an 
open-label study, the sponsor may conduct reviews of the data.which will include no 
summaries of data by treatment ann during the course of the study for the pmpose of safety 
assessment, and/or to suppo1i clinical development. 
9.4.5. Supportive Analyses 
Additional descriptive analyses of the primaiy endpoint (clinical cure rate) will be perfo1med 
for the effect of protocol-allowed additional antibiotics (eg, Gram-positive antibiotics, 
aminoglycosides). 
9.4.6. Exploratory Analysis 
 
The final PK data will be pooled with data from other studies to 
con uct a popPK ana ys1s using Nonlinear Mixed Effects Modelling [NONMEM]). Using 
these pai·ameter estimates (mean PK pai·ameters including inter individual vai·iance 
estimates), Monte Carlo simulation will be unde1iaken and potential PK/PD relationships will 
be explored. ATM and AVI plasma concentrations versus time will be depicted graphically 
in the CSR. Full details of the PK and PK/PD analysis will be given in the popPK Analysis 
Plan. These results will be repo1ied sepai·ately. 
The propo1iion of subjects who died on or before 14 days after randomization will be 
resented b treatment ann. Fmiher details on the analysis methods for
 
evaluation of health resource utilization 
will be detailed in the SAP. 
9.5. Data Monitoring Committee 
This study will use an external data monitoring cormnittee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the E-DMC Charter. The recommendations made by the E-DMC to alter the 
conduct of the study will be forwai·ded to Pfizer for final decision. Pfizer will forward such 
decisions, which may include Sllllllllai·ies of aggregate analyses of endpoint events and of 
safety data that are not endpoints, to regulato1y authorities, as appropriate. Programming and 
statistical personnel sepai·ate from the sponsor study team will be responsible for producing 
the E-DMC data outputs. The sponsor study team will not receive any unblinded summaiy 
analyses for the E-DMC review. 


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9.6. Independent Clinical Hepatologist Review of Potential Hy’s Law Cases 
With regards to any cases of potential Hy’s Law (PHL), the Pfizer Medical Monitor will 
initially review the case (as described in Appendix 4) and then the case will be referred for 
independent clinical hepatologist review. The independent clinical hepatologist will also be 
available for consultation for cases of liver enzyme test abnormalities not specifically 
meeting the criteria for PHL or liver-related SAEs. The independent clinical hepatology 
review will be unblinded to study treatment allocation. 
9.7. Independent Adjudication Committee 
An independent adjudication committee consisting of at least three experts will be convened 
at regular intervals during the study. This independent adjudication committee is the central 
blinded assessor (see Section 5.2). 
A charter will be in place for the adjudication committee. The adjudication committee will 
be blinded to study treatment and will review the clinical response assessments at EOT and 
TOC visits. 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 subjects classified as a clinical failure, and all cIAI subjects 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 subjects 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. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed. The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate. The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion. 
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities. 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 


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data and the subject's medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart. In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
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. 
11.2. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports). The records should 


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be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
11.3. 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 their actual identity and medical record ID. 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. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
12. ETHICS 
12.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 


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• 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, 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. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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 GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations. 
12.1.1. 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 the ICH GCP guidelines that the investigator 
becomes aware of. 
12.2. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 


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numbering system provided by Pfizer in order to de-identify study subjects. The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws. 
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws. 
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection. 
The investigator must ensure that each study subject or his or her legally acceptable 
representative is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC. If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then, 
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained. If the study subject does not provide his or her own consent, the source documents 
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’s assent was obtained or waived. If assent is obtained verbally, 
it must be documented in the source documents. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative before any 
study-specific activity is performed. The investigator will retain the original of each subject's 
signed consent document. 
12.3. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 


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13. DEFINITION OF END OF TRIAL 
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State. Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State. 
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV). 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. In addition, Pfizer retains the right to discontinue development of 
ATM-AVI at any time. 
If a study is prematurely terminated, Pfizer will promptly notify the investigator. After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days. As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible. 
15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in subjects) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted. US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations. 


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


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


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44. Nordmann P, Poirel L. Strategies for identification of carbapenemases-producing 
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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
 
 
Abbreviation or 
Special Term 
Explanation 
 
A-aDO2 
Alveolo-arterial oxygen difference 
ABG 
Arterial blood gas 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AmpC 
A Class C β-lactamase (Amp=ampicillinase) 
APACHE 
Acute Physiology and Chronic Health Evaluation 
APS 
Acute Physiology Score 
AST 
Aspartate aminotransferase 
ATM 
Aztreonam 
ATM-AVI 
Aztreonam-avibactam 
AUC 
Area under the plasma concentration versus time curve 
AUC(0-24,ss) 
Steady state area under the curve between time zero and 24 hours 
after dose 
AVI 
Avibactam 
BAL 
Bronchoalveolar lavage 
BAT 
Best available therapy 
CCI 
BP 
Blood pressure 
BPM 
Beats per minute 
β-hCG 
β-human chorionic gonadotropin 
BSI 
Bloodstream infections 
CAZ 
Ceftazidime 
CAZ-AVI 
Ceftazidime-avibactam 
CE 
Clinically evaluable 
CFR 
Code of Federal Regulations 
CHE 
Chronic Health Evaluation 
cIAI 
Complicated intra-abdominal infection 
CI 
Confidence interval 
CFU 
Colony-forming unit 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
CLSI 
Clinical Laboratory Standards Institute 
Cmax 
Maximum plasma concentration 
CR-BSI 
Catheter related BSI 
CrCL 
Creatinine clearance 
CRE 
Carbapenem-resistant Enterobacteriaceae 
CRF 
Case Report Form 
CRO 
Contract Research Organization 


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Abbreviation or 
Special Term 
Explanation 
CSA 
Clinical Study Agreement 
CLSI 
Clinical and Laboratory Standards Institute 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Threshold concentration 
CT 
Clinical Trial 
CTA 
Clinical trial application 
CT scan 
Computerized tomography scan 
CTX 
Cefotaximase 
CTX-M 
A type of Class A β-lactamase (CTX=cefotaximase) 
cUTI 
Complicated urinary tract infection 
CV 
Cardiovascular 
CYP 
Cytochrome P 450 
DBP 
Diastolic blood pressure 
DDI 
Drug-drug interaction 
DGR 
Dangerous Goods Regulations 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee, synonymous to Institutional Review Board 
(IRB) and Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
E-DMC 
External data monitoring committee 
EDP 
Exposure during pregnancy 
EFPIA 
European Federation of Pharmaceutical Industries and 
Associations 
EMA 
European Medicines Agency 
ELD 
Extended loading dose 
EOT 
End of treatment 
ESBL 
Extended-spectrum β-lactamase 
ESRD 
End-stage renal disease 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GGT 
Gamma-glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HAP 
Hospital-Acquired Pneumonia 
HCO3 
Hydrogencarbonate or bicarbonate 
HIV 
Human immunodeficiency virus 


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Abbreviation or 
Special Term 
Explanation 
HL 
Hy’s Law 
HPF 
High Power Field 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICD 
Informed Consent Document 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
ID 
Identifier 
IMI 
Innovative Medicines Initiative 
IND 
Investigational new drug 
INR 
International normalized ratio 
International 
Co-ordinating 
Investigator 
If a study is conducted in several countries the International 
Co-ordinating Investigator is the Investigator co-ordinating the 
investigators and/or activities internationally. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IU 
International units 
IUD 
Intrauterine device 
IV 
Intravenous(ly) 
IRT 
Interactive response technology 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
KPC 
Klebsiella pneumoniae carbapenemase 
LD 
Loading dose 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LFU 
Late Follow-up 
LH 
Luteinizing hormone 
LPF 
Low Power Field 
LSLV 
Last Subject Last Visit 
MAP 
Mean arterial pressure 
MBL 
Metallo-β-lactamase 
MDR 
Multidrug resistant 
ME 
Microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MITT 
Modified Intent-To-Treat 
Micro-ITT 
Microbiological Intent-To-Treat 
Micro-MITT 
Microbiological modified Intent-To-Treat 
MTZ 
Metronidazole 
N/A 
Not applicable 


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Abbreviation or 
Special Term 
Explanation 
NDM 
New Delhi Metallo-β-lactamase 
NONMEM 
Nonlinear Mixed Effects Modelling 
NP 
Nosocomial pneumonia 
O2 
Oxygen 
OAT 
Organic anion transporter 
OXA 
A type of Class D β-lactamase (OXA=oxacillinase) 
PaCO2 
Partial pressure of carbon dioxide in arterial blood 
PaO2 
Partial pressure of oxygen in arterial blood 
PCD 
Primary completion date 
PD 
Pharmacodynamic 
PHL 
Potential Hy’s Law 
PHT 
Pulmonary hypertension 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PMNs 
Polymorphonuclear leukocytes 
pO2 
Partial pressure of oxygen 
popPK 
Population pharmacokinetic 
PSB 
Protected-specimen brush 
PT 
Prothrombin Time 
PTA 
Probability of target attainment 
q6h 
Every 6 hours 
q8h 
Every 8 hours 
QT 
The time elapsing between the start of the Q wave and the end of 
the T wave in an electrocardiogram 
RNA 
Ribonucleic acid 
SAC 
Scientific Advisory Committee 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOA 
Schedule of Activities 
SOAP 
Sepsis Occurrence in Acutely Ill Patients 
SOP 
Standard operating procedure 
SRSD 
Single Reference Safety Document 
STAR 
Staged abdominal repair 
TBili 
Total bilirubin 
TCS 
Tata Consultancy Services 
TEAE 
Treatment-emergent adverse event 
TOC 
Test of Cure 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UN 
United Nations 


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Abbreviation or 
Special Term 
Explanation 
US 
United States 
UTI 
Urinary tract infection 
VAP 
Ventilator-associated pneumonia 
VIM 
Verona Integron encoded metallo-β-lactamase 
WBC 
White blood cells 
WHO 
World Health Organization 
WHOdrug 
World Health Organization drug dictionary 
WP2b 
Work package 2b 
 


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Appendix 2. International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
Labelling and shipment of biohazard samples 
The IATA classifies biohazardous agents into 3 categories. For transport purposes the 
classification of infectious substances according to risk groups was removed from the 
Dangerous Goods Regulations (DGR) in the 46th edition (2005). Infectious substances are 
now classified either as Category A, Category B or Exempt. There is no direct relationship 
between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure 
to it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever 
virus: 
• Are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following 
United Nation (UN) number and proper shipping name: 
• UN 3373 – Biological Substance, Category B; 
• Are to be packed in accordance with UN3373 and IATA 650. 
Exempt - all other materials with minimal risk of containing pathogens. 
• Clinical study samples will fall into Category B or exempt under IATA regulations; 
• Clinical study samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging; 
• Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content; 
• IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable; 
• Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 


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Appendix 3. Calculation of Estimated Creatinine Clearance 
Calculation of the estimated creatinine clearance 
Estimated CrCL will be calculated using the following Cockcroft-Gault formula (Cockcroft 
and Gault 1976).6 The weight obtained at Screening1 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 treatment to be administered, the subject’s estimated CrCL must be calculated using 
the most recent serum creatinine value that was obtained at the local laboratory, the subject’s 
most recent actual (not ideal) body weight, and the Cockcroft-Gault formula. 
Cockcroft-Gault formula: 
Estimated CrCL is calculated by Cockcroft-Gault as follows: 
For serum creatinine in mg/dL: 
estimated CrCL = [(140 – age) × weight in kilograms]/[72 × serum creatinine in mg/dL]; 
[× 0.85 if female]. 
For serum creatinine in μmol/L: 
estimated CrCL = [(140 – age) × weight in kilograms × constant]/[serum creatinine in 
μmol/L]; 
where constant = 1.23 for males and 1.04 for females. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 For the purpose of assessing eligibility, a patient's weight obtained during the current 
hospitalization may be used if the patient's clinical condition at the time of screening does not 
allow this assesment to be performed. 


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Appendix 4. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
1. Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of HL. It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. Specific guidance on the managing liver abnormalities can be 
found in Section 8.5.2 of the protocol. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets PHL 
criteria at any point during the study. 
The investigator participates, together with the Pfizer Medical Monitor, in review and 
assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL criteria 
are met if there is no alternative explanation for the elevations in liver biochemistry other 
than DILI caused by the IP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AE and SAE according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
2. Definitions 
Potential Hy’s Law (PHL) 
• Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available; 
• For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or 
ALT values >2 times the baseline values AND >3 × ULN; or >8 × ULN 
(whichever is smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller). 


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Hy’s Law (HL) 
The case with laboratory abnormalities defined in Potential Hy’s Law (PHL) as above, where 
no other reason, other than the IP, can be found to explain the combination of increases, eg, 
elevated ALP indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on 
the same day) the elevation in TBili, but there is no specified timeframe within which the 
elevations in transaminases and TBili must occur. 
A PHL case becomes a confirmed HL case only after all results of reasonable investigations 
have been received and have excluded an alternative etiology. 
3. Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
• ALT >3 x ULN; 
• AST >3 x ULN; 
• TBili > 2 x ULN. 
A central laboratory will be used. When a subject meets any of the identification criteria, in 
isolation or in combination, the central laboratory will immediately send an alert to the 
investigator (also sent to the Pfizer Medical Monitor). 
The investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met where this is the case the investigator will: 
• Notify the Pfizer Medical Monitor; 
• Request a repeat of the test (new blood draw) by the central laboratory; 
• Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result. 
When the identification criteria are met from central or local laboratory results the 
investigator will without delay: 
• Determine whether the subject meets PHL criteria (see 2. Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results). 


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Sites will also use local laboratories. The investigator will promptly review each new 
laboratory report and if the identification criteria are met the investigator will: 
• Notify the Pfizer Medical Monitor; 
• Determine whether the subject meets PHL criteria (see 2. Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits; 
• Promptly enter the laboratory data into the laboratory CRF. 
4. Follow-up 
4.1 Potential Hy’s Law Criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• Inform the Pfizer Medical Monitor that the subject has not met PHL criteria; 
• Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP. 
4.2 Potential Hy’s Law Criteria met 
If the subject does meet PHL criteria the investigator will: 
• Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See 6 Actions Required When Potential Hy’s Law Criteria are Met Before 
and After Starting Study Treatment); 
• Notify the Pfizer Medical Monitor who will then inform the central Study Team. 
The Pfizer Medical Monitor contacts the investigator, to provide guidance, discuss and agree 
an approach for the study subjects’ follow-up and the continuous review of data. Subsequent 
to this contact the investigator will: 
• Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated; 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Pfizer Medical Monitor; 
• If at any time (in consultation with the Pfizer Medical Monitor) the PHL case meets 
serious criteria, report it as an SAE using standard reporting procedures. 


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5. Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Pfizer 
Medical Monitor contacts the investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI caused 
by the IP. The Pfizer Safety Risk Lead will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBili elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF; 
• If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the Pfizer standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBili 
elevations other than the IP: 
• Report an SAE (report term ‘Hy’s Law’) according to Pfizer standard processes. 
• The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply; 
• As there is no alternative explanation for the HL case, a causality assessment 
of ‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above; 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined. 


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6. Actions Required When Potential Hy’s Law Criteria are Met Before and After 
Starting Study Treatment 
This section is applicable to subjects who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the investigator will: 
• Determine if there has been a significant change in the subjects’ condition# compared 
with the last visit where PHL criteria were met#: 
• If there is no significant change no action is required; 
• If there is a significant change notify the Pfizer Medical Monitor, who will 
inform the central Study Team, then follow the subsequent process described 
4.2 Potential Hy’s Law Criteria met of this Appendix. 
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBili) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the Pfizer Medical Monitor if there is any uncertainty. 
7. Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a subject meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria 
being met and answer the following question: 
• Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, eg, chronic or progressing malignant disease, 
severe infection or liver disease, or did the subject meet PHL criteria prior to starting 
study treatment and at their first on study treatment visit as described in 6 Actions 
Required When Potential Hy’s Law Criteria are Met Before and After Starting Study 
Treatment? 
If No: follow the process described in 4.2 Potential Hy’s Law Criteria met of this Appendix. 
If Yes: 
Determine if there has been a significant change in the subject’s condition# compared with 
when PHL criteria were previously met. 


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• If there is no significant change no action is required; 
• If there is a significant change follow the process described in 4.2 Potential Hy’s Law 
Criteria met of this Appendix. 
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBili) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the Pfizer Medical Monitor if there is any uncertainty. 
References 
FDA 200921 


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Appendix 5. Acute Physiology and Chronic Health Evaluation - APACHE II Score 
APACHE II Classification System 


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APACHE II Score Form 
(Knaus et al 1985)31 
Subject ID #  
Date of Assessment  
 
 
PHYSIOLOGIC 
VARIABLE 
HIGH ABNORMAL RANGE 
LOW ABNORMAL RANGE 
(Check one range per variable and write the severity score in the column to the right 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
Severity 
Score 
1. 
Temperature – Rectal (°C) 
(add 0.5oC to oral temp, 1.0oC to 
axillary temp) 
≥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) (bpm) 
≥180 
140–179 
110–139 
70–109 
55–69 
40–54 
≤39 
4. 
Respiratory rate 
(non-ventilated or ventilated) 
(breaths per minute) 
≥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 


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PHYSIOLOGIC 
VARIABLE 
HIGH ABNORMAL RANGE 
LOW ABNORMAL RANGE 
(Check one range per variable and write the severity score in the column to the right 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
Severity 
Score 
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 
(total/mm3) (in 1000s) 
≥40 
20–39.9 
15–19.9 
3–14.9 
1–2.9 
<1 
12. Glasgow Coma Scale 
(Score = 15 minus actual 
GCS) 
(Best GCS in the 24 hours prior to screening) 
(15 – GCS 
total) 
Eye 
Verbal 
Motor 
GCS total = (Eye + Verbal + Motor) 
a. 
Total Acute Physiology Score 
(APS) 
Total severity points indicated for in the column to the right 
*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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APACHE II Score Form continued 
 
 
Abbreviations: A-aDO2 = alveolo-arterial oxygen difference; ABG = arterial blood gas; APS = Acute Physiology Score; CHE = Chronic Health Evaluation; CV 
= cardiovascular; FiO2 = fraction of inspired oxygen; GCS = Glasgow Coma Scale; HCO3 = hydrogencarbonate or bicarbonate; PaO2 = partial pressure of 
oxygen in arterial blood; PHT = pulmonary hypertension 
 
 
APACHE II Score Worksheet provided to be used to calculate the APACHE II score. 
• Abstract data from the 24 hour interval prior to Screeningor during Screening. 
• Enter the value for each line item. Calculate APACHE II score using most recent local laboratory results. 
APACHE II Worksheet instruction 
A - Physiological components 
• Document one score for each of the physiological variables. Then calculate and document the total Acute Physiological Score 
(APS). 


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• The following will be accepted as core temperatures: rectal, esophageal, bladder, tympanic, or central. If the only temperature 
data available is from the oral or axillary routes, convert the temperature to an APACHE II core value using the following 
conversion factors: 
• Actual oral temperature (°C) + 0.5°C= Rectal (core) temperature; 
• Actual axillary temperature (°C) + 1.0°C = Rectal (core) temperature. 
• For the MAP value, use arterial line data if available, otherwise calculate the MAP from the cuff pressure using the following 
formula: 
MAP = 1/3 (SBP – diastolic blood pressure [DBP]) + DBP; 
(Example: BP 90/60, MAP = 1/3 (90 - 60) + 60 = 10 + 60 = 70) 
Note: If a DBP was not obtained, do not calculate a MAP, record “not done”. 
• Oxygenation: 
• In case the FiO2 is >50%, calculate the alveolo-arterial oxygen difference (A-aDO2) using the following formula, use 
ABGs results: 
A-aDO2=[(FiO2 (713)-(partial pressure of carbondioxide (PaCO2)/0.8)] - PaO2; 
(Example: FiO2=0.6; PaO2=56; and PaCO2=26: 
(0.6 x 713) minus (26 : 0.8) minus 56; 
427 - 32.5 = 395.3 - 56 = 339.3 = A-aDO2 (mm Hg); 
To calculate use FiO2 (in decimal), PaCO2 (mm Hg) and PaO2 (mm Hg). 
• If the FiO2 is < 50%, record the lowest PaO2; 
• In case there is no ABG available assume normal oxygenation (Variable score = 0). 


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• Serum creatinine (μmol/L): double point score for acute renal failure. Creatinine conversion from μmol/L to mg/dL to be: 
88.4 μmol/L= 1 mg/dL. 
• WBC Count. Record WBCs in 1000s (eg, a WBC count of 30000 cells/mm3 would be recorded as 30). 
• Arterial PH should be substituted by serum bicarbonate (HCO3) if there are no ABGs available in the previous 24 hours. 
B – Age Points 
• Circle the appropriate point for the subjects age range. 
C - Chronic Health Points 
If the subject has a history of severe organ system insufficiency or is immunocompromised assign chronic health points as follows: 
• For nonoperative or emergency postoperative subjects: 5; 
• For elective postoperative patients: 2; 
• Subject does NOT have a history of severe organ system insufficiency and is NOT immunocompromised: 0. 
They will receive the points only once (which means even if they have 2 criteria, the maximum is either 2 or 5). 
GLASGOW COMA SCALE 
For the Glasgow Coma Scale (GCS) score, determine the lowest (worst) number for each of the three factors in the scale (eye opening, 
verbal response, and motor response). Add together these 3 numbers, and then subtract this number from 15 to get the final GCS 
score. The subject's neurological status during a single neurological assessment should be evaluated. 
Since it is not possible to assess the GCS in subjects who are sedated and paralyzed, by convention the GCS is regarded as normal, 
unless it is known that there was a brain injury prior to sedation. In that case the last measured GCS is to be used; if there is no brain 
injury prior to sedation the GCS is 15, thus the neurologic score will be 0. 


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Appendix 6.  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 subjects 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 organisms (Murray et al. 2007)42 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. 
1. 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 subjects and sent to the local laboratory for culture, identification, 
and in vitro susceptibility testing. If treatment is discontinued early because the 
subject is failing therapy and the subject 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 subjects include: 
• endotracheal aspirate; 
• BAL; 
• mini-BAL; 
• PSB sample. 
Appropriate specimens from non-ventilated subjects include: 
• expectorated or induced sputum; 
• BAL; 


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• mini-BAL; 
• PSB sample. 
Note that there may be non-ventilated subjects who develop HAP and 
subsequently require intubation and mechanical ventilation. If such subjects 
require ventilation prior to the first dose of study treatment, a specimen appropriate 
for the subject should be obtained even if the subject has already provided a 
sputum sample. In addition, subjects 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 subject 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, a set 
of blood cultures should be collected, one for aerobic culturing and the other for 
anaerobic culturing. The bottles should be inoculated with 10 to 15 mL of blood per 
collection. If a subject 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. 


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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 subjects); 
• Midstream clean catch; 
• Suprapubic specimen collection using sterile technique. 
Whenever possible, urine specimens should not be obtained from indwelling 
catheters. When necessary, urine specimens in subjects with indwelling bladder 
catheters should be obtained by sterile aspiration through the catheter port or by 
puncturing the catheter tubing with a needle and syringe if a port is not present. 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. 
2. Shipment of isolates: 
The central reference laboratory will supply the local laboratory with all media containing 
transport vials and instructions for shipment of isolates to the central reference laboratory. 
The central reference laboratory will monitor and verify resistant isolates reported by the 
local laboratory. All shipment documentation for samples sent from the local laboratory to 
the central reference laboratory should be maintained and available for review by the 
Contract Research Organization (CRO) representative. 
3. Analysis of isolates: 
The local laboratory must identify all aerobic bacterial pathogens to the genus and species 
level using confirmatory, not presumptive, identification methods from blood, urine, 
respiratory and abdominal specimens. The disk diffusion method as established by the 
Clinical and Laboratory Standards Institute (CLSI) should be used to determine susceptibility 
for ATM-AVI and meropenem for all isolates. Discs with ATM-AVI and meropenem will 
be supplied by the central reference laboratory. Reporting of susceptibility results on 
ATM-AVI to the principal investigator will be detailed in the study site manual. The 
laboratory may perform any additional testing on meropenem (eg, MIC) and any additional 
agents as they normally do to provide susceptibility results of isolated aerobic 
microorganisms. Disk zone size determinations for interpretation of susceptibility for all 
isolated aerobic microorganisms will be according to CLSI methodology for comparator 
agents. All aerobic isolates should be sent to the central reference laboratory for 
confirmation of identification and susceptibility testing. Characterization of β-lactamases 
associated with the bacterial pathogens and molecular profiling (eg, pulse-field gel 
electrophoresis, whole genome sequencing) will be performed or coordinated by the central 
laboratory. 


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All anaerobic bacterial pathogens must be identified to at least the genus level. If the local 
laboratory cultures and performs susceptibility testing on anaerobic organisms, it should 
follow CLSI methodologies by either broth microdilution (Bacteroides fragilis group) or agar 
dilution MIC testing for MTZ, meropenem and possible additional comparator agents. 
Anaerobic isolates originating from subjects with intra-abdominal infections and blood 
stream infections need to be sent to the central reference laboratory for confirmation of 
identification and susceptibility testing. Anaerobic bacterial pathogens isolated from subjects 
with respiratory infections and urine tract infections do not need to be sent, but must be 
entered into the CRF as having an anaerobe present. 
The investigator should record information on all specimens according to the Investigator’s 
manual supplied by the central reference laboratory. The central reference laboratory will 
confirm pathogen identifications and susceptibility test results on all clinical isolates reported 
and shipped by the local laboratory. If discrepancies occur between the results obtained at 
the central reference laboratory and those obtained at the study site local laboratory, a CRO 
representative will request that a second sample of the isolate in question be shipped. In the 
instance of differences in pathogen identification or susceptibilities, the central reference 
laboratory results will take precedence over the local laboratory result. If microorganisms 
that are isolated at the local laboratory do not survive shipping to the central reference 
laboratory, a CRO representative will request that a second sample of the isolate in question 
be shipped. Local laboratory results may be used if a microorganism does not survive 
shipping or is not recoverable from the local laboratory. 
Appendix 7. Summary of Protocol Amendment 1 
 
Document 
Version Date Summary of Changes and Rationale 
Amendment 1 
05 July 2018 
• Updated number of sites/countries and participating 
areas based on site feasibility outcome and study 
timeline in Protocol Summary/Study Sites and 
Number of Subjects Planned and Section 1.4.1 Study 
Design and Control Group. 
• Modified wordings on Primary Objective and the 1st 
and 4th Secondary Objectives (ie, from “compared to” 
to “and”) to reflect no formal comparisons between 
treatment groups in Protocol Summary/Table 
Objectives and Section 2 Study Objectives. 
• Modified wordings on treatment day (eg, from “full 
day” to “day”; from “The duration of treatment is 5 to 
14 days for cIAI and 7 to 14 days for HAP/VAP” to 
“The recommended minimal duration of treatment is 
5 days for cIAI and 7 days for HAP/VAP. The 
maximal duration of treatment is 14 days.”) to reflect 
calendar day per Pfizer standard in Protocol 


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Summary/Duration of treatment, Section 1.4.1 Study 
Design and Control Group, Section 1.4.3 Dose 
Selection for Metronidazole, Section 3 Study Design, 
Section 5.5 Administration (Dose and Treatment 
Regimen) and Section 6.3.2 Visit 3 to 15: Ongoing 
Treatment (Days 2 to 14). 
• Replaced reference to Aztreonam and Avibactam 
with combined test product Aztreonam-Avibactam in 
Protocol Summary/Table Investigational product, 
dosage form and strength and Table 3 Identity of 
Investigational Product. 
• Deleted the reference to 1g aztreonam in Protocol 
Summary/Table Investigational product, dosage form 
and strength and Table 3 Identity of Investigational 
Product to be consistent with study drug supply in IP 
Manual. 
• Added “Note: Co-administered drug is supplied 
centrally via the sponsor”, “Note: Aztreonam and 
Metronidazole are commercial products over-labeled 
with the study clinical label” and “Note: Comparator 
drug is sourced locally under local regulatory 
conditions” in Protocol Summary/Table 
Investigational product, dosage form and strength and 
Table 3 Identity of Investigational Product for clarity. 
• Removed “first dose”, “second dose” and “third and 
subsequent doses” and added “first” before 
Maintenance Dose on Day 1 to increase clarity on 
dose description in Protocol Summary/Table 
Aztreonam-avibactam Treatment Arm, Table 
4 ATM-AVI Doses in Relationship to CrCL, Section 
5.5.1 ATM-AVI Treatment Arm and Table 
12 Pharmacokinetic ATM-AVI Sample Collection 
Time Points. 
• Modified wordings on creatinine clearance 
monitoring for consistency across the protocol in 
Project Summary/ATM-AVI Treatment Arm. 
• Changed “randomization” to “first dose of study 
treatment” in Microbiologically Evaluable Analysis 
Set and in the use of other systemic antimicrobials in 
Protocol Summary/Definition of analysis sets, 


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Section 5.9 Concomitant Treatment(s) and Section 
9.2.1.3 Microbiologically Evaluable (ME) Analysis 
Set to be consistent with Concomitant Treatment 
definition per Pfizer standard. 
• Added “Collection of imaging and surgical report in 
subjects with cIAI” at every visit except Late 
Follow-up visit in Table 1 Schedule of Activities 
Section 6.2.1 Visit 1: Eligibility/Screening 
Procedures, Section 6.3.1 Visit 2: Baseline 
Procedures and Day 1 of Treatment, 
Section 6.3.2 Visit 3 to 15: Ongoing Treatment, 
Section 6.3.3.1 Visit 16: End of Treatment and 
Section 6.3.3.2 Visit 17: Test of Cure for collecting 
source data on case adjudication of clinical responses 
for cIAI subjects. 
• Added wordings of “local lab for eligibility criteria 
confirmation” in footnote b of Table 1 Schedule of 
Activities, Section 6.3.1Visit 2: Baseline Procedures 
and Day 1 of Treatment (Day 1) for clarity. 
• Corrected wordings related to the serum HCO3 use in 
place of arterial pH if no ABGs available in footnote 
d of Table 1 Schedule of Activities and Appendix 
5 Acute Physiology and Chronic Health Evaluation. 
• Specified acceptable time frame of chest X-ray/CT 
scan (within 48 hours prior to randomization) for 
HAP/VAP subjects in footnote g of Table 1 Schedule 
of Activities, Section 6.2.1. Visit 1: 
Eligibility/Screening Procedures and Section 
7.2.6.1 Chest X-ray/ CT Scan to be consistent with 
Section 4.1.3 Additional Inclusion Criteria 
(Criterion 2) for HAP/VAP subjects. 
• Clarified blood sample collection for culture to avoid 
unnecessary repeat sampling and increase clarity and 
consistency of blood specimens for culture across 
protocol in footnote p of Table 1 Schedule of 
Activities, Section 6.3.1 Visit 2: Baseline Procedures 
and Day 1 of Treatment (Day 1), Section 6.3.2 Visit 
3 to 15: Ongoing Treatment, Section 
7.4 Microbiology and Appendix 6 Microbiological 
Assessments. 


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• 
 Specified respirato1y specimen collection to increase 
clarity on respiratory specimen Baseline definition in 
footnote r of Table 1 Schedule of Activities, Section 
6.3.1. Visit 2: Baseline Procedures and Day 1 of 
Treatment, Section 7.3 Microbiology and Appendix 
6 Microbiological Assessments. 
• 
 Updated wordings on Phase 2a study descriptions per 
Phase 2a study status in Section 1.3 Rationale for 
Conducting This Study. 
• 
fucluded local lab blood sample at Screening, 
conected PK sample volume/pregnancy test 
frequency and updated number of samples and total 
blood volume accordingly in Table 13 Volume of 
Blood to Be Drawn from Each Subject and Section 
1.6 Benefits/Risk and Ethical Assessment for clarity. 
• 
 Removed "received or who received no prior 
systemic therapy" on the statement of symptomatic 
subjects in the Note of fuclusion 7 in Section 
4.1.1 All Subjects to eliminate the potential confusion 
languages. 
• 
 Removed "before study entiy" in the last 
complicating factor urogenital procedure in Section 
4.1.4. Additional fuclusion Criteria - cUTI Subjects 
fuclusion criterion 3b ii) to eliminate the potential 
confusion languages. 
• 
• 
Changed "duration of the study'' to "duration of study 
ti·eatment" relevant to the statement of effective 
method of conu-aception in Exclusion Criterion 18 in 
Section 4.2 Exclusion Criteria (4.2.1 All Subjects) to 
increase the clarity and consistency on the time frame 
of conu-aception requirement across protocol. 


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• Changed “prior to study entry” to “prior to screening” 
in Exclusion Criterion 19 to increase the clarity on the 
reference time point about participating in other 
investigational interventional studies in Section 
4.2 Exclusion Criteria (4.2.1 All Subjects). 
• Deleted “or female condom” in the 3rd contraception 
method in Section 4.4.1 Contraception to 
accommodate globally acceptable contraception 
methods. 
• Added “or as necessitated by the clinical status of the 
subject during the period of hospitalization, eg, 
unconscious/ventilated” as acceptable obviation of 
the need for contraception in Section 
4.4.1 Contraception to accommodate the specific 
study population, eg, ventilated/unconscious subjects. 
• Modified definition of “Cure” and “Indeterminate” of 
clinical responses in Table 8 Definition of Clinical 
Response Categories at the EOT and TOC visits and 
“Indeterminate” of microbiological response in Table 
9 Definition of Microbiological Response Categories 
at the EOT and TOC Visits per FDA feedback for 
clarity. 
• Changed “100X field” to “Lower Power Field (LPF)” 
in footnote a of Table 9 Definition of Microbiological 
Response Categories at the EOT and TOC Visits and 
Appendix 6 Microbiological Assessments for clarity. 
• Changed “ATM-resistant” to “ATM-non-susceptible” 
in Section 7.1.2.1 Microbiological Response 
Assessment for clarity. 
• Removed the wordings of “(from an intra-abdominal 
culture for cIAI subjects, or an adequate respiratory 
specimen for HAP/VAP subjects or a blood culture 
for subjects with bacteraemia)” from Table 
10 Definition of Emergent Infection Categories to 
accommodate the situation of emergent infection 
arising from other sites instead of the original site of 
infection. 
• Deleted “and exact time” in the statement on ECG 
recording in CRF in Section 7.2.3 ECG as the time of 


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each of the triplicate ECGs will be provided in the 
non-CRF data transfer from the vendor and it is not 
necessary to collect the time of ECGs in the CRF. 
• Clarified PK sampling time point in reference to IV 
ATM-AVI Loading Dose, Extended Loading Dose 
and Maintenance Dose in Table 12 Pharmacokinetic 
ATM-AVI Sample Collection Time Points to be 
consistent with Figure 3 and ATM-AVI 
Pharmacokinetic Sample Collection Time Points for 
Subjects with CrCL >30 mL/min (Q6h Maintenance 
Dose) and Figure 4 ATM-AVI Pharmacokinetic 
Sample Collection Time Points for Subjects with 
CrCL >15 to ≤30 mL/min (Q8h Maintenance Dose). 
• Modified wordings on PK sample collections to 
increase clarity in Section 7.3.1 Collection of Plasma 
Samples for Analysis of Aztreonam-Avibactam. 
• Included wordings on study–qualifying 
MBL-producing-isolate to increase the clarity of 
microbiology isolate baseline in Section 7.4. 
Microbiology. 
• Specified storage time frame for microbiology 
isolates for clarity in Section 7.6.1 Storage, Re-use 
and Destruction of Biological Samples. 
• Added wordings on SAE report for fatal case due to 
disease progression to align with Pfizer standard on 
fatal case report in Section 8.4.4.2 Disease 
Progression. 
• Changed “study entry” to “randomization” for the 
starting point on renal function monitoring for clarity 
in Section 8.5.1 Renal Function. 
• Deleted “>1.5” in 2nd bullet point with the statement 
of “INR>1.5” in Section 8.5.2 Monitoring of Liver 
related Laboratory Parameters for error correction. 
• Changed “each visit” to “EOT and TOC visits” in 
reference to the clinical response assessments by the 
adjudication committee for error correction in Section 
9.7 Independent Adjudication Committee. 


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• Added “(except anaerobic bacterial pathogens 
isolated from subjects with respiratory infections and 
urine tract infections)” in the statement for required 
shipment of microbiological isolates to the central 
reference laboratory in Appendix 6 Microbiological 
Assessments for clarity. 
• Other typographical or administrative edits to 
improve readability, clarity and consistency. 


 
 
Document Approval Record 
 
 
C3601009 Protocol Amendment 2 Clean 23MAY2022 
C3601009 Protocol Amendment 2 Clean 23MAY2022 
 
 
PPD 
  
PPD 
 
 
23-May-2022 18 10 38 
Final Approval 
 
23-May-2022 18 50 10 
Final Approval 
Document Name: 
Document Title: 
Signed By: 
Date(GMT) 
Signing Capacity 

SAP_001.pdf: 
Protocol C3601009 (PF-06947387) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C3601009 
 
A PROSPECTIVE, RANDOMIZED, OPEN-LABEL, COMPARATIVE STUDY TO 
ASSESS THE EFFICACY, SAFETY AND TOLERABILITY OF 
AZTREONAM-AVIBACTAM (ATM-AVI) AND BEST AVAILABLE THERAPY 
FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO MULTI-DRUG 
RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING 
METALLO-ΒETA-LACTAMASE (MBL) 
 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
Version: 
1.0 
Date: 
21-April-2020 


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Page 2 
 
 
 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 3 
1. VERSION HISTORY ............................................................................................................ 4 
2. INTRODUCTION .................................................................................................................. 4 
2.1. Study Objectives ........................................................................................................ 4 
2.2. Study Design .............................................................................................................. 7 
2.3. Methods for Ensuring Blinding ................................................................................. 8 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................... 8 
3.1. Primary Endpoint ....................................................................................................... 8 
3.2. Secondary Endpoints ................................................................................................. 8 
3.3. Exploratory Endpoints ............................................................................................... 9 
3.4. Baseline Variables ................................................................................................... 10 
3.4.1. Baseline Clinical Laboratory and Vital Signs ............................................. 10 
3.4.2. Baseline Microbiology ................................................................................ 10 
3.5. Stratification Variables ............................................................................................ 11 
3.6. Safety Endpoints ...................................................................................................... 11 
3.6.1. Adverse Events ........................................................................................... 12 
4. ANALYSIS SETS ................................................................................................................ 12 
4.1. Efficacy Analysis Sets ............................................................................................. 12 
4.1.1. Intent-to-Treat (ITT) Analysis Set .............................................................. 12 
4.1.2. Microbiological Intent-To-Treat (micro-ITT) Analysis Set ........................ 12 
4.1.3. Microbiologically Evaluable (ME) Analysis Set ........................................ 13 
4.2. Safety Analysis Set .................................................................................................. 13 
4.3. Population Pharmacokinetic (popPK) Analysis Set ................................................. 14 
4.4. Other Analysis Sets .................................................................................................. 14 
4.4.1. All Subjects Analysis Set ............................................................................ 14 
5. GENERAL METHODOLOGY AND CONVENTIONS .................................................... 14 
5.1. Hypotheses and Decision Rules .............................................................................. 14 
5.2. General Methods ...................................................................................................... 14 
5.3. Methods to Manage Missing Data ........................................................................... 14 
6. ANALYSES AND SUMMARIES ....................................................................................... 15 


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Page 3 
 
 
6.1. Primary Endpoint ..................................................................................................... 15 
6.1.1. Primary Analysis ......................................................................................... 15 
6.1.2. Sensitivity/Robustness Analyses ................................................................. 15 
6.2. Secondary Endpoints ............................................................................................... 15 
6.3. Exploratory Endpoints ............................................................................................. 16 
6.3.1. Pharmacokinetic Analyses .......................................................................... 16 
6.4. Subset Analyses ....................................................................................................... 17 
6.5. Baseline and Other Summaries and Analyses .......................................................... 17 
6.6. Safety Summaries and Analyses .............................................................................. 18 
6.6.1. Adverse Events ........................................................................................... 18 
6.6.2. Laboratory Data .......................................................................................... 18 
6.6.3. Vital Signs ................................................................................................... 19 
6.6.4. Electrocardiogram ....................................................................................... 19 
6.6.5. Physical Examination .................................................................................. 19 
6.6.6. Detailed Infection-related Focused Physical Examination .......................... 19 
6.6.7. Extent of Exposure and Compliance ........................................................... 20 
7. INTERIM ANALYSES ....................................................................................................... 20 
8. REFERENCES ..................................................................................................................... 21 
9. APPENDICES ...................................................................................................................... 22 
LIST OF TABLES 
Table 1. 
Summary of Major Changes in SAP Amendments ..................................... 4 


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Page 4 
 
 
 
1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study C3601009 is based on the protocol dated 
05JUL2018. 
Table 1. 
Summary of Major Changes in SAP Amendments 
 
SAP Version Change 
Rationale 
1.0 
Not Applicable Not Applicable 
 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3601009. 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. 
2.1. Study Objectives 
 
Primary Objective: 
Primary Endpoint: 
To evaluate the efficacy of 
aztreonam-avibactam (ATM-AVI) and 
best available therapy (BAT) at the Test 
of Cure (TOC) visit in the 
microbiological Intent-To-Treat 
(micro-ITT) population for the treatment 
of selected serious infections that are due 
to MBL-producing Gram-negative 
bacteria. 
Proportion of subjects with clinical cure at the 
TOC visit in the micro-ITT analysis set. 
Secondary Objectives: 
Secondary Endpoint(s): 
To evaluate the efficacy of ATM-AVI 
and BAT at the TOC in the 
Microbiologically Evaluable (ME) 
population, and at the End of Treatment 
(EOT) visit in the micro-ITT and ME 
populations. 
• Proportion of subjects with clinical cure at 
the TOC visit in the ME analysis set; 
• Proportion of subjects with clinical cure at 
the EOT visit in the micro-ITT and ME 
analysis sets. 


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To assess the microbiological response to 
ATM-AVI at the EOT and TOC visits in 
the micro-ITT and ME populations. 
• Proportion of subjects with a favorable 
(defined as eradication or presumed 
eradication) per-subject microbiological 
response at the EOT and TOC visits in the 
micro-ITT and ME analysis sets; 
• Proportion of subjects with a favorable 
per-pathogen microbiological response at the 
EOT and TOC visits in the micro-ITT and 
ME analysis sets. 
To assess 28-day all cause mortality. 
Proportion of subjects who died on or before 
28 days from randomization in the 
Intent-To-Treat (ITT) and micro-ITT analysis 
sets. 
To evaluate the safety and tolerability 
profile of ATM-AVI and BAT. 
Safety and tolerability as assessed by adverse 
events, physical examination, vital signs, 
electrocardiograms, and laboratory assessments 
in the safety analysis set. 


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Page6 
 
 
 
 
Exploratory Objectives: 
Exploratory Endpoint(s): 
To evaluate the phannacokinetics (PK) of 
ATM and AVI in subjects with serious 
infections and to attempt to characterize 
the relationship between exposure and 
clinical and microbiological response for 
ATM-AVI. 
• 
PK of aztreonam and avibactam in subjects in 
the population PK analysis set; 
• 
PK/phaimacodynamic (PD) relationship 
between exposure and clinical and 
microbiological response for ATM-AVI in 
the population PK analysis set. 
To assess 14-day all-cause mo1iality. 
Proportion of subjects who died on or before 
14 days from randomization in the ITT and 
micro-ITT anal sis sets. 
To collect data to allow an explorato1y 
evaluation of health utilization*. 
• 
Length of hospital stay, including any 
readmissions up to TOC (days); 
• 
Length of study treatment (days); 
• 
Length of intensive care unit stays (days); 
• 
Transfened to the intensive cai·e unit 
(Yes/No); 
• 
Mechanical ventilation (Yes/No) for 
hospital-acquired 
pneumonia/ventilator-associated pnemnonia 
subjects; 
• 
Length of mechanical ventilation (days) for 
hospital-acquired 
pneumonia/ventilator-associated pnemnonia 
subjects; 
• 
 Subsequent unplanned surgical intervention 
after treatment success versus failure (up to 
the TOC visit) for complicated 
intra-abdominal infection subjects. 
 
*: Results of health utilization analyses will be included in the Clinical Study Report. 


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2.2. Study Design 
This is a prospective, randomized, multicenter, open-label, parallel group, comparative study 
to determine the efficacy, safety, and tolerability of ATM-AVI versus best available therapy 
(BAT) in the treatment of hospitalized adults with complicated intra-abdominal infection 
(cIAI), nosocomial pneumonia (NP) including hospital-acquired pneumonia (HAP) and 
ventilator-associated pneumonia (VAP), complicated urinary tract infection (cUTI), or 
bloodstream infections (BSI) due to MBL-producing Gram-negative bacteria. 
Adult hospitalized subjects with a confirmed diagnosis of cIAI, HAP/VAP, cUTI or BSI due 
to MBL-producing Gram-negative pathogens requiring administration of intravenous 
antibacterial treatment will be enrolled in this study. 
Approximately 60 subjects with infections due to MBL-producing Gram-negative bacteria 
will be enrolled. MBL status of the isolates will be determined at the local level before 
enrollment of subjects, and will be confirmed at the central microbiology laboratory. 
The study will consist of a Screening Visit (Visit 1), a Baseline Visit (Visit 2) on Day 1 of 
the study treatment, ongoing treatment visits (Visits 3 to 15) from Day 2 to Day 14, an EOT 
visit (Visit 16) within 24 hours after the last infusion of study treatment, a TOC visit (Visit 
17) on Day 28 (±3 days) and a LFU visit (Visit 18) on Day 45 (±3 days). Each subject is 
expected to complete the study, including the Late Follow-Up (LFU) visit. 
After obtaining written informed consent and confirming eligibility, subjects will be 
randomized in a 2:1 ratio to the ATM-AVI treatment group or the BAT treatment group 
according to a central randomization schedule (approximately 40 (ATM-AVI) subjects and 
approximately 20 (BAT) subjects per group). Subjects will be stratified at randomization 
based on infectious disease type (cIAI, HAP/VAP, cUTI and BSI). The number of subjects 
with cUTI will be no more than approximately 75% of the study population. 
Please refer to Protocol Section 5.5 more details with regard to treatment arms, dosage and 
mode of administration and duration of treatment. 
The recommended minimal duration of treatment is 5 days for cIAI, cUTI and BSI and 
7 days for HAP/VAP. The maximal duration of treatment is 14 days. Subjects will receive 
their study therapy by study center personnel while in the hospital. 
For subjects randomized to ATM-AVI, sparse blood samples will be collected for PK 
assessments by population pharmacokinetic (pop PK) analysis, and PK/PD relationships will 
be evaluated in subjects where plasma samples and clinical and microbiological response 
data have been collected. 


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2.3. Methods for Ensuring Blinding 
This is an open-label study. The investigators, site personnel, and subjects 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. 
Clinical response outcome recorded at scheduled visits (EOT and TOC) will be assessed by 
an independent adjudication committee (central assessor) in a blinded fashion with the aim of 
unbiased adjudication of the primary objective measure. Data will be provided relating to the 
subject’s clinical response without disclosing treatment arm. Details on the central 
independent adjudication committee will be provided in a separate charter. 
No interim analysis is planned and no analysis of data according to treatment arm assignment 
will be made prior to database lock, except for interim external data monitoring committee 
(E-DMC) safety reviews (See Protocol Section 9.5 and E-DMC Charter). 
Programming and statistical personnel separate from the sponsor study team will be 
responsible for producing the data outputs for the E-DMC review and will help limit access 
by the study team to individual subject and group treatment assignment until database lock 
has occurred. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
The primary efficacy outcome measure is the proportion of subjects with clinical cure (as 
determined by the Independent Clinical Adjudication Committee) at the Test of Cure (TOC) 
visit in the microbiological Intent-To-Treat (micro-ITT) analysis set. The proportion of 
subjects with clinical cure for the micro-ITT analysis set is defined as the number of subjects 
with clinical cure at TOC divided by the number of subjects in the micro-ITT analysis set. 
The Clinical Adjudication Committee (CAC) will use pre-specified criteria, as per the 
protocol, to determine clinical responses. All data will be reviewed by the CAC members 
within a Virtual Clinical Adjudication System (VCAS). The CAC will be blinded to study 
treatment allocations and investigator assessments of clinical response. All adjudication 
outcomes will be documented on electronic Adjudication Forms and stored within VCAS and 
will be transferred for merging with the clinical dataset for analysis. More details on the 
CAC can be found in the CAC Charter. 
3.2. Secondary Endpoints 
The secondary outcome measures are: 
• Proportion of subjects with clinical cure at TOC in the ME analysis set; 
• Proportion of subjects with clinical cure at the EOT in the micro-ITT and ME 
analysis sets; 


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• 
 Proportion of subjects with a favorable (defined as eradication or presumed 
eradication) per-subject microbiological response at the EOT and TOC visits in the 
micro-ITT and ME analysis sets; 
 
• 
 Proportion of subjects with favorable (defined as eradication or presumed eradication) 
per-pathogen microbiological response at the EOT and TOC visits in the micro-ITT 
and ME analysis sets; 
• 
 Propo1tion of subjects who died on or before 28 days after randomization in the ITT 
and micro-ITT analysis sets; 
 
• 
 Safety and tolerability as assessed by adverse events, physical examination, vital 
signs, ECGs, and laborato1y assessments. 
3.3. Exploratory Endpoints 
The explorato1y outcome measures are: 
• 
PK of aztreonam and avibactam in subjects in the population PK analysis set. 
 
• 
PK/PD relationship between exposure and clinical and microbiological response for 
ATM-AVI in the population PK analysis set. 
 
• 
Propo1tion of subjects who died on or before 14 days after randomization. 
 
• 
For the health utilization objective: 
 
• 
Length of hospital stay, including any readmissions up to TOC (days); 
 
• 
Length of intensive care unit (ICU) stay (days); 
 
• 
TransfeITed to the ICU (Yes/No); 
 
• 
Length of study treatment (days); 
• 
Mechanical ventilation for HAPN AP subjects (Yes/No); 
 
• 
Length of mechanical ventilation (days) for HAPN AP subjects; 
 
• 
Subsequent unplanned surgical intervention after treatment success vs failure (up 
to the TOC visit) for cIAI subjects. 
• 


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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 
Culture, identification, and determination of the MBL status of pathogens, isolated from 
adequate specimens, is performed at the local laboratory. All pathogens will then be sent to 
the central laboratory for confirmation of identification and, where appropriate, MBL 
status. If there is a discrepancy between the local and central lab identification/results, the 
central lab results will be used in the microbiological analyses. Local lab results will only be 
used in microbiological analyses if there are no central lab results available. 
Baseline Pathogens are defined as those obtained from adequate specimens closest (and 
prior) to the start of study treatment. For all specimens other than blood, if an adequate 
specimen closest (and prior) to the start of study treatment yields no pathogens and was 
obtained on a date subsequent to an adequate specimen from the same source that yielded a 
pathogen, the subject will be considered to have no baseline pathogens. However, this does 
not apply when the specimen that yields no pathogens closest to study treatment start is 
blood; any pathogens resulting from blood obtained in the 5 days prior to study treatment 
start will be considered baseline pathogens. 
Adequate specimens for culture at baseline for each infection type are outlined below: 
Collection of intra-abdominal specimen (for cIAI subjects only) 
Subject must have an adequate specimen for culture obtained from an abdominal source 
(such as tissue or aspirate suitable for isolation of both aerobic and anaerobic bacteria) during 
a surgical intervention within 5 days prior to screening from which a study-qualifying 
pathogen was isolated. Surgical intervention includes open laparotomy, percutaneous 
drainage of an abscess, or laparoscopic surgery. 
Additional specimens will be collected, as clinically appropriate, in the event of repeat 
surgical procedures prior to the start of study treatment. 
Collection of respiratory specimen (for HAP/VAP subjects only) 
Subjects must have an adequate respiratory specimen obtained within 5 days prior to 
screening for Gram stain and culture from which a study-qualifying pathogen was 
isolated. Acceptable respiratory specimens from ventilated patients include endotracheal 
aspirate, Bronchoalveolar lavage (BAL), Mini BAL, or Protected-Specimen Brush (PSB) 
sample. Acceptable respiratory specimens from non-ventilated patients include expectorated 
or induced sputum, Bronchoalveolar lavage (BAL), Mini BAL, or Protected-Specimen Brush 
(PSB) sample. Expectorated or induced sputum specimen Gram stain must show 
<10 squamous epithelial cells and >25 polymorphonuclear neutrophils per Low Power Field 
(LPF) to be suitable. 


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For subjects with HAP, repeat respiratory specimens are not required at Visit 2 (Baseline), 
unless a study-qualifying respiratory sample was obtained from a non-ventilated subject and 
the subject is subsequently ventilated (or the subject had a bronchoscopy). In this case, a 
repeat adequate respiratory specimen should be obtained prior to the first dose of study 
treatment. 
Collection of Blood (for all subjects) 
Subjects with BSI must have an adequate blood specimen obtained within 5 days prior to 
screening that contained a study-qualifying pathogen upon culture. 
All subjects require 2 sets of blood cultures (1 anaerobic and 1 aerobic bottle in each set) 
within 48 hours prior to randomization. Blood cultures should be taken at Visit 2 (Baseline) 
prior to first dose of study treatment if blood cultures are not available within 48 hours prior 
to randomization. 
Collection of Urine Specimen (for cUTI subjects only) 
Subjects must have an adequate specimen of urine for culture collected within 5 days prior to 
screening, that contained ≥105 CFU/mL of a study-qualifying pathogen upon 
culture. Another adequate specimen of urine must be obtained for culture at Visit 2 
(Baseline) prior to the first dose of study treatment. 
3.5. Stratification Variables 
Randomization will be stratified based on infectious disease type (cIAI, HAP/VAP, cUTI, 
and BSI). 
3.6. Safety Endpoints 
The safety endpoints of this study are: 
• Incidence of adverse events by study period: treatment period [from first dose to 
EOT], from EOT to LFU, and for the full study period [from first dose to LFU]; 
• Incidence of clinical laboratory abnormalities (defined as Potentially Clinically 
Significant [PCS] results) and summary of values and change from baseline in 
clinical laboratory measures by scheduled visit; 
• Incidence of vital sign abnormalities and summary of measurements and change from 
baseline in vital sign measures by scheduled visit; 
• Incidence of ECG abnormalities and summary of measurements and change from 
baseline in ECG measures by scheduled visit; 
• Incidence of abnormalities in the complete physical examination by scheduled visit. 


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3.6.1. Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage. An adverse event is considered a Treatment-Emergent Adverse Event 
(TEAE) if the event started after the study medication start date and time. 
4. ANALYSIS SETS 
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to database lock and classifications will be documented per 
standard operating procedures. When determining if subjects meet the criteria for inclusion 
in each analysis set, the study team will not have access to treatment group information 
during the assessment [exception: PopPK analysis set (which only includes subjects from the 
ATM-AVI treatment group), where the determination will be made by Clinical 
Pharmacology and Pharmacometrics]. 
4.1. Efficacy Analysis Sets 
The evaluation of subject data for subject exclusion from efficacy analysis sets will be 
completed and documented by the study team prior to database lock. The review of subject 
data for analysis set exclusion will be performed on an ongoing basis during the study. The 
review of subject data will include: 
• Programmed output produced by programming and statistical personnel separate from 
the sponsor study team; 
• Data Listings produced from the database and reviewed by Data Management and 
Clinical; 
• Reports of potentially important protocol deviations including those which may 
impact efficacy (utilizing the CORD system). 
4.1.1. Intent-to-Treat (ITT) Analysis Set 
The ITT analysis set will include all randomized subjects regardless of receipt of study drug. 
Subjects in the ITT analysis set will be analyzed according to the treatment to which they are 
randomized. The ITT analysis set will be used to evaluate selected secondary and 
exploratory objectives. The ITT analysis set will also be used to evaluate the primary 
objective, if the ITT and micro-ITT analysis sets differ. 
4.1.2. Microbiological Intent-To-Treat (micro-ITT) Analysis Set 
The microbiological Intent-To-Treat (micro-ITT) analysis set is a subset of the ITT analysis 
set and includes all subjects who have at least 1 MBL-positive Gram-negative baseline 
pathogen from an adequate specimen at the start of study treatment. The following scenarios 
would result in subjects being excluded from the micro-ITT population and included in the 
ITT population only: 


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1. Subjects with inherently resistant pathogens (for example, monomicrobial infections 
due to any Acinetobacter spp.); 
2. Subjects with an MBL-producing pathogen obtained from an adequate 
study-qualifying specimen prior to screening which was not present in the repeat (if 
applicable) adequately obtained specimens closest (and prior) to the start of study 
therapy. 
The determination of subjects’ baseline pathogens and inclusion/exclusion status for the 
micro-ITT analysis set will be decided by the study team. In their review, the study team 
will also take into account the adequacy of any specimens prior to the start of study 
treatment. 
Subjects in the micro-ITT analysis set will be analyzed according the treatment to which they 
are randomized. The micro-ITT analysis set is the primary analysis set used to evaluate the 
primary objective. It will also be used to evaluate secondary and exploratory objectives. 
4.1.3. Microbiologically Evaluable (ME) Analysis Set 
The Microbiologically Evaluable (ME) analysis set is defined as all subjects who: 
• Met the definition of the micro-ITT analysis set; 
• Received at least 48 hours of study therapy (ATM-AVI or BAT) or received 
<48 hours of study therapy before discontinuing study drug due to an AE; 
• Did not receive concomitant antibiotic therapy with potential activity against any 
baseline MBL-positive pathogens between the time of the first dose of study 
treatment and the time of TOC. This does not include those subjects 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. (If the subject had an MBL-producing isolate based on local laboratory 
results, which could not be confirmed by the central lab, the subject is excluded from 
the ME analysis set. However, for the situation where the central lab is unable to 
confirm (eg, isolate is lost or damaged), the subject would be included in the ME 
analysis set, based on the local lab results); 
• Did not have a clinical outcome of indeterminate at TOC. 
Subjects in the ME analysis set will be analyzed according to the treatment to which they are 
randomized. The ME analysis set will be used to evaluate selected secondary objectives. 
4.2. Safety Analysis Set 
The safety analysis set will be used for reporting safety data and will include all subjects who 
received any amount of study treatment. Subjects in the safety analysis sets will be analyzed 
according to the treatment they receive. 


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4.3. Population Pharmacokinetic (popPK) Analysis Set 
The population pharmacokinetic (popPK) analysis set will include all subjects who have at 
least 1 plasma concentration data assessment available for ATM or AVI and will be used to 
report all PK data. 
4.4. Other Analysis Sets 
4.4.1. All Subjects Analysis Set 
This analysis set will include all subjects enrolled into the study (ie, subjects who have 
signed an informed consent form for the study) and will be used for reporting of disposition 
and demographics. (listing only). 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
No formal hypothesis testing will be performed for this study. All analyses will be 
descriptive. 
5.2. General Methods 
All data will be presented by treatment arm. Descriptive statistics (number, mean, standard 
deviation [SD], median, minimum, and maximum) will be provided for continuous variables, 
and counts and percentages will be presented for categorical variables. Listings of individual 
subject data will also be produced. 
Categorical and qualitative variable summaries for safety will include the frequency and 
percentage of subjects who are in the particular category. In general, the denominator for the 
percentage calculation will be based upon the total number of subjects in the study 
population for each treatment group, unless otherwise specified. 
For the reporting of descriptive statistics for continuous and quantitative data, the mean and 
median values will be presented to 1 more decimal-place precision than were recorded in the 
source data. The SD will be presented to 2 more decimal-places of precision and the 
minimum and maximum values will be presented to the same decimal-places of precision as 
the source data. Percentages will be presented to 1 decimal-place of precision. 
Unless specified otherwise, all analysis will be performed using SAS®, release 9.1 or higher. 
5.3. Methods to Manage Missing Data 
For efficacy data, missing data will not be imputed. 
For safety data, missing dates will be programmatically handled according to Pfizer 
standards. 


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6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint 
6.1.1. Primary Analysis 
The primary descriptive efficacy analysis will be the estimate of the clinical cure rate and 
95% confidence interval (CI) in each treatment arm (ATM-AVI and BAT) in the micro-ITT 
analysis set. Single arm CIs will be computed using Jeffrey’s method (Brown et al. 2001; 
Cai 2005).1,2 The number and percentage of subjects who had a clinical response of clinical 
cure, clinical failure, and indeterminate in each treatment arm will be tabulated for the 
micro-ITT set at the TOC visit. 
The primary descriptive analysis will be conducted using the clinical response assessment 
determined by the blinded independent adjudication committee. The investigator’s 
assessment of clinical response will also be summarized in the micro-ITT analysis set at the 
TOC visit as a sensitivity analysis (See Section 6.1.2). In case of any discrepancy between 
the investigator’s and adjudication committee’s clinical response assessment, the 
adjudication committee’s assessment will prevail for the primary analysis. 
6.1.2. Sensitivity/Robustness Analyses 
An analysis of the Investigator’s assessment of clinical response in the micro-ITT analysis 
set at the TOC visit will be performed as a sensitivity analysis. 
Sensitivity analysis of the primary endpoint (clinical response at TOC, adjudicated response) 
will also be conducted in the micro-ITT population that considers all deaths prior to the TOC 
as clinical failures. 
6.2. Secondary Endpoints 
Secondary endpoints and corresponding analysis methods are also summarized in 
Appendix 2 Table 1. 
Secondary efficacy outcome measures (evaluating the proportion of subjects with clinical 
cure [based on adjudicated clinical response] at the EOT and TOC visits by differing analysis 
sets [eg, ME], proportion of subjects with favorable microbiological response, and those who 
died on or before 28 days after randomization [overall and by infection type], etc) will be 
assessed and presented similar to the primary endpoint. 
For the Safety analyses, please see Section 6.6. 


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6.3. Exploratory Endpoints 
The proportion of subjects who died on or before 14 days after randomization will be 
presented by treatment ann. 
Health resource utilization data will be summarized by treatment aim, total, and, where 
applicable and numbers permit, by infection type. This will include length (days) of hospital 
stay, hospital readmissions during the study (through TOC and, additionally, through LFU), 
length (days) of ICU stay, transfer to ICU, length of study treatment (calendai·and 24-hour 
days; see Section 6.6.7), mechanical ventilation (and length if needed) for HAPN AP 
subjects, and unplanned surgical intervention for cIAI subjects. Health resource utilization 
variables will also be summarized by clinical response at TOC (success/cure and failure). 
Descriptive statistics (number, mean, standai·d deviation [SD], median, minimum, and 
maximum) will be provided for duration/length of stay variables; counts and percentages will 
be presented for categorical variables. 
For health resource utilization endpoints, only events that are in progress at the time of 
randomization or that begin after randomization and on or before the date of the TOC (and 
additionally through LFU for propo1iion of hospital re-admissions) assessment will be 
included in these analyses. In addition, except for hospitalization (all patients will be 
hospitalized), duration summaries will focus on subjects who have the event. 
The length of hospital stay will be calculated as the difference between the date of discharge 
and the date of randomization plus 1. As multiple hospital stays are possible, the total 
number of calendai·days on which the subject was in hospital for the period from date of 
randomization until the TOC visit will be derived. The length of stay in ICU up to the TOC 
visit will be derived from the ICU admittance/dischai·ge dates. For subjects with multiple 
stays in ICU, the total number of calendar days on which the subject was in ICU for the 
period from date of randomization until the TOC visit will be derived. Duration of 
mechanical ventilation will be calculated similai·ly. These length of stay/duration vai·iables 
will be summarized with and without patients who died to evaluate the impact of the duration 
vai·iables for patients who died on the overall assessment of these vai·iables. 
 
6.3.1. Pharmacokinetic Analyses 
Aztreonam and avibactam plasma concentrations versus time will be depicted graphically in 
the Clinical Study Repo1i (CSR). The final phaimacokinetic data will be pooled with data 
from other studies to conduct a population phaimacokinetic analysis (using Nonlineai·Mixed 
Effects (NLME) Modelling. Using these pai·ameter estimates (mean phannacokinetic 
pai·ameters including inter individual vai·iance estimates), Monte-Cai-losimulation will be 
unde1iaken and potential phaimacokinetic/phaimacodynamic relationships will be explored. 
Full details of the phaimacokinetic and phaimacokinetic/phannacodynamic analysis will be 
given in the Population Phaimacokinetic Modeling Analysis Plan (PMAP). These results 


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will be reported separately in a Population Pharmacokinetic Modeling Analysis Report 
(PMAR). 
6.4. Subset Analyses 
Subgroup analyses of the primary analysis (clinical cure rate at TOC) will include: 
• Infection type (cIAI, HAP [overall and for VAP and non-VAP], cUTI, BSI); 
• Resistance group. Resistance groups will include: aztreonam-non-susceptible, 
meropenem-non-susceptible isolates and isolates producing ESBLs (eg., CTX-M), serine 
carbapenemases (eg, KPC), and MBL subclassification (eg, VIM, NDM, IMP); 
• Baseline renal function category: Severe (CrCl 16-30 mL/min) renal impairment, 
Moderate (CrCl 31-50 mL/min) renal impairment, Normal renal function or Mild 
renal impairment (CrCl 51-150 mL/min), Augmented renal function (CrCl ≥151 
mL/min); 
• Baseline APACHE II score category (≤10 or >10) based on the data collected from 
the eCRF; 
• For cUTI patients: acute pyelonephritis or complicated lower UTI; 
• Monomicrobial vs polymicrobial infections at baseline; 
• Geographic region (Western Europe; Eastern Europe; China; RoW); 
Further analyses for regions (eg, Asian, or other regions) and countries (eg, China) may be 
performed to satisfy local regulatory submission requirements if needed. 
Some categories listed above may be combined when they contain a small number of 
subjects with evaluable data. Other subgroups may be evaluated as numbers permit 
(eg, concomitant aminoglycoside use). 
6.5. Baseline and Other Summaries and Analyses 
Baseline variables are defined as outlined in Section 3.4. 
Demographic and baseline characteristics, including age, gender, height, weight, primary 
diagnosis, complicating factors for cUTI, mechanical ventilation status (for HAP/VAP 
patients) and APACHE II score will be summarized by treatment arm. 
Baseline microbiology will be summarized by treatment arm. Pathogens at baseline will be 
summarized overall and by infection type. Pathogens will be summarized by individual 
baseline pathogen and by pathogen type (Enterobacteriaceae, other Gram-negative 
pathogens, Gram-positive aerobes etc.), MBL-status (positive/negative), and MBL 
subclassification (eg, VIM, NDM, IMP). The number of subjects with monomicrobial vs 
polymicrobial (2, 3, 4, ≥5 pathogens) at baseline will be summarized. If numbers permit, 


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analyses by specimen type (intra-abdominal specimen, respiratory specimen, urine or blood) 
may be performed. The susceptibility profile of baseline pathogens and MIC frequency 
distributions of study treatment will also be summarized. Microbiological culture results will 
be listed. 
Medical history and Physical Exam (General and Focused) will be summarized. The clinical 
signs and symptoms of infection will be summarized by visit and treatment arm. Prior and 
Concomitant medications will be summarized. Antibiotic medications will be summarized 
and listed separately. 
The number of subjects in each of the analysis sets will be summarized. In addition, the 
number of subjects who were excluded from the analysis sets will be summarized by reasons 
for the exclusion. 
A summary of the number of subjects in each country and each center will be produced for 
all randomized subjects. 
6.6. Safety Summaries and Analyses 
Standard summary tables and listings will be generated using Pfizer’s Clinical Data Analysis 
and Reporting System (CDARS) for the following parameters: adverse events, lab 
parameters (hematology, blood chemistry, and urinalysis), vital signs, ECGs, physical 
examinations, discontinuations from study, discontinuations from treatment, and treatment 
duration. 
Unless otherwise noted, AEs will be sorted alphabetically for system organ class and then 
preferred term. 
6.6.1. Adverse Events 
TEAEs will be summarized by number and percent by system organ class (SOC) and 
preferred term (PT). All TEAEs will be summarized separately for the study periods 
(treatment period [from first dose to EOT], from EOT to LFU, and for the full study period 
[from first dose to LFU]). Deaths, TEAEs leading to discontinuation, TEAEs by SOC, 
preferred term, and relationship to study therapy, TEAEs by SOC, preferred term, and 
severity, TEAEs by SOC, preferred term, and baseline CrCl status, and SAEs will be 
summarized for the full study period using the safety analysis set. 
All AEs (including prior to first dose) and treatment emergent adverse events (TEAEs) will 
be listed. 
6.6.2. Laboratory Data 
Laboratory data (central and local) for hematology, clinical chemistry, and urinalysis will be 
summarized by study visit. Frequencies of potentially clinically significant values and 
changes from baseline occurring during the clinical study will also be presented (hematology 
and clinical chemistry). Potentially clinically significant criteria are outlined in Appendix 3. 
Shifts from low, normal, and high relative to the normal range between baseline and each 


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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 criteria for potential Hy’s Law or Hy’s Law after the start of study 
treatment at any time up to the LFU visit: The AST, ALT, total bilirubin and ALP elevations 
can occur at any time in the specific review period and do not need to occur simultaneously. 
A listing of subjects with a value of ≥3xULN for ALT or AST or a value of ≥2xULN for 
total bilirubin in any one of the AST, ALT, total bilirubin parameters at any time during the 
study (baseline or post-baseline) will be also presented. This listing will contain all the ALT, 
AST, total bilirubin and ALP study data for such subjects. 
6.6.3. Vital Signs 
Vitals signs data, including blood pressure, heart rate, and body temperature will be 
summarized by visit. The number of subjects with vital sign abnormalities in blood pressure 
and heart rate will also be summarized. Criteria for vital signs abnormalities can be found in 
Appendix 4. The vital signs data will also be listed. 
For those subjects with HAP/VAP, respiratory rate (breaths per minute) and peripheral 
oxygen saturation will be summarized. 
6.6.4. Electrocardiogram 
A single independent third-party using uniform techniques will carry out formal reading and 
interpretation of ECG data for purposes of the study. Data will be transferred to Pfizer for 
inclusion in summary analyses. 
The incidence of abnormal values (for example: elevated QT, QTcB, and QTcF values) and 
changes from baseline in the electrocardiogram parameters will be summarized by treatment 
arm. 
6.6.5. 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. 
6.6.6. Detailed Infection-related Focused Physical Examination 
Results of the detailed focused (infection-related signs and symptoms per indication) 
assessment will be summarized by visit and listed by patient. 


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6.6.7. Extent of Exposure and Compliance 
Exposure to study therapy in calendar days will be summarized by treatment group and 
overall and listed. The duration of therapy in calendar days will be calculated as follows: 
Date of last dose of study drug - date of first dose of study drug +1. 
In addition, exposure to study therapy in 24-hour days will be calculated and summarized by 
treatment group and overall and listed. The duration of therapy in 24-hour days will be 
calculated as follows. 
Date and Time of last dose of study drug - date and time of first dose of study drug. 
Compliance over the whole treatment period will be calculated as follows: 
Compliance =  Actual Number of Doses Received 
* 100 
Planned Number of Doses 
The planned number of doses will be calculated as follows: 
The planned number of doses = 1+ the nearest integer of [(Time of the last dose of study 
drug– time of the first dose of study drug)/number of hours between doses]. 
A subject is considered compliant if between 80% and 120% of the planned number of doses 
is received. Interruption in therapy is considered non-compliance only if the compliance 
criteria described above is not met. Medication compliance will be summarized (n, mean, 
standard deviation, median, minimum and maximum) by treatment group. The compliance 
will also be summarized in the following categories: <80%, ≥80% to 120%, and >120% by 
the number and percentage of subjects in each treatment group. 
Additionally, the number of infusions and the number of each individual component of study 
therapy (ATM-AVI, metronidazole, BAT) will be summarized by baseline renal function 
(Severe renal impairment, Moderate renal impairment, Normal renal function or Mild renal 
impairment, and Augmented renal function, as defined in Section 6.4). 
7. INTERIM ANALYSES 
No formal interim analysis will be conducted for this study. An external data monitoring 
committee (E-DMC) will be responsible for ongoing monitoring of the safety of subjects in 
the study according to the E-DMC Charter. 


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8. REFERENCES 
1. 
Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. 
Statistical Science 2001, 16 (2):101-117. 
2. 
Cai TT. One-sided confidence intervals in discrete distributions. J Stat Plan Inference 
2005;131(1):63-68. 


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9. APPENDICES 
Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the SAP. 
 
Abbreviation or 
special term 
Explanation 
ABG 
Arterial blood gas 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APACHE 
Acute Physiology and Chronic Health Evaluation 
AST 
Aspartate aminotransferase 
ATM 
Aztreonam 
ATM-AVI 
Aztreonam-avibactam 
AVI 
Avibactam 
BAL 
Bronchoalveolar lavage 
BAT 
Best Available Therapy 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
BSI 
Bloodstream Infection 
CAC 
Clinical Adjudication Charter 
CDARS 
Clinical Data Analysis and Reporting System 
cIAI 
Complicated intra-abdominal infection 
CI 
Confidence interval 
CORD 
Clinical Oversight Review Dashboard 
CrCl 
Creatinine clearance 
CSR 
Clinical Study Report 
cUTI 
Complicated Urinary Tract Infection 
ECG 
Electrocardiogram 
ECRF 
Electronic Case Report From 
E-DMC 
External data monitoring committee 
EOT 
End of treatment 
ESBL 
Extended-spectrum β-lactamase 
HAP 
Hospital-Acquired Pneumonia 
ICU 
Intensive care unit 
ITT 
Intent-To-Treat 
LFU 
Late Follow-up 
LLN 
Lower Limit of Normal 
LPF 
Low Power Field 
MBL 
Metallo-β-lactamase 
MDR 
Multidrug resistant 
ME 
Microbiologically Evaluable 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
Micro-ITT 
Microbiological Intent-To-Treat 
N/A 
Not applicable 
NLME 
Nonlinear Mixed Effects Modelling 
NP 
Nosocomial pneumonia 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PMAP 
Population Modeling Analysis Plan 
PMAR 
Population Modeling Analysis Report 
popPK 
Population pharmacokinetic 
PSB 
Protected-specimen brush 
PT 
Preferred Term 
RoW 
Rest of World 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TOC 
Test of Cure 
ULN 
Upper limit of normal 
VAP 
Ventilator-associated pneumonia 
VCAS 
Virtual Clinical Adjudication System 


Protocol C3601009 (PF-06947387) Statistical Analysis Plan 
 
 
Appendix 2. Table 2: Summary of Efficacy Analyses 
 
EndpointN ariable 
Analysis Set 
Statistical Method 
Timepoint 
Objective 
Clinical Cure (as assessed by the 
Adjudication Committee) 
micro-ITT 
Summa1y of Proportion 
95% CI for Treatment 
Group 
TOC 
Primaiy Endpoint 
Clinical Cure as assessed by the 
Investigator 
micro-ITT 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
TOC 
Sensitivity/Suppo1tive Analysis 
Clinical Cure where all deaths ai·e 
considered failures 
micro-ITT 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
TOC 
Sensitivity/Suppo1tive Analysis 
Clinical Cure 
ITT,ME 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
TOC 
Secondaiy Endpoint 
Clinical Cure 
micro-ITT, ITT, and 
ME 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
EOT 
Secondaiy Endpoint 
Clinical Cure by Infection Type 
micro-ITT and ME 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
EOT, TOC 
Secondaiy/Key Subset Analysis 
Clinical Cure by Resistance group. 
Resistance groups will include: 
aztreonam-non-susceptible, 
meropenem-non-susceptible isolates, 
and isolates producing ESBLs (eg, 
CTX-M), serine carbapenemases 
(eg, KPC), and MBL 
subclassification (eg, VIM, NDM, 
IMP) 
micro-ITT 
Summa1y of Propo1tion 
EOT, TOC 
Secondaiy/Key Subset Analysis 
PFIZER CONFIDENTIAL 
Page 24 
 
TMF Doc ID: 98.03 


Protocol C3601009 (PF-06947387) Statistical Analysis Plan 
 
 
Subjects with favorable per-subject 
microbiological response 
micro-ITT and ME 
Summa1y of Proportion 
TOC andEOT 
Secondaiy Endpoint 
Subjects with favorable per- 
pathogen microbiological response 
micro-ITT and ME 
Summa1y of Propo1tion 
TOC andEOT 
Secondaiy Endpoint 
Death (overall and by infection type) 
ITT and micro-ITT 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
On or before 
28 days after 
randomization 
Secondaiy Endpoint 
Death 
ITT and micro-ITT 
Summa1y of Propo1tion 
On or before 
14 days after 
randomization 
Explorato1y Endpoint 
Health Utilization 
ITT 
Summaiy 
UptoTOC 
(LFU for 
hospital 
readmissions) 
Explorato1y Endpoint 
Health Utilization by Clinical 
Response (Cure/Failure) 
ITT 
Summaiy 
UptoTOC 
(LFU for 
hospital 
readmissions) 
Explorato1y Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
PFIZER CONFIDENTIAL 
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Protocol C3601009 (PF-06947387) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 26 
 
 
Appendix 3. Criteria for Potentially Clinically Significant Lab Results 
Table 3: Clinical 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 
Albumin 
<0.5 × LLN 
>50% 
>1.5 × ULN 
>50% 
Alkaline 
phosphatase 
<0.5 × LLN 
>80% 
>3.0 × ULN 
>100% 
Alanine 
aminotransferase 
N/A 
N/A 
>3.0 × ULN 
>100% 
Aspartate 
aminotransferase 
N/A 
N/A 
>3.0 × ULN 
>100% 
Bicarbonate 
<0.7 × LLN 
>40% 
>1.3 × ULN 
>40% 
Blood urea nitrogen 
<0.2 × LLN 
>100% 
>3.0 × ULN 
>200% 
Calcium, total 
<0.7 × LLN 
>30% 
>1.3 × ULN 
>30% 
Chloride 
<0.8 × LLN 
>20% 
>1.2 × ULN 
>20% 
Creatinine 
N/A 
N/A 
>2.0 × ULN 
>100% 
Gamma-glutamyl 
transferase 
N/A 
N/A 
>3.0 × ULN 
N/A* 
Glucose 
(nonfasting) 
<0.6 × LLN 
>40% 
>3.0 × ULN 
>200% 
Inorganic 
phosphorus 
<0.5 × LLN 
>50% 
>3.0 × ULN 
>200% 
Potassium 
<0.8 × LLN 
>20% 
>1.2 × ULN 
>20% 
Sodium 
<0.85 × LLN 
>10% 
>1.1 × ULN 
>10% 
Total bilirubin 
N/A 
N/A 
>1.5 × ULN 
>100% 
Indirect Bilirubin 
N/A 
N/A 
>1.5 × ULN 
>100% 
Direct bilirubin 
N/A 
N/A 
>2.0 × ULN 
>150% 
Total protein 
<0.5 × LLN 
>50% 
>1.5 × ULN 
>50% 
LLN = lower limit of normal value provided by the central laboratory. 
ULN = upper limit of normal value provided by the central laboratory. 
N/A = not applicable. 


Protocol C3601009 (PF-06947387) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 27 
 
 
Table 4: 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 
<0.7 × LLN 
>30% 
>1.3 × ULN 
>30% 
Hematocrit 
<0.7 × LLN 
>30% 
>1.3 × ULN 
>30% 
Platelet count 
<0.65 × LLN 
>50% 
>1.5 × ULN 
>100% 
Red blood cell 
count 
<0.7 × LLN 
>30% 
>1.3 × ULN 
>30% 
White blood cell 
count (total) 
<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% 
LLN = lower limit of normal value provided by the central laboratory. 
ULN = upper limit of normal value provided by the central laboratory. 
N/A = not applicable. 


Protocol C3601009 (PF-06947387) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 28 
 
 
Appendix 4. Criteria for Vital Signs Abnormalities 
Table 5: Criteria for Vital Signs Abnormalities 
Parameter 
Criteria 
Systolic BP (mm Hg) 
• Value >150 and increase from baseline >=30. 
• Value <90 and decrease from baseline >=30. 
• Diastolic BP (mm 
Hg) 
• Value >100 and increase from baseline >= 20. 
• Value <50 and decrease from baseline >=20. 
• Heart Rate (BPM) 
• Value <40 or >120.