Clinical trial NCT03329092
Conditions: Complicated Intra-abdominal Infection Hosptial Acquired Pneumonia Ventilator Associated Pneumonia
Keywords: Complicated intra-abdominal infection Hosptial acquired pneumonia Ventilator associated pneumonia Gram negative infections Metallo-beta lactamase Multi drug resistant pathogens
Sponsor: Pfizer
Start date: 2018-04-05; Completion date: 2023-02-23
Enrollment: 422 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 3 comparative study to determine the efficacy, safety and tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) versus Meropenem (MER) ± Colistin (COL) for the treatment of serious infections due to Gram negative bacteria.

Detailed description:
A Phase 3 Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study To Determine The Efficacy, Safety And Tolerability Of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem±Colistin (MER±COL) For The Treatment Of Serious Infections Due To Gram Negative Bacteria, Including Metallo Β Lactamase (MBL) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options

Arms: arm 1: All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover arm 2: All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice
Interventions: intervention 1: ATM-AVI intervention 2: MTZ intervention 3: MER intervention 4: COL
Intervention descriptions: intervention 1: (Creatinine clearance \> 50 mL/min) 6500 mg ATM/2167 mg (loading dose, extended loading dose and maintenance dose) by iv infusion on Day 1 followed by a total daily dose of 6000 mg ATM/2000 mg AVI

(Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1417 mg AVI on Day 1 (loading dose, extended loading dose, maintenance dose) followed by total daily dose 3000 mg ATM/1000 mg AVI

(Creatinine clearance 16 - 30 mL/min) 2700 mg ATM/900 mg AVI on Day 1 (loading dose, extended loading dose maintenance dose), followed by total daily dose 2025 mg ATM/675 mg AVI intervention 2: For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h intervention 3: Where pathogen initially not suspected of being MER-resistant:

(Creatinine clearance \> 50 mL/min) 1000 mg meropenem by 30 min iv infusion q8h

(Creatinine clearance 26 - 50 mL/min) 1000mg meropenem by 30 min iv infusion q12h

(Creatinine clearance 16 - 25 mL/min) 500 mg meropenem by 30 min iv infusion q12h

Where pathogen initially suspected of being MER-resistant (Creatinine clearance \> 50 mL/min) 2000 mg meropenem by 180 min iv infusion q8h

(Creatinine clearance 26 - 50 mL/min) 2000 mg meropenem by 180 min iv infusion q12h

(Creatinine clearance 16 - 25 mL/min) 1000 mg meropenem by 180 min iv infusion q12h intervention 4: Loading dose 9 million IU by 30 -60 min iv infusion (6 million IU where weight \< 60 kg) followed by one of the following maintenance doses:

(Creatinine clearance \> 50 mL/min) after a 12h interval, commence maintenance dosing 9 million IU daily in 2 or 3 divided doses by 30 -60 min iv infusions.

(Creatinine clearance 31 - 50 mL/min) After a 24 hr interval, commence maintenance dosing of 6 million IU daily in 2 divided doses by 30 -60 min iv infusion

(Creatinine clearance 21 - 30 mL/min) After a 24 hr interval, commence maintenance dosing 5 million IU daily in 2 divided doses by 30 -60 min iv infusion

(Creatinine clearance 16 - 20 mL/min) after a 24 hr interval, commence maintenance dosing 4 million IU daily in 2 divided doses by 30 -60 min iv infusion

Protocol documents:
Prot_000.pdf: 
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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. 
 
 
 
 
A PHASE 3 PROSPECTIVE, RANDOMIZED, MULTICENTER, OPEN-LABEL, 
CENTRAL ASSESSOR-BLINDED, PARALLEL GROUP, COMPARATIVE STUDY 
TO DETERMINE THE EFFICACY, SAFETY AND TOLERABILITY OF 
AZTREONAM-AVIBACTAM (ATM-AVI) ±METRONIDAZOLE (MTZ) VERSUS 
MEROPENEM ±COLISTIN (MER ±COL) FOR THE TREATMENT OF SERIOUS 
INFECTIONS DUE TO GRAM-NEGATIVE BACTERIA, INCLUDING 
METALLO-Β-LACTAMASE (MBL) – PRODUCING MULTIDRUG RESISTANT 
PATHOGENS, FOR WHICH THERE ARE LIMITED OR NO TREATMENT 
OPTIONS 
 
 
Investigational Product Number: 
PF-06947387 
Investigational Product Name: 
Aztreonam -Avibactam 
United States (US) Investigational New 
Drug (IND) Number: 
European Clinical Trials Database 
(EudraCT) Number: 
2017-002742-68 
Protocol Number: 
C3601002 
Phase: 
3 
 
 


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Document History 
 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment 2 
18 May 2022 
Increased sample size from “approximately 375 
subjects” to “up to approximately 425 subjects”. This 
change is reflected in the Protocol Summary, Section 
3 (Study Design) and Section 9 (Data 
Analysis/Statistical Methods). This increase in patient 
numbers is in response to a slower than anticipated 
recruitment in another ATM-AVI Phase III protocol. 
The change will help ensure that there is a minimum 
of patients on the ATM-AVI treatment arm across the 
program. 
• Section 1.5 and Section 16: Updated Single 
Reference Safety Document and References list to 
reflect current and additional sources of study 
drugs or comparators (update as per PACLs dated 
05-Aug-2020, 26-Mar-2021) 
• Section 1.6: Updated risk/benefit language to 
replace “Drug induced liver injury” with 
“Increased liver transaminases” to be consistent 
with Investigator Brochure (update as per PACL 
dated 09-Nov-2021) 
• Section 5.5.1: Clarification to the study drug 
characteristics (update as per PACL dated 05-Aug- 
2020) 
• Section 7.2.3: Clarification on when ECG should 
be performed for both treatment arms (update as 
per PACL dated 05-Aug-2020) 
• Section 11.1: Added a statement on deletion of 
data in line with the current Pfizer Protocol 
template Section 11.3: Added a new section on 
Data Protection from the current Pfizer Protocol 
template 
• Sections 12.1 and 12.2: Updated language based 
on the current Pfizer Protocol template 
• Appendix 8: Details on prior amendment to the 


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protocol are now summarized in a new Appendix 
8 
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). 


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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................... 10 
LIST OF FIGURES .................................................................................................................. 10 
APPENDICES .......................................................................................................................... 11 
PROTOCOL SUMMARY ....................................................................................................... 12 
1. INTRODUCTION ................................................................................................................ 31 
1.1. Background .............................................................................................................. 31 
1.2. Mechanism of Action/Indication ............................................................................. 32 
1.3. Rationale for Conducting This Study ...................................................................... 32 
1.4. Rationale for Study Design, Doses and Control Groups ......................................... 33 
1.4.1. Study Design and Control Group ................................................................ 34 
1.4.2. Dose Selection for ATM-AVI ..................................................................... 35 
1.4.3. Dose Selection for Metronidazole ............................................................... 38 
1.4.4. Dose Selection for Meropenem ................................................................... 38 
1.4.5. Dose Selection for Colistin ......................................................................... 38 
1.5. Single Reference Safety Document ......................................................................... 38 
1.6. Benefits/Risk and Ethical Assessment ..................................................................... 39 
2. STUDY OBJECTIVES AND ENDPOINTS ....................................................................... 41 
2.1. Primary Objective .................................................................................................... 41 
2.2. Secondary Objectives .............................................................................................. 43 
2.3. Safety Objectives ..................................................................................................... 43 
2.4. Tertiary Objectives .................................................................................................. 44 
2.5. Exploratory Objectives ............................................................................................ 45 
2.6. Other Objectives ...................................................................................................... 45 
3. STUDY DESIGN ................................................................................................................. 45 
4. SUBJECT ELIGIBILITY CRITERIA ................................................................................. 49 
4.1. Inclusion Criteria ..................................................................................................... 49 
4.1.1. All Subjects ................................................................................................. 49 
4.1.2. Additional Inclusion Criteria - cIAI Subjects ............................................. 50 
4.1.3. Additional Inclusion Criteria – HAP/VAP Subjects ................................... 52 
CCI 
 
4.2. Exclusion Criteria .................................................................................................... 53 


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4.2.1. All Subjects ................................................................................................. 53 
4.2.2. Additional Exclusion Criteria – cIAI Subjects ........................................... 56 
4.2.3. Additional Exclusion Criteria – HAP/VAP Subjects .................................. 56 
4.3. Subject Enrolment and Randomization ................................................................... 56 
4.4. Randomization Criteria............................................................................................ 57 
4.5. Procedures for Handling Incorrectly Enrolled or Randomized Subjects................. 57 
4.6. Lifestyle Requirements ............................................................................................ 57 
4.6.1. Contraception .............................................................................................. 57 
4.7. Sponsor’s Qualified Medical Personnel................................................................... 58 
5. STUDY TREATMENTS ..................................................................................................... 59 
5.1. Allocation to Treatment ........................................................................................... 59 
5.2. Methods for Ensuring Blinding ............................................................................... 60 
5.3. Methods for Unblinding........................................................................................... 60 
5.4. Subject Compliance ................................................................................................. 60 
5.5. Investigational Product Supplies ............................................................................. 61 
5.5.1. Dosage Forms and Packaging ..................................................................... 61 
5.5.2. Labelling ..................................................................................................... 61 
5.5.3. Preparation and Dispensing ......................................................................... 62 
5.6. Administration (Dose and Treatment Regimen) ..................................................... 62 
5.6.1. ATM-AVI ±MTZ Treatment Arm .............................................................. 62 
5.6.2. MER ±COL Treatment Arm ....................................................................... 63 
5.6.3. Optional Aminoglycosides .......................................................................... 65 
5.6.4. Optional Gram-positive Antibiotics ............................................................ 65 
5.6.5. Changes in Renal Function during Study Treatment .................................. 65 
5.7. Investigational Product Storage ............................................................................... 66 
5.8. Investigational Product Accountability ................................................................... 66 
5.8.1. Destruction of Investigational Product Supplies ......................................... 68 
5.9. Post Study Access to Study Treatment .................................................................... 68 
5.10. Concomitant Treatment(s) ..................................................................................... 68 
5.10.1. Other Concomitant Treatment .................................................................. 72 
5.11. Drug-drug Interaction ............................................................................................ 73 
5.11.1. Aztreonam-avibactam ............................................................................... 73 
5.11.2. Coagulation and Concomitant Use of Anticoagulants ............................. 74 
5.11.3. Other Investigational Products ................................................................. 74 


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6. STUDY PROCEDURES..................................................................................................... 74 
6.1. Screening and Enrollment ....................................................................................... 74 
6.1.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1) ............................. 74 
6.2. Study Period ........................................................................................................... 76 
6.2.1. Visit 2: Baseline Procedures and Day 1 of Treatment (Day 1) .................. 76 
6.2.2. Visit 3 to 15: Ongoing Treatment (Days 2 to 14) ...................................... 78 
6.2.3. Post-Treatment Period ............................................................................... 79 
6.2.3.1. Visit 16: End of Treatment (Within 24 Hours after Last 
Infusion) ............................................................................................ 79 
6.2.3.2. Visit 17: Test of Cure (Day 28 ±3 days) ................................... 80 
6.2.3.3. Visit 18: Late Follow-up (Day 45±3 days) ............................... 82 
6.3. Discontinuation of Investigational Product ............................................................. 82 
6.3.1. Procedures for Discontinuation of a Subject from Investigational 
Product ............................................................................................................ 83 
6.4. Subject Withdrawal ................................................................................................ 83 
6.4.1. Screen Failures ........................................................................................... 84 
6.4.2. Withdrawal of Consent .............................................................................. 84 
6.4.3. Lost to Follow-up ....................................................................................... 84 
7. ASSESSMENTS ................................................................................................................. 85 
7.1. Efficacy Assessments ............................................................................................. 85 
7.1.1. Clinical Response Assessment ................................................................... 85 
7.1.2. Microbiological Response.......................................................................... 87 
7.1.2.1. Microbiological Response Assessment ..................................... 88 
7.2. Safety Assessments ................................................................................................. 89 
7.2.1. Laboratory Safety Assessments ................................................................. 89 
7.2.2. Physical Examination ................................................................................. 92 
7.2.3. ECG ............................................................................................................ 92 
7.2.4. Vital Signs .................................................................................................. 93 
7.2.4.1. Pulse and Blood Pressure ......................................................... 93 
7.2.4.2. Body Temperature .................................................................... 93 
7.2.5. Pregnancy Testing ...................................................................................... 93 
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7.2.6. Other Safety Assessments ........................................................................... 94 
7.2.6.1. Chest X-ray/ CT Scan ................................................................ 94 


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7.2.6.2. Acute Physiology and Chronic Health Evaluation .................... 94 
7.3. Microbiology ........................................................................................................... 94 
7.4. Pharmacokinetics ................................................................................................... 95 
7.4.1. Collection of Plasma Samples for Analysis of Aztreonam-Avibactam ...... 95 
7.4.2. Determination of Drng Concentration ...................................................... 100 
7.4.3. Storage and Destruction of Phannacokinetic Samples ............................. 100 
7.5. Pharmacogenomics: not applicable ....................................................................... 100 
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 ........................................ 102 
7.6.3. Chain of Custody of Biological Samples .................................................. 102 
 
8. ADVERSE EVENT REPORTING .................................................................................... 104 
8.1. Requirements ......................................................................................................... 104 
8.1.1. Additional Details on Recording Adverse Events on the CRF ................. 105 
8.1.2. Eliciting Adverse Event Information ........................................................ 105 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal Section) .......................................................................... 105 
8.1.4. Time Period for Collecting AE/SAE Infonnation ..................................... 105 
8.1.4.1. Reporting SAEs to Pfizer Safety ............................................. 106 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ................ 106 
8.1.5. Causality Assessment ................................................................................ 106 
8.1.6. Sponsor's Repo1iing Requirements to Regulato1y Authorities ................. 107 
8.2. Definitions ............................................................................................................. 107 
8.2.1. Adverse Events ......................................................................................... 107 
8.2.2. Abnonnal Test Findings ............................................................................ 108 
8.2.3. Definitions of Serious Adverse Events ..................................................... 108 
8.2.4. Hospitalization .......................................................................................... 109 
8.3. Severity Assessment. ............................................................................................. 110 


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8.4. Special Situations.................................................................................................. 110 
8.4.1. Protocol-Specified Serious Adverse Events ............................................. 110 
8.4.2. Adverse Events Based on Signs and Symptoms ...................................... 110 
8.4.3. Adverse Events Based on Examinations and Tests.................................. 110 
8.4.4. Exceptions from Standard Adverse Events Collection ............................ 111 
8.4.4.1. Lack of Effect ......................................................................... 111 
8.4.4.2. Disease Progression ................................................................ 111 
8.4.5. Potential Cases of Drug-Induced Liver Injury ......................................... 112 
8.4.6. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure .................................................. 113 
8.4.6.1. Exposure During Pregnancy ................................................... 113 
8.4.6.2. Exposure During Breastfeeding .............................................. 115 
8.4.6.3. Occupational Exposure ........................................................... 115 
8.4.7. Medication Errors..................................................................................... 115 
8.4.7.1. Overdose ................................................................................. 116 
8.5. Management of Laboratory Safety ....................................................................... 117 
8.5.1. Renal Function ......................................................................................... 117 
8.5.2. Monitoring of Liver-related Laboratory Parameters ................................ 117 
9. DATA ANALYSIS/STATISTICAL METHODS ............................................................ 118 
9.1. Sample Size Determination .................................................................................. 118 
9.2. Definitions of Analysis Sets ................................................................................. 118 
9.2.1. Efficacy Analysis Set ............................................................................... 118 
9.2.1.1. Intent-To-Treat (ITT) Analysis Set ......................................... 118 
9.2.1.2. Clinically Evaluable (CE) Analysis Set .................................. 118 
9.2.1.3. Microbiological Intent-To-Treat (micro-ITT) Analysis Set ... 119 
9.2.1.4. Microbiologically Evaluable (ME) Analysis Set .................... 119 
9.2.1.5. Modified Intent-To-Treat Analysis Set ................................... 119 
9.2.1.6. Microbiological Modified Intent-To-Treat (micro-MITT) 
Analysis Set .................................................................................... 119 
9.2.2. Safety Analysis Set .................................................................................. 120 
9.2.3. Population Pharmacokinetic (popPK) Analysis Set ................................. 120 
9.2.4. Other Analysis Sets .................................................................................. 120 
9.2.4.1. All Subjects Analysis Set ....................................................... 120 


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9.3. Outcome Measures for Analyses ........................................................................... 120 
9.3.1. Primary Outcome Variable ....................................................................... 120 
9.3.2. Secondary Outcome Variables .................................................................. 120 
9.3.3. Tertiary Outcome Variables ...................................................................... 121 
9.3.4. Exploratory Outcome Variables ................................................................ 121 
9.3.5. Safety Variables ........................................................................................ 122 
9.4. Methods for Statistical Analyses ........................................................................... 122 
9.4.1. Analysis of the Primary Variable .............................................................. 122 
9.4.2. Analysis of the Secondary/Tertiary Variable(s) ........................................ 123 
9.4.3. Subgroup Analysis .................................................................................... 123 
9.4.4. Interim Analysis ........................................................................................ 124 
9.4.5. Supportive Analyses ................................................................................. 124 
9.4.6. Exploratory Analysis ................................................................................. 124 
9.4.7. Analysis Methods for Safety Variables ..................................................... 124 
9.5. Data Monitoring Committee .................................................................................. 125 
9.6. Independent Clinical Hepatologist Review of Potential Hy’s Law Cases ............ 125 
9.7. Independent Adjudication Committee ................................................................... 125 
10. QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 126 
11. DATA HANDLING AND RECORD KEEPING ............................................................ 126 
11.1. Case Report Forms/Electronic Data Record ........................................................ 126 
11.2. Record Retention ................................................................................................. 127 
11.3. Data Protection .................................................................................................... 127 
12. ETHICS ............................................................................................................................ 128 
12.1. Regulatory and Ethical Considerations ................................................................ 128 
12.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ........................................................................................................ 129 
12.2. Subject Information and Consent ........................................................................ 129 
12.3. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .......................................................................................................................... 130 
13. DEFINITION OF END OF TRIAL ................................................................................. 130 
13.1. End of Trial in a Member State ........................................................................... 130 
13.2. End of Trial in All Other Participating Countries ................................................ 131 
14. SPONSOR DISCONTINUATION CRITERIA ............................................................... 131 


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15. PUBLICATION OF STUDY RESULTS ........................................................................ 131 
15.1. Communication of Results by Pfizer ................................................................... 131 
15.2. Publications by Investigators ............................................................................... 132 
16. REFERENCES ................................................................................................................. 134 
 
LIST OF TABLES 
Table 1. 
Schedule of Activities .......................................................................................... 25 
Table 2. 
Identity of Investigational Product ....................................................................... 61 
Table 3. 
ATM-AVI Doses in Relationship to CrCL .......................................................... 62 
Table 4. 
MER Doses in Relationship to CrCL ................................................................... 63 
Table 5. 
COL Doses in Relationship to CrCL .................................................................... 64 
Table 6. 
Allowed Concomitant Medications ....................................................................... 69 
Table 7. 
Restricted Concomitant Medications .................................................................... 71 
Table 8. 
Prohibited Concomitant Medications .................................................................... 71 
Table 9. 
Definition of Clinical Response Categories at the EOT and TOC visits .............. 86 
Table 10. Definition of Microbiological Response Categories at the EOT and TOC 
Visits, for Each Pathogen Identified at Initial/Pre Study (Study Qualifying) 
Culture ................................................................................................................... 87 
Table 11. 
Definition of Emergent Infection Categories ........................................................ 89 
Table 12. 
Laboratory Safety Variables ................................................................................. 91 
Table 13. 
Pharmacokinetic ATM-AVI Sample Collection Time Points............................... 97 
Table 14. 
Volume of Blood to Be Drawn from Each Subject ............................................. 101 
 
 
LIST OF FIGURES 
Figure 1 Study Outline ............................................................................................................ 47 
Figure 2 
Study Treatment ................................................................................................... 48 
Figure 3 
ATM-AVI Pharmacokinetic Sample Collection Time-Points for Subjects 
with CrCL >30mL/min (Q6h Maintenance Dose) ............................................... 98 
Figure 4 
ATM-AVI Pharmacokinetic Sample Collection Time-Points for Subjects 
with CrCL >15 to ≤30 mL/min (Q8h Maintenance Dose) .................................... 99 


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APPENDICES 
Appendix 1. Abbreviations .................................................................................................... 140 
Appendix 2. International Airline Transportation Association (IATA) 6.2 Guidance 
Document ........................................................................................................... 145 
Appendix 3. Calculation of Estimated Creatinine Clearance ................................................ 146 
Appendix 4. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ..................................................................................... 147 
Appendix 5. Acute Physiology and Chronic Health Evaluation - APACHE II Score .......... 153 
Appendix 6. Microbiological Assessments ........................................................................... 159 
Appendix 7. Colistin Conversion Table ................................................................................ 163 
Appendix 8. Summary of Changes from Original Protocol through Amendment ................ 164 


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PROTOCOL SUMMARY 
Background and Rationale 
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. In particular, ongoing 
surveillance studies have demonstrated an increasing frequency of antibiotic resistance 
among MDR Gram-negative bacteria. Of particular concern is the spread of metallo 
β-lactamase (MBL) producing isolates, which are often MDR. The combination product 
aztreonam-avibactam (ATM-AVI) is being developed for intravenous (IV) treatment of 
serious infections caused by Gram-negative pathogens producing MBL in addition to other 
β-lactamases. 
Study sites and number of subjects planned 
The study is planned to be performed in approximately 170 sites in up to 30 countries in the 
Americas, Africa, Europe, and Asia, in regions with emerging and/or elevated incidence of 
carbapenem resistance, including resistance caused by MBLs. 
Up to approximately 425 subjects with a diagnosis of complicated intra-abdominal infections 
or hospital-acquired pneumonia/ventilator-associated pneumonia will be randomized in this 
study, including approximately 283 randomized in the aztreonam-avibactam±metronidazole 
treatment arm and approximately 142 in the meropenem ±colistin treatment arm. 
Objectives and Endpoints 
Objectives 
Based on differing regulatory requirements for European Medicines Agency and US Food 
and Drug Administration, the following objectives and outcome measures may differ for the 
United States and non United States countries analyses as noted below. 
 
Primary Objective: 
Primary Endpoint: 
To evaluate the efficacy of 
aztreonam-avibactam ±metronidazole and 
meropenem ±colistin at Test of Cure visit 
for the treatment of serious infections due 
to Gram-negative bacteria, including 
those due to 
metallo-β-lactamase-producing multidrug 
resistant pathogens. 
Proportion of subjects with clinical cure at 
Test of Cure visit in the Intent-To-Treat and 
Clinically Evaluable analysis sets (Note: For 
non-United States countries, the 
Intent-To-Treat and Clinically Evaluable are 
considered co-primary analysis sets. For the 
US, the Intent-To-Treat is considered the 
primary analysis set, while Clinically 
Evaluable is secondary). 


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Secondary Objectives: 
Secondary Endpoint(s): 
To evaluate efficacy of 
aztreonam-avibactam ±metronidazole and 
meropenem ±colistin at the Test of Cure 
visit in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 
Proportion of subjects with clinical cure at the 
Test of Cure visit in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 
To evaluate the efficacy of 
aztreonam-avibactam ±metronidazole and 
meropenem ±colistin at the Test of Cure 
visit in key sub populations. 
• Proportion of subjects with clinical cure at 
the Test of Cure visit by infection type in 
the Intent-To-Treat and Clinically 
Evaluable analysis sets. 
• Proportion of subjects with clinical cure at 
the Test of Cure visit for subjects with 
metallo-β-lactamase-positive pathogens in 
the microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
To assess the per-subject microbiological 
response to aztreonam-avibactam 
±metronidazole and meropenem ±colistin 
at the Test of Cure visit. 
Proportion of subjects with a favorable 
per-subject microbiological response at the 
Test of Cure visit in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable 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 and microbiological 
Intent-To-Treat analysis sets. 
To evaluate the pharmacokinetics of 
aztreonam and avibactam in subjects with 
serious infections and to characterize the 
relationship between exposure and 
clinical and microbiological response for 
aztreonam-avibactam ±metronidazole 
utilization (listings to be provided in the 
Clinical Study Report, analysis to be 
reported outside of the Clinical Study 
Report). 
• Pharmacokinetics of aztreonam and 
avibactam in subjects in the population 
pharmacokinetic analysis set. 
• Pharmacokinetic/pharmacodynamic 
relationship between exposure and clinical 
and microbiological response for 
aztreonam-avibactam ±metronidazole in 
the population pharmacokinetic analysis 
set. 


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Safety Objective: 
Safety Endpoint: 
To evaluate the safety and tolerability 
profile of aztreonam-avibactam 
±metronidazole and meropenem 
±colistin. 
Safety and tolerability as assessed by adverse 
events, physical examination, vital signs, 
electrocardiograms, and laboratory 
assessments in the safety analysis set. 
 
 
Tertiary Objectives: 
Tertiary Endpoint(s): 
To evaluate the efficacy of 
aztreonam-avibactam±metronidazole and 
meropenem ±colistin at the End of 
Treatment visit. 
Proportion of subjects with clinical cure at the 
End of Treatment visit in the Intent-To-Treat, 
microbiological Intent-To-Treat, Clinically 
Evaluable and Microbiologically Evaluable 
analysis sets. 
To evaluate the efficacy of 
aztreonam-avibactam ±metronidazole and 
meropenem ±colistin at the End of 
Treatment visit in key sub populations. 
• Proportion of subjects with clinical cure at 
the End of Treatment visit by infection 
type in the Intent-To-Treat and Clinically 
Evaluable analysis sets. 
• Proportion of subjects with clinical cure at 
the End of Treatment visit for subjects 
with metallo-β-lactamase-positive 
pathogens in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 
To evaluate the efficacy of 
aztreonam-avibactam ±metronidazole and 
meropenem ±colistin at End of Treatment 
and Test of Cure visits by pathogen 
resistance types. 
Proportion of subjects with clinical cure at End 
of Treatment and Test of Cure visits by 
Pathogen resistance type 
(eg, aztreonam-non-susceptible, 
extended-spectrum β-lactamase-positive, 
carbapenamase-positive, etc) in the 
microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
To assess the per-subject microbiological 
response to aztreonam-avibactam 
±metronidazole and meropenem ±colistin 
at End of Treatment visit. 
Proportion of subjects with a favorable 
per-subject microbiological response at the 
End of Treatment in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 


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Tertiary Objectives: 
Tertiary Endpoint(s): 
To assess the microbiological response 
by pathogen and by pathogen resistance 
type to aztreonam avibactam 
±metronidazole and meropenem ±colistin 
at End of Treatment and Test of Cure 
visits. 
• Proportion of subjects with a favorable 
per-pathogen microbiological response at 
the End of Treatment and Test of Cure 
visits in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 
• Proportion of subjects with a favorable 
per-subject microbiological response by 
pathogen resistance type 
(eg, aztreonam-non-susceptible, 
extended-spectrum β-lactamase-positive, 
carbapenamase-positive, 
metallo-β-lactamase positive) at the End of 
Treatment and Test of Cure visits in the 
microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
• Proportion of subjects with a favorable 
per-pathogen microbiological response by 
pathogen resistance type 
(eg, aztreonam-non-susceptible, 
extended-spectrum β-lactamase-positive, 
carbapenamase-positive, 
metallo-β-lactamase-positive) at the End of 
Treatment and Test of Cure visits in the 
microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 


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Exploratory Objectives: 
Exploratory Endpoint(s): 
To evaluate efficacy of 
aztreonam-avibactam ±metronidazole and 
meropenem ±colistin using objective 
clinical measures. 
Composite endpoint including symptom-based 
objective clinical measures, to be defined in 
the Statistical Analysis Plan (Intent-To-Treat 
and clinically evaluable analysis sets). 
To assess 14-day all-cause mortality. 
Proportion of subjects who died on or before 
14 days from randomization in the 
Intent-To-Treat analysis set. 
To evaluate health resource utilization 
(listings to be provided in the Clinical 
Study Report, analysis to be reported 
outside of the Clinical Study Report). 
• Length of hospital stay, including any 
readmissions up to Test of Cure (days). 
• Length of study treatment (days). 
• Length of intensive care unit stay (days). 
• Transferred 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 Test of Cure visit) for 
complicated intra-abdominal infection 
subjects. 
Supportive Analyses 
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). 
An additional descriptive analysis will be performed for clinical cure at Test of Cure using 
the modified Intent-To-Treat population which comprises subjects who were randomized and 
received any amount of intravenous study drug. 
Additional descriptive analyses will also be performed for the secondary and tertiary 
outcomes of clinical cure rate and microbiological favourable response rate at End of 
Treatment and Test of Cure using the microbiological modified Intent-To-Treat which is a 
subset of the microbiological Intent-To-Treat comprising those subjects who received any 
amount of intravenous study drug. 


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Study Design 
This is a Phase 3 prospective, randomized, multicenter, open-label, central assessor-blinded, 
parallel group, comparative study to detennine the efficacy, safety, and tolerability of 
azti·eonam-avibactam ±meti·onidazole versus meropenem ±colistin in the ti·eatinent of 
hospitalized adults with complicated inti·a-abdominal infection or nosocomial pneumonia 
including hospital-acquired pneumonia and ventilator-associated pneumonia, in regions with 
endemic or emerging carbapenem resistance, and where metallo-j3-lactamase-producing 
multidrng resistant pathogens are suspected. 
The study will consist of a Screening visit (Visit 1), a Baseline visit (Visit 2) on Day 1 of the 
study ti·eatinent, ongoing ti·eatinent visits (Visits 3 to 15) from Day 2 to Day 14, an End of 
Treatinent visit (Visit 16) within 24 hours after the last infusion, a Test of Cure visit 
(Visit 17) on Day 28 (±3 days) and a Late Follow-Up visit (Visit 18) on Day 45 (±3 days). 
Subjects will be randomized in a 2:1 ratio to the azti·eonam-avibactam±meti·onidazole 
ti·eatinent ann or the meropenem±colistin h'eatment aim. Randomization will be sti·atified 
based on infectious disease type (complicated inti·a-abdominal infection and 
hospital-acquired pneumonia/ventilator-associated pneumonia). For complicated 
inti-a-abdominal infection, subjects will also be sti·atified by Acute Physiology and Chronic 
Health Evaluation score ( 10 and>10) (Appendix 5). For hospital-acquired 
pneumonia/ventilator-associated pneumonia, subjects will also be sti·atified by mechanical 
ventilation status (YIN). 
For subjects randomized to azti·eonam-avibactam±meh'onidazole, spai·se blood samples will 
be collected for population phannacokinetic assessments and 
phannacokinetic/phannacodynamic 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 visit. 
Paiiicipants in the study must be inpatients at the study site institution to receive study 
medication. 
Target Subject Population 
Adult hospitalized subjects with a confomed diagnosis of complicated inti-a-abdominal 
infection or hospital acquired pneumonia/ventilator associated pneumonia related to 
Gram-negative pathogens including, but not limited to, those infected with multidrng 


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resistant strains, and requiring administration of intravenous antibacterial treatment will be 
enrolled in this study. 
The study will randomize up to approximately 425 subjects (at least 300 subjects with 
complicated intra-abdominal infection anticipated). The number of complicated 
intra-abdominal infection subjects with a perforated appendix or appendiceal abscess will be 
limited to approximately 40% of the study population with complicated intra-abdominal 
infections. 
Study Treatments 
Duration of Treatment 
The recommended minimal duration of treatment in this study is 5 days for complicated 
intra-abdominal infections and 7 days for hospital acquired pneumonia/ventilator associated 
pneumonia. The maximal duration of treatment is 14 days. 
Investigational Product, Dosage Form and Strength 
 
Investigational product 
Dosage form and strength 
Test product 
Aztreonam-Avibactam 
Aztreonam for injection, lyophilised powder 
for solution for infusion 2 g 
Avibactam lyophilisate for concentrate for 
infusion 600 mg 
Comparators 
Meropenem 
Meropenem 1 g powder for solution for 
infusion 
Colistin 
Colistin 2 million international units powder 
for solution for infusion 
Co-administered drug 
Metronidazole 
Metronidazole 500 mg/100 ml solution for 
infusion 
 
Note: Aztreonam and avibactam will be provided as separate vials for reconstitution and mixed together in a 
saline bag for co-administration at the appropriate concentration for intravenous infusion. 
Note: Comparators and co-administered drug are supplied centrally via the sponsor. In some instances, locally 
obtained commercial supplies will be utilized in accordance with local regulations. 
Note: Aztreonam, Meropenem, Colistin and Metronidazole are commercial products over-labeled with the study 
clinical label. 
 
All investigational products will be administered by intravenous infusion. Aztreonam and 
avibactam will be supplied as vials for reconstitution. The investigational 
aztreonam-avibactam will be prepared for co-administration in saline using standard aseptic 
intravenous infusion technique (see investigational product (IP) manual). 


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Aztreonam-avibactam±metronidazole 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 treatment). 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 5.6.1. 
 
Creatinine 
Clearance 
(mL/min)* 
Loading 
dose of 
aztreonam- 
avibactam 
(by 
intravenous 
infusion 
over 
30 minutes) 
Extended 
loading dose 
of 
aztreonam- 
avibactam 
immediately 
following the 
loading dose 
(by 
intravenous 
infusion 
over 
3 hours) 
Time interval 
between end of 
extended 
loading dose 
and start of first 
maintenance 
dose 
Maintenance 
dose of 
aztreonam- 
avibactam 
(by 
intravenous 
infusion over 
3 hours) 
Frequency 
of 
aztreonam- 
avibactam 
maintenance 
dose 
>50 
500 mg 
aztreonam 
plus 167 mg 
avibactam 
1500 mg 
aztreonam 
plus 500 mg 
avibactam 
3 hours 
1500 mg 
aztreonam 
plus 500 mg 
avibactam 
Every 
6 hours 
>30 to 50 
500 mg 
aztreonam 
plus 167 mg 
avibactam 
1500 mg 
aztreonam 
plus 500 mg 
avibactam 
3 hours 
750 mg 
aztreonam 
plus 250 mg 
avibactam 
Every 
6 hours 
>15 to 30 
675 mg 
aztreonam 
plus 225 mg 
avibactam 
675 mg 
aztreonam 
plus 225 mg 
avibactam 
5 hours 
675 mg 
aztreonam 
plus 225 mg 
avibactam 
Every 
8 hours 
*Estimated creatinine clearance using Cockcroft-Gault formula rounded to the nearest whole number (see 
Appendix 3). 
 
Creatinine clearance should be monitored daily through the local laboratory from Day 1 to 
Day 4 (and Day 3 or 5 by the central laboratory, if PK samples are to be collected on 
Days 3 or 5) and then as clinically indicated. In the case that renal impairment recovers or 
deteriorates during the treatment period, the dose of aztreonam-avibactam 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 ≤15 mL/min) and there is a requirement to start 
renal replacement therapy, the Investigator should discontinue aztreonam-avibactam therapy. 
In addition to aztreonam-avibactam, subjects with complicated intra-abdominal infection in 
this treatment arm will also receive intravenous metronidazole 500 mg every 8 hours (by 


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intravenous infusion over 60 minutes), starting after the extended loading dose of 
aztreonam-avibactam has completed and maintained until the end of the intravenous study 
treatment period. The Summary of Product Characteristics (Baxter Healthcare Ltd) does not 
indicate a dose reduction for metronidazole in subjects with renal impairment. 
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. 
Meropenem ±Colistin Treatment Arm: 
Subjects will initially be given meropenem 1000 mg every 8 hours (given as an intravenous 
infusion over 30 minutes). If a meropenem-resistant pathogen is strongly suspected, a dose 
of meropenem 2000 mg every 8 hours can be used (given as an intravenous infusion over 
3 hours). Colistin (colistimethate sodium) can also be initiated, at the Investigator’s 
discretion. Colistin will be dosed based on guidance described by the European Medicines 
Agency (see Clinical Study Protocol Section 5.6.2). 
If a meropenem-resistant Gram-negative pathogen is subsequently isolated, colistin 
(colistimethate sodium) can be added (if not already started), and/or the dose of meropenem 
can be increased to 2000 mg every 8 hours (given as an intravenous infusion over 3 hours), if 
this dose was not already used initially. 
If a meropenem-susceptible Gram-negative pathogen is subsequently isolated and colistin 
(colistimethate sodium) had been initially started, the colistin (colistimethate sodium) should 
be discontinued and the dose of meropenem adjusted to the labeled dose regimen (1 g every 
8 hours intravenously over 30 min, if a meropenem dose of 2000 mg every 8 hours was 
initially started). 
Meropenem ±colistin doses will need to be adjusted for subjects with renal impairment. The 
dose of meropenem will need to be further adjusted once the susceptibility of the baseline 
Gram-negative pathogen(s) to meropenem is known. 
Subjects with hospital-acquired pneumonia/ventilator-associated pneumonia and proven or 
suspected co-infection with Pseudomonas aeruginosa may receive adjunctive therapy with 
an intravenous aminoglycoside (eg, amikacin, gentamicin or tobramycin, based upon local 
practice and epidemiology) at the Investigator's discretion at any time during the treatment 
period. For subjects receiving colistin (colistimethate sodium), adjunctive aminoglycosides 
therapy should not be used concurrently; treatment with colistin (colistimethate sodium) 
should be discontinued prior to initiating aminoglycoside therapy. 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 


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isolated or is no longer suspected, or susceptibility results indicate a carbapenem-susceptible 
strain. 
If Pseudomonas aeruginosa is isolated and is non-susceptible to meropenem, an intravenous 
aminoglycoside may be added to meropenem if not originally commenced. Colistin should 
be discontinued if meropenem and aminoglycoside are being used together. 
Statistical Methods 
The study will randomize up to approximately 425 subjects in a 2:1 randomization ratio 
(approximately 283 subjects randomized to the aztreonam-avibactam ±metronidazole 
treatment arm and approximately 142 subjects to the meropenem ±colistin treatment arm). 
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 planned 
sample size 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 all subjects analysis set will compromise all enrolled subjects for the study and will be 
used for reporting of disposition. 
The Intent-To-Treat analysis set will include all randomized subjects regardless of receipt of 
study drug. Subjects in the Intent-To-Treat analysis set will be analyzed according to the 
treatment they are randomized to. The Intent-To-Treat analysis set will be used to evaluate 
the primary, secondary and tertiary objectives. 
The safety analysis set will be used for reporting safety data and will include all subjects who 
received any amount of intravenous study treatment. Subjects in the safety analysis sets will 
be analyzed according to the treatment they receive. 
The Clinically Evaluable analysis set is defined as all subjects who: 
• Meet the definition of the Intent-To-Treat analyses. 
• Meet disease criteria for diagnosis of complicated intra-abdominal infection or 
hospital-acquired pneumonia/ventilator-associated pneumonia. 
• Received at least 48 hours of study treatment (aztreonam-avibactam±metronidazole or 
meropenem±colistin) or received <48 hours of study treatment before discontinuing study 
drug due to an adverse event. 
• Did not receive concomitant antibiotic treatment with potential activity against any 
baseline pathogens between the time of first dose of study treatment and the time of Test 
of Cure. This does not include those subjects who have received protocol-allowed 


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antibiotics or have failed study treatment and require additional antibiotics to treat their 
infection. 
• Had no important protocol deviations that may affect the assessment of efficacy (to be 
defined in the Statistical Analysis Plan). 
• Did not have a clinical outcome of indeterminate at Test of Cure. 
• Did not have monomicrobial infections due to non-eligible pathogens (eg, any 
Acinetobacter spp., Pseudomonas aeruginosa) and did not have only Gram-positive 
pathogens. 
Subjects in the Clinically Evaluable analysis set will be analyzed according to the treatment 
they are randomized to. The Clinically Evaluable analysis set will be used to evaluate 
selected primary, secondary and tertiary objectives. 
The microbiological Intent-To-Treat analysis set is a subset of the Intent-To-Treat analysis 
set and includes all subjects who have at least 1 Gram-negative pathogen in an adequate 
initial/prestudy culture. Subjects with monomicrobial infections due to any Acinetobacter 
spp., and those subjects with only Gram-positive pathogens will be excluded from the 
microbiological Intent-To-Treat analysis set. The microbiological Intent-To-Treat analysis 
set will be used to evaluate selected secondary and tertiary objectives. 
The Microbiologically Evaluable analysis set includes all subjects included in both 
microbiological Intent-To-Treat and Clinically Evaluable analysis sets, with at least 
1 Gram-negative pathogen. The Microbiologically Evaluable analysis set will be used to 
evaluate selected secondary and tertiary objectives. 
Sensitivity analyses will be performed using the modified Intent-To-Treat and 
microbiological modified Intent-To-Treat. The modified Intent-To-Treat and 
microbiological modified Intent-To-Treat are subsets of the Intent-To-Treat and 
microbiological Intent-To-Treat respectively and include all randomized subjects who 
receive any amount of intravenous study drug. 
The population pharmacokinetic analysis set includes all subjects who have at least 1 plasma 
concentration data assessment available for aztreonam-avibactam±metronidazole and will be 
used to report all pharmacokinetic 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 will be made. 


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Methodology for dealing with missing data will be specified in the Statistical Analysis Plan. 
The primary descriptive efficacy analysis (for non-United States countries) will be the 
estimate of the clinical cure rate and 95% confidence interval in each treatment arm 
(aztreonam-avibactam±metronidazole and meropenem±colistin) in the Intent-To-Treat and 
Clinically Evaluable co-primary analysis sets. The estimate of the clinical cure rate and 95% 
confidence interval in each treatment arm in the Intent-To-Treat analysis set will be the 
primary analysis for the United States. Single arm confidence intervals will be computed 
using Jeffrey’s method (Brown et al 2001; Cai 2005). 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 Intent-To-Treat and Clinically Evaluable 
analysis sets at the Test of Cure visit. 
The primary analysis will be conducted using the clinical response assessment determined by 
a blinded independent adjudication committee. The Investigator’s assessment of clinical 
response will also be summarized for the Intent-To-Treat and Clinically Evaluable analysis 
sets at the Test of Cure 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. 
Difference in clinical cure rate between treatment arms at Test of Cure visit 
(aztreonam-avibactam ±metronidazole minus meropenem ±colistin) and corresponding 
two-sided 95% confidence interval will be calculated for the Intent-To-Treat and Clinically 
Evaluable analysis sets. The two-sided 95% confidence interval for the observed difference 
in the cure rates (aztreonam-avibactam ±metronidazole group minus meropenem ±colistin 
group) will be computed using the method proposed for unstratified designs by Miettinen and 
Nurminen and an additional supporting descriptive analysis will be conducted using the 
stratified Miettinen and Nurminen method (Miettinen and Nurminen 1985), if each stratum 
has at least 3 subjects per each treatment group. 
Clinical response summaries will be presented for the overall population, and also split by 
infection type (complicated intra-abdominal infection or hospital-acquired pneumonia/ 
ventilator-associated pneumonia), and by resistance group (eg, extended-spectrum 
β-lactamase status, carbapenemase status and metallo-β-lactamase status) as 
secondary/tertiary descriptive analysis. 
Secondary and tertiary efficacy outcome measures will be presented using the same methods 
as the primary outcome measures. For descriptive secondary and tertiary outcome measures, 
number and percentage in each treatment arm will be tabulated. 
The final pharmacokinetic data will be pooled with data from other studies to conduct a 
population pharmacokinetic analysis (using Nonlinear Mixed Effects Modelling). Using 
these parameter estimates (mean pharmacokinetic parameters including inter individual 
variance estimates), Monte-Carlo simulation will be undertaken and potential 
pharmacokinetic/pharmacodynamic relationships will be explored. Aztreonam and 
avibactam plasma concentrations versus time will be depicted graphically in the Clinical 


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Study Report (CSR). Full details of the pharmacokinetic and 
pharmacokinetic/pharmacodynamic analysis will be given in the Pharmacokinetic Modeling 
Analysis Plan. These results will be reported separately. 
For exploratory efficacy 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 response endpoint utilising objective measures of clinical response will be 
detailed in the Statistical Analysis Plan. 
Regarding 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 End of 
Treatment] [treatment emergent adverse events], from End of Treatment to Late Follow-Up, 
and for the full study period [from first dose to Late Follow-Up]). All 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. 
Subgroup analyses, which may include subject characteristics, disease severity, prior 
antibiotic use, infection type and pathogen 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 information 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 
Eligibility/ 
Screeninga 
Treatment period 
EOT 
TOC 
LFU 
Visit 1 
Visit 2 
Visits 3 to 15 
Visit 16 
Visit 17 
Visit 18 
Procedures and Assessments 
Days –1 
to 1 
Day 1 
(Baselineb) 
Days 2 to 14 
Within 
24 hours 
after last 
infusion 
Day 28 
±3 days 
Day 45 
±3 days 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
X 
Demographics 
X 
Medical history 
X 
APACHE II score (see Appendix 5)c 
X 
Prior and concomitant medications 
(including prior antibiotic treatment) 
X 
X 
Daily 
X 
X 
X 
Complete physical examination 
X 
X 
X 
Assess infection-related signs and 
symptoms 
X 
X 
Daily 
X 
X 
Perform focused physical examination 
X 
X 
Daily 
X 
X 
Xd 
Vital sign measurementse 
X 
X 
Daily 
X 
X 
12-lead digital triplicate ECG 
X 
Day 3 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Eligibility/ 
Screeninga 
Treatment period 
EOT 
TOC 
LFU 
Visit 1 
Visit 2 
Visits 3 to 15 
Visit 16 
Visit 17 
Visit 18 
Procedures and Assessments 
Days –1 
to 1 
Day 1 
(Baselineb) 
Days 2 to 14 
Within 
24 hours 
after last 
infusion 
Day 28 
±3 days 
Day 45 
±3 days 
Chest X-ray or computed tomography 
scan (for HAP/VAP subjects only) 
Xf 
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 
Document whether subject is ventilated 
(for HAP/VAP subjects only) 
X 
X 
Daily 
X 
X 
Serious and non-serious adverse event 
monitoring 
X 
X 
Daily 
X 
X 
X 
Culture of abdominal site infection (for 
cIAI subjects only)g 
At surgical 
interventio 
n 
At surgical 
interventio 
n 
As clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 
Respiratory specimen for Gram- 
stain/culture (for HAP/VAP subjects 
only) 
Xh 
Xi 
As clinically 
indicated 
Xj 
X 
Blood culturesk 
Xk 
As 
clinically 
indicatedk 
As clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Eligibility/ 
Screeninga 
Treatment period 
EOT 
TOC 
LFU 
Visit 1 
Visit 2 
Visits 3 to 15 
Visit 16 
Visit 17 
Visit 18 
Procedures and Assessments 
Days –1 
to 1 
Day 1 
(Baselineb) 
Days 2 to 14 
Within 
24 hours 
after last 
infusion 
Day 28 
±3 days 
Day 45 
±3 days 
Safety laboratories (chemistry, 
hematology, urinalysis)l 
X 
X 
Central lab 
samples: Every 
3 days, starting on 
Day 4; Local lab 
serum creatinine: 
Daily from Day 2 
to Day 4, and as 
clinically 
indicated 
X 
X 
Collection of arterial blood gases 
Xm 
As 
clinically 
indicated 
As clinically 
indicated 
As clinically 
indicated 
Blood for PK analysisn 
Xo 
Day 4p 
Estimate CrCLq 
X 
X 
Daily from 
Day 2 to 
Day 4 and as 
clinically 
indicated 
As clinically 
indicated 
As 
clinically 
indicated 
Serum or urine β-hCG for women of 
childbearing potentialr 
X 
Contraception checks 
X 
X 
Daily 
X 
X 
Randomization 
X 
Administer study treatment 
X 
Daily 


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Table 1. 
Schedule of Activities 
 
Visit Name 
Eligibility/ 
Screeninga 
Treatment period 
EOT 
TOC 
LFU 
Visit 1 
Visit 2 
Visits 3 to 15 
Visit 16 
Visit 17 
Visit 18 
Procedures and Assessments 
Days –1 
to 1 
Day 1 
(Baselineb) 
Days 2 to 14 
Within 
24 hours 
after last 
infusion 
Day 28 
±3 days 
Day 45 
±3 days 
Clinical response assessment 
X 
X 
Mortality assessment 
X 
Daily 
X 
X 
Abbreviations: ABG=arterial blood gas; ALP=alkaline phosphatase; ALT=alanine aminotransferase; APACHE=Acute Physiology and Chronic Health 
Evaluation; AST=aspartate aminotransferase; ATM-AVI=aztreonam-avibactam; BAL=bronchoalveolar lavage; β-hCG=β-human chorionic gonadotropin; 
cIAI=complicated intra-abdominal infections; CrCL=creatinine clearance; ECG=electrocardiogram; EOT=end of treatment; HAP=hospital-acquired pneumonia; 
INR=international normalized ratio; LFU=late follow-up; MTZ=metronidazole; PSB=protected-specimen brush; PK=pharmacokinetics; TBili=total bilirubin; 
TOC=test of cure; ULN=upper limit of normal; VAP=ventilator-acquired pneumonia. 
a. 
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. 
b. All procedures at Visit 2 are to be done before first dose of study therapy except for PK sampling. The repeat safety lab samples (including local lab for 
eligibility criteria confirmation) and clinically relevant cultures are only required if Visit 1 and Visit 2 are separated by surgery OR are >12 hours apart (see 
Section 6.2.1). Administration of the first dose of IV study therapy marks the beginning of study treatment Day 1. 
c. 
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 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). 
d. 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. 
e. 
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 


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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. 
f. 
Performing a chest X-ray or CT scan (if not available within 48 hours prior to randomization) in subjects with HAP/VAP. 
g. Specimens must be obtained for culture at initial qualifying surgical procedure (performed within 24 hours before or after randomization). If additional 
surgical procedures are performed, additional abdominal site specimens should be obtained for microbiological culture (see Appendix 6). 
h. Cultures from respiratory specimens obtained within 48 hours prior to randomization may be used, but subjects ventilated subsequently, regardless of 
whether they meet the criteria for VAP, must have a specimen obtained while ventilated. 
i. 
Repeat of culture of respiratory specimens are not required, unless a Screening 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 via BAL, miniBAL, PSB 
sample or endotracheal aspirate at the Baseline visit (prior to the first dose of study treatment) (see Appendix 6). 
j. 
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. 
k. All subjects must have had 2 sets 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. When obtaining samples for blood culture, blood should be collected from 2 sites (see Appendix 6). All subjects require 2 sets of blood 
cultures (1 anaerobic and 1 aerobic bottle from each site, ie, 4 bottles in total). For subjects who are bacteremic at any time during the study, repeat blood 
cultures should be performed at least every 3 days, until clearance of bacteremia is documented. Blood cultures should also be obtained as clinically 
indicated. See Section 7.3 and Appendix 6 for details of sample collection. 
l. 
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 listed 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 (Section 8.5.2), 
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. 
m. For HAP/VAP subjects – obtaining arterial blood sample for ABG (required for ventilated subjects, recommended for non-ventilated subjects); for cIAI 
subjects- obtaining arterial blood sample for ABG as clinically indicated. 
n. PK sampling is only relevant for subjects randomized to ATM-AVI ±MTZ. 
o. 3 samples should be taken on Day 1 - see Table 13 and Figure 3 and Figure 4 for detailed guidance on schedule. 
p. 3 samples have to be taken on Day 4±1 day - see Table 13 and Figure 3 and Figure 4 for detailed guidance on schedule. 
q. Subjects must be frequently and closely monitored for rapidly changing CrCL through local laboratory measurement of serum creatinine. 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 5.6.5. In addition, to coincide with PK sample collection for patients 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 


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can be collected on Days 3 or 5. CrCL will therefore also be estimated on Days 3 or 5 if PK blood samples are collected on Days 3 or 5. In this case, a 
blood sample for estimation of serum creatinine will also be collected on Days 3 or 5 and sent to the central laboratory. (See Appendix 3) 
r. 
Serum or urine β-hCG for pregnancy test will performed in local laboratory for eligibility determination. 
s. 
The contraception check is an opportunity to confirm that contraception is used consistently and correctly for the duration of the study and for at least 7 days 
after the last infusion of investigational product. Also, for studies enrolling adult subjects, it is the opportunity to assess changing potential to father/bear 
children and allows for altering contraception if new disease contraindicates a selected method of contraception or if nonchildbearing status is achieved. 


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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). 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). 
One of the most common resistance mechanisms in Gram-negative pathogens is the 
production of extended-spectrum β-lactamase (ESBL) (Lucasti et al. 2013). 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). 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). 
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). 
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 
including but not limited to pneumonia and complicated intra abdominal infections (cIAIs) 
(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 Gram-negative bacteria 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. 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 enrolment 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. 
This ATM-AVI Phase 3 study is part of the Work Package 2B (WP2B) in the Innovative 
Medicines Initiative (IMI) supported COMBACTE-CARE project. IMI is a joint 
undertaking between the EU and the pharmaceutical industry association European 
Federation of Pharmaceutical Industries and Associations (EFPIA) (see IMI). 
COMBACTE-CARE (Combatting Bacterial Resistance in Europe – Carbapenem-resistence) 
is a consortium of 19 academic and 3 pharmaceutical partners focusing on carbapenem 
resistance in Europe. The study is registered in the EudraCT database with the number 
2017-002742-68. 
1.4. Rationale for Study Design, Doses and Control Groups 
In patients with hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) 
and cIAIs, Gram-negative pathogens, including those producing ESBLs 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, anaerobic organisms are not common causative 
pathogens; therefore ATM-AVI is considered to provide efficient coverage for the pathogens 
causing HAP/VAP. 
Meropenem (MER) has been selected as the comparator because of its established efficacy 
against resistant Gram-negative pathogens isolated in cIAI and HAP/VAP, for which is it 
approved and widely used in these indications due to the spectrum of activity including 
efficacy against ESBL- and AmpC- producing Enterbacteriaceae causing cIAI and 
HAP/VAP (MERREM, 2016; MERONEM SmPC, 2017). It is amongst the treatment 
options recommended as a first-line agent for the treatment of serious bacterial infections due 
to MDR Gram-negative pathogens (Kalil et al. 2016). 
The option to add concomitant therapy with colistin (COL) (colistimethate sodium) is based 
on current standard of care for proven or suspected carbapenem-resistant Enterobacteriaceae 
(CRE) (Nation et al. 2015). Both COL and tigecycline are frequently used in the treatment of 
CRE infections based on demonstrated activity against CRE, yet both agents are associated 
with significant tolerability and safety concerns. Optional COL was chosen for use in the 
comparator arm because it shows more consistent in vitro activity against MBL pathogens 
than tigecycline (Morill et al. 2015; Narayabab et al. 2016; Tängden et al. 2015). 


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The decision to select MER ±COL rather than COL monotherapy as the starting treatment 
regimen was based on current standard of care for serious infections due to Gram-negative 
bacteria, including MBL-producing MDR pathogens (IDSA 2016, Hopkins 2015-2016 and 
Solomkin et al. 2010). Since only a relatively small proportion of sites are likely to have a 
high prevalence of MBLs, many investigators may be reluctant to initiate a patient on COL 
unless they suspect the involvement of an MBL pathogen in the patient’s infection. 
Mandating COL therapy for all patients could expose patients who have only a 
MER-susceptible Gram-negative pathogen to unnecessary risks. Considering the safety 
concerns that are associated with COL, compared with the better-tolerated standard of care 
agents for Gram-negative pathogens, such as high dose MER, the use of COL will be 
optional and at the investigator’s discretion (Jaruratanasirikul et al. 2005, Keel et al. 2011, 
and Li et al. 2006). 
1.4.1. Study Design and Control Group 
This is a Phase 3 prospective, randomized, open-label, central assessor-blinded, parallel 
group, multicenter comparative study to determine the efficacy, safety and tolerability of 
aztreonam-avibactam ±metronidazole (ATM-AVI ±MTZ) versus meropenem ±colistin 
(MER ±COL) in the treatment of serious infections due to Gram-negative bacteria, including 
MBL-producing MDR pathogens for which there are limited or no treatment options. 
The comparative, 2-arm study design is sufficient to provide descriptive estimates of 
efficacy, safety and tolerability for ATM-AVI and comparator in the treatment of patients 
with cIAI or HAP/VAP. 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 ±MTZ versus MER ±COL, respectively) is chosen 
in order to enrich the safety and efficacy data for patients treated with ATM-AVI ±MTZ and 
increase the number of potential MBL-producing Gram-negative pathogens in that group. 
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 or HAP/VAP) 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). Instead, a study design with a blinded central adjudication 
committee is considered to be most appropriate for the proposed ATM-AVI ±MTZ 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, and 28 day mortality. 


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The duration of study drug treatment (5 to 14 days for cIAI 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). 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 170 sites in up to 30 countries in the 
Americas, Africa, Europe, and Asia, in regions with emerging and/or elevated incidence of 
carbapenem resistance, including resistance caused by MBLs.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), EMA “Addendum to the guideline on the 
evaluation of medicinal products indicated for treatment of bacterial infections” 
(EMA 2013), the US FDA Guidance for Industry “Antibacterial Therapies for Patients With 
an Unmet Medical Need for the Treatment of Serious Bacterial Diseases” (FDA 2017), the 
US FDA Guidance for Industry “Complicated Intra-Abdominal Infections: Developing 
Drugs for Treatment” (FDA 2015), and the US FDA Guidance for Industry 
“Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: 
Developing Drugs for Treatment” (FDA 2014). 
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 treatment 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 information collected in 
healthy volunteers and patients to construct a robust population PK model. Furthermore, 
AVI PK and safety data together with PK/PD modelling results obtained during development 
of the new ceftazidime-avibactam (CAZ-AVI) combination product Avycaz in the US 
(Zavicefta in Europe) have been taken into account (FDA prescribing information: 
AVYCAZ 2017, European Commission: Product information Zavicefta 2016). 
Patients will be monitored frequently and closely for rapidly changing creatinine clearance 
(CrCL), and the Investigator will adjust the study drug dose promptly if needed. (See 
Appendix 3) 


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Dose selection (ATM-AVI) for patients with normal renal function or mild renal impairment 
(CrCL >50 mL/min) 
For patients with serious bacterial infections where there are limited or no treatment options, 
it is recommended for β-lactams to rapidly achieve target attainment and steady state 
concentrations while prolonging time above the minimum inhibitory concentration (MIC) 
with extended infusion time and shorter dosing intervals. The rationale for the selected dose 
regimen is based on the objective of obtaining optimal exposure 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 targets are: 
• Maintain unbound ATM concentrations above an MIC for 60% of the dosing interval. 
• 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 achieved a >90% joint PTA for 
ATM and AVI based on PK/PD targets: 
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. 


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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. 
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. 


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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). This dose 
selection for MTZ is also in line with nationally approved SmPCs in Europe (Baxter 
Healthcare Ltd.) which do not indicate a need for dose adjustments in renal impairment. 
1.4.4. Dose Selection for Meropenem 
The dose of MER selected for this study (1 g IV q8h over 30 minutes) is consistent with the 
currently labeled recommendations for adult patients with cIAI (MERONEM SmPC 2017, 
MERREM 2016) and HAP/VAP (MERONEM SmPC 2017). The protocol allows for the 
option to use an increased dose of MER (2 g IV q8h) in the case of proven or suspected CRE. 
Prolonged infusion (over 3 hours) may be used if this is the standard of care or in the case of 
proven or suspected CRE. The use of increased dose MER and prolonged infusion time is an 
evolving standard of care for patients with presumed MDR Gram-negative infections, based 
on extensive PK/PD analyses indicating improved target attainment for certain high-MIC 
pathogens otherwise classified as MER-resistant, including MBL- and KPC-producing 
strains (Jaruratanasirikul et al. 2011; Roberts et al. 2009; Tsala et al. 2016). Doses are to be 
adjusted for patients with renal impairment based on frequent monitoring of CrCL. 
1.4.5. Dose Selection for Colistin 
The COL dosing regimen specified by the study protocol is consistent with recent guidance 
issued by EMA (EMA 2014a and EMA 2014b), which indicates that COL should be dosed 
and monitored as follows: a loading dose of 9 million international units (IU) over 30 to 
60 minutes, followed by 9 million IU daily in 2 or 3 divided doses as a slow IV infusion. 
Doses are to be adjusted for patients with renal impairment based on frequent monitoring of 
CrCL. Recent clinical studies indicate this dose regimen to be generally well tolerated and 
efficacious in the treatment of patients with serious blood stream infections and patients with 
ventilator-associated bacterial pneumonia (Dalfino et al. 2012; Dewan and Shoukat 2014). 
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) SmPCs (Baxter 
Healthcare Ltd.) and Metronidazole, CHINA; Metronidazole, USA. The SRSD for 
comparator Meropenem is United Kingdom (UK) MERONEM SmPC 2017, and for 
comparator Colistin is Colomycin United Kingdom (UK) SmPC 2016 and Colistimethate 
sodium, USA. 


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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) 
or nosocomial pneumonia (NP) including HAP and VAP 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 and HAP/VAP 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 5.10. 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 and 
HAP/VAP (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 comparator regimens which represent current standard of care for a cIAI 
and/or NP. 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 5.10). 
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. 
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 Limited 2014). 


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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 exposured 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). 
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). 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. 
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]; AVI: 5.7% to 8.2% [FDA prescribing 
information: AVYCAZ 2017]). 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). As 


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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 154 mL; 18 mL thereof will be used for PK analysis (see Table 14). 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. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary Objective 
Based on differing regulatory requirements for EMA and FDA, the following objectives and 
outcome measures may differ for the US and non-US countries analyses as noted below. 


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Primary Objective: 
Primary Endpoint: 
To evaluate the efficacy of 
ATM-AVI ±MTZ and MER ±COL at the 
Test of Cure (TOC) visit for the treatment 
of serious infections due to 
Gram-negative bacteria, including those 
due to MBL-producing MDR pathogens. 
Proportion of subjects with clinical cure at the 
TOC visit in the Intent-To-Treat (ITT) and 
Clinically Evaluable (CE) analysis sets (Note: 
non-US countries, the ITT and CE are 
considered co-primary analysis sets. For the 
US, the ITT is considered the primary analysis 
set, while CE is secondary). 
This protocol will use an independent adjudication committee (central blinded assessor) to 
determine whether certain investigator-reported events meet the definition of disease-related 
efficacy endpoints, using predefined endpoint criteria (see Section 9.7). 


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2.2. Secondary Objectives 
 
Secondary Objectives: 
Secondary Endpoint(s): 
To evaluate efficacy of ATM-AVI ±MTZ 
and MER ±COL at the TOC visit in the 
microbiological ITT (micro-ITT) and 
Microbiologically Evaluable (ME) 
analysis sets. 
Proportion of subjects with clinical cure at the 
TOC visit in the micro-ITT and ME analysis 
sets. 
To evaluate the efficacy of 
ATM-AVI ±MTZ and MER ±COL at the 
TOC visit in key sub populations. 
• Proportion of subjects with clinical cure at 
the TOC visit by infection type in the ITT 
and CE analysis sets. 
• Proportion of subjects with clinical cure at 
the TOC visit for subjects with 
MBL-positive pathogens in the micro-ITT 
and ME analysis sets. 
To assess the per-subject microbiological 
response to ATM-AVI ±MTZ and 
MER ±COL at the TOC visit. 
Proportion of subjects with a favorable 
per-subject microbiological response at the 
TOC visit 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 ITT and 
micro-ITT analysis sets. 
To evaluate the pharmacokinetics (PK) of 
ATM and AVI in subjects with serious 
infections and to characterize the 
relationship between exposure and 
clinical and microbiological response for 
ATM-AVI ±MTZ utilization (listings to 
be provided in the Clinical Study Report 
(CSR), analysis to be reported outside of 
the CSR. 
• PK of ATM and AVI in subjects in the 
popPK analysis set. 
• PK/ Pharmacodynamic (PD) relationship 
between exposure and clinical and 
microbiological response for 
ATM-AVI ±MTZ in the popPK analysis 
set. 
2.3. Safety Objectives 
 
Safety Objective: 
Safety Endpoint: 
To evaluate the safety and tolerability 
profile of ATM-AVI ±MTZ and 
MER ±COL. 
Safety and tolerability as assessed by adverse 
events (AEs), physical examination, vital 
signs, electrocardiograms (ECGs), and 
laboratory assessments in the safety analysis 
set. 


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2.4. Tertiary Objectives 
 
Tertiary Objective: 
Tertiary Endpoint(s): 
To evaluate the efficacy of 
ATM-AVI ±MTZ and MER ±COL at the 
End of Treatment (EOT) visit. 
Proportion of subjects with clinical cure at the 
EOT visit in the ITT, micro-ITT, CE and ME 
analysis sets. 
To evaluate the efficacy of 
ATM-AVI ±MTZ and MER ±COL at the 
EOT visit in key sub populations. 
• Proportion of subjects with clinical cure at 
the EOT visit by infection type in the ITT 
and CE analysis sets. 
• Proportion of subjects with clinical cure at 
the EOT visit for subjects with 
MBL-positive pathogens in the micro-ITT 
and ME analysis sets. 
To evaluate the efficacy of 
ATM-AVI ±MTZ and MER ±COL at 
EOT and TOC visits by pathogen 
resistance type. 
Proportion of subjects with clinical cure at 
EOT and TOC visit by pathogen resistance 
type (eg, ATM-non-susceptible, 
ESBL-positive, carbapenamase-positive, etc) 
in the micro-ITT and ME analysis sets. 
To assess the per-subject microbiological 
response to ATM-AVI ±MTZ and 
MER ±COL at the EOT visit. 
Proportion of subjects with a favorable 
per-subject microbiological response at the 
EOT in the the micro- ITT and ME analysis 
sets. 
To assess the microbiological response 
by pathogen and by pathogen resistance 
type to aztreonam 
avibactam ±metronidazole and 
meropenem ±colistin at the EOT and 
TOC visits. 
• Proportion of subjects with a favorable 
per-pathogen microbiological response at 
the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 
• Proportion of subjects with a favorable 
per-subject microbiological response by 
pathogen resistance type 
(eg, ATM-non-susceptible, ESBL-positive, 
carbapenamase-positive, MBL- positive) at 
the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 
• Proportion of subjects with a favorable 
per-pathogen microbiological response by 
pathogen resistance type 
(eg, ATM-non-susceptible, ESBL-positive, 
carbapenamase-positive, MBL-positive) at 
the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 


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2.5. Exploratory Objectives 
 
Exploratory Objectives: 
Exploratory Endpoint(s): 
To evaluate efficacy of ATM-AVI ±MTZ 
and MER ±COL using objective clinical 
measures. 
Composite endpoint including symptom-based 
objective clinical measures, to be defined in 
the Statistical Analysis Plan (SAP) (ITT and 
CE analysis sets). 
To assess 14-day all-cause m01iality. 
Proportion of subjects who died on or before 
14 days from randomization in the ITT 
analysis set. 
To evaluate health resource utilization 
(listings to be provided in the CSR, 
analysis to be repo1ied outside of the 
CSR). 
• Length of hospital stay, including any 
readmissions up to TOC (days). 
• Length of study treatment (days). 
• Length of intensive care unit (ICU) stay 
(days). 
• Transfened to the ICU (Yes/No). 
• 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. 
 
3. STUDY DESIGN 
This is a Phase 3, prospective, randomized, multicenter, open-label, central assessor-blinded 
(see Section 9.7), parallel group, comparative study to detennine the efficacy, safety, and 
tolerability of ATM-AVI ±MTZ versus MER ±COL in the treatment of hospitalized adults 
with cIAI or NP (including HAP and VAP) in regions with endemic or emerging carbapenem 
resistance, and where MBL-producing MDR pathogens are suspected. 
The study outline is provided in Figure 1, the study treatment is provided in Figure 2. 


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Final Protocol Amendment 2, 18 May 2022 
Adult hospitalized subjects with a confirmed diagnosis of complicated intra-abdominal 
infection or hospital acquired pneumonia/ventilator associated pneumonia related to 
Gram-negative pathogens including, but not limited to, those infected with multidrug 
resistant strains, and requiring administration of intravenous antibacterial treatment will be 
enrolled in this study. 
The study will randomize up to approximately 425 subjects (at least 300 subjects with cIAI 
anticipated) in regions with emerging and/or elevated incidence of carbapenem resistance, 
including MBL-producing pathogens. The number of subjects with a perforated appendix or 
appendiceal abscess will be limited to approximately 40% of the study population with cIAI. 
It is estimated that approximately 8-10% of subjects will be identified with MBL-producing 
Gram-negative pathogens. 
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). 
After obtaining written informed consent and confirming eligibility, subjects will be 
randomized in a 2:1 ratio to the ATM-AVI ±MTZ treatment arm or the MER ±COL 
treatment arm according to a central randomization schedule (approximately 283 subjects to 
ATM-AVI ±MTZ and approximately 142 subjects to MER ±COL per group). Please refer to 
Section 5.6, for more details with regard to treatment arms, dosage and mode of 
administration and duration of treatment. Subjects will be stratified at randomization based 
on infectious disease type (cIAI and HAP/VAP). For cIAI, subjects will also be stratified by 
Acute Physiology and Chronic Health Evaluation (APACHE) II score (≤10 and >10) (see 
Appendix 5). For HAP/VAP, subjects will also be stratified by mechanical ventilation status 
(Y/N). 
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. 
For subjects randomized to ATM-AVI ±MTZ, sparse blood samples will be collected for PK 
assessments by population pharmacokinetic (popPK) 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 LFU visit. Subjects will 
receive their study treatment by study center personnel while in the hospital. 


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Figure 1 Study Outline 
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Abbreviations: ATM-AVI=aztreonam-avibactam; ATM-AVI ±MTZ=ATM-AVI ±metronidazole; cIAI=complicated intra-abdominal infections; COL=colistin 
(colistimethate sodium); DoT=duration of treatment; EOT=end of treatment; HAPN AP=hospital-acquired pneumonia/ventilator-associated pneumonia; 
IU=intemational units; IV=intravenous(ly); LFU=late follow-up; MER=meropenem; MER ±COL=MER±colistin; 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± MTZ anu 
 
ATM-AVI  
 
 
 
 
 
D  = mandato1y 
 
= ootional 
Gram-positive cover 
(vancomycin or linezolid) 
 
Pseudomonas cover 
IV aminoglycoside 
Gram-positive cover 
(vancomycin or linezolid) 
IV aminoglycoside 
Gram-positive cover 
(vancomycin, linezolid, or 
daptomycin) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ATM-AVI=aztreonam-avibactam; cIAI=complicated intra-abdominal infections; COL=colistin (colistimethate sodium); 
HAPN AP=hospital-acquired pneumonia/ ventilator-associated pneumonia; IV=intravenous(ly); MER=meropenem; MER±COL=meropenem±colistin; 
MTZ=metronidazole. 
 
For details of study treatment see Section 5.6, and for details of allowed concomitant medication see Section 5.10. 
ATM-AVI± MTZ anu 
MTZ 
Gram-positive cover 
(vancomycin, linezolid, or 
daptomycin) 


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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 or HAP/VAP. 
For subjects with cIAI, a presumed diagnosis is necessary for enrolment. The diagnosis of 
cIAI will be based on the subject’s clinical syndrome or will be supported by intra-operative 
findings, including intra-operative culture of specimens. Operative intervention must be 
required and includes open laparotomy, laparoscopic surgery, and percutaneous drainage of 
an abscess. All subjects will undergo a preliminary evaluation for eligibility within the 
24-hour period prior to initiation of IV study treatment. The exact clinical diagnoses and 
brief descriptions that define the population of subjects with cIAI eligible for this study are 
given in Sections 4.1.1 and 4.1.2 and for subjects with HAP/VAP in Sections 4.1.1 and 4.1.3. 
For subjects with HAP/VAP, an established diagnosis of NP is required, as detailed in 
Section 4.1.3. 
The inclusion and exclusion criteria will be assessed by a site Investigator before enrolment 
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 


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informed consent for continuing to participate in the study as soon as possible on 
recovery, as applicable in accordance with local regulations. 
3. Subjects must have a confirmed diagnosis of HAP/VAP, or presumed diagnosis of cIAI 
requiring administration of IV antibacterial treatment (see additional Inclusion Criteria on 
cIAI and HAP/VAP for minimum disease criteria). 
4. 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; 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. 
5. Female subject of childbearing potential must have a negative serum or urine pregnancy 
test, with sensitivity of at least 25 mIU/mL. 
6. Subject must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
4.1.2. Additional Inclusion Criteria - cIAI Subjects 
1. Diagnosis of cIAI as: 
EITHER: 
Intra-operative/postoperative enrolment with visual confirmation (presence of pus 
within the abdominal cavity) of an intra-abdominal infection associated with 
peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of 
an abscess, or laparoscopic surgery. Specimens from the surgical intervention must 
be sent for culture. Subjects who undergo a surgical procedure with complete fascial 
closure are appropriate for the study. The skin incision may be left open for purposes 
of wound management as long as complete fascial closure is accomplished. The 
subject has at least 1 of the following diagnosed during the surgical intervention: 
a. Cholecystitis with gangrenous rupture or perforation or progression of the 
infection beyond the gallbladder wall; 
b. Diverticular disease with perforation or abscess; 


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c. Appendiceal perforation or peri-appendiceal abscess; 
d. Acute gastric or duodenal perforations, only if operated on >24 hours after 
diagnosis; 
e. Traumatic perforation of the intestines, only if operated on >12 hours after 
diagnosis; 
f. Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis 
associated with cirrhosis or chronic ascites); 
g. Intra-abdominal abscess (including of the liver and spleen provided that there is 
extension beyond the organ with evidence of intra-peritoneal involvement). 
OR 
Pre-operative enrollment where the following clinical criteria are met with 
confirmation of infection by surgical intervention within 24 hours (before or after) of 
randomization: 
h. Requirement for surgical intervention, defined per protocol as open laparotomy, 
percutaneous drainage of an abscess, or laparoscopic surgery; 
i. Evidence of systemic inflammatory response, with at least one of the following: 
• 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. 
j. Physical findings consistent with intra-abdominal infection, such as: 
• Abdominal pain and/or tenderness, with or without rebound; 
• Localized or diffuse abdominal wall rigidity; 
• Abdominal mass. 


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k. Supportive radiologic imaging findings of intra-abdominal infection such as 
perforated intraperitoneal abscess detected on computed tomography scan, 
magnetic resonance image, or ultrasound. 
l. Specimens from the surgical intervention will be sent for culture for isolation of 
both aerobic and anaerobic bacteria. 
2. Subject must have had or will have a surgical intervention within 24 hours (before or 
after) of randomization. A specimen from an abdominal source must be obtained for 
culture during surgical intervention. Surgical intervention includes open laparotomy, 
percutaneous drainage of an abscess, or laparoscopic surgery. Isolates taken from 
surgical wound exudates must not be used. 
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 respirato1y specimen obtained for Gram- stain and culture after the 
onset of signs and symptoms for HAPN AP and 48h prior to randomization. This 
includes culture of either expectorated sputum or a specimen of respirato1y secretions 
obtained by endotracheal aspiration in intubated subjects, or by bronchoscopy with 
bronchoalveolar lavage (BAL), mini-BAL or protected-specimen brnsh (PSB) sampling. 
See Appendix 6 for details on appropriate specimen collection for ventilated and 
non-ventilated subjects. 
 
 
4.2. Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the 
study: 
4.2.1. All Subjects 
1. Subject has an APACHE II score >30. 
2.  At Screening the subject is found to have/or strongly suspected to have an infection 
caused by a Gram-negative species not expected to respond to either ATM-AVI and/or 
MER (eg, Acinetobacter baumannii), or an infection caused by only Gram-positive 
species. The subject is allowed to paiiicipate in the study if the Investigator considers 
that the species is a colonizer which does not waiTant specific treatment. 
3. Subject has received more than one day (>24 hours) of any systemic antibiotic within 
48 hours prior to randomization. This is inclusive of all doses of any systemic antibiotic 
initiated in this time period (but not counting overlapping periods of antibiotics), eg, a 
subject who receives 4 doses of an 8 hourly regimen with the last dose given just before 
randomization is calculated as 32 hours of prior antibiotic. 


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The exception to this is a subject who is a failure of prior systemic antibiotic treatment as 
evident by either documented worsening of objective signs and symptoms of infection or 
lack of improvement in at least one objective sign or symptom of infection despite a 
minimum of 48 hours antibiotic treatment. 
For cIAI subjects, who received less than one day (<24 hours) of any systemic antibiotic 
within 48 hours prior to randomization, one dose of antibiotic may be received 
postoperatively within 6 hours of the surgical procedure (defined as 6 hours from the time 
of skin closure or, if skin closure is not performed, 6 hours from the time the wound 
dressing is applied). 
4. 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 polymixin 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. 
5. Subject is unlikely to respond to up to 14 days of study treatment. 
6. Clinical judgment by the Investigator that the subject has a high likelihood of dying 
within the specified study treatment period despite delivery of adequate antibiotics for 
treatment of the index infection. 
7. Subject has a concurrent infection that may interfere with the evaluation of response to 
the study antibiotics. 
8. Subject has known Clostridium difficile associated diarrhea. 
9. Subject has a need for effective concomitant systemic antibacterials in addition to those 
allowed per protocol, and/or systemic antifungals, and/or any prohibited medication 
(eg, probenecid) (see Section 5.10). 
10. Subjects receiving hemodialysis or peritoneal dialysis. 
11. Subject has an estimated CrCL ≤15 mL/min by Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or expected to require peritoneal dialysis, hemodialysis or hemofiltration 
during the study. 
12. Subject has acute hepatitis or acute hepatic failure, cirrhosis or chronic hepatic failure 
(any Child-Pugh class). 
13. Presence of hepatic disease as indicated by ALT or AST >3 x upper limit of normal 
(ULN) at Screening. However, subjects with AST and/or ALT up to 5 x ULN are 
eligible if these elevations are acute and are documented as being directly related to the 
infectious process being treated. 


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14. Subject has a total bilirubin (TBili) >2 x ULN, unless isolated hyperbilirubinemia is 
directly related to the acute infection or due to known Gilbert’s disease. This must be 
documented. 
15. Alkaline phosphatase (ALP) >3 x ULN. However, subjects with values >3 x ULN and 
<5 x ULN are eligible if this value is acute and directly related to the infectious process 
being treated. This must be documented. 
16. Subject has a perinephric infection. 
17. Subject has an absolute neutrophil count <500/mm3. 
18. Subject has previously been treated with the ATM-AVI. 
19. Subject has been previously enrolled in this study. 
20. 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 4.6.1). 
21. Subject is participating in or has participated in other investigational interventional 
studies (drug) within the last 30 days (or 5 times the half-life of the previously 
administered investigational compound, whichever is longer) prior to screening and/or 
during study participation. 
22. 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). 
23. Subject is unlikely to comply with protocol, eg, uncooperative attitude and unlikelihood 
of completing the study. 
24. Subject has past or current history of epilepsy or seizure disorders excluding febrile 
seizures of childhood. 
25. 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 was diagnosed with traumatic bowel perforation undergoing surgery within 
12 hours; perforation of gastroduodenal ulcers undergoing surgery within ≤24 hours. 
Other intra-abdominal processes in which the primary etiology is not likely to be 
infectious. 
2. 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. 
3. Subject has abdominal wall abscess or small-bowel obstruction without perforation or 
ischemic bowel without perforation. 
4. Subject has a prior liver, pancreas, or small-bowel transplant. 
5. Subject whose surgery will include staged abdominal repair, 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 – HAP/VAP Subjects 
1. APACHE II score <10. 
2. HAP/VAP subject has a known or high likelihood (based on any available 
microbiological results at the time of enrollment) of monomicrobial infection with a 
Gram-positive organism. 
3. Subjects with lung abscess, pleural empyema, or post-obstructive pneumonia. 
4. Subject is a recipient of a lung or heart transplant. 
5. Subjects with myasthenia gravis. 
For procedures for withdrawal of incorrectly enrolled subjects see Section 4.5. 
4.3. Subject Enrolment and Randomization 
Investigator(s) should keep a record, the subject screening log, of subjects who entered 
pre-study 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 and the enrolment call is done in the 
interactive response technology (IRT) system. 


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2. IRT system will assign the subject with a unique enrolment 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 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. 
4.4. Randomization Criteria 
All subjects being enrolled and fulfilling all eligibility criteria will be randomized in a 
2:1 ratio to receive 1 of the 2 IV dosing regimens of either the ATM-AVI ±MTZ treatment 
arm (ie, test product) or the MER±COL treatment arm (ie, comparator). 
4.5. 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. 
4.6. Lifestyle Requirements 
4.6.1. 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 


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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 
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. 
4.7. 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. 


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To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site. 
5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational products are test product Aztreonam- Avibactam 
(ATM-AVI), co-administered drug Metronidazole (MTZ), and comparators Meropenem 
(MER) and Colistin (COL). 
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 1 of the 2 IV dosing regimens of either the ATM-AVI ±MTZ treatment arm (ie, test 
product) or the MER ±COL treatment arm (ie, comparator). The randomization scheme for 
this study will be generated using the Sponsor randomization system. 
Randomization will be stratified as follows: 
• Infectious disease type (cIAI versus HAP/VAP) 
• For cIAI subjects, they will be further stratified by APACHE II score category 
(≤10 versus >10) (see Appendix 5); 


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• For HAP/VAP subjects, they will be further stratified by mechanical 
ventilation status (yes versus no). 
The IP (ATM-AVI ±MTZ or MER ±COL) should, if possible, be administered as soon as 
possible after 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 
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 the interim E-DMC reviews (See 
Section 9.5). 
Programming and statistical personnel separate from the Sponsor study team will be 
responsible for producing the data outputs and will help limit access by the study team to 
individual subject and group treatment assignment until database lock has occurred. 
5.3. Methods for Unblinding 
Only the independent adjudication committee members will be blinded during the study. 
They will not require unblinding. 
5.4. Subject Compliance 
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the CRF. 
Qualified study center personnel will administer the IV study treatment and assure treatment 
compliance. At a minimum the dose, date, and exact start and stop time of administration of 
the IV study treatment will be recorded in the appropriate sections of the CRF and checked 
by the monitor at monitoring visits. The deviation from study treatment will be reported and 
documented. 
Subject compliance with dosing administration will be verified by accounting doses 
administered. The subject dosing compliance should be within the range of 80% and 120% 
of expected doses during treatment period. Subject noncompliance cases should be discussed 
with medical monitors. 


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5.5. Investigational Product Supplies 
5.5.1. Dosage Forms and Packaging 
The identity of the IP is provided in Table 2. 
 
Table 2. 
Identity of Investigational Product 
 
Investigational product 
Dosage form and strength 
 
Test product 
Aztreonam -Avibactam 
Aztreonam 2 g powder for concentrate for 
solution for infusion 
Avibactam 600 mg powder for concentrate 
for solution for infusion 
Comparators 
Meropenem 
Meropenem 1 g powder for solution for 
infusion 
Colistin 
Colistin 2 million IU powder for solution 
for infusion. Colistimethate sodium 
equivalent to 150 mg colistin base activity 
per vial. 
Co-administered drug 
Metronidazole 
Metronidazole 500 mg/100 mL solution for 
infusion 
Note: Aztreonam and avibactam will be provided as separate vials for reconstitution and mixed together in a 
saline bag for co-administration at the appropriate concentration for intravenous infusion. 
Note: Comparators and co-administered drug are supplied centrally via the sponsor. In some instances, locally 
obtained commercial supplies will be utilized in accordance with local regulations. 
Note: Aztreonam, Meropenem, Colistin and Metronidazole are commercial products over-labeled with the study 
clinical label. 
 
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 IP Manual). 
5.5.2. 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). Label text will be translated into local 
language. 


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Labels will be provided as either a single panel label or as multi-language booklet labels. 
5.5.3. Preparation and Dispensing 
See the IP manual and package insert for instructions 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, pharmacy assistant/technician, or pharmacist) as 
allowed by local, state, and institutional guidance. 
5.6. Administration (Dose and Treatment Regimen) 
The recommended minimal duration of treatment with IV study treatment is 5 days for cIAI 
and 7 days for HAP/VAP. The maximal duration of treatment is 14 days. 
5.6.1. ATM-AVI ±MTZ 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 3 below. 
 
Table 3. 
ATM-AVI Doses in Relationship to CrCL 
 
CrCL 
(mL/min)* 
Loading dose 
of ATM-AVI 
(by IV 
infusion over 
30 minutes) 
Extended 
loading dose 
of ATM-AVI 
immediately 
following the 
loading dose 
(by IV 
infusion over 
3 hours) 
Time interval 
between end 
of extended 
loading dose 
and start of 
first 
maintenance 
dose 
Maintenance 
dose of 
ATM-AVI 
(by IV 
infusion over 
3 hours) 
Frequency 
of 
ATM-AVI 
maintenance 
dose 
>50 
500 mg ATM 
plus 167 mg 
AVI 
1500 mg ATM 
plus 500 mg 
AVI 
3 hours 
1500 mg 
ATM plus 
500 mg AVI 
q6h 
>30 to 50 
500 mg ATM 
plus 167 mg 
AVI 
1500 mg ATM 
plus 500 mg 
AVI 
3 hours 
750 mg ATM 
plus 250 mg 
AVI 
q6h 
>15 to 30 
675 mg ATM 
plus 225 mg 
AVI 
675 mg ATM 
plus 225 mg 
AVI 
5 hours 
675 mg ATM 
plus 225 mg 
AVI 
q8h 
Abbreviations: ATM-AVI= aztreonam-avibactam; CrCL=creatinine clearance; IV=intravenous(ly); 
q6h=every 6 hours; q8h=every 8 hours. 
*Estimated creatinine clearance using Cockcroft-Gault formula 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.) 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 5.6.5). 
5.6.2. MER ±COL Treatment Arm 
Subjects will initially be given IV MER 1000 mg q8 h (with or without COL). However, if 
an MER-resistant pathogen is strongly suspected, COL (ie, colistimethate sodium) can also 
be initiated, and/or a dose of MER 2000 mg q8h can be used (given as an IV infusion over 
3 hours), at the Investigator’s discretion (Jaruratanasirikul et al. 2005; Keel et al. 2011; Li et 
al. 2006). 
If a MER-resistant Gram-negative pathogen is subsequently isolated, COL can be added (if 
not already started), and/or the dose of MER can be increased to 2000 mg q8h (given as an 
IV infusion over 3 hours, if this dose was not already used initially). 
If a MER-susceptible Gram-negative pathogen is subsequently isolated and COL had been 
initially started, the COL should be discontinued and the dose of MER adjusted to the labeled 
dose regimen (1 g q8h IV over 30 minutes) (if a MER dose of 2000 mg q8h was initially 
started) (Table 4). 
Meropenem (MER) (MERONEM SmPC): 
• First day of dosing (or until the MER susceptibility of the baseline Gram-negative 
pathogen(s) is known): 
 
Table 4.  MER Doses in Relationship to CrCL 
 
CrCl (mL/min)* 
Baseline Gram-negative pathogen 
not initially suspected to be 
MER-resistant 
Dose of MER (by IV infusion 
over 30 minutes) 
Baseline Gram-negative 
pathogen strongly suspected 
to be MER-resistant ** 
Dose of MER (by IV infusion 
over 180 minutes) 
>50 
1000 mg q8h 
2000 mg q8h 
>25 to 50 
1000 mg q12h 
2000 mg q12h 
>15 to 25 
500 mg q12h 
1000 mg q12h 
Abbreviations: CrCL=creatinine clearance; IV=intravenous(ly); MER=meropenem; q8h=every 8 hours; 
q12h=every 12 hours. 
*Estimated creatinine clearance using Cockcroft-Gault formula rounded to the nearest whole number (see 
Appendix 3). 


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** Note the infusion time over 180 minutes recommended for the higher doses of meropenem is based on usual 
clinical practice for subjects with infections due to resistant pathogens (Jaruratanasirikul et al. 2005; Keel 
et al. 2011; Li et al. 2006). 
 
Meropenem ±colistin doses will need to be adjusted for subjects with renal impairment 
(Section 5.6.5). The dose of MER will need to be further adjusted once the susceptibility of 
the baseline Gram-negative pathogen(s) to MER is known (see notes above). 
Colistin (COL) (colistimethate sodium): 
This is optional study therapy that can be added to MER, at the Investigator’s discretion. 
Doses of COL are expressed as colistimethate sodium in IU, as described by EMA 2014a and 
EMA 2014b. For colistimethate sodium (IU and mg) and COL base activity (CBA) mg 
conversion table see Appendix 7 and Table 5. 
Polymyxin B may be used as an alternative to COL where COL is not available or readily 
accessible. Polymyxin B will be sourced locally and administered per local label. 
 
Table 5. 
COL Doses in Relationship to CrCL 
 
CrCl (mL/min)* 
Loading dose of 
Time interval 
Maintenance dose 
colistin 
between end of 
of COL 
(colistimethate 
loading dose and 
sodium) (First dose) 
start of maintenance 
for subjects 
dose 
≥60 kg** 
(by IV infusion over 
(by IV infusion 
30 to 60 minutes) 
over 30 to 
60 minutes) 
>50 
9 million IU 
12 hours 
9 million IU daily 
in 2 or 3 divided 
doses 
>30 to 50 
9 million IU 
24 hours 
6 million IU daily 
in 2 divided doses 
>20 to 30 
9 million IU 
24 hours 
5 million IU daily 
in 2 divided doses 
>15 to 20 
9 million IU 
24 hours 
4 million IU daily 
in 2 divided doses. 
Abbreviations: COL=colistin (colistimethate sodium); CrCL=creatinine clearance; IU=international units; 
IV=intravenous(ly). 
*Estimated creatinine clearance using Cockcroft-Gault formula rounded to the nearest whole number (see 
Appendix 3). 
**Dose of colistin should be reduced to 6 million IU for subjects below 60 kg. 


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5.6.3. 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. For subjects 
receiving colistin (colistimethate sodium), adjunctive aminoglycosides therapy should not be 
used concurrently; treatment with colistin (colistimethate sodium) should be discontinued 
prior to initiating aminoglycoside therapy. 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, or susceptibility results indicate a carbapenem susceptible strain. 
If Pseudomonas aeruginosa is isolated and is non-susceptible to meropenem, an intravenous 
aminoglycoside may be added to meropenem if not originally commenced. Colistin should 
be discontinued if meropenem and aminoglycoside are being used together. 
The need for continued dosing with an aminoglycoside should be reviewed at least after 
72 hours to mitigate potential nephrotoxic effect. 
5.6.4. Optional Gram-positive Antibiotics 
Subjects with HAP/VAP may receive optional vancomycin or linezolid and subjects with 
cIAI 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. 
5.6.5. 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 ESRDsubjects, 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 5 by the central laboratory, if PK samples are to be collected on 
Days 3 or 5) and then as clinically indicated. 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 MER ±COL 
investigational therapies. 


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5.7. 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. 
5.8. 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. 


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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 
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. 


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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. 
5.8.1. 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. 
5.9. 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. 
5.10. 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 study medication (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, 
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. 


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Concomitant medications which are allowed per protocol, restricted and prohibited are 
detailed in Table 6, Table 7, and Table 8, respectively: 
 
Table 6. 
Allowed Concomitant Medications 
 
Allowed 
Procedure/Medicatio 
n/Class of drug: 
Subjects with cIAI: 
Subjects with HAP/VAP: 
MTZ 
Subjects in the ATM-AVI±MTZ 
arm will all receive MTZ as part 
of study therapy 
(see Section 5.6.1). 
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. 


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Table 6. 
Allowed Concomitant Medications 
 
Allowed 
Procedure/Medicatio 
n/Class of drug: 
Subjects with cIAI: 
Subjects with HAP/VAP: 
IV aminoglycoside 
(eg, amikacin, 
gentamicin or 
tobramycin based 
upon local practice 
and epidemiology) 
N/A 
In the ATM-AVI ±MTZ arm, 
an IV aminoglycoside may be 
added if Pseudomonas 
aeruginosa is suspected. 
In the MER ±COL arm; 
if Pseudomonas aeruginosa is 
suspected, an IV 
aminoglycoside may be 
added to MER. In this case 
COL should not be 
commenced. 
If Pseudomonas aeruginosa 
is isolated and is susceptible 
to MER, the Investigator may 
stop COL (if this had been 
started) and an IV 
aminoglycoside may be 
added to the subject’s 
regimen. COL and an IV 
aminoglycoside should not be 
used together. 
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-cont 
aining solution 
Permitted (note that antibiotic 
peritoneal lavage is not allowed). 
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 


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Abbreviations: ATM-AVI ±MTZ =aztreonam-avibactam±metronidazole; cIAI=complicated intra-abdominal 
infection; COL=colistin (colistimethate sodium); HAP/VAP=hospital-acquired pneumonia/ventilator-associated 
pneumonia; IV=intravenous (ly); MER=meropenem; MER ±COL=meropenem±colistin; MTZ=metronidazole; 
N/A=not applicable. 
 
Table 7. 
Restricted Concomitant Medications 
 
Restricted 
Procedure/Medication 
/Class of drug: 
Subjects with cIAI: 
Subjects with HAP/VAP 
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 should be avoided unless 
clinically indicated. 
Antifungal treatment to treat 
the HAP/VAP should be 
avoided unless clinically 
indicated. 
Abbreviations: cIAI=complicated intra-abdominal infection; HAP/VAP=hospital-acquired pneumonia/ 
ventilator-associated pneumonia. 
 
Table 8. 
Prohibited Concomitant Medications 
 
Prohibited 
Procedure/Medication 
/Class of drug: 
Subjects with cIAI: 
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: ATM-AVI±MTZ =aztreonam-avibactam±metronidazole; cIAI=complicated intra-abdominal 
infection; HAP/VAP=hospital-acquired pneumonia/ventilator-associated pneumonia; IV=intravenous(ly); 
N/A=not applicable. 


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Both ATM (Mattie 1994) 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 Limited 2014). 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 COL. Based on current knowledge, further 
relevant DDIs with regard to ATM-AVI administration in this study are not to be expected 
(see Section 5.11.1). 
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 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 or HAP/VAP) 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 DDI see Section 5.11.1. 
Other medication, which is considered necessary for the patient’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 enrollment, 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. 
5.10.1. 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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5.11. Drug-drug Interaction 
5.11.1. 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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5.11.2. Coagulation and Concomitant Use of Anticoagulants 
Appropriate monitoring (according to applicable medical guidelines and institutional 
standard of care) should be unde1iaken when anticoagulants are prescribed conc01nitantly 
with antibiotics. Adjustments in the dose of oral anticoagulants may be necessaiy to 
maintain the desired level of anticoagulation. 
5.11.3. Other Investigational Products 
fufo1mation on DDis with other medicinal products and other fo1ms of interaction for 
protocol allowed antibiotics are available in the respective SmPCs for these products and 
fuvestigators ai·e recommended to refer to these for fmiher prescribing info1mation. 
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). 
Eve1y effo1i 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. Screening and Enrollment 
Prior to any study specific procedures, subjects (or their legally acceptable representative if 
applicable) must provide written info1med consent. Enrollment/Screening procedures will be 
perfo1med according to the Schedule of Activities (Table 1). At Screening, subjects will be 
assessed regai·ding eligibility criteria. Subjects who do not meet all of these criteria must not 
be enrolled in the study (see Section 4.3). 
 
6.1.1. 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 info1med consent prior to staiiing any study-specific 
procedures. 
Each subject will undergo Screening assessment procedures less than 24 hours prior to 
randoinization. Exceptions to this ai·e for respirato1y specimen for cultures and chest 
X- ray/CT scan for HAPNAP subjects which are valid if collected within 48 hours prior to 
randoinization and blood cultures which are valid if collected within 48 hours prior to 
randoinization in all subjects. Local laborato1y test results will be used to qualify subjects for 
inclusion. To this end, the following assessments need to be perfo1med in the local 
laborato1y and entered in the CRF: sernm creatinine (including calculation of CrCL), sennn 
or urine-hCG for pregnancy test, AST, ALT, ALP, TBili, and hematology as listed in 
Section 4.2. For eligibility assessment, CrCL needs to be calculated at the study site, based 


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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. Reviewing and recording prior medications (including prior antibiotic treatment). 
6. Performing complete physical examination as defined in Section 7.2.2. 
7. Assessing infection-related signs and symptoms. 
8. Performing focused physical examination (see Section 7.2.2). 
9. 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. 
10. Performing a chest X-ray or CT scan (if not available within 48 hours prior to 
randomization) in subjects with HAP/VAP. 
11. Completing the APACHE II score (Appendix 5). 
12. Completing the ventilation device status in subjects with HAP/VAP. 
13. Collecting imaging and surgical report in subjects with cIAI. 
14. Collecting AEs. 
15. Collecting specimen 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). 
16. Obtaining an appropriate respiratory specimen for Gram- stain and culture (Cultures 
from respiratory specimens obtained within 48 hours prior to randomization may be 
used, but subjects ventilated subsequently, regardless of whether they meet the 
criteria for VAP, must have a specimen obtained while ventilated). Specimens will 
be sent to local laboratory for microbiological culture and isolates and unstained 
Gram-stain slides (for induced sputum and expectorated sputums only) will be sent to 
central laboratory (for subjects with HAP/VAP only) (see Appendix 6). 


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17. 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 Screening if available within 48 hours prior to 
randomization. 
18. Obtaining blood and urine samples for safety analysis. Blood is to be sent to the local 
laboratory (for testing laboratory eligibility criteria as listed in Section 4.2.1) and 
blood and urine to the central laboratory. 
19. Collection of ABGs (ABGs are required for ventilated and recommended for 
non-ventilated HAP/VAP subjects, and for cIAI subjects as clinically indicated). 
20. Estimating CrCL using the serum creatinine results from the local laboratory. See 
Appendix 3 for CrCL calculation. 
21. Obtaining blood or urine sample for serum β-hCG for women of childbearing 
potential (local laboratory reference laboratory). 
22. Confirming highly effective contraception is being used. 
6.2. Study Period 
6.2.1. Visit 2: Baseline Procedures and Day 1 of Treatment (Day 1) 
Procedures for visit 2 will vary depending on the timing of the visits 1 and 2 relative to 
surgery. Visit 2 may occur pre- or postoperatively in subjects with cIAI. 
Local laboratory test results obtained at Visit 1 will be used to qualify subjects for inclusion 
(see Section 6.1.1). At Visit 2, safety lab samples (including local lab for eligibility criteria 
confirmation) and clinically relevant cultures (and further assessments as listed in 
points 3, 11, 13 to 16 of this section) are only required if Visit 1 and Visit 2 are separated by 
surgery or are more than 12 hours apart. If safety lab samples and clinically relevant cultures 
are required, they should be collected prior to dosing (exception: if Visit 2 occurs 
pre-operatively, study drug may be administered before collecting abdominal specimen for 
culture; see below 11). 
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. 
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). 


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3. Assessing infection-related signs and symptoms. 
4. Performing focused physical examination (see Section 7.2.2). 
5. 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. 
6. 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). 
7. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
8. Completing the ventilation device status in subjects with HAP/VAP. 
9. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
10. Collecting new AEs and reviewing ongoing AEs. 
11. Collecting specimen of abdominal site infection (if not already collected at Visit 1 
[Note: if Visit 2 occurs pre-operatively, study drug may be administered before 
collecting abdominal specimens; however, they must be collected during the 
surgery]) and sending to local laboratory for microbiology culture, and sending 
isolates to central laboratory (for subjects with cIAI only) (see Appendix 6). 
12. Collecting respiratory specimen for Gram-stain/culture (except where an adequate 
specimen was previously collected within 48 hours prior to randomization) and 
sending to local laboratory (for subjects with HAP/VAP only) if not collected at 
Screening. For subjects who were not ventilated at Screening but were intubated 
subsequently (or subjects who had a bronchoscopy performed): obtaining an 
appropriate respiratory specimen for Gram- stain and culture. Specimens will be sent 
to local laboratory for microbiological culture and isolates and unstained Gram-stain 
slides (for induced sputum and expectorated sputums only) will be sent to central 
laboratory (for subjects with HAP/VAP only) (see Appendix 6). 
13. Obtaining blood samples as clinically indicated and sending to local laboratory for 
microbiological culture, and sending isolates to central laboratory (see Appendix 6). 
14. Obtaining blood and urine samples for safety analysis. Blood is to be sent to local 
laboratory and blood and urine to the central laboratory. 
15. Collection of ABGs as clinically indicated. 
16. Estimating CrCL using the serum creatinine results from the local laboratory. See 
Appendix 3 for CrCL calculation. 
17. Confirming highly effective contraception is being used. 


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18. Collecting mortality assessment. 
19. Randomization. 
20. Commence dosing according to the randomization schedule. 
21. Following the initiation of the IV infusion of study treatment, blood samples for PK 
analysis for subjects randomized to ATM-AVI will be obtained as according to 
Table 13 and Figure 3 and Figure 4. 
6.2.2. Visit 3 to 15: Ongoing Treatment (Days 2 to 14) 
The recommended minimal duration of treatment in this study will be 5 days for cIAI and 
7 days for HAP/VAP. The maximal duration of treatment will be 14 days. Subjects, who 
require continuation of IV study treatment after 5 days (cIAI) or 7 days (HAP/VAP), will 
continue to receive their IV study treatment by study center personnel in the hospital. 
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 assessing infection-related signs and symptoms. 
3. Daily performing focused physical examination (see Section 7.2.2). 
4. 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. 
5. 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). 
6. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
7. Daily completing the ventilation device status in subjects with HAP/VAP daily. 
8. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
9. Daily collecting new AEs and reviewing ongoing AEs. 
10. 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). 


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11. 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). 
12. 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. 
13. Obtaining blood and urine samples every 3 days starting on Day 4 and sending to the 
central laboratory for safety analysis. Blood samples are to be sent to local laboratory 
daily between Days 2 and 4 (and as clinically indicated) for measurement of serum 
creatinine. 
14. Collection of ABGs as clinically indicated. 
15. Obtaining blood samples for PK analysis on Day 4 (Subjects randomized to 
ATM-AVI ±MTZ only) (Day 4 PK samples can be collected on Day 4 ±1 day, see 
Table 13 and Figure 3 and Figure 4 for schedule). 
16. 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. 
17. Confirming daily that highly effective contraception is being used. 
18. Collecting mortality assessment daily. 
19. Daily dosing according to the randomization schedule. 
6.2.3. Post-Treatment Period 
6.2.3.1. 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. Assessing infection-related signs and symptoms. 
4. Performing focused physical examination (see Section 7.2.2). 


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5. 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. 
6. Performing a chest X-ray or CT scan in subjects with HAP/VAP as clinically 
indicated. 
7. Completing the ventilation device status in subjects with HAP/VAP. 
8. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
9. Collecting new AEs and reviewing ongoing AEs. 
10. 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). 
11. 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). 
12. 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). 
13. Obtaining blood and urine samples for safety analysis and sending to central 
laboratory. Blood samples should be sent to the local laboratory as clinically 
indicated for measurement of serum creatinine. 
14. Collection of ABGs as clinically indicated. 
15. Estimating CrCL as clinically indicated, using the serum creatinine results from the 
local laboratory. See Appendix 3 for CrCL calculation. 
16. Confirming highly effective contraception is being used. 
17. Assessing clinical response. 
18. Collecting mortality assessment. 
6.2.3.2. 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. 


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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. Assessing infection-related signs and symptoms. 
4. Performing focused physical examination (see Section 7.2.2). 
5. 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. 
6. Performing a chest X-ray or CT scan (as clinically indicated) in subjects with 
HAP/VAP. 
7. Completing the ventilation device status in subjects with HAP/VAP. 
8. Collecting imaging and surgical report (as clinically indicated) in subjects with cIAI. 
9. Collecting new AEs and reviewing ongoing AEs. 
10. 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). 
11. 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). 
12. 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). 
13. Obtaining blood and urine samples for safety analysis and sending to central 
laboratory. Blood samples should be sent to the local laboratory as clinically 
indicated for measurement of serum creatinine. 
14. Estimating CrCL as clinically indicated, using the serum creatinine results from the 
local laboratory. See Appendix 3 for CrCL calculation. 
15. Confirming highly effective contraception is being used. 
16. Assessing clinical response. 
17. Collecting mortality assessment. 


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6.2.3.3. 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. Performing focused physical examination (see Section 7.2.2). 
2. Collecting new AEs and reviewing ongoing AEs. 
3. Reviewing prior and concomitant medications (including prior and concomitant 
antibiotic treatment). 
6.3. 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. 
• 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). 


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• 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 MER ±COL or whether an immediate dose change or a short 
period of continued observation is required. 
• Treatment failure (refer to Table 9). 
• 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. 
6.3.1. 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 6.4), 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 6.4. 
6.4. 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 enrolment/randomization 
code cannot be reused. Withdrawn subjects will not be replaced. 


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6.4.1. Screen Failures 
Screening failures are subjects who do not fulfil 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). 
6.4.2. 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. 
6.4.3. 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. 


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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. 
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 9): 


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Table 9. 
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 or HAP/VAP) 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 
infectiona. 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 the 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. 
Abbreviations: AE=adverse event; cIAI=complicated intra-abdominal infection; EOT=end of treatment; 
HAP=hospital-acquired pneumonia; TOC=test of cure; VAP=ventilator-acquired pneumonia. 
a. Further antibiotics for the index infection should only be initiated for ongoing or worsening signs and 
symptoms of the infection. 
 
If a subject is assessed as a clinical failure at the EOT visit, this assessment will be carried 
forward to the TOC visit. 
In addition, an exploratory assessment of clinical response based on objective measures of 
signs and symptoms of infection will be collected. 


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7.1.2. Microbiological Response 
For each pathogen identified at Baseline, microbiological outcome at EOT and TOC will be 
determined as shown in Table 10. 
 
Table 10. 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 of causative pathogen from an appropriately obtained 
specimena at the site of infection. 
Presumed 
eradication 
Repeat culture of specimens were not performed/clinically indicated in 
a subject who had a clinical response of cure. 
Persistence 
Causative organism is still present from an appropriately obtained 
specimen at the site of infection. If the causative organism displays 
≥4-fold higher MIC to study therapy after treatment with IV study 
therapy, the response will also be categorized as “Persistence with 
increasing MIC”. 
Presumed 
persistence 
Subject was assessed as a clinical failure and repeat culture of 
specimens were not performed/clinically indicated. 
Indeterminate 
microbiological 
response 
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. 
Abbreviations: BAL=bronchoalveolar lavage; cIAI=complicated intra-abdominal infection; EOT=end of 
treatment; IV=intravenous(ly); MIC=minimum inhibitory concentration; PSB=protected-specimen brush; 
TOC=test of cure. 
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 laproscopic), 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 specimen 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 blood, two sets of blood cultures 
should be collected (ie, 4 bottles) from 2 different sites for aerobic and anaerobic incubation. One set of 
blood cultures must be obtained through a venipuncture. Collect samples, ideally over a period of 2 hours 
at least 10 to 20 minutes apart from separate sites. 
 
If a pathogen is assessed as persistence or persistence with increasing MIC at the EOT visit, 
this assessment will be carried forward to the TOC visit. 


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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. 
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 10. 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. 
Per-resistance Type Microbiological Response Assessments 
Microbiological response (per subject and per pathogen) will be presented for the subgroup 
of subjects with a pathogen in the given resistance group (eg, ATM-non-susceptible, 
ESBL-positive, carbapenamase-positive, and MBL-positive). Per-pathogen microbiological 
response will be presented separately for ATM-non-susceptible, ESBL-positive, 
carbapenamase-positive, and MBL-positive pathogens. 
Emergent Infections 
New pathogens that appear after Baseline are categorized in Table 11 and will be 
summarized separately. 


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Table 11. Definition of Emergent Infection Categories 
 
Emergent 
infection 
Definition 
Superinfection 
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. 
New infection 
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. 
Abbreviations: cIAI=complicated intra-abdominal infection; EOT=end of treatment; HAP=hospital-acquired 
pneumonia; VAP=ventilator-acquired 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). 
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 12. 
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 listed in Section 4.2) and subject management 
throughout the study. Local laboratory test results will be entered in the CRF 
(see Section 6.1.1). 
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 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, 


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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 12. Laboratory Safety Variables 
 
Clinical chemistry 
Hematology 
Arterial blood 
gasesb 
Urinalysis 
Albumin 
Partial pressure of 
oxygen (PaO2) 
Total protein 
Hematocrit 
Partial pressure of 
carbon dioxide 
(PaCO2) 
Appearance (color, 
clarity) 
ALT 
Hemoglobin 
pH 
Bilirubin 
AST 
INR (at baseline and 
as clinically 
indicated) 
Oxygen saturation 
Glucose 
ALP 
Platelet count 
Bicarbonate (HCO3) 
Ketones 
Bilirubin (total, 
direct and indirect) 
Red blood cell count 
Leukocyte esterase 
Bicarbonate 
WBC count (total and 
differential) 
Nitrite 
Blood urea nitrogen 
pH 
Calcium, total 
Protein 
Chloride 
Specific gravity 
Serum creatininea 
Urobilinogen 
Glucose 
(nonfasting) 
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 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. 


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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 6.3 and 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. 
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 focused (infection-related abdominal or respiratory signs and symptoms per 
indication) assessment 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. 
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 (see Table 1). The ECG on 
Day 3 should be performed at maximum plasma concentration (Cmax) which is immediately 
(within 30 minutes) after an infusionis 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 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 at 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 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 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. 
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, cIAI and HAP/VAP subjects will be assessed by using the Acute Physiology 
and Chronic Health Evaluation (APACHE) II score (see Appendix 5). Subjects with cIAI 
will also be stratified at randomization based on APACHE score. 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 
subjects with cIAI. Where ABGs are not available at screening, serum bicarbonate is to be 
used to calculate APACHE II score. 
7.3. Microbiology 
Cultures of abdominal site infections (for cIAI subjects only) 
Specimens must be obtained for culture from an initial qualifying surgical procedure 
performed within 24 hours before or after randomization and sent to the local laboratory for 
microbiological culture. This will be treated as the baseline culture. 
Additional specimens will be collected for culture, 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 specimens will be sent to the local laboratory for microbiological culture, and isolates 
will be sent to the central laboratory. 


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Respiratory specimen for Gram-stain/culture (for HAP/VAP subjects only) 
Cultures from respiratory specimens obtained within 48 hours prior to randomization may be 
used. Repeat respiratory specimens at Baseline are not required, unless a Screening sample 
was obtained from a non-ventilated subject and the subject is subsequently ventilated (or has 
bronchoscopy). In this case, an appropriate respiratory specimen should be obtained via 
BAL, miniBAL, PSB sample or endotracheal aspirate 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 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 Blood for Culture (for all subjects) 
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 performed at Baseline 
prior to first dose of study treatment if blood cultures are not available within 48 hours prior 
to randomization. For subjects who are found to be bacteremic, blood cultures should be 
repeated at least every 3 days until clearance of bacteremia is documented. If a negative 
culture report has not been achieved by the time of the EOT visit, a set of repeat blood 
cultures should be obtained at the EOT visit. Blood cultures should also be obtained as 
clinically indicated (see Table 1). 
All specimens will be sent to the local laboratory for microbiological culture, and isolates 
will be sent to the central laboratory. 
Further details are provided in Appendix 6. 
7.4. Pharmacokinetics 
PK sampling will be employed to achieve further information on the PK of ATM-AVI in the 
subject population. 
7.4.1. 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 ±MTZ 
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 


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should be taken on both Day 1 and Day 4 of study treatment. To provide greater flexibility, 
Day 4 PK samples can be collected on Day 4 ±1 day [Note: A 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]. 
All subjects randomized to ATM-AVI will have 3 blood samples collected for determination 
of study drug in plasma for both Day 1 and Day 4 (a total of 6 samples per subject). These 
samples will be taken as scheduled in the Schedule of Activities (Table 1) and at the times 
presented in Table 13 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. 
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 13). 


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Table 13. Pharmacokinetic ATM-AVI Sample Collection Time Points 
 
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 maintenance 
infusion: 
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 (7.5 to 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) 
 
Dayl 
■ l•I 
Extended LD 
II 
maintenance 
• • • • • • • • • • • • 
-1 
0 
0.5 
1 
2 
3 
4 
5 
6 
7 
8 
9 • • • 
11 
12 
10 
PK Sample time from start of LD !] = 25-30 min 
fJ = 3.25-3.5 hr 11111 = 5.5-6
Day4 
,., ' - 
• • • • • • • • 
0 
1 
2 
3 
4 
5 
6 
7 
5 hr 
• 
9 
• 
8 
• 
10 • 
11 • 
12 
PK Sample time from start of IV infusion 
2.75-3 hr 
•= 3.5-4.5 hr 
= 5-6 hr 
PK Sample number 
••• 
ATM-AVI Infusion I Hours 
Abbreviations: ATM-AVI= aztreonam-avibactam; CrCL = creatinine clearance; IV= intravenous(ly); LD = loading dose; PK= pharmacokinetics; 
q6h = every 6 how-s. 


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-··-  •  
• • • 
• • • • • • • • • • • • •
• 
• 
• 
 
Figure 4 
 ATM-AVI Pharmacokinetic Sample Collection Time-Points for Subjects with CrCL >15 to30 mL/min (Q8h 
Maintenance Dose) 
 
Dayl 
 
• 
 
 
[) 
D 
Extended LO 
 
M  
maintenance 
• • 
• 
• 
• 
-1 
0 
0.5 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
 
PK Sample time from start of LO I! = 25 - 30 min 
fl =3.25 - 3.5 hr 
Ill.II  =7.5-8.5 hr 
 
Day4 
,., • - 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 
 
PK Sample time from start of IV infusion 
 
= 2.75 - 3 hr  
=3.5-4.Shr- 
=7-8hr 
PK Sample number 
ATM-AVI Infusion 
Hours 
Abbreviations: ATM-AVI= aztreonam-avibactam; CrCL = creatinine clearance; IV= intravenous(ly); LD = loading dose; PK= pharmacokinetics; 
q8h = every 8 how-s. 


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The date, starting 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 administration 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 PK analysis. A 
PK/PD analysis will be performed if adequate microbiological response data are collected. 
PK/PD analyses will be reported separately. 
7.4.2. Determination of Drug Concentration 
Samples for determination of ATM and AVI concentration in plasma will be analyzed using 
an appropriate validated bioanalytical method in compliance with Pfizer & vendor standard 
operating procedures (SOPs). Full details of the bioanalytical methods used will be 
described in a separate bioanalytical report. 
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 determination 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. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the PK samples and reported in a separate bioanalytical report. 
Additional analyses may be conducted on the biological samples to further investigate the 
presence and/or identity of drug metabolites and validate the analytical method. Results from 
such analyses may be reported separately from the CSR. 
7.4.3. Storage and Destruction of Pharmacokinetic Samples 
PK samples will be disposed of 12 months after the Bioanalytical Report finalization unless 
requested for future analyses. 
Any residual back-up PK samples may be used for future CCI 
 (in 
this case, residual back-up PK samples will be shipped to Sponsor assigned biostorage; see 
details in the Laboratory Manual). This is optional and will require additional informed 
consent from subjects (See Section 7.6). 
7.5. Pharmacogenomics: not applicable 
Pharmacogenomics samples will not be taken during the study. 
7.6. Biological Samples 
The subject’s consent to the use of donated biological samples is mandatory. Optional 
CCI 
 samples will utilize the PK samples, so no additional draw of blood is needed. 


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Samples for safety, microbiological and PK analyses will be collected as per the inclusion 
criteria, Schedule of Activities (Table 1) and PK sampling schedule (Table 13). The volume 
of blood to be drawn from each subject is displayed in Table 14. All samples will be 
processed and analyzed using sensitive and validated bioanalytical methods. 
The number of samples taken, as well as the volume required for each analysis, may be 
changed during the study as new data on ATM-AVI become available. Aspects of the 
subject management may require additional samples, which might also increase the volume 
of blood drawn. 
 
Table 14. Volume of Blood to Be Drawn from Each Subject 
 
Assessment 
Sample volume 
(mL) 
Number of 
samples 
Total volume 
(mL) 
Safety 
Clinical 
chemistry 
5 
Minimum 8, 
maximum 11a 
Minimum 40, 
maximum 55 
Hematology 
2.5 
Minimum 6, 
maximum 9a 
Minimum 15, 
maximum 22.5 
Pregnancy testb 
2.5 
Minimum 0, 
maximum 1 
Minimum 0, 
maximum 2.5 
Pharmacokinetic 
sampling 
2 
6 
12 
Blood culture 
10 - 15 
Minimum 4 
40 - 60 
Arterial blood 
gases 
2 
Minimum 0, 
maximum 1 
Minimum 0, 
maximum 2 
Totalc 
107 – 154 
Abbreviation: β-hCG=β-human 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 chemistry panel are 
required on Day 2 and Day 3 for serum creatinine for estimation of CrCL. 
b. Determination of urine or serum β-hCG for women of childbearing potential at Screening (Visit 1) only. 
c. 
If the subject is found to be bacteremic, the total volume required for blood culture will increase by a 
further 60 mL for each follow up sample being drawn. 
 
7.6.1. Storage, Re-use and Destruction of Biological Samples 
Samples will be stored until the end of the study and then destroyed; unused PK samples 
(with consent) will be stored for up to 15 years for CCI 
analysis; microbiology isolates 
will be kept at least five years after the study drug is submitted to the regulatory authorities 
for marketing approval. 


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7.6.2. Labelling and Shipment of Biological Samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A 
criteria), see Appendix 2 ‘International Airline Transportation Association (IATA) 
6.2 Guidance Document’. 
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 7.3). 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. 
Samples retained for further use are registered in the Sponsor assigned biostorage during the 
entire life cycle. 


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8. ADVERSE EVENT REPORTING 
8.1. Requirements 
The table below summarizes the requirements for recording safety events on the CRF and for 
repo1iing safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Repo1i Fo1m 
to Pfizer Safety. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Non-serious AE 
All 
None 
Exposure to the 
investigational product 
under study during 
pregnancy or 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure 
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
breastfeeding, and 
occupational exposure 
associated with an AE) 
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be repo1ied as described in the following 
paragraphs. 
Events listed in the table above that require repo1iing to Pfizer Safety on the CT SAE Repo1i 
Fonn within 24 hours of awareness of the event by the investigator are to be repo1ied 
regardless of whether the event is dete1mined by the investigator to be related to an 
investigational product under study. In paiiicular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, i1Tespective of the extent of available 
event info1mation. This time frame also applies to additional new (follow-up) info1mation on 
previously fo1wai·ded repo1is. In the rare situation that the investigator does not become 
immediately aware of the occmTence of an event, the investigator must report the event 
within 24 hours after leaining of it and document the time of his/her first awareness of the 
event. 
For each event, the investigator must pursue and obtain adequate info1mation both to 
dete1mine 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 info1mation in an expedited fashion. 
This infonnation is more detailed than that recorded on the CRF. In general, this will include 


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a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality. Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided. In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety. Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request. 
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.1.1. Additional Details on Recording Adverse Events on the CRF 
All events detailed in the table above will be recorded on the AE page(s) of the CRF. It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information. 
8.1.2. Eliciting Adverse Event Information 
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/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. 


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For subjects who are screen failures, the active collection period ends when screen failure 
status is determined. 
8.1.4.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form. 
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety. 
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment. 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF 
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF. 
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
Any AEs/SAEs that are unresolved at the subject’s last AE/SAE assessment in the study are 
followed up by the Investigator for as long as medically indicated, but without further 
recording in the CRF. 
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. 


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8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations. 
8.2. Definitions 
8.2.1. Adverse Events 
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage. Examples of AEs include, but are not limited to: 
• Abnormal test findings; 
• Clinically significant signs and symptoms; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• 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. 


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8.2.2. Abnormal Test Findings 
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
recording as an AE. 
8.2.3. Definitions of 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. 


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8.2.4. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance. 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE. Examples include: 
• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality); 
• Social admission (eg, subject has no place to sleep); 
• Administrative admission (eg, for yearly physical examination); 
• Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
• 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. 


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Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE. For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE. 
8.3. Severity Assessment 
 
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE. For purposes of 
consistency, these intensity grades are defined as follows: 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
8.4. Special Situations 
8.4.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. 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. 


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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. 
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. 


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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: 
• 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. 


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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 
abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 
8.4.6. 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 
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• 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). 
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 
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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. 
 
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; 


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• 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 5.6. 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. 
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. 


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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 MER±COL 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 (and completing the relevant CRFs modules); 
• 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. 
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 
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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 up to approximately 425 subjects in a 2:1 randomization ratio 
(approximately 283 subjects to ATM-AVI ±MTZ and approximately 142 subjects to 
MER ±COL) with serious infections proven or strongly suspected to be caused by MDR 
pathogens, including those producing MBLs. Current literature indicates that the prevalence 
of infections caused by pathogens producing MBLs could range from 17% to 31% (Azim et 
al. 2010; De et al. 2010; Lascols et al. 2011; Mouloudi et al. 2010 and Walsh et al. 2011), but 
we anticipate a more conservative estimate for prevalence of 8-10% in the study. 
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 planned 
sample size 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. 
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 primary, secondary and 
tertiary objectives. 
9.2.1.2. Clinically Evaluable (CE) Analysis Set 
The CE analysis set is defined as all subjects who: 
• Meet the definition of the ITT analyses. 
• Meet disease criteria for diagnosis of cIAI, or HAP/VAP. 


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• Received at least 48 hours of study treatment (ATM-AVI ±MTZ or MER ±COL) or 
received <48 hours of study treatment before discontinuing study drug due to an AE. 
• Did not receive concomitant antibiotic treatment with potential activity against any 
baseline pathogens between the time of the first dose of study treatment and the time 
of TOC. This does not include those subjects who have received protocol-allowed 
antibiotics, or have failed study treatment and require additional antibiotics to treat 
their infection. 
• Had no important protocol deviations that may affect the assessment of efficacy (to 
be defined in the SAP). 
• Did not have a clinical outcome of indeterminate at TOC. 
• Do not have monomicrobial infections due to non-eligible pathogens (any 
Acinetobacter spp., Pseudomonas aeruginosa) and do not have only Gram-positive 
pathogens. 
Subjects in the CE analysis set will be analyzed according to the treatment they are 
randomized to. The CE analysis set will be used to evaluate selected primary, secondary and 
tertiary objectives. 
9.2.1.3. 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 Gram-negative pathogen in an adequate 
initial/prestudy culture. Subjects with inherently resistant pathogens (monomicrobial 
infections due to any Acinetobacter spp.), and those subjects with only Gram-positive 
pathogens will be excluded from the micro-ITT analysis set. The micro-ITT analysis set will 
be used to evaluate selected secondary and tertiary objectives. 
9.2.1.4. Microbiologically Evaluable (ME) Analysis Set 
The ME analysis set includes all subjects included in both micro-ITT and CE analysis sets, 
and had at least 1 Gram-negative pathogen. The ME analysis set will be used to evaluate 
selected secondary and tertiary objectives. 
9.2.1.5. Modified Intent-To-Treat Analysis Set 
The modified ITT (MITT) analysis set will include all randomized subjects who receive any 
amount of study drug. Subjects in the MITT analysis set will be analyzed according to the 
treatment they received. The MITT analysis set will be used in the sensitivity analysis of the 
primary endpoint. 
9.2.1.6. Microbiological Modified Intent-To-Treat (micro-MITT) Analysis Set 
The microbiological modified ITT (micro-MITT) analysis set is a subset of the micro-ITT 
analysis set and includes all subjects who receive any amount of study drug. The 


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micro-MITT analysis set will be used in sensitivity analysis of microbiological response 
endpoints. 
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 (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-AVI±MTZ and will be used 
to report all PK data. 
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. Outcome Measures for Analyses 
9.3.1. Primary Outcome Variable 
The primary efficacy outcome measure is the proportion of subjects with clinical cure at 
TOC in the ITT and CE analysis sets. For the US regulatory submission, the ITT analysis set 
will be used for the primary analysis while CE analysis set will be the secondary analysis. 
The proportion of subjects with clinical cure for the ITT analysis set is defined as the number 
of subjects with clinical cure at TOC divided by the number of subjects in the ITT analysis 
set. Details are included in the SAP. 
9.3.2. Secondary Outcome Variables 
The secondary outcome measures are: 
• Proportion of subjects with clinical cure at TOC visit in the micro-ITT and ME 
analysis sets. 
• Proportion of subjects with clinical cure at the TOC visits by infection type in the ITT 
and CE analysis sets. 
• Proportion of subjects with clinical cure at the TOC visit for subjects with 
MBL-positive pathogens in the micro-ITT and ME analysis sets. 
• Proportion of subjects with a favorable per-subject microbiological response at the 
TOC visit 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. 


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• PK of ATM and AVI in subjects with cIAI or HAP/VAP infections. 
• PK/PD relationship between exposure and clinical and microbiological response for 
ATM-AVI. 
9.3.3. Tertiary Outcome Variables 
• Proportion of subjects with clinical cure at the EOT visit in the ITT, micro-ITT, CE 
and ME analysis sets. 
• Proportion of subjects with clinical cure at the EOT visit by infection type in the ITT 
and CE analysis sets. 
• Proportion of subjects with clinical cure at the EOT visit for subjects with 
MBL-positive pathogens in the micro-ITT and ME analysis sets. 
• Proportion of subjects with clinical cure at the EOT and TOC visits by pathogen 
resistance type (eg, ATM-non-susceptible, ESBL- positive, carbapenamase- positive, 
etc) in the micro-ITT and ME analysis sets. 
• Proportion of subjects with a favorable per-subject microbiological response at the 
EOT visit 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. 
• Proportion of subjects with a favorable per-subject microbiological response by 
pathogen resistance type (eg, ATM-non-susceptible, ESBL-positive, 
carbapenamase-positive, MBL- positive) at the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 
• Proportion of subjects with a favorable a per-pathogen microbiological response by 
per-resistance type (eg, ATM-non-susceptible, ESBL-positive, 
carbapenamase-positive, MBL-positive) at the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 
9.3.4. Exploratory Outcome Variables 
The exploratory outcome measures assessing the outcomes are: 
• Summary of total score for the composite endpoint of symptom-based objective 
clinical measures (ITT and CE analysis sets). 
• Proportion 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); 


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• Length of ICU stay (days); 
• Transferred to the ICU (Yes/No); 
• Length of study treatment (days); 
• Mechanical ventilation (Yes/No) for HAP/VAP subjects; 
• Length of mechanical ventilation (days) for HAP/VAP subjects; 
• Subsequent unplanned surgical intervention after treatment success vs failure 
(up to the TOC visit) for cIAI subjects. 
9.3.5. Safety Variables 
The following safety data will be collected: AEs, physical examination, vital signs, ECGs 
and laboratory values. 
9.4. Methods for Statistical Analyses 
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. 
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 will be made. 
Methodology for dealing with missing data will be specified in the SAP. 
Important protocol deviations are defined as any important variations from the protocol that 
could affect the assessment of efficacy and will be defined in the SAP. An important 
protocol deviation may include: 
1. Those who entered the study even though they did not satisfy the entry 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 treatment. 
5. Those identified through review of all protocol deviations reported during the study. 
9.4.1. Analysis of the Primary Variable 
The primary descriptive efficacy analysis (for non-US countries) will be the estimate of the 
clinical cure rate and 95% confidence interval (CI) in each treatment arm (ATM-AVI ±MTZ 


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and MER ±COL) in the ITT and CE co-primary analysis sets. The estimate of the clinical 
cure rate and 95% CI in each treatment arm in the ITT analysis set will be the primary 
analysis for the US. Single arm CIs will be computed using Jeffrey’s method (Brown et al. 
2001; Cai 2005). 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 ITT and CE analysis sets at the TOC visit. 
The primary descriptive analysis will be conducted using the clinical response assessment 
determined by a blinded independent adjudication committee (Section 9.7). The 
Investigator’s assessment of clinical response will also be summarized in the ITT and CE 
analysis sets 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. 
Difference in clinical cure rate between treatment arms at TOC visit (ATM-AVI ±MTZ 
minus MER ±COL) and corresponding two-sided 95% CI will be calculated for the ITT and 
CE analysis sets. The two-sided 95% CI for the observed difference in the cure rates 
(ATM-AVI ±MTZ group minus MER ±COL group) will be computed using the method 
proposed for unstratified designs by Miettinen and Nurminen and an additional supporting 
descriptive analysis will be conducted using the stratified Miettinen and Nurminen method 
(Miettinen and Nurminen 1985), if each stratum has at least 3 subjects per each treatment 
group. 
9.4.2. Analysis of the Secondary/Tertiary Variable(s) 
Secondary and tertiary efficacy outcome measures will be assessed and presented using the 
same methods as described in Section 9.4.1. For descriptive secondary/tertiary 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 or HAP/VAP), 
and by resistance group (eg, ESBL status, carbapenemase status, and MBL status). 
The final PK data will be pooled with data from other studies to conduct a popPK analysis 
(using Nonlinear Mixed Effects Modelling [NONMEM]). 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. 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 
reported separately. 
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. 
9.4.3. Subgroup Analysis 
Subgroup analysis may include subject characteristics, disease severity, prior antibiotic use, 
infection type and pathogen resistance type. More details on the subgroup analyses will be 
provided in the SAP. 


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9.4.4. Interim Analysis 
No formal 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 arm during the course of the study for the purpose of safety 
assessment, and/or to support clinical development. 
9.4.5. Supportive Analyses 
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). 
An additional descriptive analysis will be performed for clinical cure at TOC using the MITT 
population which comprises subjects who were randomized and received any amount of IV 
study drug. 
Additional descriptive analyses will be performed for the secondary and tertiary outcomes of 
clinical cure rate and microbiological favourable response rate at EOT and TOC using the 
micro-MITT which is a subset of the micro-ITT comprising those subjects who have 
received any amount of IV study drug. 
Sensitivity analyses will be performed using the modified Intent-To-Treat and 
microbiological modified Intent-To-Treat. The modified Intent-To-Treat and 
microbiological modified Intent-To-Treat are subsets of the Intent-To-Treat and 
microbiological Intent-To-Treat respectively and include all randomized subjects who 
receive any amount of intravenous study drug. 
Details of sensitivity analyses will be fully documented in the SAP. 
9.4.6. Exploratory Analysis 
Subjects will be summarized by the value of their composite score of symptom-based 
objective clinical measures. 
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 response endpoint utilizing objective measures of 
clinical response and evaluation of health resource utilization will be detailed in the SAP. 
9.4.7. Analysis Methods for Safety Variables 
AEs will be summarized by means of counts summaries by 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. 


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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. 
9.5. Data Monitoring Committee 
This study will use an external data monitoring committee (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 forwarded to Pfizer for final decision. Pfizer will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data that are not endpoints, to regulatory authorities, as appropriate. 
Programming and statistical personnel separate from the Sponsor study team will be 
responsible for producing the E-DMC analyses. The Sponsor study team will not receive any 
unblinded summary analyses intended for the E-DMC review. 
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 hepatology review will be 
unblinded to study treatment allocation. The independent clinical hepatologist also will be 
available for consultation for cases of liver enzyme test abnormalities not specifically 
meeting the criteria for PHL or qualifying as liver-related SAEs. 
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. 


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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 clinically evaluable (CE) and 
Microbiologically Evaluable (ME) analysis sets. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed. The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate. The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion. 
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities. 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
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. 


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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 
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 either an encrypted electronic 
and/or paper form and will be password protected or secured in a locked room, as applicable 


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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: 
• 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 
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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 
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. 


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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. 
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. 


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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. 
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. 


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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. 
Publication of the results of the study will be in accordance with Pfizer and 
COMBACTE-CARE publication policies. 
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. 
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. 


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If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control. If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues. 


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16. REFERENCES 
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Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. 
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Crandon JL, Nicolau DP: Human Simulated Studies of Aztreonam and 
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Organisms, Including Metallo-β- Lactamase Producers. Antimicrob Agents Chemother. 
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Dalfino L, Puntillo F, Mosca A, Monno R, Spada ML, Coppolecchia S, et al. High- 
dose, extended-interval colistin administration in critically ill patients: Is this the right 
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Dewan A, Shoukat M. Evaluation of risk of nephrotoxicity with high dose, extended- 
interval colistin administration. IJCCM. 2014;18:427-430. 
10. De AS, Kumar SH, Baveja SM. Prevalence of metallo-β-lactamase producing 
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11. EMA Guideline on the evaluation of medicinal products indicated for treatment of 
bacterial infections. European Medicines Agency 2011, London, UK 
(EMA/CPMP/EWP/558/95 Rev 2, 15 December 2011). 
12. EMA Addendum to the guideline on the evaluation of medicinal products indicated for 
treatment of bacterial infections. European Medicines Agency 2013, London, UK 
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13. European Medicines Agency Assessment Report. Polymyxin-based medicines. 
European Medicines Agency 2014, London, UK (EMA/707128/2014, 
23 October 2014). 
14. European Medicines Agency completes review of polymyxin-based medicines. 
Recommendations issued for safe use in patients with serious infections resistant to 
standard antibiotics. European Medicines Agency 2014, London, UK 
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15. ER Squibb & Sons Limited. Azactam (ATM) 1g or 2g Powder for Solution for Injection 
or Infusion (vial). United Kingdom Summary of Product Characteristics. Uxbridge, UK: 
The Company, eMC 2014. Available at http://www.medicines.org.uk/emc/medicine/549 
(last accessed: 15 August 2016). 
16. European Commission EudraLex Volume 4: EU Guidelines to Good Manufacturing 
Practice, Medicinal Products for Human and Veterinary Use. Annex 13: Investigational 
Medicinal Products, 03 February 2010. 
17. European Commission: Community register of medicinal products for human use. 
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infusion. Accessed on 24 November 2016. Available at 
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21. Guidance for Industry: Antibacterial Therapies for Patients With an Unmet Medical 
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22. Highlights of prescribing information. U.S. Department of Health and Human Services, 
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http://www.hopkinsmedicine.org/amp/guidelines/Antibiotic_guidelines.pdf (last 
accessed: 24 March 2017). 
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s_by_Organ_System/Lower/Upper_Respiratory/Hospital- 
Acquired_Pneumonia_(HAP)/. 
25. See http://www.imi.europa.eu/ (last accessed: 20 March 2017). 
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agents for Gram-negative antibiotic resistant pathogens. 
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27. Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the Pharmacodynamics of 
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28. Jaruratanasirikul S, Limapichat T, Jullangkoon M, Aeinlang N, Ingviya N, 
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29. Johnson AP, Woodford N. Global spread of antibiotic resistance: the example of New 
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2013, 62 (Pt4): 499–513. 
30. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. 
Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 
2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the 
American Thoracic Society. Clin Infect Dis. 2016;63:e61-e111. 
31. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med 1985 Oct;13(10):818-29. 
32. Keel RA, Sutherland CA, Crandon JL, Nicolau DP. Stability of doripenem, imipenem 
and meropenem at elevated room temperatures. Letters to the editor, Int J Antimicrobial 
Agents 2011, 37: 174-85. 
33. Lascols C, Hackel M, Marshall SH, Hujer AM, Bouchillon S, Badal R, et al. Increasing 
prevalence and dissemination of NDM-1 metallo-β-lactamase in India: data from the 
SMART study (2009). J Antimicrob Chemo 2011;66(9):1992-7. 


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34. Li C, Kuti JL, Nightingale CH, Nicolau DP. Population Pharmacokinetic Analysis and 
Dosing Regimen Optimization of Meropenem in Adult Patients. J Clin Pharmacol 
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35. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy 
and safety of ceftazidime/avibactam plus Metronidazole versus meropenem in the 
treatment of complicated intra-abdominal infections in hospitalized adults: results of a 
randomized, double-blind, Phase II trial. J Antimicrob Chemother 2013;68(5):1183-92. 
36. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CC, et al. 
Multidrug resistant, extensively drug-resistant and pandrug-resistant bacteria: an 
international expert proposal for interim standard definitions for acquired resistance. 
Clin Microbiol Infect 2012; 18: 268–281. 
37. Mattie H. Clinical pharmacokinetics of aztreonam. An update. Clin Pharmacokinet. 
1994; 26(2): 99-106. 
38. MERREM (US prescribing information). Wilmington, Delaware: AstraZeneca 
Pharmaceuticals LP; 2016. 
39. MERONEM IV 1g UK Summary of Product Characteristics; Pfizer Ltd.; Available 
from https://www.medicines.org.uk/emc/product/9834/smpc 
40. Moellering RC. NDM-1 — A Cause for Worldwide Concern. N Engl J Med 2010; 363 
(25):2377-2379. 
41. Miettinen O, Nurminen M. Comparative Analysis of Two Rates. Statistics in Medicine 
1985: 213-226. 
42. Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment Options for Carbapenem 
Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015;2:1-15. 
43. Mouloudi E, Protonotariou E, Zagorianou A, Josifidis E, Karapanagiotou A, 
Giasnetsova T, et al. Bloodstream infections cause by metallo-β-lactamases/Klebsiella 
pneumoniae carbapenemase-producing K. pneumoniae among intensive care unit 
patients in Greece: risk factors for infection and impact of type of resistance on 
outcomes. Infect Control Hosp Epidemiol 2010;31(12):1250-6. 
44. Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, editors. Manual of 
Clinical Microbiology. Washington DC; American Society for Microbiology; 2007 
(Available upon request). 
45. Narayanan N, Johnson L, MacDougall C. Beyond Susceptible and Resistant, Part III: 
Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases. 
J Pediatr Pharmacol Ther. 2016;21:110-119. 


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46. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, et al. Framework for 
optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin 
consensus. Lancet Infect Dis. 2015 Feb;15:225-34. 
47. Nordmann P, Poirel L. Strategies for identification of carbapenemases-producing 
Enterobacteriaceae. J. Antimicrob Chemother. 2013;68 (3):487-489. 
48. Payen D, De Pont AC, SakrY, Spies C, Reinhart K, Vincent JL A Positive Fluid 
Balance is Associated With a Worse Outcome in Patients With Acute Renal Failure. 
Critical Care 2008; 12:R74. 
49. Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J. 
Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: 
intermittent bolus versus continuous administration? Monte Carlo dosing simulations 
and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64:142–150. 
50. Solomkin JS, Mazuski JE, Bradley JS; Rodvold KA, Goldstein EJC, Baron EJ, et al. 
Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and 
Children: Guidelines by the Surgical Infection Society and the Infectious Diseases 
Society of America. Clinical Infectious Diseases 2010;50:133–64. 
51. Tängdén T, Giske CG. Global dissemination of extensively drug-resistant 
carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, 
treatment and infection control. J Intern Med. 2015;277:501-512. 
52. Tarral A, Merdjan H. Effect of Age and Sex on the Pharmacokinetics and Safety of 
Avibactam in Healthy Volunteers. Clin Ther. 2015; 37:877-886. 
53. Tsala M, Vourli S, Kotsakis S, Daikos GL, Tzouvelekis L, Zerva L, et al. 
Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing 
Klebsiella pneumoniae isolates: clinical implications. J Med Microbiol. 
2016;65:211-218. 
54. Vinks AA, van Rossem RN, Mathôt RA, Heijerman HG, Mouton JW. Pharmacokinetics 
of aztreonam in healthy subjects and patients with cystic fibrosis and evaluation of dose 
exposure relationships using monte carlo simulation. Antimicrob Agents Chemother. 
2007 Sep; 51(9): 3049-55. 
55. Walsh TR, Weeks J, Livermore SM, Toleman MA. Dissemination of NDM-1 positive 
bacteria in the New Delhi environment and its implications for human health: an 
environmental point prevalence study. Lancet Infect Dis 2011; 11(5):355-62. 
56. Aztreonam 2 g for injection (USP). Fresenius Kabi USA, LLC; Lake Zurich IL 60047, 
USA 
57. Metronidazole 500 mg/ 100 mL; BAXTER HEALTHCARE (SHANGHAI) CO., LTD; 
No. 388, Tingzhu Road, Jinshan District, Shanghai 201506, CHINA 


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58. Metronidazole 500 mg/ 100 mL; Hospira, Inc, Lake Forest, IL 60045, USA 
59. Colistimethate sodium (equivalent to 150 mg colistin base activity per vial) (USP); 
Fresenius Kabi USA, LLC; Lake Zurich IL 60047, USA 


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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 
ATM-AVI±MTZ 
Aztreonam-avibactam±metronidazole 
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 
BP 
Blood pressure 
BPM 
Beats per minute 
β-hCG 
β-human chorionic gonadotropin 
CAZ 
Ceftazidime 
CAZ-AVI 
Ceftazidime-avibactam 
CBA 
Colistin base activity 
CE 
Clinically evaluable 
CHE 
Chronic Health Evaluation 
cIAI 
Complicated intra-abdominal infection 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
CLSI 
Clinical Laboratory Standards Institute 
Cmax 
Maximum plasma concentration 
COL 
Colistin (colistimethate sodium) 
COMBACTE-CARE 
Combatting Bacterial Resistance in Europe – 
Carbapenem-resistance 
A consortium which consists of 19 academic and 3 pharmaceutical 
partners focusing on carbapenem resistance in Europe 
CrCL 
Creatinine clearance 
CRE 
Carbapenem-resistant Enterobacteriaceae 
CRF 
Case Report Form 


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Abbreviation or 
special term 
Explanation 
 
CRO 
Contract Research Organization 
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) 
CV 
Cardiovascular 
CYP 
Cytochrome P 450 
DBP 
Diastolic blood pressure 
DDI 
Drug-drug interaction 
DGR 
Dangerous Goods Regulations 
DILI 
Drug Induced Liver Injury 
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 
HL 
Hy’s Law 


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Abbreviation or 
special term 
Explanation 
 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
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 
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 
MER 
Meropenem 
MER ±COL 
Meropenem ±colistin 
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 
NDM 
New Delhi Metallo-β-lactamase 
NONMEM 
Nonlinear Mixed Effects Modelling 


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Abbreviation or 
special term 
Explanation 
 
NP 
Nosocomial pneumonia 
O2 
Oxygen 
OAT 
Organic anion transporter 
OXA 
A type of Class D β-lactamase (OXA=oxacillinase) 
PACL 
Protocol Administrative Change Letter 
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 
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 
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 
SRSD 
Single Reference Safety Document 
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 
US 
United States 
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). 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; 
• Complete the relevant CRF modules as information becomes available; 
• 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: 


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Determine if there has been a significant change in the subject’s condition# compared with 
when PHL criteria were previously met: 
• 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 2009 


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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 
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 


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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 
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 screening or 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. 


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• In case there is no ABG available assume normal oxygenation (Variable score = 0). 
• Serum creatinine (μmol/L): double point score for acute renal failure. Creatinine conversion from μmol/L to mg/dL to be: 
88.4 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) 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) 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: Intra-abdominal specimens should be obtained for culture 
at initial qualifying surgical procedure (performed within 24 hours before or after 
randomization). If additional surgical procedures are performed, additional 
abdominal site specimens should be obtained for microbiological culture. 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: Baseline respiratory specimens (see below) must be obtained 
for culture within 48 hours prior to randomization and after development of signs and 
symptoms of NP (ideally before receipt of any systemic antibiotics). An adequate 
and appropriate baseline respiratory pecimen should be sent to the local laboratory for 
Gram-stain (expectorated and induced sputum only) and culture. Isolated organisms 
need to be identified, and tested for in vitro susceptibility. 
Appropriate specimens from ventilated subjects include: 
• endotracheal aspirate; 
• BAL; 
• mini-BAL; 
• PSB sample. 


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Appropriate specimens from non-ventilated subjects include: 
• expectorated or induced sputum; 
• BAL; 
• 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 patient 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 
Lower 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. 
In some circumstances, subjects may have multiple respiratory specimens obtained 
after the onset of signs and symptoms of pneumonia within 48 hours prior to 
randomization. The baseline respiratory culture is defined as the last respiratory 
culture obtained via BAL, mini-BAL or PSB prior to randomization. If BAL, 
mini-BAL or PSB specimens are not available, the baseline respiratory culture will be 
defined as the last respiratory culture obtained via endotracheal aspirate prior to 
randomization. If none of these are available, the baseline culture is defined as the 
last sputum culture obtained prior to randomization. In case a repeat respiratory 
specimen is obtained after randomization, but prior to the first dose of study 
treatment, this will be defined as baseline. 


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The status and/or results of the baseline respiratory culture (ie, whether the results are 
pending or known; pathogen(s) identification and/or the susceptibility profile of the 
identified pathogens) should be used to determine whether the protocol requirements 
for open-label Gram-positive or Gram-negative agents have been met as described in 
Section 5.10. Only baseline cultures should be used for determining the need for 
open-label agents. 
c. Blood specimen: Blood cultures should be performed 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. Two sets of blood should be collected 
(ie, 4 bottles) from 2 different sites for aerobic and anaerobic incubation. Each bottle 
should be inoculated with 10 to 15 mL of blood for a total of 40 to 60 mL per 
collection. One set of blood cultures must be obtained through a venipuncture. 
Collect samples, ideally over a period of 2 hours at least 10 to 20 minutes apart from 
separate sites. If a subject is on antibiotics, blood cultures should ideally be taken 
immediately before the next dose. Organisms isolated from blood cultures obtained 
within 48 hours prior to randomization or at Screening/Baseline will be assigned a 
microbiologic response similar to those given for pathogens isolated from cultures of 
abdominal or respiratory specimens (see Table 10 for list of response categories). 
Details concerning the collection of blood cultures are provided in the laboratory 
manual. 
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, 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 


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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. 
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 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 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. 


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Appendix 7. Colistin Conversion Table 
 
Olistimethate Sodium 
Colistimethate Sodium 
Colistin-base Activity 
(IU) 
(mg) 
(mg)* 
12 500 
1 
0.4 
150 000 
12 
5 
1 000 000 
80 
34 
4 500 000 
360 
150 
9 000 000 
720 
300 
Abbreviations: CBA = colistin base activity; IU = international unit. 
* Based on a nominal potency of the drug substance of 12,500 IU/mg or 0.424 mg CBA/mg: both IU and mg 
CBA are expressions of potency and have only approximate relation to the mass. The calculation for the 
conversion of CBA (mg) to colistimethate sodium (IU) for the purpose of following the dosing regimen in IU, 
should be modified if the potency stated by the manufacturer is different to the nominal potency used in this 
conversion table. 
 
Reference 
European Medicines Agency completes review of polymyxin-based medicines. 
Recommendations issued for safe use in subjects with serious infections resistant to standard 
antibiotics. European Medicines Agency 2014, London, UK (EMA/643444/2014, 
24 October 2014). 


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Appendix 8. Summary of Changes from Original Protocol through Amendment 
 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment 1 
05 July 2018 
• Increased sample size per FDA feedback in 
Protocol Summary/Study sites and number of 
subjects planned, Target Subject Population and 
Statistical Methods, Section 3 Study Design, 
Section 9.1. Sample Size Determination. 
Per FDA guideline "Antibacterial Therapies for 
Patients With an Unmet Medical Need for the 
Treatment of Serious Bacterial Diseases Guidance 
for Industry (August 2017)": In general, a safety 
database for a drug that is the subject of a 
streamlined development program should include 
approximately 300 patients at the dose and 
duration of therapy proposed for marketing. The 
number of subjects was increased to meet FDA 
guideline. 
• Increased number of countries and sites 
corresponding to the increase of sample size in 
Protocol Summery and Section 1.4.1 Study Design 
and Control Group. 
• Modified wordings on the Primary Objective and 
the 1st two Secondary Objectives (ie, from 
“compared to” to “and”) to reflect no formal 
comparisons between treatment groups and 
included study analysis sets in the 1st Secondary 
Objective to differentiate from the Primary 
Objective in Protocol Summary/Table Objectives 
and Section 2 Study Objectives. 
• Changed “aztreonam-resistant” or 
“ATM-resistant” to “aztreonam-non-susceptible” 
or “ATM-non-susceptible” in Protocol Summary/ 
Table Objectives, Section 2 Study Objectives, 
Section 7.1.2.1 Microbiological Response 
Assessment and Section 9.3.3 Tertiary Outcome 
Variables for clarity. 
• 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 


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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 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 5.6 Administration (Dose and Treatment 
Regimen) and Section 6.2.2 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 2 Identity of Investigational Product. 
• Deleted the reference to 1g aztreonam and 1 mIU 
colisitn in Protocol Summary/Table 
Investigational product, dosage form and strength 
and Table 2 Identity of Investigational Product to 
be consistent with study drug supply in IP Manual. 
• Added “Note: Comparators and co-administered 
drug are supplied centrally via the sponsor. In 
some instances, locally obtained commercial 
supplies will be utilized in accordance with local 
regulations” and “Note: Aztreonam, Meropenem, 
Colistin and Metronidazole are commercial 
products over-labeled with the study clinical label” 
in Protocol Summary Table Investigational 
product, dosage form and strength and 
Table 2-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 ±metronidazole treatment 
arm, Table 3 ATM-AVI Doses in Relationship to 
CrCL, Section 5.6.1 ATM-AVI ±MTZ and 
Table 13 Pharmacokinetic ATM-AVI Sample 
Collection Time Points. 


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• Modified wordings on creatinine clearance 
monitoring for consistency across the protocol in 
Project Summary/Aztreonam-avibactam 
±metronidazole treatment arm. 
• Changed “randomization” to “first dose of study 
treatment” in Clinically Evaluable Analysis Set 
and in the use of other systemic antimicrobials in 
Protocol Summary/Definition of analysis sets, 
Section 5.10 Concomitant Treatment(s) and 
Section 9.2.1.2 Clinically Evaluable (CE) Analysis 
Set to be consistent with Concomitant Treatment 
definition per Pfizer standard. 
• Deleted “(and wound examination for cIAI 
subjects)” in study procedure “Performing focused 
physical examination (and wound examination for 
cIAI subjects) (see Section 7.2.2)” to avoid 
redundancy with Section 7.2.2 Physical 
Examination in Table 1 Schedule of Activities, 
Section 6.1.1 Visit 1: Eligibility/Screening 
Procedures, Section 6.2.1 Visit 2: Baseline 
Procedures and Day 1 of Treatment, Section 6.2.2 
Visit 3 to 15: Ongoing Treatment, Section 6.2.3.1 
Visit 16: End of Treatment, Section 6.2.3.2 
Visit 17: Test of Cure andVisit 18: Late Follow up 
(Day 45 ±3 days). 
• 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 6.1.1 Visit 1: Eligibility/Screening 
Procedures, Section 6.2.1 Visit 2: Baseline 
Procedures and Day 1 of Treatment, Section 6.2.2 
Visit 3 to 15: Ongoing Treatment, Section 6.2.3.1 
Visit 16: End of Treatment and Section 6.2.3.2 
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 6.2.1 Visit 2: Baseline 
Procedures and Day 1 of Treatment (Day 1) for 
clarity. 


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• Corrected wordings related to the serum HCO3 use 
in place of arterial pH if no ABGs available in 
footnote c 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 Section 6.1.1. Visit 1: 
Eligibility/Screening Procedures, Footnote f of 
Table 1 Schedule of Activities 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. 
• Specified respiratory specimen collection to 
increase clarity on respiratory specimen reference 
time point and Baseline definition across the 
protocol in footnotes h and i of Table 1 Schedule 
of Activities, Section 6.1.1. Visit 1: 
Eligibility/Screening Procedures, Section 6.2.1. 
Visit 2: Baseline Procedures and Day 1 of 
Treatment, Section 7.3 Microbiology and 
Appendix 6 Microbiological Assessments. 
• 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 k of Table 1 
Schedule of Activities, Section 6.1.1 Visit 1: 
Eligibility/Screening Procedures, Section 6.2.2. 
Visit 3 to 15: Ongoing 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. 
• Included local lab blood sample at Screening, 
corrected PK sample volume/pregnancy test 
frequency and updated number of samples and 
total blood volume accordingly in Table 14 
Volume of Blood to Be Drawn from Each Subject 
and Section 1.6 Benefits/Risk and Ethical 


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Assessment for clarity. 
• Changed colistin infusion duration from “30 min” 
to “30-60 min” in Figure 1 Study Outline for 
consistency across protocol. 
• Changed comparator group name from MER-COL 
to MER ±COL in Figure 2 Study Treatment for 
consistency across protocol. 
• Changed “duration of the study” to “duration of 
study treatment” relevant to the statement of 
effective method of contraception in Exclusion 
Criterion 20 in Section 4.2 Exclusion Criteria 
(4.2.1 All Subjects) to increase the clarity and 
consistency on the time frame of contraception 
requirement across protocol. 
• Changed “prior to study entry” to “prior to 
screening” in Exclusion Criterion 21 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 4.6.1 
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 4.6.1 Contraception to accommodate the 
specific study population, 
eg, ventilated/unconscious subjects. 
• Changed “study drug” to “test product” for 
ATM-AVI to differentiate from comparator for 
MER ±COL/The change is clarification in 
Section 4.4 Randomization Criteria and 
Section 5.1 Allocation to Treatment. 
• Changed “MER-positive” to “MER-resistant” in 
Section 5.6.2 MER ±COL Treatment Arm for 


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PFIZER CONFIDENTIAL 
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clarity. 
• Added wordings on optional aminoglycosides in 
Section 5.6.3 Optional Aminoglycosides to align 
with the texts in Protocol Summary/Meropenem 
±colistin treatment arm. 
• Added wordings of “and administered per local 
label” on Polymyxin B (the alternative to Colistin) 
to provide the guidance on Polymyxin B 
administration in Section 5.6.2 MER±COL 
Treatment Arm. 
• Changed “enrollment” to either “informed 
consent” or “the start IV study treatment” in 
Table 8 Prohibited Concomitant Medications to 
increase the clarity on time frame for Prohibited 
Concomitant Medications. 
• Modified definition of “Cure” and “Indeterminate” 
of clinical responses in Table 9 Definition of 
Clinical Response Categories at the EOT and TOC 
visits and “Indeterminate” of microbiological 
response in Table 10 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 10 Definition of 
Microbiological Response Categories at the EOT 
and TOC Visits and Appendix 6 Microbiological 
Assessments for clarity. 
• Removed the wordings of “(from an 
intra-abdominal culture for cIAI subjects or an 
adequate respiratory specimen for HAP/VAP 
subjects)” from Table 11 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 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 


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CRF. 
• Clarified PK sampling time point in reference to 
IV ATM-AVI Loading Dose, Extended Loading 
Dose and Maintenance Dose in Table 13 
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 and 
drug concentration measurements to increase 
clarity in Section 7.4.1 Collection of Plasma 
Samples for Analysis of Aztreonam-Avibactam 
and Section 7.4.2 Determination of Drug 
Concentration per Pfizer Clinical Pharmacology 
protocol template. 
• 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. 
• Adding wordings on COMBACTE-CARE 


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PFIZER CONFIDENTIAL 
Page 171 
 
 
 
publication policies for clarity in 15.2 Publications 
by Investigators. 
• Added “(except anaerobic bacterial pathogens 
isolated from subjects with respiratory infections)” 
in the statement for required shipment of 
microbiological isolates to the central reference 
laboratory in Appendix 6 Microbiological 
Assessments for clarity. 
• Clarified Intra-abdominal specimen collection for 
culture to increase clarity and consistency of 
Intra-abdominal specimens for culture across 
protocol in Appendix 6 Microbiological 
Assessments. 
• Other typographical or administrative edits to 
improve readability, clarity and consistency. 
Original protocol 
20 October 
2017 
Not applicable (N/A) 


 
Signed By: 
Date(GMT) 
Signing Capacity 
 
Document Approval Record 
 
 
C3601002 Protocol Amendment 2 Clean 18May22 
C3601002 Protocol Amendment 2 Clean 18May22 
 
PPD 
 
23-May-2022 18 11 06 
Final Approval 
Document Name: 
Document Title: 

SAP_001.pdf: 
Protocol C3601002 (PF-06947387) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C3601002 
 
 
A PHASE 3 PROSPECTIVE, RANDOMIZED, MULTICENTER, OPEN-LABEL, 
CENTRAL ASSESSOR-BLINDED, PARALLEL GROUP, COMPARATIVE STUDY TO 
DETERMINE THE EFFICACY, SAFETY AND TOLERABILITY OF AZTREONAM- 
AVIBACTAM (ATM-AVI) ± METRONIDAZOLE (MTZ) VERSUS MEROPENEM ± 
COLISTIN (MER ± COL) FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO 
GRAM-NEGATIVE BACTERIA, INCLUDING METALLO-Β-LACTAMASE (MBL) – 
PRODUCING MULTIDRUG-RESISTANT PATHOGENS, FOR WHICH THERE ARE 
LIMITED OR NO TREATMENT OPTIONS 
 
 
 
 
Statistical Analysis Plan 
(SAP) 
Version: 
2 
Date: 
25-JUN-2020 


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TABLE OF CONTENTS 
1. VERSION HISTORY ..................................................................................................................4 
2. INTRODUCTION ........................................................................................................................5 
2.1. Study Objectives ..............................................................................................................5 
2.2. Study Design ....................................................................................................................9 
2.3. Methods for Ensuring Blinding .....................................................................................10 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................11 
3.1. Primary Endpoint ...........................................................................................................11 
3.2. Secondary Endpoints .....................................................................................................11 
3.3. Tertiary Endpoints .........................................................................................................12 
3.4. Exploratory Endpoints ...................................................................................................12 
3.5. Baseline Variables .........................................................................................................13 
3.5.1. Baseline Clinical Laboratory and Vital Signs ...................................................13 
3.5.2. Baseline Microbiology ......................................................................................13 
3.6. Stratification Variables ..................................................................................................15 
3.7. Safety Endpoints ............................................................................................................15 
3.7.1. Adverse Events .................................................................................................15 
4. ANALYSIS SETS ......................................................................................................................15 
4.1. Efficacy Analysis Sets ...................................................................................................16 
4.1.1. Intent-to-Treat (ITT) Analysis Set ....................................................................16 
4.1.2. Clinically Evaluable (CE) Analysis Set ............................................................16 
4.1.3. Microbiological Intent-To-Treat (micro-ITT) Analysis Set ..............................17 
4.1.4. Microbiologically Evaluable (ME) Analysis Set ..............................................17 
4.1.5. Modified Intent-To-Treat Analysis Set .............................................................17 
4.1.6. Microbiological  Modified  Intent-To-Treat  (micro-MITT)  Analysis 
Set .................................................................................................................17 
4.2. Safety Analysis Set ........................................................................................................18 
4.3. Population Pharmacokinetic (popPK) Analysis Set .......................................................18 
4.4. Other Analysis Sets ........................................................................................................18 
4.4.1. All Subjects Analysis Set ..................................................................................18 
5. GENERAL METHODOLOGY AND CONVENTIONS ..........................................................18 
5.1. Hypotheses and Decision Rules ....................................................................................18 


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5.2. General Methods ............................................................................................................ 18 
5.3. Methods to Manage Missing Data ................................................................................. 19 
6. ANALYSES AND SUMMARIES ............................................................................................. 19 
6.1. Primary Endpoint ........................................................................................................... 19 
6.1.1. Primary Analysis ............................................................................................... 19 
6.1.2. Sensitivity/Robustness Analyses ....................................................................... 20 
6.2. Secondary Endpoints ..................................................................................................... 20 
6.2.1. Pharmacokinetic Analyses ................................................................................ 21 
6.3. Tertiary Endpoints ......................................................................................................... 21 
6.4. Exploratory Endpoints ................................................................................................... 21 
6.5. Subset Analyses ............................................................................................................. 22 
6.6. Baseline and Other Summaries and Analyses ................................................................ 23 
6.7. Safety Summaries and Analyses .................................................................................... 24 
6.7.1. Adverse Events ................................................................................................. 24 
6.7.2. Laboratory Data ................................................................................................ 24 
6.7.3. Vital Signs ......................................................................................................... 25 
6.7.4. Electrocardiogram ............................................................................................. 25 
6.7.5. Physical Examination ........................................................................................ 25 
6.7.6. Detailed Infection-related Focused Physical Examination ................................ 25 
6.7.7. Extent of Exposure and Compliance ................................................................. 25 
7. INTERIM ANALYSES ............................................................................................................. 26 
8. REFERENCES ........................................................................................................................... 26 
9. APPENDICES ............................................................................................................................ 27 


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1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study C3601002 is based on protocol amendment I 
dated 05JUL2018. 
Table 1 Summary of Major Changes in SAP Amendments 
 
SAP Version 
Change 
Rationale 
Version 2/ 
Amendment 1 
Included details 
 Detail included for clarity as the clinical 
regarding the Clinical 
 response detennined by the Clinical 
Adjudication 
 Adjudication Committee will be used in 
Committee in Section 
the analyses of the clinical response 
3.1 
efficacy endpoints. 
Details added in Section 
3.5.2 regarding baseline 
microbiology 
Details added to described how baseline 
pathogens will be defined. 
Modified descriptions 
of some safety 
endpoints/analysis 
Modified for clarity and to be consistent 
with Pfizer standard safety data repo1ting. 
Definition of treatment­ 
emergent adverse event 
modified to: An adverse 
event is considered a 
Treatment-Emergent 
Adverse Event (TEAE) 
if the event sta1ted after 
the study medication 
start date and time. 
The TEAE definition was modified per 
Pfizer guidance. 
Removed 3-tier 
approach to adverse 
event safety analysis. 
It was decided to not include the 3-tier AE 
approach since statistical comparisons are 
not conducted for efficacy analysis in this 
descriptive study; thus, they should not be 
conducted for safety analysis either. 
However, pre-specified events of clinical 
impo1tance (previously planned as Tier 1 
AEs) will be evaluated. 
Inclusion of details in 
Details provided for clarity and 
on the efficac  anal sis set 


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determination of 
efficacy analysis sets. 
determination process. 
Details added regarding 
the evaluation of the 
95% CI for the 
difference in the clinical 
cure rates between the 
treatment groups in 
Section 6.1. 
Details are provided to outline that the 
evaluation of the 95% CI for the difference 
in cure rates is pre-specified and to provide 
the power associated with evaluating the 
95% CI versus various lower bound 
values. 
Details added for the 
health resource 
utilization analysis in 
Section 6.4. 
More details added for the health resource 
utilization analyses for clarity and it is also 
noted that the results of these analyses will 
be included in the clinical study report 
(noted in Section 2.1). 
Addition of Criteria for 
Vital Signs 
Abnormalities 
(Appendix 4). 
Criteria outlined for evaluation of vital 
signs abnormalities, which is planned as 
part of the safety analysis. 
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 C3601002. 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 ± metronidazole 
and meropenem ± colistin at Test of Cure 
visit for the treatment of serious 
infections due to Gram-negative bacteria, 
including those due to 
metallo-β-lactamase-producing 
multidrug-resistant pathogens. 
Proportion of subjects with clinical cure at Test 
of Cure visit in the Intent-To-Treat and Clinically 
Evaluable analysis sets (Note: For non-United 
States countries, the Intent-To-Treat and 
Clinically Evaluable are considered co-primary 
analysis sets. For the US, the Intent-To-Treat is 
considered the primary analysis set, while 
Clinically Evaluable is secondary). 


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Secondary Objectives: 
Secondary Endpoint(s): 
To evaluate efficacy of 
aztreonam-avibactam ± metronidazole 
and meropenem ± colistin at the Test of 
Cure visit in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 
Proportion of subjects with clinical cure at the 
Test of Cure visit in the microbiological 
Intent-To-Treat and Microbiologically Evaluable 
analysis sets. 
To evaluate the efficacy of 
aztreonam-avibactam ± metronidazole 
and meropenem ± colistin at the Test of 
Cure visit in key sub populations. 
• Proportion of subjects with clinical cure at 
the Test of Cure visit by infection type in the 
Intent-To-Treat and Clinically Evaluable 
analysis sets. 
• Proportion of subjects with clinical cure at 
the Test of Cure visit for subjects with 
metallo-β-lactamase-positive pathogens in 
the microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
To assess the per-subject microbiological 
response to aztreonam-avibactam ± 
metronidazole and meropenem ± colistin 
at the Test of Cure visit. 
Proportion of subjects with a favorable 
per-subject microbiological response at the Test 
of Cure visit in the microbiological 
Intent-To-Treat and Microbiologically Evaluable 
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 and microbiological 
Intent-To-Treat analysis sets. 
To evaluate the pharmacokinetics of 
aztreonam and avibactam in subjects with 
serious infections and to characterize the 
relationship between exposure and 
clinical and microbiological response for 
aztreonam-avibactam ± metronidazole 
utilization (listings to be provided in the 
Clinical Study Report, analysis to be 
reported outside of the Clinical Study 
Report). 
• Pharmacokinetics of aztreonam and 
avibactam in subjects in the population 
pharmacokinetic analysis set. 
• Pharmacokinetic / pharmacodynamic 
relationship between exposure and clinical 
and microbiological response for 
aztreonam-avibactam ± metronidazole in the 
population pharmacokinetic analysis set. 


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Safety Objective: 
Safety Endpoint: 
To evaluate the safety and tolerability 
profile of aztreonam-avibactam ± 
metronidazole and meropenem ± colistin. 
Safety and tolerability as assessed by adverse 
events, physical examination, vital signs, 
electrocardiograms, and laboratory assessments 
in the safety analysis set. 
 
 
Tertiary Objectives: 
Tertiary Endpoint(s): 
To evaluate the efficacy of 
aztreonam-avibactam ± metronidazole 
and meropenem ± colistin at the End of 
Treatment visit. 
Proportion of subjects with clinical cure at the 
End of Treatment visit in the Intent-To-Treat, 
microbiological Intent-To-Treat, Clinically 
Evaluable and Microbiologically Evaluable 
analysis sets. 
To evaluate the efficacy of 
aztreonam-avibactam ± metronidazole 
and meropenem ± colistin at the End of 
Treatment visit in key sub populations. 
• Proportion of subjects with clinical cure at 
the End of Treatment visit by infection type 
in the Intent-To-Treat and Clinically 
Evaluable analysis sets. 
• Proportion of subjects with clinical cure at 
the End of Treatment visit for subjects with 
metallo-β-lactamase-positive pathogens in 
the microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
To evaluate the efficacy of 
aztreonam-avibactam ± metronidazole 
and meropenem ± colistin at End of 
Treatment and Test of Cure visits by 
pathogen resistance types. 
Proportion of subjects with clinical cure at End 
of Treatment and Test of Cure visits by Pathogen 
resistance type (e.g., aztreonam-non-susceptible, 
extended-spectrum β-lactamase-positive, 
carbapenamase-positive, etc.) in the 
microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
To assess the per-subject microbiological 
response to aztreonam-avibactam ± 
metronidazole and meropenem ± colistin 
at End of Treatment visit. 
Proportion of subjects with a favorable 
per-subject microbiological response at the End 
of Treatment in the microbiological 
Intent-To-Treat and Microbiologically Evaluable 
analysis sets. 


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Tertiary Objectives: 
Tertiary Endpoint(s): 
To assess the microbiological response 
by pathogen and by pathogen resistance 
type to aztreonam-avibactam ± 
metronidazole and meropenem ± colistin 
at End of Treatment and Test of Cure 
visits. 
• Proportion of subjects with a favorable 
per-pathogen microbiological response at the 
End of Treatment and Test of Cure visits in 
the microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 
• Proportion of subjects with a favorable 
per-subject microbiological response by 
pathogen resistance type (e.g., 
aztreonam-non-susceptible, 
extended-spectrum β-lactamase-positive, 
carbapenamase-positive, metallo-β-lactamase 
positive) at the End of Treatment and Test of 
Cure visits in the microbiological 
Intent-To-Treat and Microbiologically 
Evaluable analysis sets. 
• Proportion of subjects with a favorable 
per-pathogen microbiological response by 
pathogen resistance type (e.g., 
aztreonam-non-susceptible, 
extended-spectrum β-lactamase-positive, 
carbapenamase-positive, 
metallo-β-lactamase-positive) at the End of 
Treatment and Test of Cure visits in the 
microbiological Intent-To-Treat and 
Microbiologically Evaluable analysis sets. 


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Exploratory Objectives: 
Exploratory Endpoint(s): 
To evaluate efficacy of 
aztreonam-avibactam ± metronidazole 
and meropenem ± colistin using objective 
clinical measures. 
Composite endpoint including symptom-based 
objective clinical measures (Intent-To-Treat and 
Clinically Evaluable analysis sets). 
To assess 14-day all-cause mortality. 
Proportion of subjects who died on or before 
14 days from randomization in the 
Intent-To-Treat analysis set. 
To evaluate health resource utilization* 
• Length of hospital stay, including any 
readmissions up to Test of Cure (days). 
• Length of study treatment (days). 
• Length of intensive care unit stay (days). 
• Transferred 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 Test of Cure visit) for complicated 
intra-abdominal infection subjects. 
*: Results of health utilization analyses will be included in the Clinical Study Report. 
2.2. Study Design 
This is a Phase 3 prospective, randomized, multicenter, open-label, central assessor-blinded, 
parallel group, comparative study to determine the efficacy, safety, and tolerability of 
aztreonam-avibactam ± metronidazole and meropenem ± colistin in the treatment of 
hospitalized adults with complicated intra-abdominal infection or nosocomial pneumonia 
including hospital-acquired pneumonia and ventilator-associated pneumonia, in regions with 
endemic or emerging carbapenem resistance, and where metallo-β-lactamase-producing 
multi-drug resistant pathogens are suspected. 


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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 visit (Visit 16) within 24 hours after the last infusion, a Test of Cure visit (Visit 
17) on Day 28 (±3 days) and a Late Follow-Up visit (Visit 18) on Day 45 (±3 days). 
Subjects will be randomized in a 2:1 ratio to the aztreonam-avibactam ± metronidazole 
treatment arm or the meropenem ± colistin treatment arm. Randomization will be stratified 
based on infectious disease type (complicated intra-abdominal infection and hospital- 
acquired pneumonia/ventilator-associated pneumonia). For complicated intra-abdominal 
infection, subjects will also be stratified by Acute Physiology and Chronic Health Evaluation 
score (≤10 and >10) (Protocol Appendix 5). For hospital-acquired pneumonia/ventilator- 
associated pneumonia, subjects will also be stratified by mechanical ventilation status (Y/N). 
The study will randomize approximately 375 subjects (approximately 300 subjects with 
complicated intra-abdominal infection and approximately 75 subjects with hospital acquired 
pneumonia/ventilator associated pneumonia). It is estimated that approximately 25 subjects 
will be identified with metallo-β-lactamase-producing Gram-negative pathogens in the 
aztreonam-avibactam ± metronidazole treatment arm, and approximately 12 subjects in the 
meropenem ± colistin treatment arm. 
The number of complicated intra-abdominal infection subjects with a perforated appendix or 
appendiceal abscess will be limited to approximately 40% of the study population with 
complicated intra-abdominal infections. 
For subjects randomized to aztreonam-avibactam ± metronidazole, sparse blood samples will 
be collected for population pharmacokinetic assessments and 
pharmacokinetic/pharmacodynamic relationships will be evaluated in subjects where plasma 
samples and clinical and microbiological response data have been collected. 
Each subject is expected to complete the study, including the Late Follow-Up visit. 
Participants in the study must be inpatients at the study site institution to receive study 
medication. 
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 will be assessed at EOT and TOC by an independent clinical 
adjudication committee (central assessor) in a blinded fashion with the aim of unbiased 
adjudication of the primary objective measure. Data will be provided to the adjudication 
committee 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. 


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No interim analysis is planned and no analysis of data according to treatment arm assignment 
will be made prior to database lock, except for analyses conducted 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 Intent-To-Treat (ITT) and Clinically Evaluable (CE) co-primary analysis sets. 
For the US regulatory submission, the ITT analysis set will be used for the primary analysis 
while CE analysis set will be the secondary analysis set. For the non-United States countries, 
the ITT and CE analysis sets are co-primary analysis sets. The proportion of subjects with 
clinical cure for the ITT analysis set is defined as the number of subjects with clinical cure at 
TOC divided by the number of subjects in the ITT analysis set. The proportion of subjects 
with clinical cure for the CE analysis set is defined as the number of subjects with clinical 
cure at TOC divided by the number of subjects in the CE 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 the TOC visit in the micro-ITT and ME 
analysis sets; 
• Proportion of subjects with clinical cure at the TOC visit by infection type in the ITT 
and CE analysis sets; 
• Proportion of subjects with clinical cure at the TOC visit for subjects with 
MBL-positive pathogens in the micro-ITT and ME analysis sets; 
• Proportion of subjects with a favorable per-subject microbiological response at the 
TOC visit in the micro-ITT and ME analysis sets; 


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• Proportion of subjects who died on or before 28 days after randomization in the ITT 
and micro-ITT analysis sets; 
• PK of ATM and AVI in subjects with cIAI or HAP/VAP infections; 
• PK/PD relationship between exposure and clinical and microbiological response for 
ATM-AVI; 
• Safety and tolerability as assessed by adverse events, physical examination, vital 
signs, electrocardiograms, and laboratory assessments in the safety analysis set. 
Per-subject and per-pathogen (Section 3.3 Tertiary Endpoint) microbiological responses that 
are presumed based on clinical response will be based on the adjudicated clinical response. 
3.3. Tertiary Endpoints 
• Proportion of subjects with clinical cure at the EOT visit in the ITT, micro-ITT, CE 
and ME analysis sets; 
• Proportion of subjects with clinical cure at the EOT visit by infection type in the ITT 
and CE analysis sets; 
• Proportion of subjects with clinical cure at the EOT visit for subjects with 
MBL-positive pathogens in the micro- ITT and ME analysis sets; 
• Proportion of subjects with clinical cure at the EOT and TOC visits by pathogen 
resistance type (e.g., ATM- non-susceptible, ESBL- positive, 
carbapenamase-positive, etc.) in the micro-ITT and ME analysis sets; 
• Proportion of subjects with a favorable per-subject microbiological response at the 
EOT visit 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; 
• Proportion of subjects with a favorable per-subject microbiological response by 
pathogen resistance type (e.g., ATM- non-susceptible, ESBL- positive, 
carbapenamase- positive, MBL-positive) at the EOT and TOC visits in the micro-ITT 
and ME analysis sets; 
• Proportion of subjects with a favorable a per-pathogen microbiological response by 
pathogen-resistance type (e.g., ATM- non-susceptible, ESBL- positive, 
carbapenamase- positive, MBL-positive) at the EOT and TOC visits in the micro-ITT 
and ME analysis sets. 
3.4. Exploratory Endpoints 
The exploratory outcome measures are: 
• Summary of total score for the composite endpoint of symptom-based objective 
clinical measures (ITT and CE analysis sets); 
• Proportion 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 ICU stay (days); 
• Transferred to the ICU (Yes/No); 


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• Length of study treatment (days); 
• Mechanical ventilation (Yes/No) for HAP/VAP subjects; 
• Length of mechanical ventilation (days) for HAP/VAP subjects; 
• Subsequent unplanned surgical intervention after treatment success vs failure 
(up to the TOC visit) for cIAI subjects. 
3.5. Baseline Variables 
3.5.1. Baseline Clinical Laboratory and Vital Signs 
Baseline clinical laboratory (Hematology, Clinical Chemistry, etc.) and vital signs values will 
be defined as the last non-missing value observed before treatment begins. 
3.5.2. Baseline Microbiology 
The central lab results will be used in the microbiological analyses. Local lab results will 
only be used in microbiological analyses when central lab results are not available. 
Baseline pathogens are defined as those obtained from adequate specimens closest (and 
prior) to the start of study treatment. Any pathogens resulting from blood obtained in the 48 
hours prior to study treatment start will be considered baseline pathogens. 
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. Analysis of the pathogens from the previous adequate specimen, 
as baseline pathogens, may be conducted if a sufficient number of subjects fall into this 
scenario. 
Adequate specimens for culture at baseline for each infection type are outlined below: 
Cultures of abdominal site infections (for cIAI subjects only) 
Specimens must be obtained for culture from an initial qualifying surgical procedure within 
24 hours before or after randomization and sent to the local laboratory for microbiological 
culture. This will be treated as the baseline culture. 
Respiratory specimen for Gram-stain/culture (for HAP/VAP subjects only) 
Respiratory specimens: Baseline respiratory specimens (see below) must be obtained for 
culture within 48 hours prior to randomization and after development of signs and symptoms 
of HAP/VAP (ideally before receipt of any systemic antibiotics). An adequate and 
appropriate baseline respiratory specimen should be sent to the local laboratory for 
Gram-stain (expectorated and induced sputum only) and culture. Isolated organisms need to 
be identified, and tested for in vitro susceptibility. 
Appropriate specimens from ventilated subjects include: 
• endotracheal aspirate; 


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• BAL; 
• Mini-BAL; 
• PSB sample. 
Appropriate specimens from non-ventilated subjects include: 
• expectorated or induced sputum; 
• BAL; 
• 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 samples from expectorated or induced sputum must show 
<10 squamous epithelial cells and >25 polymorphonuclear neutrophils per Lower Power 
Field (LPF) upon a Gram-stain. 
In some circumstances, subjects may have multiple respiratory specimens obtained after the 
onset of signs and symptoms of pneumonia within the 48 hours prior to randomization. The 
baseline respiratory culture is defined as the last respiratory culture obtained via BAL, 
mini-BAL or PSB prior to randomization. If BAL, mini-BAL or PSB specimens are not 
available, the baseline respiratory culture will be defined as the last respiratory culture 
obtained via endotracheal aspirate prior to randomization. If none of these are available, the 
baseline culture is defined as the last sputum culture obtained prior to randomization. In case 
a repeat respiratory specimen is obtained after randomization, but prior to the first dose of 
study treatment, this will be defined as baseline. 
Collection of Blood for Culture (for all subjects) 
Blood cultures should be performed at the Baseline visit prior to the first dose of study 
treatment, if blood cultures are not available within 48 hours prior to randomization. Any 
blood cultures obtained within 48 hours prior to randomization will be valid. 


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3.6. Stratification Variables 
Randomization will be stratified based on infectious disease type (complicated 
intra-abdominal infection and hospital-acquired pneumonia/ventilator-associated 
pneumonia). For complicated intra-abdominal infection, subjects will also be stratified by 
Acute Physiology and Chronic Health Evaluation score (≤10 and >10). For hospital-acquired 
pneumonia/ventilator-associated pneumonia, subjects will also be stratified by mechanical 
ventilation status (Y/N). 
3.7. 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. 
3.7.1. 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. 
In addition to standard AE summaries, pre-specified events of clinical importance, 
maintained in the product’s Safety Review Plan, will be summarized. These will include the 
following categories of events: AEs potentially related to liver disorder, Clostridium difficile 
colitis and hypersensitivity/anaphylaxis. The list will be finalized prior to database lock. 
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 


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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 the primary, secondary and tertiary 
objectives. 
4.1.2. Clinically Evaluable (CE) Analysis Set 
The CE analysis set is defined as all subjects who: 
• Met the definition of the ITT analysis set; 
• Met disease criteria for diagnosis of cIAI, or HAP/VAP; 
• Received at least 48 hours of study treatment (ATM-AVI ± MTZ or MER ± COL) or 
received <48 hours of study treatment before discontinuing study drug due to an AE; 
• Did not receive concomitant antibiotic treatment with potential activity against any 
baseline pathogens between the time of first dose of study treatment and the time of 
TOC. This does not include those subjects who have received protocol-allowed 
antibiotics, or have failed study treatment and require additional antibiotics to treat 
their infection; 
• Did not receive prior antibiotics other than as outlined as acceptable in Exclusion 
Criteria #3 in the protocol; 


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• Had no important protocol deviations that may affect the assessment of efficacy. The 
criteria for identifying important protocol deviations will be finalized as part of the 
final evaluability review before database lock. Protocol Deviations will be tracked 
and documented throughout the study in the Clinical Oversight Review Dashboard 
(CORD) system; 
• Did not have a clinical outcome of indeterminate at TOC; 
• Did not have monomicrobial infections due to non-eligible pathogens (any 
Acinetobacter spp., Pseudomonas aeruginosa) and do not have only Gram-positive 
pathogens. 
Subjects in the CE analysis set will be analyzed according to the treatment to which they are 
randomized. The CE analysis set will be used to evaluate selected primary, secondary and 
tertiary objectives. 
4.1.3. 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 Gram-negative baseline pathogen from an 
adequate specimen obtained prior to the start of study treatment. Subjects with inherently 
resistant pathogens (for example, monomicrobial infections due to any Acinetobacter spp.), 
and those subjects with only Gram-positive pathogens will be excluded from the micro-ITT 
analysis set. Subjects in the micro-ITT analysis set will be analyzed according to the 
treatment to which they are randomized. The micro-ITT analysis set will be used to evaluate 
selected secondary and tertiary objectives. 
4.1.4. Microbiologically Evaluable (ME) Analysis Set 
The ME analysis set includes all subjects commonly included in both micro-ITT and CE 
analysis sets and includes subjects who have at least 1 etiologic pathogen from an adequate 
baseline culture regardless of susceptibility to study agents. 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 and tertiary objectives. 
4.1.5. Modified Intent-To-Treat Analysis Set 
The modified ITT (MITT) analysis set will include all randomized subjects who receive any 
amount of study drug. Subjects in the MITT analysis set will be analyzed according to the 
treatment they received. The MITT analysis set will be used in the sensitivity analysis of the 
primary endpoint. 
4.1.6. Microbiological Modified Intent-To-Treat (micro-MITT) Analysis Set 
The microbiological modified ITT (micro-MITT) analysis set is a subset of the micro-ITT 
analysis set and includes all subjects who receive any amount of study drug. Subjects in the 
micro-MITT analysis set will be analyzed according to the treatment they received. The 
micro-MITT analysis set will be used in sensitivity analysis of microbiological response 
endpoints. 


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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. The safety analysis set is the same as the MITT 
analysis set. Subjects in the safety analysis set will be analyzed according to the treatment 
they receive. 
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. Any comparisons between 
treatment arms will only be assessed as evidence of an effect. There will be no adjustment for 
multiplicity. 
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. 


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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. 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoint 
6.1.1. Primary Analysis 
The prima1y descriptive efficacy analysis (for non-US countries) will be the estimate of the 
clinical cure rate and 95% confidence interval (CI) in each treatment aim (ATM-AVI± MTZ 
and MER± COL) in the ITT and CE co-prima1y analysis sets. The estimate of the clinical 
cure rate and 95% CI in each treatment aim in the ITT analysis set will be the primary 
analysis for the US. Single aim Cis will be computed using Jeffrey's method (Brown et al. 
2001; Cai 2005). The number and percentage of subjects who had a clinical response of 
clinical cure, clinical failure, and indetenninate in each treatment aim will be tabulated for 
the ITT and CE analysis sets at the TOC visit (Day 28 ± 3 days). 
The prima1y descriptive analysis will be conducted using the clinical response assessment 
dete1mined by a blinded independent clinical adjudication committee. The Investigator's 
assessment of clinical response will also be summarized in the ITT and CE analysis sets 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 prima1y analysis. 
Difference in clinical cure rate between treatment anns at TOC visit (ATM-AVI± MTZ 
minus MER± COL) and coITesponding two-sided 95% CI will be calculated for the ITT and 
CE analysis sets. The two-sided 95% CI for the observed difference in the cure rates 
(ATM-AVI± MTZ group minus MER± COL group) will be computed using the method 
proposed for unstratified designs by Miettinen and Nunninen and an additional suppo1iing 
descriptive analysis will be conducted using the stratified Miettinen and Nunninen method 
(Miettinen and Nmminen 1985), if each stratum has at least 3 subjects per each treatment 
group. 
 


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6.1.2. Sensitivity/Robustness Analyses 
An analysis of the Investigator’s assessment of clinical response in the ITT and CE analysis 
sets at the TOC visit will be performed as a sensitivity analysis. 
A sensitivity analysis will be performed for clinical response at TOC (adjudicated response) 
using the MITT population which includes subjects who were randomized and received any 
amount of study drug. 
Sensitivity analysis of the primary endpoint (clinical response at TOC, adjudicated response) 
will also be conducted in the ITT population that considers all deaths prior to the TOC as 
clinical failures. 
A sensitivity analysis of the use of concomitant antibiotics (other than those allowed per the 
protocol – Gram positive coverage and aminoglycosides) on the primary endpoint (clinical 
response at TOC) in the ITT population will be conducted. Subjects who receive at least 1 
dose of a restricted/prohibited concomitant medication will be included in this analysis of the 
primary endpoint. 
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 TOC visit by differing analysis sets {e.g., 
ME], by MBL status and infection type; proportion of subjects with favorable per-subject 
microbiological response, and those who died on or before 28 days after randomization 
[overall and by infection type]) will be assessed and presented similar to the primary 
endpoint. 
In addition to an analysis of clinical response at TOC by infection type, additional efficacy 
(clinical and microbiological), safety, and baseline analyses by infection type will be 
conducted to evaluate the cIAI and HAP/VAP populations separately. These analyses will be 
outlined in the Analysis and Reporting Plan. 
Additional descriptive analyses will also be performed for the secondary and tertiary (refer to 
Section 6.3) outcomes of clinical cure rate and microbiological favorable response rate at 
EOT and TOC using the microbiological modified Intent-To-Treat population. which is a 
subset of the micro-ITT population comprising those subjects who received any amount of 
intravenous study drug. 
For the Safety analyses, please see Section 6.7. 


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6.2.1. Pharmacokinetic Analyses 
Aztreonam and avibactam plasma concentrations versus time will be depicted graphically in 
the Clinical Study Report (CSR). The final pharmacokinetic data will be pooled with data 
from other studies to conduct a population pharmacokinetic analysis (using Nonlinear Mixed 
Effects [NLME] Modelling). Using these parameter estimates (mean pharmacokinetic 
parameters including inter individual variance estimates), Monte-Carlo simulation will be 
undertaken and potential pharmacokinetic/pharmacodynamic relationships will be explored. 
Full details of the pharmacokinetic and pharmacokinetic / pharmacodynamic analysis will be 
given in the Pharmacokinetic Modeling Analysis Plan (PMAP). These results will be 
reported separately in a Population Pharmacokinetic Modeling Analysis Report (PMAR). 
6.3. Tertiary Endpoints 
Tertiary endpoints and corresponding analysis methods are also summarized in Appendix 2 
Table 1. 
Tertiary efficacy outcome measures (evaluating the proportion of subjects with clinical cure 
[based on adjudicated clinical response] at the EOT visit by differing analysis sets, MBL 
status and infection type; proportion of subjects with favorable microbiological response at 
EOT) will be assessed and presented using similar methods as used for the primary endpoint. 
For descriptive tertiary outcome measures, number and percentage in each treatment arm will 
be tabulated. Response summaries will be presented for the proportion of subjects with a 
favorable clinical, per-subject microbiological, and per-pathogen microbiological response at 
the EOT and TOC visits overall and by resistance type. Resistance type will include: 
aztreonam-non-susceptible, meropenem-non-susceptible isolates and isolates producing 
ESBLs, serine carbapenemases, and MBLs (selected analyses for MBL status is secondary). 
6.4. Exploratory Endpoints 
Subjects will be summarized by the value of their composite score of symptom-based 
objective clinical measures. This analysis is dependent on development of a composite score 
of symptom-based objective clinical measures and validation. If available prior to completion 
of this study (prior to database lock), this analysis will be conducted. 
The proportion of subjects who died on or before 14 days after randomization will be 
presented by treatment arm. 
Health resource utilization data will be summarized by treatment arm, 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 of ICU stay, transfer to ICU, length of study treatment (calendar and 24-hour days; see 
Section 6.7.7), mechanical ventilation (and length if needed) for HAP/VAP subjects, and 
unplanned surgical intervention for cIAI subjects. Descriptive statistics (number, mean, 
standard deviation [SD], median, minimum, and maximum) will be provided for 


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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 proportion of hospital re-admissions) assessment will be 
included in these analyses. In addition, except for hospitalization (all subjects 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 calendar 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/discharge 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 similarly. These length of stay/duration variables 
will be summarized with and without subjects who died to evaluate the impact of the 
duration variables for subjects who died on the overall assessment of these variables. 
6.5. Subset Analyses 
Subgroup analyses of the primary endpoint (clinical cure rate at TOC) will include: 
• 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). 
• For cIAI subjects: APACHE II score category (≤10 or > 10) based on the data 
collected from the eCRF. 
• For cIAI subjects: Diagnosis of Appendicitis (Appendiceal perforation or 
peri-appendiceal abscess) vs non appendicitis diagnosis. 
• For HAP/VAP subjects: Mechanical Ventilation status at baseline (Yes/No), based on 
the data collected from the eCRF. 
• Prior systemic antibiotic use (yes/ [≤24 hr / >24 hr] / no) within 48 hr window prior to 
first dose of study treatment. 
• Monomicrobial vs polymicrobial infections at baseline (vs no pathogen). 
• Concomitant Aminoglycoside Use – Subjects who receive at least 1 dose of protocol 
allowed aminoglycoside therapy during the study treatment period vs subjects who 
receive none. 


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• Geographic region (Western Europe; Eastern Europe; China; RoW). 
• Further analyses for regions (e.g., Asian, or other regions) and countries (e.g., 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. 
As noted in secondary and tertiary endpoints, response summaries will be presented by 
infection type (complicated intra-abdominal infection or hospital-acquired 
pneumonia/ventilator-associated pneumonia), and by MBL status and pathogen resistance 
type. 
6.6. Baseline and Other Summaries and Analyses 
Baseline variables are defined as outlined in Section 3.5. 
Demographic and baseline characteristics, including age, gender, height, weight, primary 
diagnosis, mechanical ventilation status (for HAP/VAP subjects) 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, by pathogen type (Enterobacteriaceae, other Gram-negative pathogens, 
Gram-positive aerobes, etc.), by MBL status (positive/negative), and by resistance type 
(including aztreonam non-susceptible, meropenem non-susceptible isolates and isolates 
producing ESBLs, serine carbapenemases). The number of subjects with monomicrobial vs 
polymicrobial (2, 3, 4, ≥5 pathogens) at baseline will be summarized. If numbers permit, 
analyses by specimen type (intra-abdominal specimen, respiratory specimen or blood) may 
be performed. The susceptibility profile of baseline pathogens and MIC frequency 
distributions to 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. 


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6.7. 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. 
6.7.1. 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, pre-specified AEs of 
clinical importance, and SAEs will be summarized for the full study period using the safety 
analysis set. 
In addition, AEs will be summarized by subjects who received non-study concomitant 
antibiotics (i.e. excluding protocol-allowed study antibiotic treatments) at any time during the 
treatment period versus those who did not receive antibiotics during the treatment period. In 
this summary all adverse events will be included regardless of whether they occurred prior to 
starting the antibiotic or not. 
All AEs, including prior to first dose and treatment emergent adverse events (TEAEs), will 
be listed. 
6.7.2. 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 
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. 


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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. 
6.7.3. 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. 
For those subjects with HAP/VAP, respiratory rate (breaths per minute) and peripheral 
oxygen saturation will be summarized. 
6.7.4. 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. 
6.7.5. 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. 
6.7.6. Detailed Infection-related Focused Physical Examination 
Results of the detailed focused (infection-related abdominal or respiratory signs and 
symptoms per indication) assessment will be summarized by visit. 
6.7.7. 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. 


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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, meropenem) 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 outlined in Section 6.5). 
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. 
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. 
3. 
Miettinen O, Nurminen M. Comparative Analysis of Two Rates. Statistics in Medicine 
1985: 213-226. 


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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 
ATM-AVI ± MTZ 
Aztreonam-avibactam ± metronidazole 
AVI 
Avibactam 
BAL 
Bronchoalveolar lavage 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
CAC 
Clinical Adjudication Committee 
CDARS 
Clinical Data Analysis and Reporting System 
CE 
Clinically evaluable 
cIAI 
Complicated intra-abdominal infection 
CI 
Confidence interval 
COL 
Colistin (colistimethate sodium) 
CORD 
Clinical Oversight Review Dashboard 
CrCl 
Creatinine clearance 
CSR 
Clinical Study Report 
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 
Multi-drug resistant 
ME 
Microbiologically Evaluable 


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Abbreviation or 
special term 
Explanation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MER 
Meropenem 
MER ± COL 
Meropenem ± colistin 
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 
NLME 
Nonlinear Mixed Effects 
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 
US 
United States 
VAP 
Ventilator-associated pneumonia 
VCAS 
Virtual Clinical Adjudication System 


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Appendix 2. Table 1: Summary of Efficacy Analyses 
 
EndpointN ariable 
Analysis Set 
Statistical Method 
Timepoint 
Objective 
Clinical Cure (as assessed by the 
CAC) 
ITT and CE 
Summa1y of Proportion 
95% CI for Treatment 
Group and Difference 
TOC 
Primaiy Endpoint 
(US = ITT, Non-US = CE & ITT) 
Clinical Cure (as assessed by the 
CAC) 
CE 
Summa1y of Propo1tion 
95% CI for Treatment 
Group and Difference 
TOC 
Seconda1y Endpoint (for US) 
Clinical Cure as assessed by the 
Investigator 
ITT and CE 
Summa1y of Propo1tion 
95% CI for Treatment 
Group and Difference 
TOC 
Sensitivity/Suppo1tive Analysis 
Clinical Cure 
MITT 
Summa1y of Propo1tion 
95% CI for Treatment 
Group and Difference 
TOC 
Sensitivity/Suppo1tive Analysis 
Clinical Cure where all deaths are 
considered failures 
ITT 
Summa1y of Propo1tion 
95% CI for Treatment 
Group and Difference 
TOC 
Sensitivity/Suppo1tive Analysis 
Clinical Cure by 
restricted/prohibited concomitant 
antibiotics use 
ITT and CE 
Summa1y of Proportion 
95% CI for Treatment 
Group and Difference 
TOC 
Sensitivity/Suppo1tive Analysis 
Clinical Cure 
micro-ITT and ME 
Summa1y of Propo1tion 
95% CI for Treatment 
Group and Difference 
TOC 
Secondaiy Endpoint 
Clinical Cure by Infection Type 
ITT and CE 
Summa1y of Propo1tion 
95% CI for Treatment 
Group and Difference 
TOC 
Secondaiy Endpoint 
Clinical Cure by MBL status 
(positive/negative) 
micro-ITT and ME 
Summa1y of Proportion 
TOC 
Secondaiy Endpoint 


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EndpointN ariable 
Analysis Set 
Statistical Method 
Timepoint 
Objective 
Subjects with favorable per-subject 
microbiological response 
micro-ITT and ME 
Summa1y of Proportion 
95% CI for Treatment 
Group 
TOC 
Secondaiy Endpoint 
Death (overall and by infection type) 
ITT and micro-ITT 
Summa1y of Proportion 
95% CI for Treatment 
Group and Difference 
On or before 
28 days after 
randomization 
Secondaiy Endpoint 
Subjects with favorable per-subject 
microbiological response 
micro-MITT 
Summa1y of Propo1tion 
TOC andEOT 
Secondaiy Sensitivity/Suppo1tive 
Analysis 
Clinical Cme 
ITT, micro-ITT, CE, 
andME 
Summa1y of Proportion 
95% CI for Treatment 
Group and Difference 
EOT 
Te1tiaiy Endpoint 
Clinical Cure by Infection Type 
ITT and CE 
Summa1y of Proportion 
95% CI for Treatment 
Group and Difference 
EOT 
Te1tiaiy Endpoint 
Clinical Cme by MBL status 
micro-ITT and ME 
Summary of Propo1tion 
EOT 
Te1tiary Endpoint 
Clinical Cure by Pathogen 
Resistance Type (aztreonam-non- 
susceptible, meropenem-non- 
susceptible isolates, and isolates 
producing ESBLs, serine 
cai·bapenemases) 
micro-ITT and ME 
Summa1y of Proportion 
TOC andEOT 
Te1tiaiy Endpoint 
Subjects with favorable per-subject 
microbiological response 
micro-ITT and ME 
Summa1y of Propo1tion 
95% CI for Treatment 
Group 
EOT 
Te1tiaiy Endpoint 
Subjects with favorable per- 
pathogen microbiological response 
micro-ITT and ME 
Summa1y of Proportion 
TOC andEOT 
Te1tiaiy Endpoint 


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EndpointN ariable 
Analysis Set 
Statistical Method 
Timepoint 
Objective 
Subjects with favorable per-subject 
microbiological response by 
Pathogen Resistance Type 
(aztreonam-non-susceptible, 
meropenem-non-susceptible isolates, 
and isolates producing ESBLs, 
serine cai·baoenemases. and MBLs) 
micro-ITT and ME 
Summa1y of Proportion 
TOC andEOT 
Te1iiaiy Endpoint 
Subjects with favorable per- 
pathogen microbiological response 
micro-MITT 
Summa1y of Proportion 
TOC andEOT 
Te1iiaiy Sensitivity/Suppo1iive 
Analysis 
Total Score for the Composite 
Endpoint of Symptom-Based 
Objective Clinical Measures 
ITT and CE 
Summaiy 
Explorato1y Endpoint 
Death 
ITT and micro-ITT 
Summa1y of Propo1iion 
On or before 
14 days after 
randomization 
Explorato1y Endpoint 
Health Utilization 
ITT and CE 
Summaiy 
UptoTOC 
(LFU for 
hospital 
readmissions) 
Explorato1y Endpoint 


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Appendix 3. Criteria for Potentially Clinically Significant Lab Results 
Table 1: 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 


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Table 2: 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 


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Appendix 4. Criteria for Vital Signs Abnormalities 
Table 1: 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