Clinical trial NCT04927312
Conditions: Complicated Intra-abdominal Infection
Keywords: Ceftazidime-avibactam, Metronidazole, complicated intra-abdominal infection
Sponsor: Pfizer
Start date: 2021-10-01; Completion date: 2022-09-15
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study C3591036 is a Phase 3 study to assess the efficacy and safety of PF-06947386 in Japanese adult patients with complicated intra-abdominal infection requiring hospitalization. This is a multicenter, open-label, single-arm study. All eligible participants will receive intravenous infusion of PF-06947386 followed by intravenous infusion of metronidazole.

Detailed description:

Arms: arm 1: Multiple intravenous infusion of ceftazidime-avibactam followed by intravenous infusion of metronidazole, repeated every 8 hours for 5-14 days.
Interventions: intervention 1: PF-06947386 intervention 2: Metronidazole
Intervention descriptions: intervention 1: Ceftazidime-Avibactam powder for concentrate for solution for infusion 2.0 g/ 0.5 g. Dosage will be adjusted based on renal function after enrollment. intervention 2: Metronidazole 0.5 g solution for injection.

Protocol documents:
Prot_000.pdf: 
PF-06947386 
Protocol C3591036 
Final Protocol Amendment 1, 21 July 2021 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
 
A PHASE 3, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO ASSESS 
THE EFFICACY AND SAFETY OF CEFTAZIDIME-AVIBACTAM (PF-06947386) 
PLUS METRONIDAZOLE IN JAPANESE ADULT PATIENTS WITH 
COMPLICATED INTRA-ABDOMINAL INFECTION REQUIRING 
HOSPITALIZATION 
 
 
Study Intervention Number: 
PF-06947386 
Study Intervention Name: 
Ceftazidime-Avibactam 
US IND Number: 
Not applicable (N/A) 
 
EudraCT Number: 
N/A 
Protocol Number: 
C3591036 
Phase: 
3 
Short Title: A Phase 3 Study to Assess Efficacy and Safety of PF-06947386 in Japanese 
Adult Participants With Complicated Intra-abdominal Infections 
 
 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


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Protocol C3591036 
Final Protocol Amendment 1, 21 July 2021 
PFIZER CONFIDENTIAL 
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Protocol Amendment Summary of Changes Table 
 
Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Amendment 1 21 July 2021 
Summary and rationale for changes are shown below 
with revised language shown as underlined text. 
Section 1.1 Number of Participants, Section 4.1, 
Section 9.2: 
 Following Pharmaceuticals and Medical Devices 
Agency (PMDA) feedback, added language about 
the anticipated number of enrolled participants 
who meet the definition of sepsis patients subset. 
Although it is uncertain whether the definition of 
the sepsis patients subset (Section 9.3) is met at 
the timing of study entry, 3 to 5 enrolled 
participants are anticipated to meet the definition 
of the sepsis patients subset. 
Section 1.3 Schedule of Activities, Section 8.1.7.2: 
 Clarified the explanation about initial qualifying 
procedure. 
Original language: 
initial qualifying procedure (performed within 24 
hours of entry) 
Revised language: 
initial qualifying procedure [performed within 24 
hours of entry for preoperative enrollment (see 
Section 5.1, inclusion criterion 3)] 
Section 5.2 Exclusion Criterion 21: 
• Clarifications were made in the text about using 
concomitant systemic antibacterials or systemic 
antifungals. 
Original language: 
Participant needs effective concomitant systemic 
antibacterials (oral, IV, or intramuscular) or 
systemic antifungals in addition to that designated 
in the study group, except vancomycin, linezolid, 
or daptomycin if started for known or suspected 


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Final Protocol Amendment 1, 21 July 2021 
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MRSA or Enterococcus species as per protocol 
Section 6.5 
Revised language: 
Participant needs effective concomitant systemic 
antibacterials (eg, oral, IV, or intramuscular) or 
systemic antifungals in addition to study 
regimens, except vancomycin, linezolid, or 
daptomycin if started for known or suspected 
MRSA or Enterococcus species as per protocol 
Section 6.5 
Section 6.1.1.2, Table 6 footnote: 
• Added language describing the impact of 
initiating hemodialysis during the treatment 
period. 
PF-06947386 and metronidazole are removed by 
hemodialysis.  Dosing of PF-06947386 and 
metronidazole on hemodialysis days should occur 
after completion of hemodialysis.  In cases where 
hemodialysis is needed but scheduling the dosing 
of PF-06947386 and metronidazole after 
completion of hemodialysis is not feasible, or if 
the investigator has concerns for the participant to 
continue with dosing, discontinuation from study 
treatment may be considered, as needed. 
Section 6.3.1: 
• As cIAI patients require immediate medical 
attention, modifications were made to enable the 
start of study regimens when eligibility of the 
study participant is confirmed by the investigator 
or designee, as clarified in PACL dated 22 June 
2021. 
Original language: 
Registration will be performed centrally by the 
sponsor or designee for all participants. Following 
full assessment and determination that the 
participant meets all eligibility criteria, the 
investigator or designee will fax or email a 
complete the registration form to the sponsor or 
designee. The sponsor or designee will assign a 
participant identification number, which will be 


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Protocol C3591036 
Final Protocol Amendment 1, 21 July 2021 
PFIZER CONFIDENTIAL 
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used on all CRF pages and other trial-related 
documentation or correspondence referencing that 
participant and fax or email to the site. 
No participant shall receive IP until the 
investigator or designee has received the above 
information from the sponsor or designee: 
confirmation of the participant’s enrollment. 
Revised language: 
Following full assessment and determination that 
the participant meets all eligibility criteria, the 
investigator or designee may administer IP to the 
participant. 
The investigator or designee will fax or email a 
completed registration form to the sponsor. The 
investigator or designee shall receive the 
enrollment number from the sponsor via fax or 
email. 
Section 6.5: 
• Clarifications were made in the text describing the 
use of antifungals and added language shown in 
underlined text below. 
Topical antibacterial and topical antifungals are 
permitted except that they may not be applied to 
the surgical site.  It is anticipated that in instances 
of clinical failure, alternative “rescue” 
antibacterial therapy to treat the cIAI would be 
instituted.  Systemic antifungal therapy should be 
avoided unless clinically indicated. 
Section 8.1.3: 
• Added “abdominal pain” to the definition of 
abdominal signs and symptoms, as clarified in 
PACL dated 22 June 2021. 
Original language: 
Abdominal signs and symptoms will be defined as 
nausea, vomiting, tenderness to palpation, rebound 
tenderness, guarding, mass, ascites, chills. 
Revised language: 


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Protocol C3591036 
Final Protocol Amendment 1, 21 July 2021 
PFIZER CONFIDENTIAL 
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Abdominal signs and symptoms will be defined as 
abdominal pain, nausea, vomiting, tenderness to 
palpation, rebound tenderness, guarding, mass, 
ascites, chills. 
Section 9.4.2: 
• For ensuring consistency in this document, added 
“MITT” to the analysis sets on which 
supplemental analyses for the primary endpoint 
will be performed as shown in underlined text 
below. 
Supplemental analyses will be performed on the 
MITT, mMITT, ME, and eME analysis sets. 
Section 10.4.4: 
• The following modifications were made as there 
are no available female condoms and spermicides 
that are currently approved in Japan, as clarified in 
PACL dated 22 June 2021. 
Original language: 
Male or female condom with or without 
spermicide. 
* Not approved in Japan 
Revised language: 
Male or female* condom with or without 
spermicide*. 
* Not approved in Japan 
In addition, minor typographical/editorial errors were 
corrected throughout the document. 
Original 
protocol 
19 April 2021 
N/A 
 
This amendment incorporates all revisions to date, including amendments made at the request 
of country health authorities and IRBs/ECs. 


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TABLE OF CONTENTS 
LIST OF TABLES........................................................................................................................ 11 
LIST OF FIGURES ...................................................................................................................... 11 
1. PROTOCOL SUMMARY .................................................................................................... 12 
1.1. Synopsis ....................................................................................................................... 12 
1.2. Schema ......................................................................................................................... 19 
1.3. Schedule of Activities ................................................................................................. 20 
2. INTRODUCTION.................................................................................................................. 25 
2.1. Study Rationale ........................................................................................................... 25 
2.2. Background .................................................................................................................. 25 
2.2.1. Mechanism of Action/Indication ................................................................... 25 
2.2.2. Development of PF-06947386 in Japan ........................................................ 26 
2.2.3. Rationale for Conducting This Study ........................................................... 26 
2.2.4. Clinical Overview........................................................................................... 27 
2.2.4.1. Pharmacokinetics/Pharmacodynamics in Japanese, 
Chinese and Non-Asian Populations ................................................... 27 
2.2.4.2. Results of Clinical Studies in Patients With cIAI ...................... 29 
2.3. Benefit/Risk Assessment ............................................................................................ 32 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ........................................................... 34 
4. STUDY DESIGN ................................................................................................................... 38 
4.1. Overall Design ............................................................................................................. 38 
4.2. Scientific Rationale for Study Design ........................................................................ 39 
4.3. Justification for Dose .................................................................................................. 39 
4.4. End of Study Definition .............................................................................................. 40 
5. STUDY POPULATION ........................................................................................................ 41 
5.1. Inclusion Criteria ......................................................................................................... 41 
5.2. Exclusion Criteria ........................................................................................................ 43 
5.3. Lifestyle Considerations ............................................................................................. 47 
5.3.1. Contraception.................................................................................................. 47 
5.4. Screen Failures ............................................................................................................ 47 
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration .......................................................................................... 47 


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6. STUDY INTERVENTION ...................................................................................................... 47 
6.1. Study Intervention(s) Administered ........................................................................... 47 
6.1.1. Administration ................................................................................................ 48 
6.1.1.1. Dosing Intervals in Patients With Normal Renal Function 
and Patients With Mild Renal Impairment (CrCL >50 mL/min) ...... 48 
6.1.1.2. Dose Regimen Adjustments for Patients Whose CrCL 
Drops ≤50 mL/min While on IV Study Intervention ......................... 49 
6.2. Preparation/Handling/Storage/Accountability .......................................................... 51 
6.2.1. Preparation and Dispensing ........................................................................... 52 
6.3. Measures to Minimize Bias: Randomization and Blinding ....................................... 52 
6.3.1. Allocation to Study Intervention ................................................................... 52 
6.4. Study Intervention Compliance .................................................................................. 52 
6.5. Concomitant Therapy.................................................................................................. 52 
6.6. Dose Modification ....................................................................................................... 54 
6.7. Intervention After the End of the Study ..................................................................... 54 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .............................................................................. 54 
7.1. Discontinuation of Study Intervention ....................................................................... 54 
7.2. Participant Discontinuation/Withdrawal From the Study......................................... 54 
7.2.1. Withdrawal of Consent .................................................................................. 55 
7.3. Lost to Follow-up ........................................................................................................ 55 
8. STUDY ASSESSMENTS AND PROCEDURES .................................................................. 56 
8.1. Efficacy Assessments .................................................................................................. 57 
8.1.1. APACHE II Score .......................................................................................... 57 
8.1.2. Imaging Test ................................................................................................... 57 
 
 
 
 
 
 
8.1.6. Clinical Response ........................................................................................... 58 
8.1.6.1. Adjudication Committee.............................................................. 59 
8.1.7. Microbiological Assessments ........................................................................ 60 
CCI 


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8.1.7.1. Blood Culture ............................................................................... 60 


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8.1.7.2. Culture of Abdominal Infection Site........................................... 60 
8.1.8. Microbiological Response Assessments ....................................................... 60 
8.1.8.1. Per-Pathogen Microbiological Assessments After 
Completion of All Follow-up Visits.................................................... 60 
8.1.8.2. Per-Patient (Overall) Microbiological Response        
Assessments .......................................................................................... 61 
8.1.8.3. Microbiological Response ........................................................... 61 
8.1.8.4. MIC Among Pathogens ............................................................... 62 
8.1.8.5. Emergent Infections ..................................................................... 62 
8.2. Safety Assessments ..................................................................................................... 63 
8.2.1. Medical and Surgical History, Medication History ..................................... 63 
8.2.2. Height and Weight.......................................................................................... 63 
8.2.3. Pulse Rate, Blood Pressure, Respiratory Rate.............................................. 63 
8.2.4. Heart Rate ....................................................................................................... 63 
8.2.5. Clinical Safety Laboratory Assessments ...................................................... 63 
8.2.6. Pregnancy Testing .......................................................................................... 64 
8.3. Adverse Events and Serious Adverse Events ............................................................ 64 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ....... 65 
8.3.1.1. Reporting SAEs to Pfizer Safety ................................................. 65 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 65 
8.3.2. Method of Detecting AEs and SAEs ............................................................. 66 
8.3.3. Follow-up of AEs and SAEs .......................................................................... 66 
8.3.4. Regulatory Reporting Requirements for SAEs ............................................ 66 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure............................................................................................................... 66 
8.3.5.1. Exposure During Pregnancy........................................................ 67 
8.3.5.2. Exposure During Breastfeeding .................................................. 68 
8.3.5.3. Occupational Exposure. ............................................................... 69 
8.3.6. Cardiovascular and Death Events .................................................................. 69 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................................. 69 
8.3.8. Adverse Events of Special Interest ............................................................... 69 
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8.3.8.1. Lack of Efficacy ........................................................................... 69 
8.3.9. Medical Device Deficiencies ......................................................................... 69 
8.3.10. Medication Errors ......................................................................................... 69 
8.4. Treatment of Overdose ............................................................................................... 70 
8.5. Pharmacokinetics ......................................................................................................... 71 
8.6. Pharmacodynamics ...................................................................................................... 72 
8.7. Genetics ........................................................................................................................ 72 
8.7.1. Specified Genetics .......................................................................................... 72 
8.7.2. Banked Biospecimens for Genetics ............................................................... 72 
8.8. Biomarkers ................................................................................................................... 72 
8.8.1. Banked Biospecimens for Biomarkers .......................................................... 72 
8.9. Immunogenicity Assessments .................................................................................... 72 
8.10. Health Economics...................................................................................................... 72 
9. STATISTICAL CONSIDERATIONS .................................................................................... 72 
9.1. Estimands and Statistical Hypotheses ........................................................................ 73 
9.1.1. Estimands........................................................................................................ 73 
9.2. Sample Size Determination ........................................................................................ 75 
9.3. Analysis Sets ................................................................................................................ 76 
9.4. Statistical Analyses ..................................................................................................... 79 
9.4.1. General Considerations .................................................................................. 79 
9.4.2. Primary Endpoint(s) ....................................................................................... 79 
9.4.3. Secondary Endpoint(s)................................................................................... 79 
 
 
 
 
 
 
9.5. Interim Analyses .......................................................................................................... 81 
9.6. Data Monitoring Committee or Other Independent Oversight Committee ............. 81 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .............................................................................................................. 82 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................ 82 
10.1.1. Regulatory and Ethical Considerations ...................................................... 82 
CCI 


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10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................... 82 
10.1.2. Financial Disclosure .................................................................................... 83 
10.1.3. Informed Consent Process ........................................................................... 83 
10.1.4. Data Protection ............................................................................................. 84 
10.1.5. Dissemination of Clinical Study Data ........................................................ 84 
10.1.6. Data Quality Assurance ............................................................................... 85 
10.1.7. Source Documents ....................................................................................... 86 
10.1.8. Study and Site Start and Closure ................................................................. 87 
10.1.9. Publication Policy ........................................................................................ 88 
10.1.10. Sponsor’s Qualified Medical Personnel .................................................... 88 
10.2. Appendix 2: Clinical Laboratory Tests .................................................................... 90 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................... 91 
10.3.1. Definition of AE ........................................................................................... 91 
10.3.2. Definition of SAE ........................................................................................ 92 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs ....................... 93 
10.3.4. Reporting of SAEs ....................................................................................... 96 
10.4. Appendix 4: Contraceptive Guidance ...................................................................... 98 
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................... 98 
10.4.2. Female Participant Reproductive Inclusion Criteria .................................. 98 
10.4.3. Woman of Childbearing Potential ............................................................... 98 
10.4.4. Contraception Methods ................................................................................ 99 
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ....... 101 
10.6. Appendix 6: APACHE II Classification System................................................... 103 
10.7. Appendix 7: SOFA Score ....................................................................................... 105 
10.8. Appendix 8: Calculation of Estimated CrCL ........................................................ 106 
10.9. Appendix 9: ECG Findings of Potential Clinical Concern ................................... 107 
10.10. Appendix 10: Abbreviations ................................................................................. 109 
11. REFERENCES ..................................................................................................................... 112 


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LIST OF TABLES 
Table 1. 
PK Parameters of Ceftazidime and Avibactam (Geometric Mean 
[CV%]) for 2.0 g Ceftazidime + 0.5 g Avibactam 2 Hour IV 
Infusion q8h in Japanese (Study D4280C00010), Chinese (Study 
D4280C00020), and Non-Asian Participants (Study D4280C00011 
Part A) ........................................................................................................... 28 
Table 2. 
Comparison of Ceftazidime and Avibactam Exposure and Target 
Attainment in Phase 3 Patients Stratified Across Different Races ........... 28 
Table 3. 
Primary Analysis: Clinical Response at TOC: RECLAIM and 
RECLAIM3 (CE and MITT Analysis Sets) ............................................... 30 
Table 4. 
Clinical Response at TOC, by Common (Combined Frequency of 
≥10) Baseline Gram-Negative Pathogen (Pooled Phase 2/3 cIAI 
Studies, mMITT Analysis Sets) .................................................................. 31 
Table 5. 
Ceftazidime/Avibactam Adjustments for Patients With Normal 
Renal Function and Patients With Mild Renal Impairment ...................... 48 
Table 6. 
Dose Regimens and Infusion Times for Patients Whose Estimated 
CrCL Drops Below 50 mL/min While on IV Study Intervention ............. 50 
Table 7. 
Definitions of Clinical Response at the EOT, TOC, LFU, and Early 
Termination/Discontinuation Visits ............................................................ 58 
Table 8. 
Microbiological Response Categories at Day 1 (Baseline), EOT, 
TOC, LFU, and Early Termination/Discontinuation Visits ....................... 61 
Table 9. 
Emergent Infections ..................................................................................... 62 
Table 10. 
Protocol-Required Safety Laboratory Assessments ................................... 90 
Table 11. 
APACHE II Score Form ............................................................................ 103 
Table 12. 
SOFA Score ................................................................................................ 105 
Table 13. 
qSOFA Criteria........................................................................................... 105 
 
 
LIST OF FIGURES 
Figure 1. 
Study Outline ................................................................................................ 19 
Figure 2. 
Schematic of Dosing Intervals for Patients With Normal Renal 
Function /Mild Renal Impairment (for an Arbitrary 24 Hour Period) ...... 49 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 3 Study to Assess Efficacy and Safety of PF-06947386 in Japanese 
Adult Participants With Complicated Intra-abdominal Infections 
 
Rationale 
 
Ceftazidime is an injectable third generation cephalosporin antibiotic which has been in 
clinical use worldwide for more than 25 years for the treatment of infections caused by 
aerobic Gram-negative pathogens.  Ceftazidime has been shown to be safe and effective in 
adult and pediatric patients for a range of indications.  However, over the past 15 years, 
resistance to ceftazidime has been increasing worldwide. The most common mechanism of 
resistance is bacterial production of β-lactamases, in particular, ESBLs.  In order to counter 
ceftazidime resistance and restore antibacterial activity to ceftazidime, a combination product 
has been developed in which ceftazidime is combined with avibactam, a novel non-β-lactam 
β-lactamase inhibitor. 
 
PF-06947386 has received regulatory approval in 78 countries/regions as of August 2020 
including approval in the US in February 2015 and in the EU in June 2016. PF-06947386 is 
indicated in the US and Europe for the treatment of adults with cIAI, cUTI and HAP/VAP. 
In Europe, it is also indicated for the treatment of infections due to aerobic Gram-negative 
organisms in adult patients with limited treatment options and, in 2020, it was approved for 
the treatment of bacteremia associated with, or suspected to be associated with, any of the 
above infections. 
 
The PK of ceftazidime and avibactam is sufficiently similar across indications, and in 
Japanese, non-Japanese and non-Asian patient populations, therefore, dose adjustment based 
on race is not required.  Population PK modeling/simulation analysis has demonstrated 
sufficient exposure and high PTA in Japanese patients at the adult doses currently approved 
outside of Japan. 
 
There are no notable differences in diagnostics and treatment for cIAI between Japan and 
overseas.  These infections require operative intervention or percutaneous drainage in 
conjunction with broad spectrum antibacterial therapy.  Almost all intra-abdominal infections 
are polymicrobial and are caused by organisms from the gastrointestinal tract, including 
aerobes and facultative and obligate anaerobes. Gram-negative Enterobacterales are most 
commonly isolated.  Currently, ESBLs producing pathogens are increasing among the 
Enterobacterales, such as Escherichia coli. 


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For the treatment of cIAI, broad-spectrum single agent (β-lactam/β-lactamase inhibitor 
combination drugs, carbapenem) or combination therapy regimens (concomitant use of 
cephem antibiotics) are recommended*. 
 
The in vitro activity of ceftazidime-avibactam and comparator antibiotics was determined 
against year 2017 clinical isolates using the broth microdilution methodology recommended 
by CLSI. A total of 6046 isolates were obtained from hospitalized patients in 23 medical 
centers within 6 countries (Australia, Japan, South Korea, Philippines, Taiwan, and Thailand) 
from the Asia Pacific region in 2017.  Ceftazidime-avibactam had potent activity against the 
majority of clinical isolates studied, in particular against Gram-negative organisms for the 
target pathogens in the package insert. The MIC of domestic clinical isolates in 2017 was the 
same as that of clinical isolates in overseas. 
 
The efficacy and safety of PF-06947386 have been demonstrated in patients with cIAI, cUTI 
and HAP/VAP in confirmatory global studies. Japanese patients were included in studies in 
patients with cUTI and HAP/VAP. 
 
Based on the above, PF-06947386 is expected to be efficacious in Japanese patients with 
cIAI and no new safety issues have been identified in Japanese patients when avibactam is 
added to ceftazidime at the same dose used in the global studies.  In addition, this drug is 
considered to contribute to the treatment of AMR. 
 
Objectives, Estimands, and Endpoints 
 
Objectives 
Estimands 
Endpoints 
Primary: 
Primary: 
Primary: 
• 
To assess the efficacy of PF- 
06947386 plus metronidazole 
• 
Estimand 1: the primary estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI. 
A composite estimand strategy will be used. 
Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
• 
Clinical response at the 
TOC visit 
 
 
* Takesue Y. Antibiotic selection and duration of administration in patients with intra-abdominal infections 
according to the grade of severity: In comparison with the Surgical Infection Society revised guidelines of the 
management of intra-abdominal infection. Journal of Japan Society for Surgical Infection 2019;16(2):80-6. 


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Objectives 
Estimands 
Endpoints 
the clinical assessment will not be considered. 
Proportion of participants with clinical cure will 
be calculated. 
• 
Estimand 2: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI. 
A composite estimand strategy will be used. 
Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7. Proportion of participants 
with clinical cure will be calculated. 
• 
Estimand 3: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have ≥1 baseline pathogens. A composite 
estimand strategy will be used.  Intercurrent 
events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7. Proportion of participants 
with clinical cure will be calculated. 
• 
Estimand 4: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have at least 1 Gram-negative aerobic 
pathogen in the initial/prestudy culture regardless 
of susceptibility. A composite estimand strategy 
will be used.  Intercurrent events of death where 
cIAI is clearly noncontributory etc. will be 
regarded as indeterminate clinical response. 
Intercurrent events of death related to intra- 
abdominal infection, or additional antibiotics for 
ongoing symptoms of intra-abdominal infection 
etc. will be regarded as a failure clinical response. 
For details, see Table 7.  All data after 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 


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Objectives 
Estimands 
Endpoints 
considered. All data after other intercurrent 
events that affect the clinical assessment will not 
be considered. Proportion of participants with 
clinical cure will be calculated. 
• 
Estimand 5: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have at least 1 Gram-negative aerobic 
pathogen in the initial/prestudy culture that is 
susceptible. A composite estimand strategy will 
be used.  Intercurrent events of death where cIAI 
is clearly noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the clinical assessment will not be considered. 
Proportion of participants with clinical cure will 
be calculated. 
Secondary: 
Secondary: 
Secondary: 
• 
To determine the efficacy of PF- 
06947386 plus metronidazole 
• 
To determine the per-patient 
microbiological response of PF- 
06947386 plus metronidazole 
• 
Estimands 6 - 10: the estimands of the 
secondary endpoints 
Same as Estimands 1 - 5 
• 
Estimand 11: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have ≥1 baseline pathogens. A 
composite estimand strategy will be used. 
Intercurrent events of lost to follow-up and death 
where cIAI is clearly noncontributory etc. will be 
regarded as indeterminate microbiological 
response. For details, see Table 8. Proportion of 
participants with favorable microbiological 
response will be calculated. 
• 
Estimand 12: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
• 
Clinical response at 
EOT, and LFU visits 
• 
Per-patient 
microbiological 
response at EOT, TOC, 
and LFU visits 


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Objectives 
Estimands 
Endpoints 
• 
To determine the per-pathogen 
microbiological response of PF- 
06947386 plus metronidazole 
• 
To evaluate the safety and 
tolerability profile of PF- 
06947386 plus metronidazole in 
the treatment of patients with 
cIAIs 
terms of microbiological response in patients 
with cIAI who have at least 1 Gram-negative 
aerobic pathogen in the initial/prestudy culture 
regardless of susceptibility.  A composite 
estimand strategy will be used.  Intercurrent 
events of lost to follow-up and death where cIAI 
is clearly noncontributory etc. will be regarded as 
indeterminate microbiological response. For 
details, see Table 8.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the microbiological assessment will not be 
considered. Proportion of participants with 
favorable microbiological response will be 
calculated. 
• 
Estimand 13: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have at least 1 Gram-negative 
aerobic pathogen in the initial/prestudy culture 
that is susceptible.  A composite estimand 
strategy will be used.  Intercurrent events of lost 
to follow-up and death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate microbiological response.  For 
details, see Table 8.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the microbiological assessment will not be 
considered. Proportion of participants with 
favorable microbiological response will be 
calculated. 
• 
Estimands 14 - 16: the estimands of the 
secondary endpoints 
Same as Estimands 11 - 13 
N/A 
• 
Per-pathogen 
microbiological 
response at EOT, TOC, 
and LFU visits 
• 
Per-pathogen 
microbiological 
response at EOT, TOC, 
and LFU visits by MIC 
categories 
• 
AEs and SAEs, all 
cause mortality, reasons 
for discontinuations of 
IV study intervention 
and study, vital sign 
measurements, and 
potentially clinically 


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Overall Design 
 
Study C3591036 will assess the efficacy and safety of PF-06947386 in Japanese patients 
with cIAI requiring hospitalization. This is a multicenter, open-label, single-arm study. The 
study will have a maximum duration of approximately 6 weeks for each participant. This 
includes a 5-14 days of IV study period, TOC visit at Day 28, and LFU visit at Day 42. 
 
Number of Participants 
 
Approximately 60 participants will be enrolled to study intervention such that there will be 
approximately 50 evaluable participants in the CE analysis set. Although it is uncertain 
whether the definition of the sepsis patients subset (Section 9.3) is met at the timing of study 
Objectives 
Estimands 
Endpoints 
• 
To evaluate the 
pharmacokinetics of the 
individual components of PF- 
06947386 in patients with cIAIs 
• 
To investigate safety and 
efficacy for patients with sepsis 
(if available) 
N/A 
N/A 
significant changes in 
laboratory parameters 
during the entire study 
• 
Ceftazidime and 
avibactam plasma 
concentrations by 
nominal sampling 
window 
• 
Selected efficacy and 
safety endpoints as 
described above 
CCI 


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entry, 3 to 5 enrolled participants are anticipated to meet the definition of the sepsis patients 
subset. 
 
Note: “Enrolled” means a participant’s, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
 
Intervention Groups and Duration 
 
Eligible participants with CrCL >50 mL/min will be given an IV dose of 2.5 g PF-06947386 
(ceftazidime 2.0 g/avibactam 0.5 g) q8h with infusion time of 2 hours for 5-14 days.  For 
participants enrolled into the study whose CrCL drops to ≤50 mL/min while on IV 
investigational drug therapy, dosage adjustment is required depending on the degree of renal 
impairment based on the CrCL value.  All eligible participants will receive metronidazole 
(0.5 g) intravenously with an infusion duration of 60 minutes. When both PF-06947386 and 
metronidazole are administered at the same time, metronidazole will be administered 
immediately after administration of PF-06947386. 
 
Data Monitoring Committee or Other Independent Oversight Committee: Yes 
 
This study will use an adjudication committee. The adjudication committee is independent 
of the study team and includes only external members. The adjudication committee will 
consist of 2 or more external infectious disease specialists especially intra-abdominal 
infection. The adjudication committee charter describes the role of the adjudication 
committee in more detail. The adjudication committee will review investigators’ 
assessments, including clinical response, based on the collected data for consistency of 
evaluation in the study. If a discrepancy exists between the adjudication committee and 
investigators, the assessment by the adjudication committee will prevail.  For details, see 
Section 8.1.6.1. 
 
Statistical Methods 
 
The primary endpoint for the study is clinical response at the TOC visit. The proportion and 
the 95% CI will be calculated. The primary analysis will be performed on the CE analysis 
set. 
 
In this study, no formal hypothesis testing will be conducted. 
 
As an efficacy evaluation criterion, it will be confirmed that the point estimate of proportion 
of patients with clinical cure at TOC visit in the CE analysis set (the primary analysis) is 
≥78%. 
 
Safety endpoints such as AEs, laboratory test results, and vital sign measurements will be 
summarized and evaluated descriptively. 


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1.2. Schema 
Figure 1. 
Study Outline 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
For patients with normal renal function and patients with mild renal impairment. 
b. 
If it is not possible to perform the TOC visit on study Day 28 (eg, the patient is on holiday), the allowed visit window is 
Day 28 to 35. 
c. 
If it is not possible to perform the LFU visit on study Day 42 (eg, the patient is on holiday), the allowed visit window is 
Day 42 to 49. 
Visit 18 
Day 42 visitc 
Late Follow-Up 
(LFU) 
Visit 17 
Day 28 visitb 
Test of Cure 
(TOC) 
Visit 16
End of Treatment 
(EOT) 
Visit 2 to 15 
Days 1 to 14 
PF-06947386 
(Ceftazidime/Avibactam) 
plus Metronidazole 
Visit 1 
Days -1 to 1 
Eligibility/ 
Screening 
Treatment period 
Minimum of 5 full days (15 dosesa) of IV study intervention 
Maximum of 14 days (42 dosesa) of IV study intervention 


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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
 
Protocol Activity 
Screening 
Baseline/ 
first 
IV Infusiona 
Treatment 
End of 
Treatment 
Test of 
Curee 
Late 
Follow-Upf 
Early 
Termination/ 
Discontinuationb 
Visit Number 
Visit 1 
Visit 2 
Visits 
3 to 15 
Visit 16 
Visit 17 
Visit 18 
 
Study Day 
Days -1 to 1 
Day 1c 
Days 
2 to 14c 
within 24 
hrs after 
completion 
of last IV 
infusion 
Day 28 visit 
(Day 28-35) 
Day 42 visit 
(Day 42-49) 
 
Study Procedures 
Informed consent 
X 
 
Inclusion/Exclusion criteria 
X 
X 
 
APACHE II scored 
X 
 
Demographics 
X 
 
Medical and surgical history 
X 
 
Clinical/Safety Assessments 
CCI 
 
 
 
 
 
Pulse rate, blood pressure, 
respiratory ratej 
X 
X 
Daily 
X 
X 
X 
X 
Heart ratek 
X 
 
Height/weight 
Xl 
Repeat weight only to calculate CrCL 
when clinically indicated. 
 
Imaging testm 
When available 


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Protocol Activity 
Screening 
Baseline/ 
first 
IV Infusiona 
Treatment 
End of 
Treatment 
Test of 
Curee 
Late 
Follow-Upf 
Early 
Termination/ 
Discontinuationb 
Visit Number 
Visit 1 
Visit 2 
Visits 
3 to 15 
Visit 16 
Visit 17 
Visit 18 
Study Day 
Days -1 to 1 
Day 1c 
Days 
2 to 14c 
within 24 
hrs after 
completion 
of last IV 
infusion 
Day 28 visit 
(Day 28-35) 
Day 42 visit 
(Day 42-49) 
Description of operative 
procedure 
From initial qualifying procedure [performed within 24 hours of entry for preoperative enrollment (see Section 5.1, inclusion 
criterion 3)] and any additional procedures performed during the study period. 
Clinical response assessmentn 
X 
X 
X 
X 
Microbiological response 
assessmentn 
X 
X 
X 
X 
Serious and non-serious 
adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
Investigator case 
summary/operative 
notes/discharge summaryo 
When available 
Laboratory assessments 
Estimated CrCLp 
X 
Xh 
As clinically indicated: 
use local serum 
creatinine 
measurements 
Blood and urine for safetyq 
X 
X 
Day 2, and every 3 days 
thereafter while on IV 
therapy 
X 
X 
X 
X 
β-hCGr 
X 
X 
X 
X 
Contraception check 
X 
X 
X 
X 
X 
X 
Study Medication 
Study drug infusion 
(PF-06947386, 
metronidazole)s 
X 
Xa, c 
PK blood samplingt 
X 


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Protocol Activity 
Screening 
Baseline/ 
first 
IV Infusiona 
Treatment 
End of 
Treatment 
Test of 
Curee 
Late 
Follow-Upf 
Early 
Termination/ 
Discontinuationb 
Visit Number 
Visit 1 
Visit 2 
Visits 
3 to 15 
Visit 16 
Visit 17 
Visit 18 
Study Day 
Days -1 to 1 
Day 1c 
Days 
2 to 14c 
within 24 
hrs after 
completion 
of last IV 
infusion 
Day 28 visit 
(Day 28-35) 
Day 42 visit 
(Day 42-49) 
Prior and concomitant 
treatment/antibiotics 
X 
X 
Daily 
X 
X 
X 
X 
Microbiology 
Blood cultureu 
X 
Day 2, and every 3 days 
thereafter while on IV 
therapy 
X 
X 
X 
X 
Culture of abdominal 
infection siteu 
Cultures must be obtained at initial qualifying procedure [performed within 24 hours of entry for preoperative enrollment 
(see Section 5.1, inclusion criterion 3)]. If additional procedures are performed, additional abdominal site cultures should be 
obtained. Cultures from the wound/procedure site should be obtained only if clinically indicated through study end. 
Abbreviations: β-hCG, beta-human chorionic gonadotropin; cIAI, complicated intra-abdominal infection; CrCL, creatinine clearance; EOT, End of Treatment; 
IV, intravenous; LFU, Late Follow-Up; PK, pharmacokinetic(s); TOC, Test of Cure. 
 
a. 
The first dose of IV study intervention is given at Visit 2 on Study Day 1. All assessments during Visit 2 must occur prior to first dose of IV study 
intervention. 
b. If a participant terminates early from study drug treatment or discontinues from participation in the study, procedures for “Early Termination/ 
Discontinuation” will be conducted. In addition, if possible, any AEs that occur prior to use of other treatments for cIAI and pregnancy must be reported for 
a minimum of approximately 28 days after the last administration of the study drug up to study end. These contacts may occur via telephone, postal mail, or 
other means of communication with the participant. 
c. 
Study Day 1 is the day of the first administration of study intervention. Participants will receive a minimum of 5 full days (15 doses) of IV study intervention 
up to a maximum of 14 days (42 doses) of study intervention. Dosing may occur on Day 15 depending on the time of day when the first dose of IV study 
intervention is given on Study Day 1. 
d. Calculate APACHE II score using most recent local laboratory results. Use of temperature obtained rectally in determining the APACHE II score is 
preferred but not mandatory. See Section 10.6. If ABG is not clinically indicated, the APACHE II score should be calculated using serum bicarbonate and 
oxygenation should be presumed normal. 


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e. 
For example, if a patient is enrolled on the first day of the month, the TOC visit should be performed on the 28th day of the month. If it is not possible to 
perform the TOC visit after 28 calendar days from the day of the first IV infusion, the allowed visit window is 28 to 35 calendar days after the day of the first 
IV infusion. 
f. 
If it is not possible to perform the LFU visit after 42 calendar days from the day of the first IV infusion, the allowed visit window is 42 to 49 calendar days 
from the day of the first IV infusion. 
g. Surgical wound examination should occur daily even if inspection is limited by the presence of surgical dressing (within the first 24 to 48 hours after surgery) 
or the presence of a negative pressure wound therapy device. A full examination of the wound unimpeded by the surgical dressing should occur starting 
approximately 24 to 48 hours after surgery or earlier if the surgeon feels it is safe to remove the dressing. For patients with negative pressure wound therapy 
devices, a thorough wound evaluation should occur when a full dressing change is performed. 
h. Assessment is only required at Visit 2 if Visit 1 and Visit 2 occur on different days or are separated by surgery. 
C 
j. 
Assess pulse rate and blood pressure after patient is resting in supine position for at least 5 minutes (see Section 8.2.3). 
k. Heart rate may be evaluated either in the 12-lead electrocardiogram or in the monitor electrocardiogram. 
l. 
Recently measured height and weight results may be used if patient is not ambulatory at the time of Screening. 
m. Imaging tests are not required for the study, but the results should be submitted if done as part of the diagnosis. Imaging tests include plain abdominal 
radiographs, computed tomography scans, ultrasound, and/or magnetic resonance image scans with or without contrast. 
n. If a patient fails or relapses between scheduled visits, the assessment should be recorded as an unscheduled visit. 
o. All required documentation including surgical reports and imaging results may be submitted if requested by the Adjudication Committee. See Section 8.1.6.1 
for information regarding the Adjudication Committee. 
p. Calculate estimated CrCL using Cockcroft-Gault formula (See Section 10.8). For details regarding dosing in renal impairment see Section 6.1.1. 
q. Safety labs should be collected at Screening, Baseline (only if surgery occurs between Screening and Baseline visits or if >12 hours has passed between 
Screening and Baseline visit), every 3 days while on IV therapy (Day 2, Day 5, Day 8, etc.), EOT, TOC, LFU, and Early Termination/Discontinuation visits. 
See Section 8.2.5. 
r. 
At Screening, serum β-hCG must be performed as part of screening/eligibility. If the results of β- hCG are not available prior to dosing of study intervention, 
a patient may begin therapy on the basis of a negative urine β-hCG, but a serum test must still be obtained. At time points other than screening, pregnancy 
tests may be urine or serum tests, but must have a sensitivity of at least 25 mIU/mL. 
s. 
If necessary, a 1-time dosing interval adjustment is allowed after the first dose of IV study intervention to create a suitable dosing schedule going forward 
with an 8-hours (±30 minutes) dosing interval. The dosing interval adjustment must be such that the second dose is given a minimum of 4 hours and a 
maximum of 8 hours after the first dose (ie, a 1-time 4-hour dosing interval is allowed between the first and the second dose). If a 1-time dosing interval 
adjustment is implemented for the second dose, all further dosing times will be calculated based on the time of the second dose. 
t. 
Blood samples for PK will be collected on either Day 3 or Day 4, following a dose administration that is convenient for sample collections. Three samples 
will be collected at the following times: 1) anytime from 15 minutes prior to stopping until 15 minutes after stopping PF-06947386 infusion, 2) anytime 
between 30 minutes and 90 minutes after stopping PF-06947386 infusion, and 3) anytime between 300 minutes (5 hours) and 360 minutes (6 hours) after 
stopping PF-06947386 infusion but before the next dose. All efforts will be made to obtain 3 samples, 1 from each of the 3 time windows, for each 


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participant. For example, 1) 10 minutes prior to stopping the first PF-06947386 infusion on Day 3, 2) 60 minutes after stopping the first PF-06947386 
infusion on Day 4, 3) 5 hours after stopping the second PF-06947386 infusion on Day 3, etc. Blood for PK must NOT be drawn from the same arm used for 
IV drug administration. See Section 8.5. 
u. 
If blood cultures are positive, the assessment is to be repeated at the scheduled time points. Blood cultures should also be performed as clinically indicated. 
For instructions on collection and processing of blood cultures and abdominal site cultures, see Section 8.1.7. 


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2. INTRODUCTION 
PF-06947386 is currently being developed in hospitalized adult participants with cIAI in 
Japan. 
 
2.1. Study Rationale 
PF-06947386 is a combination drug that contains ceftazidime, the third generation 
cephalosporin antibiotic (β-lactam) and avibactam, a new β-lactamase inhibitor. The purpose 
of the study is to assess the efficacy and safety data in Japanese hospitalized patients with 
cIAI. 
 
2.2. Background 
2.2.1. Mechanism of Action/Indication 
Ceftazidime is an injectable third generation cephalosporin antibiotic which has been in 
clinical use worldwide for more than 25 years for the treatment of infections caused by 
aerobic Gram-negative pathogens.  Ceftazidime has been shown to be safe and effective in 
adult and pediatric patients for a range of indications.  However, over the past 15 years, 
resistance to ceftazidime has been increasing worldwide. The most common mechanism of 
resistance is bacterial production of β-lactamases, in particular, ESBLs.  In order to counter 
ceftazidime resistance and restore antibacterial activity to ceftazidime, a combination product 
has been developed in which ceftazidime is combined with avibactam, a novel non-β-lactam 
β-lactamase inhibitor. 
 
Ceftazidime has a wide antibacterial spectrum that includes Gram-positive bacteria and 
Gram-negative bacteria, and especially, it shows strong antibacterial mechanism against 
glucose non-fermenting Gram-negative bacilli due to its high outer-membrane permeability 
in Gram-negative rods.  Ceftazidime shows antibacterial activity against Gram-negative 
pathogens such as Escherichia coli, Citrobacter freundii, Klebsiella oxytoca, 
Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, 
Morganella morganii, Providencia spp., Haemophilus influenzae, Pseudomonas aeruginosa. 
 
Avibactam inhibits the class A β-lactamase enzymes including ESBLs and 
Klebsiella pneumoniae carbapenemase-type β-lactamases (KPCs), and unlike previous β- 
lactamase-inhibitors, avibactam also inhibits class C β-lactamases such as the 
chromosomally-encoded AmpC enzymes (AmpC type cephalosporinase) found in 
Enterobacterales and P. aeruginosa and plasmid-encoded class C β-lactamases, for example 
CMY-2; and some of the class D β-lactamases (eg OXA-48 type carbapenemase). However, 
it does not inhibit class B metallo-β-lactamases. 
 
Avibactam binds to class A enzymes with a lower inhibition IC50 as compared to currently 
marketed β-lactamase inhibitors, ie clavulanic acid, tazobactam and sulbactam.  In addition, 
avibactam is a potent inhibitor of class C enzymes whereas clavulanic acid, tazobactam and 
sulbactam lack any clinically useful activity.  Also, avibactam does not induce class C β- 
lactamase production. 


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A fixed dose combination of ceftazidime-avibactam was approved for use in adults by the 
FDA in February 2015, and in children aged 3 months and older (cIAI in combination with 
metronidazole, or cUTI) in March 2019 and is marketed under the tradename Avycaz1.  In 
June 2016, the European Commission granted European Union marketing authorization for 
the use of PF-06947386 in adults under the tradename Zavicefta®2.  Currently, 
ceftazidime-avibactam was also approved for pediatric use in the EU. 
 
PF-06947386 has received regulatory approval in 78 countries/regions as of August 2020. 
PF-06947386 is indicated in the US and Europe for the treatment of adults with cIAI, cUTI, 
and HAP, including VAP.  In Europe, it is also indicated for the treatment of infections due 
to aerobic Gram-negative organisms in adult patients with limited treatment options and, in 
2020, it was approved for the treatment of bacteremia associated with, or suspected to be 
associated with, any of the above infections. 
 
2.2.2. Development of PF-06947386 in Japan 
In Japan, PF-06947386 was co-developed by AstraZeneca and Forest Research Institute for 
the treatment of cUTI, cIAI and HAP including VAP.  This drug was approved in February 
2015 in the US and in June 2016 in the EU.  Thereafter, in August 2016, Pfizer took on the 
responsibility for development and commercialization in countries except the United States 
and Canada. AstraZeneca conducted the multi-regional Phase 3 studies (RECAPTURE for 
cUTI, REPROVE for HAP/VAP) which included Japanese patients. Participation from 
Japan was continued until 2014.  Pfizer decided to take on the responsibility to develop this  
drug in Japan with consideration that AMR is one of the important issues in Japan.  It is 
considered highly necessary to develop new drugs that are effective for resistant bacteria, and 
this drug is considered to contribute to the treatment of AMR. 
 
2.2.3. Rationale for Conducting This Study 
As shown in Section 2.2.4.1, the PK of ceftazidime and avibactam was sufficiently similar 
across indications, and in Japanese, non-Japanese and non-Asian participants, therefore, dose 
adjustment based on race is not required.  Population PK modeling/simulation analysis has 
demonstrated sufficient exposure and high PTA in Japanese patients at the adult doses 
currently approved outside of Japan. 
 
There are no notable differences in diagnostics or treatment for cIAI between Japan and 
overseas. These infections require operative intervention or percutaneous drainage in 
conjunction with broad spectrum antibacterial therapy.  Almost all intra-abdominal infections 
are polymicrobial and are caused by organisms from the gastrointestinal tract, including 
aerobes and facultative and obligate anaerobes. Gram-negative Enterobacterales are isolated 
most commonly3.  Currently, ESBL producing pathogens are increasing in the 
Enterobacterales such as Escherichia coli4. 
 
For the treatment of cIAI, broad-spectrum single agent (β-lactam/β-lactamase inhibitor 
combination drugs, carbapenem) or combination therapy regimens (concomitant use of 
cephem antibiotics) are recommended4. 


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The in vitro activity of ceftazidime-avibactam and comparator antibiotics was determined 
against year 2017 clinical isolates using the broth microdilution methodology recommended 
by CLSI. A total of 6046 isolates were obtained from hospitalized patients in 23 medical 
centers within 6 countries (Australia, Japan, South Korea, Philippines, Taiwan, and Thailand) 
from the Asia Pacific region in 2017.  Ceftazidime-avibactam had potent activity against the 
majority of clinical isolates studied, in particular against Gram-negative organisms for the 
target pathogens in the package insert.  The MIC of domestic clinical isolates in 2017 was the 
same as that of clinical isolates in overseas. 
 
As shown in Section 2.2.4.2, the efficacy and safety of PF-06947386 have been demonstrated 
in patients with cIAI, cUTI and HAP/VAP in confirmatory global studies. Japanese patients 
were included in studies in patients with cUTI and HAP/VAP. 
 
Based on the above, PF-06947386 is expected to be efficacious in Japanese patients with 
cIAI and no new safety issues have been identified in Japanese patients when avibactam is 
added to ceftazidime at the same dose used in the global studies.  In addition, this drug is 
considered to contribute to the treatment of AMR. 
 
2.2.4. Clinical Overview 
Brief descriptions of completed clinical studies are provided below from the viewpoints of 
PK/PD in Section 2.2.4.1 and results of clinical studies in patients with cIAI in 
Section 2.2.4.2. 
 
2.2.4.1. Pharmacokinetics/Pharmacodynamics in Japanese, Chinese and Non-Asian 
Populations 
The activity of ceftazidime and avibactam is directly on the infecting bacteria, so the 
mechanism of action and the PK/PD target is assumed to be the same regardless of race.  It 
was demonstrated that the in vitro activity of ceftazidime-avibactam against isolates from 
Japanese patients is similar to non-Asian populations, providing evidence that 
microbiological etiology is comparable.  Therefore, PK data can be used to extrapolate 
clinical efficacy from non-Japanese populations to Japanese patients.  Like other β-lactam 
antibiotics, ceftazidime-avibactam was found to be a drug with low ethnic sensitivity.  The 
effect of race on PK of ceftazidime and avibactam has been assessed, as described below, and 
it was concluded that dose adjustment by race is not required. 
 
The steady state PK parameters of ceftazidime and avibactam in healthy Japanese, Chinese 
and non-Asian participants are listed in Table 1.  The mean exposure of ceftazidime was 
slightly higher in Japanese (29% Css,max and 13% AUCss) and Chinese (27% Css,max and 4% 
AUCss) compared with non-Asian. Also the mean exposure of avibactam was slightly higher 
in Japanese (5% Css,max and 8% AUCss) and Chinese (23% Css,max and 11% AUCss) compared 
with non-Asian; however, the observed differences in PK between these studies are modest, 
so dose adjustments based on race are not considered warranted. 


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Table 1. 
PK Parameters of Ceftazidime and Avibactam (Geometric Mean 
[CV%]) for 2.0 g Ceftazidime + 0.5 g Avibactam 2 Hour IV Infusion 
q8h in Japanese (Study D4280C00010), Chinese (Study D4280C00020), 
and Non-Asian Participants (Study D4280C00011 Part A) 
PK parameters 
Japanese participants 
(N=7) 
 
Ceftazidime 
Non-Asian 
participants 
(N=12) 
Chinese participants 
(N=12) 
Css,max (µg/mL) 
113.1 (15.3) 
87.7 (16.7) 
111.1 (14.6) 
AUCss (µg.h/mL) 
348.2 (17.2) 
308.2 (15.8) 
321.5 (15.5) 
Avibactam 
 
Css,max (µg/mL) 
15.0 (20.6) 
14.3 (19.1) 
17.6 (18.1) 
AUCss (µg.h/mL) 
42.2 (14.4) 
39.2 (21.7) 
43.6 (19.1) 
Source: Study D4280C00010 CSR Errata list and Addendum, Study D4280C00011 CSR, and Study D4280C00020 
CSR 
 
Furthermore, the potential impact of race on ceftazidime and avibactam PK in patients was 
explored using the final population PK model for PF-06947386 (CAZ-MS-09). Similar 
results were observed for Japanese vs non-Asian patients as those of healthy participants.  In 
the final model, Japanese race was not identified as a key covariate in the ceftazidime or 
avibactam population PK models.  Predicted ceftazidime and avibactam exposures at steady 
state (Css,max and AUCss,24), and rates of attainment for the joint target [ie, 50% fT>MIC  
(percentage of time over the 50% dosing interval that free ceftazidime concentrations exceed 
MIC) for ceftazidime and 50% fT>1.0  mg/L (percentage of time over the 50% dosing 
interval that free avibactam concentrations exceed the threshold concentration) for 
avibactam], were calculated for each race subgroup from the Phase 3 cUTI, cIAI, and 
HAP/VAP studies using the population PK model-estimated post-hoc PK parameters. Mean 
predicted exposures were slightly higher in the 45 Japanese patients (13 patients with 
HAP/VAP from REPROVE; 32 patients with cIAI from RECAPTURE) compared to the 
Caucasian/Other group (total 1209 patients with cUTI, cIAI, and HAP/VAP), with Japanese 
having approximately 32% higher Css,max and 20% higher AUCss,24 for ceftazidime and 
approximately 34% higher Css,max and 21% higher AUCss,24 for avibactam compared with 
Caucasian/Other.  This slightly higher exposure resulted in 100% target attainment in 
Japanese patients (Table 2). 
 
Table 2. 
Comparison of Ceftazidime and Avibactam Exposure and Target 
Attainment in Phase 3 Patients Stratified Across Different Races 
 
Covariate 
N 
CAZ 
CAZ 
AVI 
AVI 
Target attainment 
Category: 
Race 
Css,max 
(μg/mL) 
AUCss,24 
(μg.h/mL) 
Css,max 
(μg/mL) 
AUCss,24 
(μg.h/mL) 
(%) 
(95%CI) 
Caucasian/ 
Other 
1209 
68.6 (112.9) 
848 (125.0) 
12 (159.4) 
135 (161.3) 
98.3 (97.6, 99.1) 


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Table 2. 
Comparison of Ceftazidime and Avibactam Exposure and Target 
Attainment in Phase 3 Patients Stratified Across Different Races 
 
Covariate 
Category: 
Race 
N 
CAZ 
Css,max 
(μg/mL) 
CAZ 
AUCss,24 
(μg.h/mL) 
AVI 
Css,max 
(μg/mL) 
AVI 
AUCss,24 
(μg.h/mL) 
Target attainment 
(%) 
(95%CI) 
Asian 
248 
82.2 (118.4) 
968 (121.9) 
14.9 (166.5) 
166 (170.8) 
99.6 (98.8, 100.0) 
non-Chinese/ 
non- 
Taiwanese/ 
non-Japanese 
Chinese & 
262 
77.6 (112.5) 
884 (120.5) 
14.7 (154.9) 
151 (155.1) 
98.9 (97.6, 100.0) 
Taiwanese 
Japanese 
45 
90.4 (82.6) 
1021 (94.8) 
16.1 (134.3) 
164 (130.9) 
100.0 (N/A) 
Note: Geometric mean (%CV) are reported for Css,max and AUCss,24. Target attainment rates are reported as the 
observed percent (95% CI) of patients who achieved the joint target of 50% fT >PF-06947386 MIC of 8 mg/L for 
ceftazidime and 50% fT >1.0 mg/L for avibactam. 
Source: CAZ-MS-09 Population Pharmacokinetic Report, Table 13 
 
 
2.2.4.2. Results of Clinical Studies in Patients With cIAI 
The results of overseas clinical studies in cIAI patients are provided below. 
 
2.2.4.2.1. Clinical Efficacy in Studies for Complicated Intra-Abdominal Infections 
(RECLAIM, RECLAIM3) 
The Phase 3 studies RECLAIM and RECLAIM3 were multinational, multicenter, 
randomized, double-blind comparative studies of PF-06947386 plus metronidazole with the 
exception of vancomycin, linezolid, or daptomycin which are used for the treatment of 
known or suspected MRSA or Enterococcus spp. 
In RECLAIM, due to the difference between the guidelines issued by the FDA and EMA, 
two separate primary objectives and two separate SAPs were developed for US and for 
ROW, respectively.  The RECLAIM protocol is aligned with the FDA SAP, whereas this 
protocol describes the analyses defined in the ROW SAP.  In both RECLAIM and 
RECLAIM3, the primary endpoint was to assess the non-inferiority of PF-06947386 plus 
metronidazole compared to meropenem with respect to clinical cure at TOC (28 calendar 
days from randomization) visit.  In both studies, non-inferiority was to be concluded if the 
lower limit of the 95% CI (corresponding to a 97.5% 1-sided lower bound) for the difference 
in the primary outcome variable between the treatment groups was greater than -12.5% for 
the primary outcome variable.  In RECLAIM, the co-primary analysis sets were the MITT 
analysis set and patients who are CE at TOC; in RECLAIM3, the primary analyses set was 
the CE at TOC. 
No Japanese patients were enrolled in either RECLAIM or RECLAIM3. 


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Result of primary analysis 
 
The non-inferiority of PF-06947386 plus metronidazole compared to meropenem was 
demonstrated in relation to clinical response at the TOC visit in both RECLAIM and 
RECLAIM3 (Table 3).  Clinical response at different time points (EOT, LFU) and analysis 
sets was broadly consistent with the conclusion of non-inferiority of PF-06947386 plus 
metronidazole compared to meropenem. 
 
 
Table 3. 
Primary Analysis: Clinical Response at TOC: RECLAIM and 
RECLAIM3 (CE and MITT Analysis Sets) 
 
 
Analysis set 
Number (%) of patients 
Response 
PF-06947386 + MTZ 
Meropenem 
Differencea (%) 95% CIb 
RECLAIM 
MITT 
N=520 
N=523 
Clinical cure 
429 (82.5) 
444 (84.9) 
-2.4 (-6.90, 2.10) 
Clinical failure 
47 (9.0) 
39 (7.5) 
Indeterminate 
44 (8.5) 
40 (7.6) 
CE 
N=410 
N=416 
Clinical cure 
376 (91.7) 
385 (92.5) 
-0.8 (-4.61, 2.89) 
Clinical failure 
34 (8.3) 
31 (7.5) 
RECLAIM3 
CE 
N=177 
N=184 
Clinical cure 
166 (93.8) 
173 (94.0) 
-0.2 (-5.53, 4.97) 
Clinical failure 
11 (6.2) 
11 (6.0) 
a. 
Difference = difference in clinical cure rates (PF-06947386 + metronidazole treatment group minus meropenem 
treatment group). 
b. 
The CI for the difference was calculated using the unstratified Miettinen and Nurminen 
method. Percentages were based on total number of patients in the treatment group (N). 
Source: EU-CTD 2.5, Table 4 
 
2.2.4.2.2. Clinical Efficacy by Causative Pathogen for Complicated Intra-Abdominal 
Infections: Pooled Phase 2/3 cIAI Studies 
Across the pooled Phase 2/3 cIAI studies (RECLAIM, RECLAIM3, Study 2002, REPRISE- 
cIAI), PF-06947386 plus metronidazole demonstrated clinical efficacy (cure rate ≥70% and 
similar to comparator) against Gram-negative organisms that are amongst the most common 
causative pathogens in cIAI: E. coli, K. pneumoniae, P. aeruginosa, K. oxytoca, C. freundii 
and E. cloacae (Table 4). 


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Table 4. 
Clinical Response at TOC, by Common (Combined Frequency of ≥10) 
Baseline Gram-Negative Pathogen (Pooled Phase 2/3 cIAI Studies, mMITT 
Analysis Sets) 
 
 
 
Baseline pathogen 
Number of patients with cure / Total number of patients (%) 
PF-06947386 + MTZ (N=651) 
Comparator (N=662) 
All 
534/651 (83.2) 
568/661 (85.9) 
 
 
Enterobacterales 
429/528 (81.3) 
490/562 (87.2) 
Citrobacter freundii complex 
19/26 (73.1) 
11/14 (78.6) 
Enterobacter aerogenes 
4/6 (66.7) 
9/10 (90.0) 
Enterobacter cloacae 
19/22 (86.4) 
22/28 (78.6) 
Escherichia coli 
340/419 (81.1) 
389/442 (88.0) 
Klebsiella oxytoca 
21/25 (84.0) 
19/22 (86.4) 
Klebsiella pneumoniae 
72/92 (78.3) 
81/100 (81.0) 
Proteus mirabilis 
8/13 (61.5) 
13/15 (86.7) 
Proteus vulgaris group 
6/7 (85.7) 
2/3 (66.7) 
Gram-negative other than Enterobacterales 
Comamonas testosteroni 
5/5 (100) 
8/8 (100) 
Pseudomonas aeruginosa 
51/59 (86.4) 
57/62 (91.9) 
 
 
A patient can have more than 1 pathogen. Multiple isolates of the same species in the same patient are counted only once 
regardless of source (intra-abdominal or blood) using the isolate with the highest MIC to study drug received. 
Source: EU-CTD 2.5, Table 5 
 
 
2.2.4.2.3. Adverse Events in Complicated Intra-Abdominal Infections: Pooled Phase 2/3 
cIAI Studies 
Adverse events in patients with cIAI are summarized below.  No change to the expected 
safety profile of ceftazidime were identified by the coadministration of avibactam and 
metronidazole. Further details are shown in the IB. 
 
Common Adverse Events in cIAI Patients 
 
The incidence of AEs up to the last visit in patients with cIAI was similar between treatment 
groups [46.4% (398/857 participants) and 44.1% (381/863 participants) in the PF-06947386 
plus metronidazole and comparator treatment groups, respectively]. 
 
The most common AEs up to the last visit in patients with cIAI in the PF-06947386 plus 
metronidazole and comparator treatment groups, respectively, were nausea [7.8% (67/857 
participants) and 4.1% (35/863 participants)] and diarrhea [7.0% (60/857 participants) and 
4.4% (38/863 participants)]; these were similar to the overall patient population in pooled 
Phase 2/3 cIAI studies. 


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Intensity 
 
Up to the last visit in patients with cIAI, almost all AEs were mild or moderate in the 
PF-06947386 plus metronidazole treatment group and the comparator treatment group. The 
percentages of patients with severe AEs in the same treatment groups were 4.8% (41/857 
participants) and 6.3% (54/863 participants), respectively. 
 
The most common severe AEs were generally similar to the overall patient population in 
pooled Phase 2/3 cIAI studies.  Acute kidney injury [0.5% (4/857 participants) and 0.1% 
(1/863 participants)] was the most common preferred term in the PF-06947386 plus 
metronidazole treatment group, and respiratory failure [0.4% (3/ 857 participants) and 0.6% 
(5/857 participants)]. 
 
2.3. Benefit/Risk Assessment 
Patients enrolled into this clinical study will have cIAI 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 therapy for their 
infection. The potential benefit of the study, in general, is the identification of a novel 
antibiotic combination product that is an effective treatment for cIAI in Japan, in the face of 
the changing pattern of antibiotic resistance.  Risks of participation in the study for each 
participant are mitigated in that the study patients are closely monitored and will be managed 
with appropriate therapies as determined by the investigator who is providing treatment. 
 
The risk considerations for this study encompass the known and potential risks for the 
development product PF-06947386 and its component products ceftazidime and avibactam, 
as well as the risks associated with other treatments that might be administered as described 
in this protocol. Other treatments include the marketed product metronidazole. As the risks 
for these marketed products are widely available in their respective prescribing information, 
these risks are not discussed within this section. 
 
The full risk profile for ceftazidime is described in the prescribing information for the 
product (refer to local ceftazidime product labeling). Important risks as laid out in the 
warnings and precautions in product labeling for ceftazidime include the following: 
 
• Elevated levels of ceftazidime used in patients with renal impairment have been 
associated with neurological sequelae such as tremor, myoclonus, seizures, 
encephalopathy and coma. 
 
• Antibiotic associated diarrhea, Clostridioides difficile diarrhea, colitis, and 
pseudomembranous colitis. 
 
• Bacterial overgrowth with non-susceptible organisms. 
 
• Inadvertent intra-arterial administration of ceftazidime can result in distal necrosis. 


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• Hypersensitivity reactions.  Though patients with hypersensitivity and serious allergic 
reactions to cephalosporins, carbapenem or other β-lactam antibiotics are excluded from 
the trial, first-time episodes of such reactions could occur. 
 
The known and potential risks of receiving the developmental antibiotic combination 
PF-06947386 are expected to be similar to those seen with ceftazidime and cephalosporins in 
general. Thus far, no unique risks have been identified for the avibactam component or the 
combination of ceftazidime and avibactam. However, ceftazidime and avibactam are 
eliminated via the kidneys, therefore, the dose should be reduced according to the degree of 
renal impairment.  Neurological sequelae, including tremor, myoclonus, non-convulsive 
status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported 
with ceftazidime when the dose has not been reduced in patients with renal impairment. The 
risks of ceftazidime and avibactam are considered acceptable. 
 
While it is anticipated that PF-06947386 will have similar efficacy for the treatment of cIAIs, 
it is possible that efficacy will not be demonstrated. For each patient in the trial, appropriate 
treatment of the cIAI is determined by the clinical investigator, based on the clinical response 
of the patients. 
 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06947386 may be found in the IB, which is the SRSD for this study. 
The SRSD for metronidazole is the Japan Package Insert5. 


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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
 
Objectives 
Estimands 
Endpoints 
Primary: 
Primary: 
Primary: 
• 
To assess the efficacy of PF- 
06947386 plus metronidazole 
• 
Estimand 1: the primary estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI. 
A composite estimand strategy will be used. 
Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the clinical assessment will not be considered. 
Proportion of participants with clinical cure will 
be calculated. 
• 
Estimand 2: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI. 
A composite estimand strategy will be used. 
Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7. Proportion of participants 
with clinical cure will be calculated. 
• 
Estimand 3: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have ≥1 baseline pathogens. A composite 
estimand strategy will be used.  Intercurrent 
events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
• 
Clinical response at the 
TOC visit 


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Objectives 
Estimands 
Endpoints 
details, see Table 7. Proportion of participants 
with clinical cure will be calculated. 
• 
Estimand 4: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have at least 1 Gram-negative aerobic 
pathogen in the initial/prestudy culture regardless 
of susceptibility. A composite estimand strategy 
will be used.  Intercurrent events of death where 
cIAI is clearly noncontributory etc. will be 
regarded as indeterminate clinical response. 
Intercurrent events of death related to intra- 
abdominal infection, or additional antibiotics for 
ongoing symptoms of intra-abdominal infection 
etc. will be regarded as a failure clinical response. 
For details, see Table 7.  All data after 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 
considered. All data after other intercurrent 
events that affect the clinical assessment will not 
be considered. Proportion of participants with 
clinical cure will be calculated. 
• 
Estimand 5: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have at least 1 Gram-negative aerobic 
pathogen in the initial/prestudy culture that is 
susceptible. A composite estimand strategy will 
be used. Intercurrent events of death where cIAI 
is clearly noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Table 7.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the clinical assessment will not be considered. 
Proportion of participants with clinical cure will 
be calculated. 


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Objectives 
Estimands 
Endpoints 
Secondary: 
Secondary: 
Secondary: 
• 
To determine the efficacy of PF- 
06947386 plus metronidazole 
• 
To determine the per-patient 
microbiological response of PF- 
06947386 plus metronidazole 
• 
Estimands 6 - 10: the estimands of the 
secondary endpoints 
Same as Estimands 1 - 5 
• 
Estimand 11: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have ≥1 baseline pathogens. A 
composite estimand strategy will be used. 
Intercurrent events of lost to follow-up and death 
where cIAI is clearly noncontributory etc. will be 
regarded as indeterminate microbiological 
response.  For details, see Table 8. Proportion of 
participants with favorable microbiological 
response will be calculated. 
• 
Estimand 12: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have at least 1 Gram-negative 
aerobic pathogen in the initial/prestudy culture 
regardless of susceptibility.  A composite 
estimand strategy will be used.  Intercurrent 
events of lost to follow-up and death where cIAI 
is clearly noncontributory etc. will be regarded as 
indeterminate microbiological response.  For 
details, see Table 8.  All data after intercurrent 
events of receiving insufficient amount of study 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the microbiological assessment will not be 
considered. Proportion of participants with 
favorable microbiological response will be 
calculated. 
• 
Estimand 13: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have at least 1 Gram-negative 
aerobic pathogen in the initial/prestudy culture 
that is susceptible.  A composite estimand 
strategy will be used.  Intercurrent events of lost 
to follow-up and death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate microbiological response.  For 
details, see Table 8.  All data after intercurrent 
events of receiving insufficient amount of study 
• 
Clinical response at 
EOT, and LFU visits 
• 
Per-patient 
microbiological 
response at EOT, TOC, 
and LFU visits 


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Objectives 
Estimands 
Endpoints 
• 
To determine the per-pathogen 
microbiological response of PF- 
06947386 plus metronidazole 
• 
To evaluate the safety and 
tolerability profile of PF- 
06947386 plus metronidazole in 
the treatment of patients with 
cIAIs 
• 
To evaluate the 
pharmacokinetics of the 
individual components of PF- 
06947386 in patients with cIAIs 
• 
To investigate safety and 
efficacy for patients with sepsis 
(if available) 
drug or any protocol deviations that affect 
assessment of efficacy will not be considered. 
All data after other intercurrent events that affect 
the microbiological assessment will not be 
considered. Proportion of participants with 
favorable microbiological response will be 
calculated. 
• 
Estimands 14 - 16: the estimands of the 
secondary endpoints 
Same as Estimands 11 - 13 
N/A 
N/A 
N/A 
• 
Per-pathogen 
microbiological 
response at EOT, TOC, 
and LFU visits 
• 
Per-pathogen 
microbiological 
response at EOT, TOC, 
and LFU visits by MIC 
categories 
• 
AEs and SAEs, all 
cause mortality, reasons 
for discontinuations of 
IV study intervention 
and study, vital sign 
measurements, and 
potentially clinically 
significant changes in 
laboratory parameters 
during the entire study 
• 
Ceftazidime and 
avibactam plasma 
concentrations by 
nominal sampling 
window 
• 
Selected efficacy and 
safety endpoints as 
described above 
CCI 


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This protocol will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related efficacy endpoints, 
using predefined endpoint criteria. 
 
 
4. STUDY DESIGN 
4.1. Overall Design 
Study C3591036 will assess the efficacy and safety of PF-06947386 in Japanese hospitalized 
participants with cIAI. This is a multicenter, open-label, single-arm study.  The study will 
have a maximum duration of approximately 6 weeks for each participant. This includes a 5- 
14 days of IV study period, TOC visit at Day 28, and LFU visit at Day 42. 
 
Approximately 60 participants will be enrolled to study intervention such that there will be 
approximately 50 evaluable participants in the CE analysis set. Although it is uncertain 
whether the definition of the sepsis patients subset (Section 9.3) is met at the timing of study 
entry, 3 to 5 enrolled participants are anticipated to meet the definition of the sepsis patients 
subset. 
 
Note: “Enrolled” means a participant’s, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process.  Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
 
To be eligible to enroll in this study, participants must have cIAI at Screening visit.  The full 
list of eligibility criteria for the study is included in Section 5. 
 
Eligible participants with CrCL >50 mL/min will be given an IV dose of 2.5 g PF-06947386 
(ceftazidime 2.0 g/avibactam 0.5 g) q8h with infusion time of 2 hours for 5-14 days.  For 
participants enrolled into the study whose CrCL drops to ≤50 mL/min while on IV 
investigational drug therapy, dosage adjustment is required depending on the degree of renal 
impairment based on the CrCL value (Section 6).  All eligible participants will receive 
metronidazole (0.5 g) intravenously with an infusion duration of 60 minutes. When both PF- 
06947386 and metronidazole are administered at the same time, metronidazole will be 
administered immediately after administration of PF-06947386. 
CCI 


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4.2. Scientific Rationale for Study Design 
Japanese patients were enrolled in the two multinational, multicenter, randomized, double- 
blind, comparative studies in cUTI and HAP/VAP patients which were conducted as pivotal 
studies for PF-06947386. On the other hand, Japanese patients were not enrolled in the 
studies in cIAI patients. 
 
Since the efficacy and safety have been confirmed in clinical studies in cUTI and HAP/VAP 
patients, including Japanese patients, as representative diseases, this study is being conducted 
to evaluate the efficacy and safety in Japanese cIAI patients as a multicenter, open-label, 
single-arm study in accordance with the Guidelines for Clinical Evaluation of Antibacterial 
Drugs. 
 
Human reproductive safety data are limited for PF-06947386, but there is no suspicion of 
human teratogenicity based on the intended pharmacology of the compound. Therefore, the 
use of a highly effective method of contraception is required (see Appendix 4). 
 
4.3. Justification for Dose 
The dose of PF-06947386 was selected on the basis of achieving pre-determined exposure 
targets for both ceftazidime and avibactam simultaneously in at least 90% of patients.  These 
exposure targets were based on the activity of PF-06947386 in surveillance studies and 
nonclinical PK/PD studies. 
 
The exposure target for ceftazidime was achieving or exceeding a free systemic ceftazidime 
concentration of 8 mg/L for at least 50% of the dosing interval (50% fT> PF-06947386 MIC 
of 8 mg/L). A PF-06947386 MIC of 8 mg/L was chosen because it was observed to include 
MICs obtained against ≥90% of clinical isolates of Enterobacterales and P. aeruginosa in 
contemporary global surveillance studies.  Specifically, the PF-06947386 MIC90 against 
P. aeruginosa was 8 mg/L in multiple studies, and the MIC90 values against unselected 
clinical isolates of species of Enterobacterales were 1 mg/L or lower.  The exposure target 
for avibactam was achieving or exceeding a free systemic avibactam concentration of 1 mg/L 
for 50% of the dosing interval (50% fT>CT of 1 mg/L). The 1 mg/L exposure target for 
avibactam was a critical CT that was determined from nonclinical in vitro and in vivo 
experiments. 
 
Population PK models of ceftazidime and avibactam were developed using data from the 
Phase 1 PF-06947386 and ceftaroline fosamil-avibactam studies, along with the data 
collected in patients with cUTI and cIAI in the Phase 2 and Phase 3 PF-06947386 studies. 
These population PK models of ceftazidime and avibactam were then used to explore PK/PD 
relationships in the Phase 2 and Phase 3 studies and to conduct simulations to evaluate the 
PTA, using the targets outlined above.  The PTA analyses were used to support dose 
adjustments for PF-06947386 in patients with renal impairment and PF-06947386 
breakpoints.  Susceptibility interpretive criteria of Enterobacterales and P. aeruginosa for 
PF-06947386 are ≤8 mg/L, respectively. 


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In summary, dose selection and breakpoint justification was based on a prediction of 90% of 
the patient population achieving exposures that simultaneously maintained 50% fT> PF- 
06947386 MIC of 8 mg/L for ceftazidime and 50% fT>CT of 1 mg/L for avibactam. 
 
The population PK models of ceftazidime and avibactam (CAZ-MS-09) were used to 
calculate individual PK profiles of ceftazidime and avibactam for patients with cIAI from the 
Phase 3 studies RECLAIM, RECLAIM3, and REPRISE where individual exposure 
prediction was available.  In >90% of patients, exposure exceeded the joint PK/PD targets 
(50% fT>MIC for PF-06947386 MIC up to 8 mg/L for ceftazidime and 50% fT>CT of 1 
mg/L for avibactam) derived from nonclinical studies.  Using the same population PK model 
to simulate exposures of 5000 patients with cIAI, the joint PTA against the PK/PD targets 
was >90% up to PF-06947386 MIC of 8 mg/L. 
 
Taken together, the results of the studies in cIAI validate that the proposed dose achieves 
adequate exposure in the majority of patients with normal renal function and is associated 
with therapeutic efficacy. 
 
A dose regimen of 2.0 g ceftazidime plus 0.5 g avibactam given as a 2 hour IV infusion, q8h, 
for patients with normal renal function has been demonstrated to be an effective dose for the 
treatment of patients with cIAI. This dose regimen is the approved dose in other regions and 
would provide the comparable exposures and PTA between non-Japanese and Japanese 
patients based on the data from population PK and PK/PD analysis. Furthermore, this dose is  
predicted to be effective against at least 90% of isolates of Enterobacterales and 
P. aeruginosa, which are the pathogens for which PF-06947386 will provide the most 
benefit. Each doses for patients with renal impairment (Section 6.1.1.2) is predicted to 
achieve in ≥94.9% of patients the exposure targets for efficacy against isolates of 
Enterobacterales and P. aeruginosa with a PF-06947386 MIC of up to 8 mg/L, which are the 
pathogens for which PF-06947386 will provide the most benefit. 
 
The proposed PF-06947386 dose regimens overall support the following breakpoint with a 
≥90% PTA for patients with cIAI, cUTI, and HAP/VAP: 
MIC of 8 mg/L for Enterobacterales and P. aeruginosa for the PK/PD target of 50% fT>PF- 
06947386 MIC for ceftazidime and 50% fT>CT of 1 mg/L for avibactam. 
 
The dose of metronidazole for intra-abdominal infections is within the dosage which 
approved in Japan. 
 
4.4. End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last scheduled procedure shown in the SoA. 
 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
for the last participant in the trial globally. 


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5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
Age and Sex: 
 
1. Age ≥20 years at the time of the Screening visit. 
 
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
 
Type of Participant and Disease Characteristics: 
 
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
 
3. Must have clinical evidence of cIAI as follows: 
 
i. Preoperative enrollment where the following clinical criteria are met with 
confirmation of infection by surgical intervention within 24 hours of entry: 
a. Requirement for surgical intervention, defined per protocol as open laparotomy, 
percutaneous drainage of an abscess, or laparoscopic surgery 
b. Evidence of systemic inflammatory response, with at least one of the following: 
 
• Fever (defined as body temperature >38°C) or hypothermia with a core body 
temperature <35°C 
 
• Elevated white blood cells (>12000 cells/mm3) 
 
• Drop in blood pressure (however, systolic blood pressure must be >90 mmHg 
without pressor support) 
 
• Increased heart rate (>90 bpm) and respiratory rate (>20 breaths/min) 
 
• Hypoxia 


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• Altered mental status 
 
c. 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 
 
d. Supportive imaging findings of intra-abdominal infection such as perforated 
intraperitoneal abscess detected on computed tomography scan, magnetic 
resonance image, or ultrasound. 
 
e. Intention to send specimens from the surgical intervention for culture. 
 
ii. Intra-operative/post-operative enrollment 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.  Patients who undergo a surgical procedure with complete 
fascial closure are appropriate for the trial.  The skin incision may be left open for 
purposes of wound management as long as complete fascial closure is 
accomplished. The patient must have at least one 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 
c. Appendiceal perforation or peri-appendiceal abscess 
d. Acute gastric or duodenal perforations, only if operated on >24 hours after 
perforation occurs 
e. Traumatic perforation of the intestines, only if operated on >12 hours after 
perforation occurs 
f. Secondary peritonitis (but not spontaneous bacterial peritonitis associated with 
cirrhosis and chronic ascites) 
g. Intra-abdominal abscess (including of liver or spleen provided that there is 
extension beyond the organ with evidence of intraperitoneal involvement) 


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To note, 
Participants who meet the following clinical and microbiological criteria are considered to 
have sepsis in this protocol: 
 
Clinical: Total score ≥2 in SOFA for ICU patients, 2 items or more in qSOFA for 
non-ICU patients (Section 10.7) 
 
Microbiological: The most relevant pathogens (ie, aerobic Gram-negative bacteria - 
either Enterobacterales or aerobic Gram-negative pathogens other than 
Enterobacterales) isolated from the blood at Baseline regardless of 
susceptibility. 
 
Informed Consent: 
 
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol. 
 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
 
Medical Conditions: 
 
1. Participant is 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. Participant has abdominal wall abscess or bowel obstruction without perforation or 
ischemic bowel without perforation 
 
3. Participant has simple cholecystitis, or simple appendicitis, or infected necrotizing 
pancreatitis, or pancreatic abscess 
 
4. Participant whose surgery will include staged abdominal repair, or “open abdomen” 
technique, or marsupialization.  This criterion is intended to exclude participants in 
whom the abdomen is left open, particularly those for whom reoperation is planned. 
 
5. Participant is known at study entry to have cIAI caused by pathogens resistant to the 
study antimicrobial agents 
 
6. Participant has evidence of sepsis with shock not responding to IV fluid challenge or 
anticipated to require the administration of vasopressors for >24 hours 
 
7. Participant has perinephric infections 


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8. Participant is receiving hemodialysis or peritoneal dialysis, or has indwelling 
peritoneal dialysis catheter 
 
9. Participant has suspected intra-abdominal infections due to fungus, parasites (eg, 
amebic liver abscess), virus, or tuberculosis 
 
10. Participant has a known history of serious allergy, hypersensitivity (eg, anaphylaxis), 
or any serious reaction to cephalosporin antibiotics or other β-lactam antibiotics or 
metronidazole 
 
11. Participant is considered unlikely to survive the 6- to 8-week study period or has a 
rapidly progressive or terminal illness 
 
12. Participant with concurrent infection that may interfere with the evaluation of 
response to the study antibiotic 
 
13. Participant has past (prior 6 months) or current history of acute hepatitis. Participant 
has past or current history of chronic hepatitis, cirrhosis, acute hepatic failure, and/or 
acute decompensation of chronic hepatic failure. 
 
14. Participant has past or current history of epilepsy or seizure disorders excluding 
febrile seizures of childhood 
 
15. Participant is chronically immunocompromised as evidenced by any of the following: 
 
a. Human immunodeficiency virus infection, with either a current acquired immune 
deficiency syndrome defining condition (eg, Kaposi’s sarcoma, 
Pneumocystis carinii pneumonia) or a CD4+ T lymphocyte count <200/mm3 at 
the time of study entry 
 
b. Metastatic or hematological malignancy requiring chemotherapeutic interventions 
within 6 weeks prior to first IV infusion 
 
c. Immunosuppressive therapy for organ transplantation 
 
16. Participant is in a situation or has a condition that, in the investigator’s opinion, may 
interfere with optimal participation in the study. 
 
17. Participant has known inflammatory bowel disease (ulcerative colitis or Crohn’s 
disease) 
 
18. Participant has known or suspected Clostridioides difficile associated diarrhea 
 
19. Participant is pregnant or breastfeeding. A serum β-hCG pregnancy test must be 
conducted for women of childbearing potential at Screening visit.  If the results of 
the serum β-hCG cannot be obtained prior to dosing of IP, a participant may be 
enrolled on the basis of a negative urine pregnancy test, though serum β-hCG must 


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still be obtained.  If either test is positive, the participant must be excluded. Since 
urine and serum tests may miss a pregnancy in the first days after conception, relevant 
sexual history, including methods of contraception, should be considered.  Any 
participant whose sexual history suggests the possibility of early pregnancy must be 
excluded. 
 
20. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
 
Prior/Concomitant Therapy: 
 
21. Participant needs effective concomitant systemic antibacterials (eg, oral, IV, or 
intramuscular) or systemic antifungals in addition to study regimens, except 
vancomycin, linezolid, or daptomycin if started for known or suspected MRSA or 
Enterococcus species as per protocol Section 6.5 
 
22. Participant has received systemic antibacterial agents within the 72-hour period prior 
to study entry, unless either of the following pertains: 
 
a. Participant has a new infection (not considered a treatment failure) and both of the 
following are met: 
 
• Participant received no more than 24 hours of total prior antibiotic therapy 
 
• Participant received ≤1 dose of a treatment regimen post operatively and 
antibiotics were not received more than 6 hours post procedure (defined as 6 
hours from the time of skin closure or, if skin closure was not performed, 6 
hours from the time the wound dressing was applied) 
 
b. Participant is considered to have failed the previous treatment regimen.  In this 
case, preoperative treatment of any duration with non-study systemic 
antimicrobial therapy for peritonitis or abscess is permitted provided that all of the 
following are met: 
 
• The treatment regimen has been administered for at least 72 hours and is 
judged to have failed. 
 
• The participant has an operative intervention that is just completed or is 
intended no more than 24 hours after study entry. 
 
• Findings of infection were documented at surgery. 
 
• Specimens for bacterial cultures and susceptibility testing are taken at 
operative intervention 


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• No further non-study antibacterials are administered after first IV infusion. 
 
c. Participant has received systemic antibiotic agents no more than 24 hours (no 
more than one daily dose) within the 72-hour period prior to study entry. 
 
23. Use of potent inhibitors of organic anion transporters OAT1 and/or OAT3 (eg, 
probenecid, or PAH) are prohibited. 
 
24. Participant has previously been treated with ceftazidime-avibactam. 
 
Prior/Concurrent Clinical Study Experience: 
 
25. Participant is participating in any other clinical study that involves the administration 
of an investigational medication at the time of presentation, during the course of the 
study, or who has received treatment with an investigational medication in the 30 
days prior to study enrollment. 
 
26. Participant had been previously enrolled in this study 
 
Diagnostic Assessments: 
 
27. Estimated CrCL ≤50 mL/min calculated by Cockcroft-Gault method6. Refer to 
Appendix 8 for calculating estimated CrCL. 
 
28. Hematocrit <25% or hemoglobin <8 g/dL 
 
29. Absolute neutrophil count <1000/mm3 
30. Platelet count <75000/mm3 
 
31. Bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to the acute 
infection or known Gilbert’s disease 
 
32. ALT or AST >3 × ULN values at Screening.  Participants with elevations of AST 
and/or ALT up to 5 × ULN are eligible if these elevations are acute and directly 
related to the infectious process being treated. This must be documented. 
 
33. Alkaline phosphatase >3 × ULN. Participants with values >3.0 × ULN and <5.0 × 
ULN are eligible if this value is acute and directly related to the infectious process 
being treated. This must be documented. 
 
Other Exclusions: 
 
34. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 


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5.3. Lifestyle Considerations 
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant from the permitted list of contraception methods (see Appendix 4 Section 10.4.4) 
and will confirm that the participant has been instructed in its consistent and correct use.  At 
time points indicated in the SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart (participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception). 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner. 
 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention/enrolled in the study.  A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any AE. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
 
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration 
Not applicable. 
 
6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol. 
 
For the purposes of this protocol, study intervention refers to PF-06947386 and 
metronidazole. 
 
6.1. Study Intervention(s) Administered 
 
Intervention Name 
PF-06947386 (ceftazidime- 
avibactam) 
Metronidazole 
Type 
Drug 
Drug 
Dose Formulation 
Powder for concentrate for 
solution for infusion 
Solution for injection 


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Unit Dose Strength(s) 
2.0 g ceftazidime and 0.5 g 
avibactam 
0.5 g 
Route of 
Administration 
Intravenous 
Intravenous 
Use 
Experimental 
Experimental 
IMP or NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and 
Labeling 
Study intervention will be 
provided in vials. Each vial will 
be labeled as required per 
country requirement. 
Study intervention will be provided in 
vials. Each vial will be labeled as 
required per country requirement. 
6.1.1. Administration 
Patients will receive PF-06947386 (2.0 g of ceftazidime and 0.5 g of avibactam) 
intravenously, immediately followed by an IV administration of metronidazole (0.5 g). 
Participants will receive a minimum of 5 full days (15 doses) of IV study intervention up to a 
maximum of 14 full days (42 doses) of study intervention. 
 
The first dose of IV study intervention is given at Visit 2 on Study Day 1. 
 
Dosing intervals for patients with normal renal function and mild renal impairment are 
described in Section 6.1.1.1. 
 
For patients enrolled into the study whose CrCL drops to ≤50 mL/min while on IV study  
intervention, follow the instructions in Section 6.1.1.2. 
 
6.1.1.1. Dosing Intervals in Patients With Normal Renal Function and Patients With 
Mild Renal Impairment (CrCL >50 mL/min) 
IP will be administered q8h (±30 minutes) as described in Figure 2. 
 
Table 5. 
Ceftazidime/Avibactam Adjustments for Patients With Normal Renal 
Function and Patients With Mild Renal Impairment 
CrCL 
(mL/min)a 
Investigational product 
Dose, interval, duration 
Normal or Mild 
impairment: (>50) 
PF-06947386 (ceftazidime- 
avibactam) 
2.0 g ceftazidime/ 0.5 g avibactam q8h ±30 
minutes over 120 minutes ±10 minutes at a 
constant rate of infusion 
Metronidazole 
Metronidazole 0.5 g q8h ±30 minutes over 
60 minutes ±5 minutes at a constant rate of 
infusion 
 
a. 
Estimated CrCL using Cockcroft-Gault formula (Section 10.8). 


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Figure 2. Schematic of Dosing Intervals for Patients With Normal Renal Function 
/Mild Renal Impairment (for an Arbitrary 24 Hour Period) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If necessary, a 1‑time dosing interval adjustment is allowed after the first dose of IV study 
intervention to create a suitable dosing schedule going forward with an 8-hour (±30 minutes) 
dosing interval. The dosing interval adjustment must be such that the second dose is given a 
minimum of 4 hours and a maximum of 8 hours after the first dose (ie, a 1-time 4-hour 
dosing interval is allowed between the first and the second dose). If a 1-time dose interval 
adjustment is implemented for the second dose, all further dosing times will be calculated 
based on the time of the second dose. 
 
For example, if the first dose is started at 10 AM, the second dose would be due at 6 PM. A 
1-time adjustment of dosing time would allow the second dose to be started between 2 PM 
and 6 PM. All future doses would be given at 8 hours (±30 minutes) from the time the 
second dose was actually administered. If the timing of a dose fluctuates from the scheduled 
time (eg, started 15 minutes early for a dose scheduled for 4 PM), the next dose should still 
be administered 8 hours from the scheduled dose, which would be 12 AM. 
 
6.1.1.2. Dose Regimen Adjustments for Patients Whose CrCL Drops ≤50 mL/min While 
on IV Study Intervention 
If a patient’s estimated CrCL falls below the threshold for study inclusion, subsequent to 
study entry and while still on IV study intervention, retesting should be performed promptly. 
 
Because the CrCL determination is only an estimate of renal function, in instances where the 
CrCL is below 50 mL/min, the investigator should use his or her discretion in determining 
24 h 
(±30 min) 
16 h 
(±30 min) 
8 h 
(±30 min) 
0 h 
(±30 min) 
Metronidazole 0.5 g 
60 min (±5 min) infusion, q8h 
PF-06947386 (ceftazidime 2.0 g/avibactam 0.5 g) 
120 min (±10 min) infusion, q8h 


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whether an immediate dose adjustment, a short period of continued observation, or 
discontinuation of therapy is warranted. Once a dose adjustment is decided upon, the 
investigator should inform the dispensing pharmacist immediately.  The pharmacist should 
then provide the appropriate dose adjustments as outlined in Table 6. 
 
Since a decline in renal function may be transient, CrCL should be closely monitored in 
patients demonstrating renal dysfunction at any point before or during the study to ensure 
that therapeutic doses are being administered. 
 
Table 6. 
Dose Regimens and Infusion Times for Patients Whose Estimated CrCL 
Drops Below 50 mL/min While on IV Study Intervention 
CrCL 
(mL/min)a, b 
Investigational product 
Dose, interval, duration 
50 to 31 
PF-06947386 (ceftazidime- 
avibactam) 
1 g ceftazidime/ 0.25 g avibactam q8h ±30 
minutes over 120 minutes ±10 minutes at a 
constant rate of infusion 
Metronidazole 
Metronidazole 0.5 g q8h ±30 minutes over 
60 minutes ±5 minutes at a constant rate of 
infusion 
30 to 16 
PF-06947386 (ceftazidime- 
avibactam) 
0.75 g ceftazidime/ 0.1875 g avibactam 
every 12 hours ±30 minutes over 120 
minutes ±10 minutes at a constant rate of 
infusion 
Metronidazole 
Metronidazole 0.5 g q8h ±30 minutes over 
60 minutes ±5 minutes at a constant rate of 
infusion 
15 to 6 
PF-06947386 (ceftazidime- 
avibactam) 
0.75 g ceftazidime/ 0.1875 g avibactam 
every 24 hours ±30 minutes over 120 
minutes ±10 minutes at a constant rate of 
infusion 
Metronidazole 
Metronidazole 0.5 g q8h ±30 minutes over 
60 minutes ±5 minutes at a constant rate of 
infusion 
< 6 
PF-06947386 (ceftazidime- 
avibactam) 
0.75 g ceftazidime/ 0.1875 g avibactam 
every 48 hours ±30 minutes over 120 
minutes ±10 minutes at a constant rate of 
infusion 
Metronidazole 
Metronidazole 0.5 g q8h ±30 minutes over 
60 minutes ±5 minutes at a constant rate of 
infusion 
 
a. 
Estimated CrCL using Cockcroft-Gault formula (Section 10.8). 
b. 
PF-06947386 and metronidazole are removed by hemodialysis. Dosing of PF-06947386 and metronidazole on 
hemodialysis days should occur after completion of hemodialysis.  In cases where hemodialysis is needed but 
scheduling the dosing of PF-06947386 and metronidazole after completion of hemodialysis is not feasible, or if 
the investigator has concerns for the participant to continue with dosing, discontinuation from study treatment 
may be considered, as needed. 


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6.2. Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business. 
 
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual. 
 
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
 
5. Study interventions should be stored in their original containers. 
 
6. See the IP manual for storage conditions of the study intervention once reconstituted 
or diluted. 
 
7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent.  All study interventions will be accounted for 
using a study intervention accountability form/record. 
 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer. 


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Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP manual. 
 
6.2.1. Preparation and Dispensing 
See the IP manual for instructions on how to prepare the study intervention for 
administration. Study intervention should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, state, and institutional guidance. A second staff member will verify the dispensing. 
 
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Study Intervention 
This is an open-label, single-arm study. 
 
Following full assessment and determination that the participant meets all eligibility criteria, 
the investigator or designee may administer IP to the participant. 
 
The investigator or designee will fax or email a completed registration form to the sponsor. 
The investigator or designee shall receive the enrollment number from the sponsor via fax or 
email. 
 
6.4. Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
 
The site will complete the required dosage Preparation Record located in the IP manual.  The 
use of the Preparation Record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system. The existing clinical site’s documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose. This may be used in place of the Preparation Record after 
approval from the sponsor and/or designee. 
 
6.5. Concomitant Therapy 
All prescription, over-the-counter medications, and dietary and herbal supplements being 
taken by the patient during the 30 days prior to first IV infusion (considered prior treatment) 
and from first IV infusion through study end (considered concomitant treatments) must be 
documented on the appropriate pages of the eCRF.  Medications that are considered to 
maintain their effect during the 30 days prior to first infusion, such as medications with long 
dosing intervals, must be documented on the appropriate pages of the eCRF even if they are 
taken more than 30 days prior to first IV infusion.  Systemic antibiotics should be 


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documented for the entire duration of the study (from 30 days prior to first IV therapy 
through study end). 
 
Surgical history will be collected at Screening.  Non-drug procedures conducted during the 
30 days prior to first IV infusion (considered prior treatment) and from first IV infusion 
through study end (considered concomitant treatments) must be documented on the 
appropriate pages of the eCRF. 
 
If Enterococcus species or MRSA is one of the pathogens suspected or isolated and, in the 
opinion of the investigator, specific therapy is indicated, then vancomycin, linezolid, or 
daptomycin may be added to study regimens according to the usual practice of the 
investigator. If vancomycin, linezolid, or daptomycin is started empirically to cover MRSA 
or Enterococcus species, and if final culture results did not isolate MRSA or Enterococcus 
species, then the investigator should discontinue the additional Gram-positive coverage that 
was empirically added. 
 
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) between the date and time of first IV infusion and study end, and the investigator 
considers addition of nonstudy antibiotics essential to the safety and wellbeing of the patient, 
additional antibiotics may be added.  If possible, the investigator should attempt to choose 
antibiotics that will not have antibacterial activity against the patient’s cIAI baseline 
pathogens to avoid confounding the assessment of the effect of study intervention. Antibiotic 
peritoneal lavage is not permitted (peritoneal lavage with saline or other nonantibacterial 
containing solution is allowed). Topical antibacterial and topical antifungals are permitted 
except that they may not be applied to the surgical site.  It is anticipated that in instances of 
clinical failure, alternative “rescue” antibacterial therapy to treat the cIAI would be instituted. 
Systemic antifungal therapy should be avoided unless clinically indicated.  A known 
requirement for antifungal therapy at first IV infusion would exclude the patient from 
enrollment based on exclusion criterion 21. 
 
Other medications, which are considered necessary for the patients’ safety and well-being, 
may be given at the discretion of the investigator and recorded in the appropriate sections of 
the eCRF.  If analgesic medications are needed for pain, the use of analgesic medication 
without antipyretic properties is preferred. Should a patient require immunosuppressive 
agents or chemotherapy after starting IV study intervention, the investigator should contact 
the Pfizer Medical Monitor or designee before initiating therapy. Continued patient study 
participation will be determined based upon assessment of the safety risk to the patient if he 
or she were to continue in the study.  Patients who have completed IV study intervention and 
are in the follow-up period should remain in the study as they are not actively on IV study 
intervention but being followed for outcomes. 
 
Use of potent inhibitors of organic anion transporters OAT1 and/or OAT3 (eg, probenecid, or 
PAH) are prohibited during the study because they have the potential to alter (decrease) the 
clearance of avibactam when coadministered. 


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In this study, metronidazole is also administered in combination with PF-06947386. 
Therefore, the package insert of the metronidazole should also be referred to for the 
precautions regarding co-administration. 
 
6.6. Dose Modification 
For patients enrolled into the study whose CrCL drops to ≤50 mL/min while on IV study 
intervention, follow the instructions in Section 6.1.1.2. 
 
6.7. Intervention After the End of the Study 
No intervention will be provided to study participants at the end of the study. 
 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation).  Reasons for definitive discontinuation of study 
intervention include the following: 
 
• Request by the participant or legally authorized representative to terminate treatment 
 
• Investigator judgment that continued dosing is not in the best interest of the  
participant 
 
• Request by the Sponsor to terminate treatment 
 
• Anaphylaxis or other serious allergic reaction to the study intervention, or other AEs 
or confirmed laboratory abnormality, judged by the investigator to be a significant 
safety concern 
 
• Positive pregnancy test at any time during the study treatment period 
 
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention. 
 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following: 
 
• Refused further follow-up; 
 
• Lost to follow-up; 
 
• Death; 


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• Study terminated by sponsor; 
 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
 
Lack of completion of all or any of the withdrawal/early termination procedures will not be  
viewed as protocol deviations so long as the participant’s safety was preserved. 
 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law. 
 
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to attend a required study visit: 


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


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actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner. 
 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior to 
initiation of the study. 
 
The total blood sampling volume for individual participants in this study is approximately 
maximum 185 mL. The actual collection times of blood sampling may change.  If blood 
culture is positive at Baseline, additional samples will be collected. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days. 
 
8.1. Efficacy Assessments 
8.1.1. APACHE II Score 
APACHE II score will be calculated APACHE II score using most recent local laboratory 
results at Screening (see Section 10.6). Use of temperature obtained rectally in determining 
the APACHE II score is preferred but not mandatory.  If ABG is not clinically indicated, the 
APACHE II score should be calculated using serum bicarbonate and oxygenation should be 
presumed normal. 
 
8.1.2. Imaging Test 
Imaging tests are not required for the study, but the results should be submitted if done as 
part of the diagnosis.  Imaging tests include plain abdominal radiographs, computed 
tomography scans, ultrasound, and/or magnetic resonance image scans with or without 
contrast. 
 
 
 
 
 
 
 
 
 
 
 
 
CCI 


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C 
C 
I 
 
 
 
 
 
 
 
8.1.6. Clinical Response 
Clinical response definitions at the EOT, TOC, LFU, and Early Termination/Discontinuation 
visits are cure, failure, and indeterminate. Reasons for failure will be indicated according to 
the clinical response definitions in Table 7.  If a patient fails or relapses between scheduled 
visits, the assessment should be recorded as an unscheduled visit. 
 
Table 7. 
Definitions of Clinical Response at the EOT, TOC, LFU, and Early 
Termination/Discontinuation Visits 
 
 
Clinical response 
Definition 
 
Cure 
Complete resolution or significant improvement of signs and symptoms of the 
index infection such that no further antimicrobial therapy, drainage, or surgical 
intervention is necessary. 
 
Note: Patients who receive coverage for MRSA or Enterococcus, as allowed per 
protocol, can still have a response definition of cure. 


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Table 7. 
Definitions of Clinical Response at the EOT, TOC, LFU, and Early 
Termination/Discontinuation Visits 
 
 
Clinical response 
Definition 
 
Failure 
Patients who meet any 1 of the criteria below will be considered a treatment 
failure: 
• 
Death related to intra-abdominal infection 
• 
Persisting or recurrent infection within the abdomen documented by the 
findings at re-intervention either percutaneously or operatively 
• 
Postsurgical wound infections defined as an open wound with signs of local 
infection such as purulent exudates, erythema, or warmth that requires 
additional antibiotics and/or nonroutine wound care 
• 
Patient who receives treatment with additional antibiotics for ongoing 
symptoms of intra-abdominal infection (including patients prematurely 
discontinued from study drug due to an AE who require additional antibiotics 
for cIAI) 
• 
Patient previously met criteria for failure 
Indeterminate 
Study data are not available for evaluation of efficacy for any reason, including: 
• 
Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response cannot be made 
• 
Death where cIAI is clearly noncontributory 
• 
Circumstances that preclude classification as a cure or failure 
 
 
 
8.1.6.1. Adjudication Committee 
The adjudication committee will consist of 2 or more external infectious disease specialists 
especially intra-abdominal infection.  The adjudication committee will review investigators’ 
clinical assessments based on the collected data (imaging test results if available, signs and 
symptoms of intra-abdominal infection, wound examination, temperature, WBC, CRP, and 
microbiological data, description of operative procedure, investigator case summary, 
operative notes, discharge summary) for consistency of evaluation in the study.  The data are 
reviewed with masking the information of the site and the investigator to avoid biases.  The 
committee would request to the principal investigator (or subinvestigator) to provide other 
information as necessary.  If a discrepancy exists after the data are cleaned, the assessment by 
the adjudication committee will prevail.  In addition, patients assessed by the adjudication 
committee as having inadequate initial infection source control will be re-classified as 
indeterminate and will be excluded from the CE and ME analysis sets. 
 
All required documentation including surgical reports and imaging results may be submitted 
if requested by the Adjudication Committee. 
 
There may be instances when copies of medical records to support the adjudication 
committee review are requested by Pfizer. In this case, all participant identifiers, with the 
exception of the participant number, must be redacted on the copies of medical records 
before submission to Pfizer. 


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8.1.7. Microbiological Assessments 
8.1.7.1. Blood Culture 
Blood cultures must be obtained at Screening.  If blood cultures are positive, the assessment 
is to be repeated upon knowledge of a positive result until sterilization is confirmed in 
accordance with the SoA for the timing and frequency. As a general rule, culture and 
organism identification should be performed at the local or regional laboratory unless there 
are difficulties to conduct the procedures at the study site, but it is acceptable to use the 
central laboratory.  Send all isolates to the central laboratory for organism identification and 
susceptibility testing. 
 
Refer to the study specific clinical and microbiology laboratory manual for specific 
procedures pertaining to the collection, processing, storage, and shipment of blood culture or 
isolates. 
 
8.1.7.2. Culture of Abdominal Infection Site 
Cultures must be obtained at initial qualifying procedure [performed within 24 hours of entry 
for preoperative enrollment (see Section 5.1, inclusion criterion 3)]. If additional procedures 
are performed, additional abdominal site cultures should be obtained.  Cultures from the 
wound/procedure site should be obtained only if clinically indicated through study end. As a 
general rule, Gram stain (if applicable), culture and organism identification should be 
performed at the local or regional laboratory unless there are difficulties to conduct the 
procedures at the study site, but it is acceptable to use the central laboratory. Send all isolates 
to the central laboratory for organism identification and susceptibility testing. 
 
Refer to the study specific microbiology and clinic laboratory manual for specific procedures 
pertaining to the collection, processing, storage, and shipment of other specimens/tissues for 
culture or isolates. 
 
8.1.8. Microbiological Response Assessments 
The per-patient and per-pathogen microbiological response of PF-06947386 plus 
metronidazole in mMITT and ME analysis sets for patients with cIAI at the EOT, TOC, 
LFU, and Early Termination/Discontinuation visits is a secondary outcome.  If a patient fails 
or relapses between scheduled visits, the assessment should be recorded as an unscheduled 
visit. 
 
Microbiological response will be assessed per-patient and per-pathogen according to the 
definitions listed below. It is based on outcome per-pathogen isolated at the initial visit 
(considered as causative) and on the isolation of pathogens during the course of treatment or 
the post treatment period. 
 
8.1.8.1. 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 8. Microbiological responses other 


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than “indeterminate” will be classified as “favorable” or “unfavorable”. Favorable 
microbiological response assessments include “eradication”, “presumed eradication” and 
“colonization”.  Unfavorable microbiological response assessments include “persistence”, 
“persistence with increasing MIC”, and “presumed persistence”. Patients with a 
microbiological response assessment of “indeterminate” will be considered to be 
nonevaluable for the ME analysis set.  “Superinfection” and “new infection” will be 
considered separately (Table 9). 
 
8.1.8.2. Per-Patient (Overall) Microbiological Response Assessments 
Overall microbiological response will also be assessed as “favorable” or “unfavorable” for 
each patient. “Eradication” and “presumed eradication” as well as “colonization” will be 
considered as “favorable” microbiological response in the analyses. 
 
For patients from whom only 1 causative pathogen is isolated, the overall microbiological 
response assessment will be based on the microbiological response assessment for that 
pathogen. 
 
For patients from whom more than 1 baseline pathogen is isolated, the overall 
microbiological response assessment will be “favorable” only if the microbiological response 
assessment for each of the baseline pathogens isolated is “favorable”. 
 
8.1.8.3. Microbiological Response 
Per-pathogen microbiological response and per-patient microbiological response will be 
categorized according to the definitions in Table 8. 
 
 
Table 8. 
Microbiological Response Categories at Day 1 (Baseline), EOT, TOC, 
LFU, and Early Termination/Discontinuation Visits 
Microbiological 
response 
Definition 
 
Eradication 
Absence of causative pathogen from appropriately obtained specimens at the 
site of infection. 
Presumed eradication 
Repeat cultures were not performed/clinically indicated in a patient who had a 
clinical response of cure. 
Colonization 
Obvious symptoms and signs of the infection have resolved in response to the 
treatment, but the initial causative bacteria are detected at the same site. 
Persistence 
Causative organism still present at or beyond the EOT visit from a culture of 
intra-abdominal abscess, peritonitis, or surgical wound infection. 
Persistence with 
increasing MIC 
Continued presence of the causative organism in a culture of the intra- 
abdominal abscess, peritonitis, or surgical wound infection obtained during or 
upon completion of treatment with IV study intervention, and the pathogen 
that was susceptible to IV study intervention pre-treatment displays a ≥4-fold 
higher MIC to IV study intervention after treatment with IV study 
intervention. 
Presumed persistence 
Patient was previously assessed as a clinical failure and repeat cultures were 
not performed/clinically indicated. 


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Table 8. 
Microbiological Response Categories at Day 1 (Baseline), EOT, TOC, 
LFU, and Early Termination/Discontinuation Visits 
Microbiological 
response 
Indeterminate 
microbiological response 
Definition 
 
Study data are not available for evaluation of efficacy, for any reason 
including: 
• 
Patient lost to follow-up such that a determination of microbiological 
response cannot be made 
• 
Death where cIAI is clearly noncontributory 
• 
Circumstances that preclude classification as eradication, presumed 
eradication, colonization, persistence, persistence with increasing MIC, 
and presumed persistence 
• 
Patient with no pathogen isolated from a cIAI culture obtained at 
Baseline or for whom a culture was not obtained. 
 
 
 
Microbiological response for blood pathogens should be classified similarly to the 
classifications for baseline pathogens noted in Table 8. 
 
8.1.8.4. MIC Among Pathogens 
The clinical cure and per-pathogen microbiological response at the EOT, TOC, and LFU 
visits will be evaluated for MIC categories.  The MIC categories to be used are: <0.008, 
0.015, 0.03, 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, and >256 μg/mL. 
 
8.1.8.5. Emergent Infections 
Pathogens first appearing after Baseline in patients with a baseline pathogen are categorized 
in Table 9 and will be summarized separately. 
 
Table 9. 
Emergent Infections 
Emergent 
Infection 
 
 
Definition 
 
Superinfection 
Emergence of new pathogen during treatment with IV study intervention, either at 
the site of infection or at a distant site with emergence or worsening of signs and 
symptoms of infection. 
New infection 
Emergence of new pathogen after completion of treatment with IV study 
intervention, either at the site of infection or at a distant site with emergence or 
  
worsening of signs and symptoms of infection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI 


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8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues. 
 
8.2.1. Medical and Surgical History, Medication History 
Medical history and surgical history will be collected at Screening. Complete medication 
history of all prescription or nonprescription drugs, and dietary and herbal supplements taken 
within 30 days prior to the planned first dose will be collected. 
 
8.2.2. Height and Weight 
Height and weight will be measured at Screening visit.  Recently measured height and weight 
results may be used if patient is not ambulatory at the time of Screening.  Body mass index 
will be calculated.  After the Screening visit, weight should be measured as clinically 
indicated. 
 
8.2.3. Pulse Rate, Blood Pressure, Respiratory Rate 
Pulse rate, blood pressure, and respiratory rate will be measured at Screening, Day 1 
(Baseline), daily during treatment with study intervention, and EOT, TOC, LFU, and Early 
Termination /Discontinuation visits (SoA). A semiautomatic blood pressure recording device 
should be used where available, with an appropriate cuff size. The patients will be required 
to rest in a supine position for at least 5 minutes prior to pulse rate and blood pressure 
measurements. Respiratory rate will be collected in breaths per minute. 
 
8.2.4. Heart Rate 
Heart rate will be measured at Screening.  Heart rate may be evaluated either in the 12-lead 
ECG or in the monitor ECG. 
 
ECG values of potential clinical concern are listed in Appendix 9. 
 
8.2.5. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.  All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 


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All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
 
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury. 
 
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during 
the active treatment period (or when potential pregnancy is otherwise suspected) and at the 
end of the study. Pregnancy tests may also be repeated if requested by IRBs/ ECs or if 
required by local regulations.  If a urine test cannot be confirmed as negative (e.g., an 
ambiguous result), a serum pregnancy test is required. 
 
At Screening visit, serum β-hCG must be performed as part of screening/eligibility.  If the  
results of β-hCG are not available prior to dosing of study intervention, a patient may begin 
therapy on the basis of a negative urine β-hCG, but a serum test must still be obtained. The 
participant must be excluded if the serum pregnancy result is positive. 
 
8.3. Adverse Events and Serious Adverse Events 
The definitions of an AE and an SAE can be found in Appendix 3. 
 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative). 
 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
 
Each participant will be questioned about the occurrence of AEs in a nonleading manner. 
 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 


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8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days after the last administration of the study intervention. 
 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment. 
 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
 
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
 
Investigators are not obligated to actively seek AEs or SAEs after the participant has  
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form. 
 
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 


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8.3.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 
8.3.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
 
Further information on follow-up procedures is given in Appendix 3. 
 
8.3.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure 
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 


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8.3.5.1. Exposure During Pregnancy 
An EDP occurs if: 
 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
 
• A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 
 
• A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy: 
 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion or skin contact. 
 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion or skin contact then exposes his female partner prior to 
or around the time of conception. 
 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
 
• If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until study end. 
 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 


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Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
 
• Spontaneous abortion including miscarriage and missed abortion; 
 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
 
8.3.5.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact. 
 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF.  However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file. 
 
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 


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authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
 
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care. 
 
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form. Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file. 
 
8.3.6. Cardiovascular and Death Events 
Cardiovascular and death events will be reported according to AE reporting procedures. 
 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
 
8.3.8. Adverse Events of Special Interest 
Not applicable. 
 
8.3.8.1. Lack of Efficacy 
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE. 
 
8.3.9. Medical Device Deficiencies 
Not applicable. 
 
8.3.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
 
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 


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Safety Event 
Recorded on the CRF 
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
 
Medication errors include: 
 
• Medication errors involving participant exposure to the study intervention; 
 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the  
CRF. 
 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
 
8.4. Treatment of Overdose 
For this study, any dose of PF-06947386 and metronidazole greater than daily dose of study 
intervention defined in Section 6.1.1 within a 24-hour time period will be considered an 
overdose. 
 
Pfizer does not recommend specific treatment for an overdose.  To note, both ceftazidime 
and avibactam can be partially removed by hemodialysis. 
 
In the event of an overdose, the investigator should: 
 
1. Contact the medical monitor within 24 hours. 
 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06947386 and 
metronidazole (whichever is longer). 
 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 


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4. Overdose is reportable to Safety only when associated with an SAE. 
 
5. Obtain a blood sample for PK analysis within 12 hours from the date of the last dose 
of study intervention if requested by the medical monitor (determined on a 
case-by-case basis). 
 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
 
8.5. Pharmacokinetics 
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL plasma, will be 
collected for measurement of plasma concentrations of ceftazidime and avibactam as 
specified in the SoA.  Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual or by the sponsor. The actual date and time (24-hour 
clock time) of each sample and initiation/end of each infusion will be recorded. 
 
All efforts will be made to obtain 3 samples, 1 from each of the 3 time windows, for each 
participant for PK sample collection as specified in the SoA. Missed collection of samples or 
collection of samples outside of the allowed window will not be captured as protocol 
deviations, as long as the exact time of the collection is noted in the source documents and 
the CRF.  Blood for PK must NOT be drawn from the same arm used for IV drug 
administration. 
 
 
 
Genetic analyses will not be performed on these plasma samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained. 
 
Samples collected for measurement of plasma concentrations of ceftazidime and avibactam 
will be analyzed using a validated analytical method in compliance with applicable SOPs. 
 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment.  The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
Samples will be used to evaluate the PK of ceftazidime and avibactam. CCI 


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8.6. Pharmacodynamics 
Ceftazidime is a β-lactam antimicrobial agent, and it is expected that the time that the plasma 
concentration of ceftazidime exceeds the MIC (%T >MIC) of the infecting organism will be 
correlated with efficacy.  Thus, the %T >MIC, will be calculated from an appropriate PK 
model after the ceftazidime plasma concentrations are collected and analyzed. The collection 
of ceftazidime plasma concentrations is described in Section 8.5, and the detailed method to 
calculate %T >MIC will be included in the separate PK/PD analysis plan. 
 
It is assumed that the percentage above a threshold concentration of avibactam is associated 
with avibactam’s effect on inhibiting β-lactamase.  An appropriate PK/PD index for 
avibactam, such as the percentage of time above a threshold concentration (%T > the critical 
threshold concentration of avibactam), will be calculated with a PK model after avibactam 
plasma concentrations are collected and analyzed. The collection of avibactam plasma 
concentration is described in Section 8.5, and the detailed method to calculate avibactam 
exposure measures will be included in the separate PK/PD analysis plan. 
 
8.7. Genetics 
8.7.1. Specified Genetics 
Genetics (specified analyses) are not evaluated in this study. 
 
8.7.2. Banked Biospecimens for Genetics 
Banked biospecimens for Genetics are not collected in this study. 
 
8.8. Biomarkers 
Biomarkers are not evaluated in this study. 
 
8.8.1. Banked Biospecimens for Biomarkers 
Banked biospecimens for Biomarkers are not collected in this study. 
 
8.9. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
 
8.10. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 


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9.1. Estimands and Statistical Hypotheses 
In this study, no formal hypothesis testing will be conducted. 
 
As an efficacy evaluation criterion, it will be confirmed that the point estimate of proportion 
of patients with clinical cure at TOC visit in the CE analysis set (the primary analysis) is 
≥78%. 
 
9.1.1. Estimands 
Estimand 1: This estimand will be the primary estimand of the primary endpoint and will be 
the estimated average treatment effect on the clinical response at TOC visit for 
PF-06947386 + metronidazole for all patients with cIAI. A composite estimand 
strategy will be used. Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as indeterminate clinical response. 
Intercurrent events of death related to intra-abdominal infection, or additional 
antibiotics for ongoing symptoms of intra-abdominal infection etc. will be 
regarded as a failure clinical response. For details, see Table 7.  All data after 
intercurrent events of receiving insufficient amount of study drug or any 
protocol deviations that affect assessment of efficacy will not be considered. 
All data after other intercurrent events that affect the clinical assessment will 
not be considered.  Proportion of participants with clinical cure will be 
calculated. 
 
Estimand 2: This estimand will be the supportive estimand of the primary endpoint and will 
be the estimated average treatment effect on the clinical response at TOC visit 
for PF-06947386 + metronidazole for all patients with cIAI. A composite 
estimand strategy will be used.  Intercurrent events of death where cIAI is 
clearly noncontributory etc. will be regarded as indeterminate clinical response. 
Intercurrent events of death related to intra-abdominal infection, or additional 
antibiotics for ongoing symptoms of intra-abdominal infection etc. will be 
regarded as a failure clinical response. For details, see Table 7. Proportion of 
participants with clinical cure will be calculated. 
 
Estimand 3: This estimand will be the supportive estimand of the primary endpoint and will 
be the estimated average treatment effect on the clinical response at TOC visit 
for PF-06947386 + metronidazole for all patients with cIAI who have ≥1 
baseline pathogens.  A composite estimand strategy will be used.  Intercurrent 
events of death where cIAI is clearly noncontributory etc. will be regarded as 
indeterminate clinical response.  Intercurrent events of death related to intra- 
abdominal infection, or additional antibiotics for ongoing symptoms of intra- 
abdominal infection etc. will be regarded as a failure clinical response.  For 
details, see Table 7.  Proportion of participants with clinical cure will be 
calculated. 
 
Estimand 4: This estimand will be the supportive estimand of the primary endpoint and will 
be the estimated average treatment effect on the clinical response at TOC visit 


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for PF-06947386 + metronidazole for all patients with cIAI who have at least 1 
Gram-negative aerobic pathogen in the initial/prestudy culture regardless of 
susceptibility.  A composite estimand strategy will be used. Intercurrent events 
of death where cIAI is clearly noncontributory etc. will be regarded as 
indeterminate clinical response.  Intercurrent events of death related to intra- 
abdominal infection, or additional antibiotics for ongoing symptoms of intra- 
abdominal infection etc. will be regarded as a failure clinical response.  For 
details, see Table 7.  All data after intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations that affect assessment of 
efficacy will not be considered.  All data after other intercurrent events that 
affect the clinical assessment will not be considered. Proportion of participants 
with clinical cure will be calculated. 
 
Estimand 5: This estimand will be the supportive estimand of the primary endpoint and will 
be the estimated average treatment effect on the clinical response at TOC visit 
for PF-06947386 + metronidazole for all patients with cIAI who have at least 1 
Gram-negative aerobic pathogen in the initial/prestudy culture that is 
susceptible.  A composite estimand strategy will be used.  Intercurrent events of 
death where cIAI is clearly noncontributory etc. will be regarded as 
indeterminate clinical response.  Intercurrent events of death related to intra- 
abdominal infection, or additional antibiotics for ongoing symptoms of intra- 
abdominal infection etc. will be regarded as a failure clinical response. For 
details, see Table 7.  All data after intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations that affect assessment of 
efficacy will not be considered.  All data after other intercurrent events that 
affect the clinical assessment will not be considered.  Proportion of participants 
with clinical cure will be calculated. 
 
Estimands 6-10: These estimands will be the same estimands as Estimands 1-5 but these 
estimands will be the estimands of the secondary endpoints and will be the 
estimated average treatment effects on the clinical response at EOT, and LFU 
visits. 
 
Estimand 11: This estimand will be the estimand of the secondary endpoints and will be the 
estimated average treatment effects on the per-patient microbiological response 
at EOT, TOC, and LFU visits for PF-06947386 + metronidazole for all patients 
with cIAI who have ≥1 baseline pathogens. A composite estimand strategy will 
be used.  Intercurrent events of lost to follow-up and death where cIAI is clearly 
noncontributory etc. will be regarded as indeterminate microbiological 
response. For details, see Table 8.  Proportion of participants with favorable 
microbiological response will be calculated. 
 
Estimand 12: This estimand will be the estimand of the secondary endpoints and will be the 
estimated average treatment effects on the per-patient microbiological response 
at EOT, TOC, and LFU visits for PF-06947386 + metronidazole for all patients 


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with cIAI who have at least 1 Gram-negative aerobic pathogen in the 
initial/prestudy culture regardless of susceptibility.  A composite estimand 
strategy will be used.  Intercurrent events of lost to follow-up and death where 
cIAI is clearly noncontributory etc. will be regarded as indeterminate 
microbiological response. For details, see Table 8. All data after intercurrent 
events of receiving insufficient amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be considered. All data after other 
intercurrent events that affect the microbiological assessment will not be 
considered. Proportion of participants with favorable microbiological response 
will be calculated. 
 
Estimand 13: This estimand will be the estimand of the secondary endpoints and will be the 
estimated average treatment effects on the per-patient microbiological response 
at EOT, TOC, and LFU visits for PF-06947386 + metronidazole for all patients 
with cIAI who have at least 1 Gram-negative aerobic pathogen in the 
initial/prestudy culture that is susceptible.  A composite estimand strategy will 
be used.  Intercurrent events of lost to follow-up and death where cIAI is clearly 
noncontributory etc. will be regarded as indeterminate microbiological 
response. For details, see Table 8.  All data after intercurrent events of 
receiving insufficient amount of study drug or any protocol deviations that 
affect assessment of efficacy will not be considered. All data after other 
intercurrent events that affect the microbiological assessment will not be 
considered. Proportion of participants with favorable microbiological response 
will be calculated. 
 
Estimands 14-16: These estimands will be the same estimands as Estimands 11-13 but these 
estimands will be the estimands of the secondary endpoints and will be the 
estimated average treatment effects on the per-pathogen microbiological 
response at EOT, TOC, and LFU visits. 
 
9.2. Sample Size Determination 
In the previous global Phase 3 studies for cIAI (RECLAIM and RECLAIM3), the point 
estimate of proportion of patients with clinical cure at TOC visit in the CE analysis set was 
approximately 90% in both ceftazidime-avibactam + metronidazole and active comparator 
(meropenem) treatment groups. 
 
The threshold value will be set to 78% which is calculated by subtracting the non-inferiority 
margin of both studies 12.5% from the proportion of patients with clinical cure. When the 
point estimate of proportion of patients with clinical cure at TOC visit in the CE analysis set 
becomes greater than or equal to the threshold value, the efficacy is considered to be shown 
in this study.  The expected value of proportion of patients with clinical cure is greater than 
or equal to 78% in this study, it is considered that this drug would contribute as one of the 
antibacterial drugs. 


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When 60 patients are treated, the CE analysis set at TOC visit will have approximately 50 
evaluable patients based on the results of the previous studies. Under the assumption of 50 
patients in the CE analysis set at TOC visit and 90% of true proportion of patients with 
clinical cure, the probability of meeting the criterion stated above is approximately 99%. 
 
In addition, causal pathogens are relatively easy to detect because patients with cIAI are often 
treated with drainage. When 60 patients are treated, it is considered that a considerable 
number of strains can be collected for species in which clinical isolation is relatively rare. 
 
Although it is uncertain whether the definition of the sepsis patients subset (Section 9.3) is 
met at the timing of study entry, 3 to 5 enrolled participants are anticipated to meet the 
definition of the sepsis patients subset. 
 
9.3. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Analysis Set 
Description 
MITT analysis set 
The MITT analysis set includes all enrolled participants 
who: 
1. Meet the disease definition of cIAI (see Section 5.1, 
inclusion criterion 3). 
2. Receive any amount of study drug. 
mMITT analysis set 
The mMITT analysis set includes all enrolled participants 
who: 
1. Meet the disease definition of cIAI (see Section 5.1, 
inclusion criterion 3). 
2. Receive any amount of study drug. 
3. Have at least 1 etiologic pathogen identified at study 
entry (regardless of isolate susceptibilities).  Participants 
with a bacterial species typically not expected to respond 
to the study drug (eg, Acinetobacter spp., 
Stenotrophomonas spp.) are excluded (ie, if the study drug 
is considered inadequate to treat the pathogen in most 
clinical circumstances). 
CE analysis set 
Participants are included who meet the following criteria: 
1. Have an appropriate diagnosis of cIAI (see Section 5.1, 
inclusion criterion 3). As an exception, participants with a 
bacterial species typically not expected to respond to the 


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study drug (eg, Acinetobacter spp., Stenotrophomonas 
spp.) are excluded. 
 
2. EITHER 
 
(a) Receive therapy for ≥48 hours, with ≥80% of the 
scheduled drug administered over the number of days 
administered 
 
OR 
 
(b) Receive therapy <48 hours before discontinuing 
treatment due to an AE. 
 
3. Is evaluated with a clinical response of cure or failure. 
Participants with a clinical response of failure at a previous 
visit are not excluded from subsequent timepoints for visits 
that are out of window. 
 
4. Have no important protocol deviations that will affect 
assessment of efficacy at the relevant timepoint. 
 
5. Do not receive any prior antibiotics other than protocol- 
allowed antibiotics with specified duration in Section 5.2, 
exclusion criterion 22.  Determination of duration in some 
circumstances is done manually. 
 
6. Do not receive concomitant antibiotic therapy with 
potential activity against any of the baseline aerobic 
pathogens between the time of first IV infusion and the 
time of the relevant timepoint culture, respectively, except 
for protocol-allowed antibiotics for the coverage of 
Enterococcus spp. and MRSA.  This does not include 
participants who have failed and require additional 
antibiotic therapy. Topical antibacterials and antifungals 
are permitted except that they are not being applied to the 
surgical site.  (Note that if topical antibacterials and 
antifungals are applied to the surgical site this does not 
lead to exclusion from the CE analysis set). Potential 
activity against any of the baseline aerobic pathogens is 
determined by manual review by comparing the 
susceptibility profile of the baseline aerobic pathogens to 
the antibiotic received.  When no baseline pathogens are 
identified, a conservative approach is taken and the patient 
is excluded from the CE analysis set. 


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7. Consider to have adequate initial infection source 
control. 
ME analysis set 
Participants are included who meet the following criteria: 
1. Include in a subset of CE participants. 
2. Have at least 1 Gram-negative aerobic pathogen in the 
initial/prestudy culture that is susceptible. 
eME analysis set 
Participants are included who meet the following criteria: 
1. Include in a subset of CE participants. 
2. Have at least 1 Gram-negative aerobic pathogen in the 
initial/prestudy culture regardless of susceptibility. 
Sepsis patients subset 
1. Include in a subset of eME participants. 
2. Satisfy both clinical and microbiological criteria 
Clinical: Total score ≥ 2 in SOFA for ICU patients, 2 items 
or more in qSOFA for non-ICU patients (Section 10.7) at 
Baseline 
Microbiological: The most relevant pathogens (ie, aerobic 
Gram-negative bacteria -either Enterobacterales or aerobic 
Gram-negative pathogens other than Enterobacterales) 
isolated from the blood at Baseline regardless of 
susceptibility. 
Sepsis evaluable patients 
subset 
1. Include in a subset of eME participants. 
2. Satisfy both clinical and microbiological criteria 
Clinical: Satisfy at least one following criteria at Baseline. 
1) body temperature ≥38°C or <36°C, 2) WBC 
>12000 cells/mm3 or <4000 cells/mm3, or immature 
neutrophil >10%, 3) heart rate >90 bpm, 4) systolic blood 
pressure <90 mmHg, 5) CRP ≥20 mg/dL 
Microbiological: The most relevant pathogens (ie, aerobic 
Gram-negative bacteria -either Enterobacterales or aerobic 
Gram-negative pathogens other than Enterobacterales) 


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isolated from the blood at Baseline regardless of 
susceptibility. 
Safety analysis set 
The Safety analysis set includes all participants who 
receive any amount of IV study intervention. 
PK analysis set 
The PK analysis set includes all participants who have at 
least 1 plasma concentration data value available for either 
CAZ or AVI. 
 
9.4. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
 
9.4.1. General Considerations 
Descriptive summaries will be provided where appropriate for each of the primary, 
secondary, andCCI 
.  In general, summaries will be presented for 
the MITT and mMITT analysis sets, and the ME, eME, and CE analysis sets at the  
appropriate visit. 
 
Continuous and quantitative variable summaries will include as appropriate the number of 
patients/pathogens, mean, SD, median, and ranges (minimum and maximum).  Plasma 
concentrations will be summarized by the number of participants, mean, CV, median, and 
ranges (minimum and maximum). 
 
Categorical and qualitative variable summaries will include as appropriate the frequency and 
percent of patients/pathogens that are in each category.  In general, the denominator for each 
percent calculation is based upon the total number of patients/pathogens in the analysis 
population. 
 
9.4.2. Primary Endpoint(s) 
The primary endpoint for the study is clinical response at the TOC visit. 
 
The proportion and the 95% CI will be calculated. The primary analysis will be performed 
on the CE analysis set.  Supplemental analyses will be performed on the MITT, mMITT, ME, 
and eME analysis sets. 
 
9.4.3. Secondary Endpoint(s) 
The secondary endpoints for the study are as follows. 
 
• Clinical response at EOT and LFU visits 


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• Per-patient microbiological response at EOT, TOC, and LFU visits 
 
• Per-pathogen microbiological response at EOT, TOC, and LFU visits 
 
• Per-pathogen microbiological response at EOT, TOC, and LFU visits by MIC 
categories 
 
• AEs and SAEs, all cause mortality, reasons for discontinuations of IV study 
intervention and study, vital sign measurements, and potentially clinically significant 
changes in laboratory parameters during the entire study 
 
• Ceftazidime and avibactam plasma concentrations by nominal sampling window 
 
• For patients with sepsis, selected efficacy and safety endpoints from endpoints for the 
overall population 
 
For clinical response at each visit, the proportion and the 95% CI will be calculated. 
Analyses will be performed on the CE, MITT, mMITT, ME, and eME analysis sets. 
 
For a favorable per-patient or per-pathogen microbiological response at each visit, the 
proportion and the 95% CI (per-patient only, when N is enough to calculate) will be 
calculated. Patients with “Indeterminate” are not included in the denominator. Analyses will 
be performed on the mMITT, ME, and eME analysis sets. 
 
AEs and SAEs (including local tolerability), discontinuations, and changes in vital signs, and 
clinical laboratory parameters will be descriptively summarized, and will be presented in 
tabular and/or graphical format.  No imputation will be made for missing safety data. 
 
All safety analyses will be performed on the safety population. 
 
Ceftazidime and avibactam plasma concentrations by nominal sampling window will be 
summarized through appropriate data tabulations, descriptive statistics, and graphical 
presentation.  An appropriate population PK model will be used for the purpose of estimating 
PK parameters and the time above MIC. Additional details of the methodology will be 
captured in a separate modeling plan and the results will also be reported separately. 
 
For patients with sepsis, safety and efficacy will be investigated. Analyses will be performed 
in the sepsis patients subset and the sepsis evaluable patients subset. 
 
 
 
 
 
 
 
 
 
 
CCI 


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C 
C 
I 
 
 
 
 
 
 
 
 
 
 
9.5. Interim Analyses 
No formal interim analysis will be conducted for this study.  As this is an open-label 
study, the sponsor may conduct reviews of the data during the course of the study for the 
purpose of safety assessment. 
 
9.6. Data Monitoring Committee or Other Independent Oversight Committee 
This study will use an adjudication committee. The adjudication committee is independent 
of the study team and includes only external members. The adjudication committee will 
consist of 2 or more external infectious disease specialists especially intra-abdominal 
infection. The adjudication committee charter describes the role of the adjudication 
committee in more detail. The adjudication committee will review investigators’ 
assessments, including clinical response, based on the collected data for consistency of 
evaluation in the study. If a discrepancy exists between the adjudication committee and 
investigators, the assessment by the adjudication committee will prevail.  For details, see 
Section 8.1.6.1 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
• Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and CIOMS International Ethical Guidelines; 
 
• Applicable ICH GCP guidelines; 
 
• Applicable laws and regulations, including applicable privacy laws. 
 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor and submitted to an IRB/EC 
by the investigator and reviewed and approved by the IRB/EC before the study is initiated. 
 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
 
The investigator will be responsible for the following: 
 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of. 


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


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10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law. 
 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred.  All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification.  In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
 
10.1.5. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
 
www.clinicaltrials.gov 
 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
 
EudraCT 
 
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements. 


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


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


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


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10.1.9. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results. 
 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
 
10.1.10. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand (SToD) 
system. 
 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention 
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to 
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or 
problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 


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intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study. The contact number is not intended for use by the participant directly, 
and if a participant calls that number, he or she will be directed back to the investigator site. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues. 
Results will be reported by the local laboratory. 
Table 10. Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Dipstick 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Eosinophils (Abs, %) 
Lymphocytes (Abs, %) 
Monocytes (Abs, %) 
Neutrophils (Abs, %) 
Neutrophils, immature (Abs, %) 
Basophils (Abs, %) 
BUN 
Creatinine 
Glucose (non-fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
AST 
ALT 
GGT 
Bilirubin (total and 
direct) 
Alkaline phosphatase 
Albumin 
Total protein 
CRP 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
FSHa 
β-hCGb 
a. For confirmation of postmenopausal status only. 
b. At Screening, serum β-hCG must be performed as part of screening/eligibility.  If the results of β-hCG are 
not available prior to dosing of study intervention, a patient may begin therapy on the basis of a negative 
urine β-hCG, but a serum test must still be obtained. At time points other than Screening, pregnancy tests 
  
may be urine or serum tests, but must have a sensitivity of at least 25 mIU/mL.  
 
Investigators must document their review of each laboratory safety report. 


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


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


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


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


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


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


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


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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 7 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
 
OR 
 
• Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
 
10.4.2. Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
 
• Is not a WOCBP (see definitions below in Section 10.4.3). 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described below 
during the intervention period (for a minimum of 28 days after the last dose of 
study intervention).  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 


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Women in the following categories are not considered WOCBP: 
 
1. Premenopausal female with 1 of the following: 
 
• Documented hysterectomy; 
 
• Documented bilateral salpingectomy; 
 
• Documented bilateral oophorectomy. 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
 
2. Postmenopausal female: 
 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  In addition, a 
 
• high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 
 
• Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
 
1. Intrauterine device. 
 
2. Intrauterine hormone-releasing system. 
 
3. Bilateral tubal occlusion. 
 
4. Vasectomized partner: 


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• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  The spermatogenesis cycle is 
approximately 90 days. 
 
5. Sexual abstinence: 
 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
 
6. Male or female* condom with or without spermicide*. 
 
7. Cervical cap*, diaphragm*, or sponge with spermicide*. 
 
8. A combination of male condom with either cervical cap*, diaphragm*, or sponge 
with spermicide* (double-barrier methods). 
 
* Not approved in Japan 


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.” 
 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks.  The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample).  In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded. 
 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
 
• Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
 
• For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller). 
 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller). 


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected. 
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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


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Table 11. APACHE II Score Form (Continued) 
Glasgow Coma Scale 
(Eyes, Motor, and 
Verbal) 
B 
C 
APACHE II Score 
 
Age points 
Chronic Health points 
Eyes open 
4 - spontaneously 
3 - to speech 
2 - to pain 
1 - no response 
 
Motor response 
6 - to verbal command 
5 - localizes to pain 
4 - withdraws to pain 
3 - flexion to pain 
2 - extension to pain 
1 - no response 
 
Verbal 
5 - oriented 
4 - confused 
3 - inappropriate words 
2 - incomprehensible 
sounds 
1 - no response 
≤44 
45-54 
55-64 
65-74 
≥75 
0    If any of the 5 chronic health evaluation 
2 categories is answered yes give +5 points for non- 
3 operative or emergency postoperative patient and 
5    give +2 points if elective postoperative patient 
6 
 
Liver 
Cirrhosis with portal 
  
hypertension. or encephalopathy 
Cardiovascular    Class IV angina or at rest or 
  
with minimal self care activities 
Pulmonary 
Chronic hypoxemia or 
hypercapnia or polycythemia of 
pulmonary hypertension >40 
mmHg 
Kidney 
Chronic peritoneal or 
  
hemodialysis  
Immune 
Immune compromised host 
APACHE II Score 
= A: APS points 
+ B: Age points 
+ C: Chronic Health points 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference: Knaus et al., 19857 


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10.7. Appendix 7: SOFA Score 
Table 12. SOFA Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
Platelets (103/µL) 
≥150 
<150 
<100 
<50 
<20 
SOFA Score 
Sum of the 6 individual points= 
 
Reference: Egi et al., 20208 
 
 
Table 13. qSOFA Criteria 
 
Altered mentation (GCS <15) 
Respiratory rate ≥22 breaths/min 
Systolic blood pressure ≤100 mmHg 
Reference: Egi et al., 20208 
 
 
Criteria 
Score 
0 
1 
2 
3 
4 
Nervous system 
Glasgow coma scale 
15 
13-14 
10-12 
6-9 
<6 
Respiratory system 
PaO2/FiO2 (mmHg) 
≥400 
<400 
<300 
<200 and 
<100 and 
mechanically 
mechanically 
ventilated 
ventilated 
Cardiovascular system 
MAP ≥70 
MAP <70 
dopamine 
dopamine 
dopamine 
<5 µg/kg/min 
or 
5-15 µg/kg/min 
or 
>15 µg/kg/min 
or 
dobutamine 
norepinephrine 
norepinephrine 
(any dose) 
≤0.1 µg/kg/min 
>0.1 µg/kg/min 
or 
or 
epinephrine 
epinephrine 
≤0.1 µg/kg/min 
>0.1 µg/kg/min 
Liver 
bilirubin (mg/dL) 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
≥12.0 
Kidneys 
creatinine (mg/dL) 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
≥5.0 
urine output (mL/day) 
<500 
<200 


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10.8. Appendix 8: Calculation of Estimated CrCL 
Estimated CrCL will be calculated using the following Cockcroft-Gault formula6. The 
weight obtained at Screening should be used to qualify for entry into the study.  In order to 
determine the need to adjust the dose and/or dosing interval of IV study intervention to be 
administered, the patient’s estimated CrCL must be calculated using the most recent serum 
creatinine value that was obtained at the local laboratory, the patient’s most recent actual (not 
ideal) body weight, and the Cockcroft-Gault formula. 
 
Cockcroft-Gault formula: 
 
Estimated CrCL is calculated by Cockcroft-Gault as follows: 
 
1. For serum creatinine in mg/dL: 
estimated CrCL = [(140 – age) × weight in kilograms] / 
[72 × serum creatinine in mg/dL] 
[× 0.85 if female] 
 
2. 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 


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10.9. Appendix 9: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 msec. 
• New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline. 
• New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 msec. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset left bundle branch block (QRS >120 msec). 
• New-onset right bundle branch block (QRS >120 msec). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 
• In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer; 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 
• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 


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monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as 
torsades de pointes)). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>30 seconds’ duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs. 


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10.10. Appendix 10: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
A-aDO2 
alveolar-arterial oxygen tension difference 
ABG 
arterial blood gas 
Abs 
absolute 
AE 
adverse event 
ALT 
alanine aminotransferase 
AMR 
antimicrobial resistance 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
APS 
acute physiology score 
AST 
aspartate aminotransferase 
AUCss 
area under the plasma concentration curve at steady-state 
AUCss,24 
total daily area under the plasma concentration-time curve at 
steady-state 
AVI 
avibactam 
β-hCG 
beta-human chorionic gonadotropin 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CAZ 
ceftazidime 
CD4 
cluster of differentiation 4 
CE 
clinically evaluable 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
cIAI 
complicated intra-abdominal infection 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CLSI 
Clinical and Laboratory Standards Institute 
CONSORT 
Consolidated Standards of Reporting Trials 
CrCL 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSR 
clinical study report 
Css,max 
maximum plasma concentration at steady-state 
CT 
clinical trial 
CTD 
Common Technical Document 
cUTI 
complicated urinary tract infection 
CV 
coefficient of variation 
DILI 
drug-induced liver injury 
EC 
ethics committee 
ECG 
electrocardiogram 


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Abbreviation 
Term 
eCRF 
electronic case report form 
EDP 
exposure during pregnancy 
EMA 
European Medicines Agency 
eME 
extended-microbiologically evaluable 
EOT 
End of Treatment 
ESBL 
extended-spectrum β-lactamase 
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-glutamyltransferase 
HAP 
hospital-acquired pneumonia 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IMP 
investigational medicinal product 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
investigational product 
IPAL 
Investigational Product Accountability Log 
IP manual 
investigational product manual 
IRB 
Institutional Review Board 
IV 
intravenous 
KPC 
Klebsiella pneumoniae carbapenemase-type β-lactamase 
LFT 
liver function test 
LFU 
late follow-up 
MAP 
mean arterial pressure 
ME 
microbiologically evaluable 
MIC 
minimum inhibitory concentration 
MIC90 
minimum concentration to inhibit 90% of strains 
MITT 
modified intent-to-treat 
mMITT 
microbiological modified intent-to-treat 
MRSA 
methicillin-resistant Staphylococcus aureus 
MTZ 
metronidazole 
N 
number of patients in a group 


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Abbreviation 
Term 
N/A 
not applicable 
NIMP 
noninvestigational medicinal product 
OAT 
organic anion transporter 
PACL 
Protocol Administrative Change Letter 
PAH 
p aminohippuric acid 
PaO2 
partial pressure of oxygen 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
prothrombin time 
PTA 
probability of target attainment 
q8h 
every 8 hours 
qSOFA 
quick Sequential Organ Failure Assessment 
qual 
qualitative 
RBC 
red blood cell 
ROW 
rest of world 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 
SOFA 
Sequential Organ Failure Assessment 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SToD 
study team on demand 
SUSAR 
suspected unexpected serious adverse reaction 
TBili 
total bilirubin 
TOC 
test of cure 
ULN 
upper limit of normal 
US 
United States 
VAP 
ventilator associated pneumonia 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 


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11. REFERENCES 
1. 
Avycaz. (ceftazidime-avibactam) [United States Package Insert]. Irvine, CA, USA: 
Allergan Inc; 2020. 
 
2. 
Zavicefta. (ceftazidime-avibactam) [European Summary of Product Characteristics]. 
Ringaskiddy, County Cork, Ireland: Pfizer Ireland Pharmaceuticals; 2020. 
 
3. 
Mazuski JE, Sawyer RG, Nathens AB, et al. The surgical infection society guidelines on 
antimicrobial therapy for intra-abdominal infections: an executive summary. Surg Infect 
(Larchmt). 2002;3(3):161-73. 
 
4. 
Takesue Y. Antibiotic selection and duration of administration in patients with intra- 
abdominal infections according to the grade of severity: In comparison with the 
Surgical Infection Society revised guidelines of the management of intra-abdominal 
infection. Journal of Japan Society for Surgical Infection. 2019;16(2):80-6. 
 
5. 
Anaemetro®. Intravenous infusion 500mg. (metronidazole) [Japan Package Insert]. 
Shibuya, Tokyo: Pfizer Japan Inc; 2020. 
 
6. 
Cockcroft DW, Gault HM. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
 
7. 
Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13(10):818-29. 
 
8. 
Egi M, Ogura H, Yatabe T, et al. The Japanese clinical practice guidelines for 
management of sepsis and septic shock 2020 (J-SSCG 2020). Journal of the Japanese 
Society of Intensive Care Medicine. 2021;28(supp.):S1-411. 

SAP_001.pdf: 
Protocol C3591036 (PF-06947386) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
 
Protocol C3591036 
 
 
 
 
A PHASE 3, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO ASSESS 
THE EFFICACY AND SAFETY OF CEFTAZIDIME-AVIBACTAM (PF-06947386) 
PLUS METRONIDAZOLE IN JAPANESE ADULT PATIENTS WITH 
COMPLICATED INTRA-ABDOMINAL INFECTION REQUIRING 
HOSPITALIZATION 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
Version: 
3 
Date: 
21 Sep 2022 


Protocol C3591036 (PF-06947386) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 2 
 
 
TABLE OF CONTENTS 
LIST OF TABLES.......................................................................................................................... 4 
LIST OF FIGURES ........................................................................................................................ 4 
APPENDICES .................................................................................................................................................... 4 
1. VERSION HISTORY .............................................................................................................. 5 
2. INTRODUCTION ................................................................................................................... 8 
2.1. Study Objectives, Endpoints, and Estimands .............................................................. 8 
2.1.1. Primary Estimand(s) ...................................................................................... 12 
2.1.2. Secondary Estimand(s) .................................................................................. 13 
2.1.3. Additional Estimand(s) .................................................................................. 13 
2.2. Study Design ............................................................................................................... 13 
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................... 14 
3.1. Primary Endpoint(s) .................................................................................................... 14 
3.2. Secondary Endpoint(s) ................................................................................................ 14 
CCI  
 
3.4. Baseline Variables ....................................................................................................... 14 
3.5. Safety Endpoints.......................................................................................................... 15 
3.5.1. Adverse Events ............................................................................................... 15 
3.5.2. Laboratory Data .............................................................................................. 16 
3.5.3. Other Safety Endpoints .................................................................................. 16 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ................................................... 16 
5. GENERAL METHODOLOGY AND CONVENTIONS .................................................... 19 
5.1. Hypotheses and Decision Rules ................................................................................. 19 
5.2. General Methods ......................................................................................................... 20 
5.2.1. Analyses for Binary Endpoints...................................................................... 20 
5.2.2. Analyses for Continuous Endpoints.............................................................. 20 
5.2.3. Analyses for Categorical Endpoints.............................................................. 20 
5.2.4. Analyses for Time-to-Event Endpoints......................................................... 20 
5.3. Methods to Manage Missing Data .............................................................................. 20 
5.3.1. Concentrations Below the Limit of Quantification ...................................... 21 


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5.4. Definition of susceptibility criteria for Ceftazidime-avibactam ............................... 21 
5.5. Definition of Ceftazidime resistance .......................................................................... 22 
6. ANALYSES AND SUMMARIES.......................................................................................... 22 
6.1. Primary Endpoint(s) .................................................................................................... 22 
6.1.1. Clinical response at the TOC visit ................................................................ 22 
6.1.1.1. Main Analysis .............................................................................. 22 
6.1.1.2. Sensitivity/Supplementary Analyses ........................................... 22 
6.2. Secondary Endpoint(s) ................................................................................................ 23 
6.2.1. Clinical response at EOT and LFU visits ..................................................... 23 
6.2.2. Per-patient microbiological response at EOT, TOC, and LFU visits ......... 23 
6.2.3. Per-pathogen microbiological response at EOT, TOC, and LFU visits ..... 23 
6.2.4. Per-pathogen microbiological response at EOT, TOC, and LFU visits 
by MIC categories................................................................................................ 23 
6.2.5. Pharmacokinetic Analysis ............................................................................. 24 
CCI  
 
 
 
 
 
 
 
 
 
6.4. Subset Analyses ........................................................................................................... 25 
6.5. Baseline and Other Summaries and Analyses............................................................ 26 
6.5.1. Baseline Summaries ....................................................................................... 26 
6.5.2. Study Conduct and Participant Disposition .................................................. 27 
6.5.3. Study Treatment Exposure ............................................................................ 27 
6.5.4. Concomitant Medications and Nondrug Treatments ................................... 27 
6.6. Safety Summaries and Analyses................................................................................. 28 
6.6.1. Adverse Events ............................................................................................... 28 
6.6.2. Laboratory Data .............................................................................................. 28 
6.6.3. Vital Signs ...................................................................................................... 28 


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6.6.4. Electrocardiograms ........................................................................................ 28 
6.6.5. Physical Examination..................................................................................... 28 


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7. INTERIM ANALYSES......................................................................................................... 29 
7.1. Introduction.................................................................................................................. 29 
7.2. Interim Analyses and Summaries ............................................................................... 29 
8. REFERENCES ....................................................................................................................... 29 
9. APPENDICES ........................................................................................................................ 30 
 
 
LIST OF TABLES 
Table 1. 
Summary of Changes ................................................................................................. 5 
Table 2. 
Protocol-Required Safety Laboratory Assessments................................................ 16 
Table 3. 
Definition of susceptibility criteria for Ceftazidime-avibactam ............................ 22 
Table 4. 
Definition of susceptibility criteria for Ceftazidime .............................................. 22 
 
 
LIST OF FIGURES 
Figure 1. 
Study Outline ............................................................................................................ 13 
 
 
APPENDICES 
Appendix 1. Summary of Efficacy Analyses .............................................................................. 30 
Appendix 2. Data Derivation Details ........................................................................................... 32 
Appendix 2.1. Definitions of Clinical Response at the EOT, TOC, LFU, and Early 
Termination/Discontinuation Visits ........................................................................ 32 
Appendix 2.2. Microbiological Response Categories at Day 1 (Baseline), EOT, TOC, 
LFU, and Early Termination/Discontinuation Visits .............................................. 32 
Appendix 2.3. Emergent Infections ............................................................................................. 33 
Appendix 3. List of Abbreviations .............................................................................................. 33 


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1. VERSION HISTORY 
 
Table 1. 
Summary of Changes 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
 
1 
17 Jun 2021 
Original 
19 Apr 2021 
N/A 
N/A 
2 
11 Jul 2022 
Amendment 1 
21 July 2021 
Clarified the 
details 
Clarified the 
details 
 
 
Clarified the 
details 
 
 
 
 
 
 
CCI 
Section 3.4 
Added definition of baseline. 
Section 3.5.1 
Updated the definition of TEAE because 
time is not collected in the C3591036 
study. 
Section 4 
• 
Added clarification that CE, ME, and 
eME analysis sets are prepared for 
each EOT, TOC, and LFU. 
• 
Added clarification that Sepsis 
patients subset and Sepsis evaluable 
patients subset are based on eME at 
TOC analysis population. 
 
 
Updated the 
details 
 
 
Clarified the 
details 
 
Clarified the 
details 
 
Updated the 
analysis 
 
 
Updated the 
analysis 
 
Updated the 
analysis 
Section 5.3 
Added details of the method to manage 
missing data for clinical and 
microbiological response assessments. 
Section 5.4, Section 5.5 
Added definition of susceptibility criteria 
for CAZ-AVI and ceftazidime resistance. 
Section 6 
Clarified analysis populations used for 
each analysis. 
Section 6 
Deleted analyses regarding reason for 
clinical failure and indeterminate clinical 
response. 
Section 6 
Updated and clarified the details for 
listing. 
Section 6.2.5 
Updated and clarified the details for 
pharmacokinetic analysis. 
 
PFIZER CONFIDENTIAL 


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CCI 
 
 
 
 
 
 
 
 
 
 
 
 
Updated the 
analysis 
Updated the 
analysis 
 
 
Updated the 
analysis 
 
Clarified the 
details 
 
 
 
 
 
Updated the 
analysis 
 
Updated the 
analysis 
Section 6.4 
Added the analysis regarding forest plots. 
Section 6.5.1 
Added analyses regarding MIC for CAZ- 
AVI and other drugs for pathogens 
isolated in this study, if available. 
Section 6.5.2 
Deleted the analysis regarding the reasons 
for exclusion from analysis sets. 
Section 6.5.3 
• 
Deleted the analysis regarding IV 
infusions and individual component 
of study therapy (Total number of IV 
infusions). 
• 
Added definition of study treatment 
compliance. 
Section 6.6.1 
Added the analysis regarding adverse 
events of special interest. 
Section 6.6.3 
• 
Added the analysis regarding change 
from baseline. 
• 
Added the analysis for box and 
whisker plots. 
Overall 
Minor edits for the description 
maintenance. 
3 
21 Sep 2022 
Amendment 1 
21 July 2021 
Clarified the 
details 
 
 
Clarified the 
details 
Section 5.3.1 
Added description on handling of 
concentrations below the limit of 
qualification. 
Section 6 
Added clarification that assessment by the 
adjudication committee will prevail when 


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Clarified the 
details 
 
 
Updated the 
analysis 
 
 
Updated the 
analysis 
 
Updated the 
analysis 
 
 
CCI 
both investigator and the adjudication 
committee assessment are available. 
Section 6 
Clarified the definition of all patients 
(updated “all patients” to “all enrolled 
patients”). 
Section 6.2.2 
Deleted the analysis regarding emergent 
infections for eME at TOC and ME at 
TOC analysis sets. 
Section 6.2.3 
Added description on the listing for 
microbiological culture results. 
Section 6.2.5 
Updated parameters for the summay of 
the plasma concentration as same as 
Section 5.2.2. 
 
 
Updated the 
analysis 
 
 
Updated the 
analysis 
 
 
Updated the 
analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Updated the 
analysis 
Section 6.4 
Deleted the subset analysis regarding 
clinical cure rate at EOT, TOC, and LFU 
visits for MITT and mMITT analysis sets. 
Section 6.4 
Updated the subset analyses for sepsis 
patients subset and sepsis evaluable 
patients subset. 
Section 6.5.1 
Deleted the analysis regarding 
demographic characteristics, patient 
characteristics, and disease characteristics 
for mMITT and CE at TOC analysis sets. 
Updated the analysis for the prior 
systemic antibiotics use from “72 hours 
before enrollment” to “3 days before 
enrollment including the day of 
enrollment”, and added the analysis for 
the secondary diagnosis. 
Deleted the analyses regarding pathogens 
for ME at TOC analysis set. 
Section 6.5.4 


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Deleted the analysis regarding prior 
systemic antibiotic medications for CE at 
TOC analysis set. 
Added description on the analysis for 
prior medications other than prior 
systemic antibiotic medications. 
Updated the 
analysis 
Section 6.6.1 
Added description on the listings for the 
event terms for adverse events of special 
interest and medication errors. 
Updated the 
analysis 
Section 6.6.2 
Added description on the listings for Hy's 
Law values. 
Updated the 
analysis 
Section 6.6.3 
Deleted weight and BMI from box and 
whisker plots. 
Changed the analysis set for the listing 
from all patients to the safety population. 
Updated the 
analysis 
Section 6.6.4 
Added description on the listings for 
electrocardiogram data. 
 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3591036. 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, Endpoints, and Estimands 
 
Objectives 
Estimands 
Endpoints 
Primary: 
Primary: 
Primary: 
• 
To assess the efficacy of PF- 
06947386 plus metronidazole 
• 
Estimand 1: the primary estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI. 
A composite estimand strategy will be used. 
Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Appendix 2.1. All data after 
• 
Clinical response at the 
TOC visit 


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Objectives 
Estimands 
Endpoints 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 
considered. All data after other intercurrent 
events that affect the clinical assessment will not 
be considered. Proportion of participants with 
clinical cure will be calculated. 
• 
Estimand 2: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI. 
A composite estimand strategy will be used. 
Intercurrent events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Appendix 2.1. Proportion of 
participants with clinical cure will be calculated. 
• 
Estimand 3: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have ≥1 baseline pathogens. A composite 
estimand strategy will be used.  Intercurrent 
events of death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Appendix 2.1.  Proportion of 
participants with clinical cure will be calculated. 
• 
Estimand 4: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have at least 1 Gram-negative aerobic 
pathogen in the initial/prestudy culture regardless 
of susceptibility. A composite estimand strategy 
will be used. Intercurrent events of death where 
cIAI is clearly noncontributory etc. will be 
regarded as indeterminate clinical response. 
Intercurrent events of death related to intra- 


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Objectives 
Estimands 
Endpoints 
abdominal infection, or additional antibiotics for 
ongoing symptoms of intra-abdominal infection 
etc. will be regarded as a failure clinical response. 
For details, see Appendix 2.1. All data after 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 
considered. All data after other intercurrent 
events that affect the clinical assessment will not 
be considered. Proportion of participants with 
clinical cure will be calculated. 
• 
Estimand 5: the supportive estimand of the 
primary endpoint 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of clinical response in patients with cIAI 
who have at least 1 Gram-negative aerobic 
pathogen in the initial/prestudy culture that is 
susceptible. A composite estimand strategy will 
be used. Intercurrent events of death where cIAI 
is clearly noncontributory etc. will be regarded as 
indeterminate clinical response. Intercurrent 
events of death related to intra-abdominal 
infection, or additional antibiotics for ongoing 
symptoms of intra-abdominal infection etc. will 
be regarded as a failure clinical response. For 
details, see Appendix 2.1. All data after 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 
considered.  All data after other intercurrent 
events that affect the clinical assessment will not 
be considered. Proportion of participants with 
clinical cure will be calculated. 
Secondary: 
Secondary: 
Secondary: 
• 
To determine the efficacy of PF- 
06947386 plus metronidazole 
• 
To determine the per-patient 
microbiological response of PF- 
06947386 plus metronidazole 
• 
Estimands 6 - 10: the estimands of the 
secondary endpoints 
Same as Estimands 1 - 5 
• 
Estimand 11: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have ≥1 baseline pathogens. A 
composite estimand strategy will be used. 
Intercurrent events of lost to follow-up and death 
where cIAI is clearly noncontributory etc. will be 
regarded as indeterminate microbiological 
response.  For details, see Appendix 2.2. 
Proportion of participants with favorable 
microbiological response will be calculated. 
• 
Clinical response at 
EOT, and LFU visits 
• 
Per-patient 
microbiological 
response at EOT, TOC, 
and LFU visits 


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Objectives 
Estimands 
Endpoints 
• 
Estimand 12: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have at least 1 Gram-negative 
aerobic pathogen in the initial/prestudy culture 
regardless of susceptibility.  A composite 
estimand strategy will be used.  Intercurrent 
events of lost to follow-up and death where cIAI 
is clearly noncontributory etc. will be regarded as 
indeterminate microbiological response.  For 
details, see Appendix 2.2. All data after 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 
considered. All data after other intercurrent 
events that affect the microbiological assessment 
will not be considered. Proportion of participants 
with favorable microbiological response will be 
calculated. 
• 
Estimand 13: the estimand of the secondary 
endpoints 
The trial will estimate the average treatment 
effect of PF-06947386 plus metronidazole in 
terms of microbiological response in patients 
with cIAI who have at least 1 Gram-negative 
aerobic pathogen in the initial/prestudy culture 
that is susceptible.  A composite estimand 
strategy will be used.  Intercurrent events of lost 
to follow-up and death where cIAI is clearly 
noncontributory etc. will be regarded as 
indeterminate microbiological response.  For 
details, see Appendix 2.2. All data after 
intercurrent events of receiving insufficient 
amount of study drug or any protocol deviations 
that affect assessment of efficacy will not be 
considered. All data after other intercurrent 
events that affect the microbiological assessment 
will not be considered. Proportion of participants 
with favorable microbiological response will be 
calculated. 
• 
To determine the per-pathogen 
microbiological response of PF- 
06947386 plus metronidazole 
• 
To evaluate the safety and 
tolerability profile of PF- 
06947386 plus metronidazole in 
• 
Estimands 14 - 16: the estimands of the 
secondary endpoints 
Same as Estimands 11 - 13 
N/A 
• 
Per-pathogen 
microbiological 
response at EOT, TOC, 
and LFU visits 
• 
Per-pathogen 
microbiological 
response at EOT, TOC, 
and LFU visits by MIC 
categories 
• 
AEs and SAEs, all 
cause mortality, reasons 
for discontinuations of 


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This protocol will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related efficacy endpoints, 
using predefined endpoint criteria. 
 
2.1.1. Primary Estimand(s) 
See section 2.1 (Estimand 1 is the primary estimand of the primary endpoint and Estimands 
2-5 are the supportive estimands of the primary endpoint). 
Objectives 
Estimands 
Endpoints 
the treatment of patients with 
cIAIs 
• 
To evaluate the 
pharmacokinetics of the 
individual components of PF- 
06947386 in patients with cIAIs 
• 
To investigate safety and 
efficacy for patients with sepsis 
(if available) 
N/A 
N/A 
IV study intervention 
and study, vital sign 
measurements, and 
potentially clinically 
significant changes in 
laboratory parameters 
during the entire study 
• 
Ceftazidime and 
avibactam plasma 
concentrations by 
nominal sampling 
window 
• 
Selected efficacy and 
safety endpoints as 
described above 
CCI  
 


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2.1.2. Secondary Estimand(s) 
See section 2.1 (Estimands 6-16 are the estimands of the secondary endpoints). 
 
2.1.3. Additional Estimand(s) 
Not Applicable 
 
2.2. Study Design 
Study C3591036 will assess the efficacy and safety of PF-06947386 in Japanese hospitalized 
participants with cIAI. This is a multicenter, open-label, single-arm study. The study will 
have a maximum duration of approximately 6 weeks for each participant. This includes a 5- 
14 days of IV study period, TOC visit at Day 28, and LFU visit at Day 42. The study outline 
is shown in Figure 1. 
 
Eligible participants with CrCL >50 mL/min will be given an IV dose of 2.5 g PF-06947386 
(ceftazidime 2.0 g/avibactam 0.5 g) q8h with infusion time of 2 hours for 5-14 days. For 
participants enrolled into the study whose CrCL drops to ≤50 mL/min while on IV 
investigational drug therapy, dosage adjustment is required depending on the degree of renal 
impairment based on the CrCL value (protocol Section 6). All eligible participants will 
receive metronidazole (0.5 g) intravenously with an infusion duration of 60 minutes. When 
both PF-06947386 and metronidazole are administered at the same time, metronidazole will 
be administered immediately after administration of PF-06947386. 
 
Figure 1. 
Study Outline 
 
 
 
 
 
 
 
 
 
 
a. 
For participants with normal renal function and participants with mild renal impairment. 
b. 
If it is not possible to perform the TOC visit on study Day 28 (eg, the participant is on holiday), the allowed visit 
window is Day 28 to 35. 
c. 
If it is not possible to perform the LFU visit on study Day 42 (eg, the participant is on holiday), the allowed visit 
window is Day 42 to 49. 
Visit 18 
Day 42 visitc 
Late Follow-Up 
(LFU) 
Visit 17 
Day 28 visitb 
Test of Cure 
(TOC) 
Visit 16
End of Treatment 
(EOT) 
Visit 2 to 15 
Days 1 to 14 
PF-06947386 
(Ceftazidime/Avibactam) 
plus Metronidazole 
Visit 1 
Days -1 to 1 
Eligibility/ 
Screening 
Treatment period 
Minimum of 5 full days (15 dosesa) of IV study intervention 
Maximum of 14 days (42 dosesa) of IV study intervention 


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
The primary endpoint for the study is clinical response at the TOC visit. 
The assessment by the adjudication committee will be used. 
3.2. Secondary Endpoint(s) 
The secondary endpoints for the study are as follows. 
 
• Clinical response at EOT and LFU visits 
 
• Per-patient microbiological response at EOT, TOC, and LFU visits 
 
• Per-pathogen microbiological response at EOT, TOC, and LFU visits 
 
• Per-pathogen microbiological response at EOT, TOC, and LFU visits by MIC 
categories 
 
• Ceftazidime and avibactam plasma concentrations by nominal sampling window 
 
• For patients with sepsis, selected efficacy and safety endpoints from endpoints for the 
overall population 
 
The assessment by the adjudication committee will be used for the clinical and 
microbiological responses. 
 
CCI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4. Baseline Variables 
The following baseline variables will be assessed. Baseline variables will be those collected 
on Day 1 prior to the initial administration or the last measurement obtained as the screening 
assessment.  In cases where there are multiple measurements for the same assessment, the 


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measurement obtained at a timing closest to the initial administration will be defined as the 
baseline variable. 
 
• APACHE II score 
 
• Demographics (age, sex, ethnicity, race) 
 
• Medical and surgical history 
 
• Abdominal signs and symptoms examination; wound examination 
 
• Temperature 
 
• Pulse rate, blood pressure, respiratory rate 
 
• Heart rate 
 
• estimated CrCl 
 
• Height, weight, body mass index (BMI) 
 
• Imaging test (when available) 
 
• Description of operative procedure [from initial qualifying procedure {performed 
within 24 hours of entry for preoperative enrollment (see protocol Section 5.1, 
inclusion criterion 3)}] 
 
• Prior and concomitant treatment/antibiotics 
 
• Blood culture 
 
• Culture of abdominal infection site [at initial qualifying procedure {performed within 
24 hours of entry for preoperative enrollment (see protocol Section 5.1, inclusion 
criterion 3)}] 
 
3.5. Safety Endpoints 
3.5.1. Adverse Events 
The MedDRA adverse event dictionary will be used to map Adverse Event (AE) to Preferred 
Terms (PTs) and System Organ Classes (SOCs). 
 
A Treatment Emergent Adverse Event (TEAE) is defined as an AE that emerges or worsens 
during the effective duration of treatment. All events that start on or after the first dosing day 
will be flagged as TEAEs.  The algorithm will not consider any events that started prior to 
the first dose date. 


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3.5.2. Laboratory Data 
The following safety laboratory tests will be performed at times defined in the SoA section of 
the protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues. 
 
Results will be reported by the local laboratory. 
 
Table 2. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Dipstick 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Eosinophils (Abs, %) 
Lymphocytes (Abs, %) 
Monocytes (Abs, %) 
Neutrophils (Abs, %) 
Neutrophils, immature (Abs, %) 
Basophils (Abs, %) 
BUN 
Creatinine 
Glucose (non-fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
AST 
ALT 
GGT 
Bilirubin (total and direct) 
Alkaline phosphatase 
Albumin 
Total protein 
CRP 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
FSHa 
β-hCGb 
a. For confirmation of postmenopausal status only. 
b. At Screening, serum β-hCG must be performed as part of screening/eligibility.  If the results of β-hCG are 
not available prior to dosing of study intervention, a patient may begin therapy on the basis of a negative 
urine β-hCG, but a serum test must still be obtained. At time points other than Screening, pregnancy tests 
may be urine or serum tests, but must have a sensitivity of at least 25 mIU/mL. 
 
3.5.3. Other Safety Endpoints 
Vital signs, weight,  and BMI will be evaluated. 
 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
For purposes of analysis, the following analysis sets are defined: 
 
Analysis Set 
Description 
MITT analysis set 
The MITT analysis set includes all enrolled participants 
who: 
1. Meet the disease definition of cIAI (see protocol Section 
5.1, inclusion criterion 3). 


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2. Receive any amount of study drug. 
mMITT analysis set 
The mMITT analysis set includes all enrolled participants 
who: 
1. Meet the disease definition of cIAI (see protocol Section 
5.1, inclusion criterion 3). 
2. Receive any amount of study drug. 
3. Have at least 1 etiologic pathogen identified at study 
entry (regardless of isolate susceptibilities).  Participants 
with a bacterial species typically not expected to respond 
to the study drug (eg, Acinetobacter spp., 
Stenotrophomonas spp.) are excluded (ie, if the study drug 
is considered inadequate to treat the pathogen in most 
clinical circumstances). 
CE analysis set* 
Participants are included who meet the following criteria: 
1. Have an appropriate diagnosis of cIAI (see protocol 
Section 5.1, inclusion criterion 3). As an exception, 
participants with a bacterial species typically not expected 
to respond to the study drug (eg, Acinetobacter spp., 
Stenotrophomonas spp.) are excluded. 
2. EITHER 
(a) Receive therapy for ≥48 hours, with ≥80% of the 
scheduled drug administered over the number of days 
administered 
OR 
(b) Receive therapy <48 hours before discontinuing 
treatment due to an AE. 
3. Is evaluated with a clinical response of cure or failure. 
Participants with a clinical response of failure at a previous 
visit are not excluded from subsequent timepoints for visits 
that are out of window. 
4. Have no important protocol deviations that will affect 
assessment of efficacy at the relevant timepoint. 
5. Do not receive any prior antibiotics other than protocol- 
allowed antibiotics with specified duration in protocol 


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Section 5.2, exclusion criterion 22. Determination of 
duration in some circumstances is done manually. 
6. Do not receive concomitant antibiotic therapy with 
potential activity against any of the baseline aerobic 
pathogens between the time of first IV infusion and the 
time of the relevant timepoint culture, respectively, except 
for protocol-allowed antibiotics for the coverage of 
Enterococcus spp. and MRSA.  This does not include 
participants who have failed and require additional 
antibiotic therapy. Topical antibacterials and antifungals 
are permitted except that they are not being applied to the 
surgical site.  (Note that if topical antibacterials and 
antifungals are applied to the surgical site this does not 
lead to exclusion from the CE analysis set).  Potential 
activity against any of the baseline aerobic pathogens is 
determined by manual review by comparing the 
susceptibility profile of the baseline aerobic pathogens to 
the antibiotic received.  When no baseline pathogens are 
identified, a conservative approach is taken and the patient 
is excluded from the CE analysis set. 
7. Consider to have adequate initial infection source 
control. 
ME analysis set* 
Participants are included who meet the following criteria: 
1. Include in a subset of CE participants. 
2. Have at least 1 Gram-negative aerobic pathogen in the 
initial/prestudy culture that is susceptible. 
eME analysis set* 
Participants are included who meet the following criteria: 
1. Include in a subset of CE participants. 
2. Have at least 1 Gram-negative aerobic pathogen in the 
initial/prestudy culture regardless of susceptibility. 
Sepsis patients subset** 
1. Include in a subset of eME participants. 
2. Satisfy both clinical and microbiological criteria 


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Clinical: Total score ≥ 2 in SOFA for ICU patients, 2 items 
or more in qSOFA for non-ICU patients (protocol Section 
10.7) at Baseline 
Microbiological: The most relevant pathogens (ie, aerobic 
Gram-negative bacteria -either Enterobacterales or aerobic 
Gram-negative pathogens other than Enterobacterales) 
isolated from the blood at Baseline regardless of 
susceptibility. 
Sepsis evaluable patients 
subset** 
1. Include in a subset of eME participants. 
2. Satisfy both clinical and microbiological criteria 
Clinical: Satisfy at least one following criteria at Baseline. 
1) body temperature ≥38°C or <36°C, 2) WBC 
>12000 cells/mm3 or <4000 cells/mm3, or immature 
neutrophil >10%, 3) heart rate >90 bpm, 4) systolic blood 
pressure <90 mmHg, 5) CRP ≥20 mg/dL 
Microbiological: The most relevant pathogens (ie, aerobic 
Gram-negative bacteria -either Enterobacterales or aerobic 
Gram-negative pathogens other than Enterobacterales)  
isolated from the blood at Baseline regardless of 
susceptibility. 
Safety analysis set 
The Safety analysis set includes all participants who 
receive any amount of IV study intervention. 
PK analysis set 
The PK analysis set includes all participants who have at 
least 1 plasma concentration data value available for either 
CAZ or AVI. 
*: Analysis population will include at EOT, TOC, and LFU. 
**: Analysis population for eME at TOC will be used. 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
In this study, no formal hypothesis testing will be conducted. 
 
As an efficacy evaluation criterion, it will be confirmed that the point estimate of proportion 
of patients with clinical cure at TOC visit in the CE analysis set (the primary analysis) is 
≥78%. 


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5.2. General Methods 
Descriptive summaries will be provided where appropriate for each of the primary, 
secondary, and CCI 
.  In general, summaries will be presented for 
the MITT and mMITT analysis sets, and the ME, eME, and CE analysis sets at the 
appropriate visit. 
 
5.2.1. Analyses for Binary Endpoints 
Bianry variable summaries will include as appropriate the number of patients/pathogens, 
frequency, and proportion and the 95% confidence interval (CI) calculated by Clopper- 
Pearson method.  In general, the denominator for each proportion calculation is based upon 
the total number of patients/pathogens in the study population. 
 
5.2.2. Analyses for Continuous Endpoints 
Continuous and quantitative variable summaries will include as appropriate the number of 
patients/pathogens, mean, SD, median, and ranges (minimum and maximum). CCI 
 
Plasma concentrations will 
be summarized by the number of patients, mean, CV, median, and ranges (minimum and 
maximum). 
 
5.2.3. Analyses for Categorical Endpoints 
Categorical and qualitative variable summaries will include as appropriate the frequency and 
percent of patients/pathogens who are in each category.  In general, the denominator for each 
percent calculation is based upon the total number of patients/pathogens in the study 
population. 
 
5.2.4. Analyses for Time-to-Event Endpoints 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate.  Graphs will describe the 
number of participants at risk over time. The median, quartiles, and probabilities of an event 
at particular points in time will be estimated by the Kaplan-Meier method. 
 
5.3. Methods to Manage Missing Data 
Clinical and microbiological response assessment results at early termination will be imputed 
to the nearest scheduled assessment.  In the case of non-responders (failure or unfavorable), 
assessment results for all subsequent visits will be handled as non-responders. Similarly, in 
the case of indeterminate, assessment results for all subsequent visits will be handled as 
indeterminate. Such imputed data will be annotated in the relevant listings. 
 
For the other endpoints, in general, missing data will not be imputed. 


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5.3.1. Concentrations Below the Limit of Quantification 
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings, BLQ values will be reported as “<LLQ”, where “LLQ” 
will be replaced with the value for the lower limit of quantification (LLQ). 
 
5.4. Definition of susceptibility criteria for Ceftazidime-avibactam 
When baseline pathogens as determined by the adjudication committee meet the following 
criteria, the MIC values of each baseline pathogen will be categorized as Susceptible, 
Intermediate, or Resistant according to the Clinical and Laboratory Standards Institute 
(CLSI) criteria1 (Table 3).  Because MIC values by the central laboratory are reported as 
ceftazidime concentration only, classification will be performed based on the values of 
ceftazidime concentration in the following table. 


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Table 3. 
Definition of susceptibility criteria for Ceftazidime-avibactam 
 
 
Interpretative categories and MIC break points, µg/mL 
 
Susceptible 
Intermediate 
Resistant 
Enterobacterales 
Pseudomonas aeruginosa 
≤8/4 
≤8/4 
- 
- 
≥16/4 
≥16/4 
Before and after "/" are Ceftazidime concentration and Avibactam concentration, respectively. 
 
5.5. Definition of Ceftazidime resistance 
Ceftazidime resistance is defined as those bacterial isolates whose susceptibility-to- 
ceftazidime results are intermediate or resistant using CLSI criteria1 (ceftazidime minimum 
inhibitory concentrations ≥8 µg/mL for Enterobacterales and ≥16 µg/mL for Pseudomonas 
aeruginosa). 
 
Table 4. 
Definition of susceptibility criteria for Ceftazidime 
 
 
Interpretative categories and MIC break points, µg/mL 
 
Susceptible 
Intermediate 
Resistant 
Enterobacterales 
≤4 
8 
≥16 
Pseudomonas aeruginosa 
≤8 
16 
≥32 
 
6. ANALYSES AND SUMMARIES 
When both investigator and the adjudication committee assessment are available, the 
assessment by the adjudication committee will be summarized and listed. 
 
6.1. Primary Endpoint(s) 
6.1.1. Clinical response at the TOC visit 
6.1.1.1. Main Analysis 
The number of patients, frequency, and proportion and the 95% CI will be calculated for the 
CE at TOC analysis set. 
 
6.1.1.2. Sensitivity/Supplementary Analyses 
The same summary as the main analysis will be generated on the MITT, mMITT, ME at 
TOC, and eME at TOC analysis sets. 
 
Clinical response will be listed for all enrolled patients. 


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6.2. Secondary Endpoint(s) 
6.2.1. Clinical response at EOT and LFU visits 
The number of patients, frequency, and proportion and the 95% CI will be calculated for the 
MITT, mMITT, CE (CE at EOT and CE at LFU), ME (ME at EOT and ME at LFU), and 
eME (eME at EOT and eME at LFU) analysis sets. 
 
Clinical response will be listed for all enrolled patients. 
 
6.2.2. Per-patient microbiological response at EOT, TOC, and LFU visits 
The number of patients, frequency, and proportion and the 95% CI (calculate when N ≥ 10) 
will be calculated for the mMITT, ME (ME at EOT, ME at TOC, and ME at LFU), and eME 
(eME at EOT, eME at TOC, and eME at LFU) analysis sets. Patients with “Indeterminate” 
are not included in the denominator.  Patients with superinfection or new infection 
assessment will be handled as “Persist” based on the Guideline for Clinical Evaluation of 
Antibacterial Drugs2. 
 
Per-patient microbiological response will be listed for all enrolled patients. 
 
Emergent infections (the number of patients with a superinfection, and the number of patients 
with a new infection) will be summarized for the mMITT analysis set. For the definition of 
emergent infections, see Appendix 2.3. 
 
6.2.3. Per-pathogen microbiological response at EOT, TOC, and LFU visits 
The number of patients/pathogens, frequency, and proportion will be calculated for the 
mMITT, ME (ME at EOT, ME at TOC, and ME at LFU), and eME (eME at EOT, eME at 
TOC, and eME at LFU) analysis sets.  Patients with “Indeterminate” are not included in the 
denominator. 
 
Per-pathogen microbiological response assessments at EOT, TOC, and LFU visits will be 
summarized for the mMITT, ME (ME at EOT, ME at TOC, and ME at LFU), and eME 
(eME at EOT, eME at TOC, and eME at LFU) analysis sets. 
 
Microbiological culture results will be listed for all enrolled patients. 
 
6.2.4. Per-pathogen microbiological response at EOT, TOC, and LFU visits by MIC 
categories 
The number of patients/pathogens, frequency, and proportion will be calculated for the 
mMITT, ME, and eME analysis sets.  Patients with “Indeterminate” are not included in the 
denominator.  MIC categories will be grouped by susceptibility (Susceptible, Intermediate, 
Resistant) to CAZ-AVI for specific pathogens (Section 5.4). 
 
Per-pathogen microbiological response assessments will be listed for all enrolled patients. 
MIC categories and susceptibility (Susceptible, Intermediate, Resistant) to CAZ-AVI and 
ceftazidime (Section 5.4 and Section 5.5) will be added as well as drug-resistance (AmpC, 
ESBL, and Carbapenemase) and genotype for specific pathogens. 
-2019 


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6.2.5. Pharmacokinetic Analysis 
The PK analysis set defined in Section 4 will be used for all PK analysis.  Nominal sample 
window is defined as 1) anytime from 15 minutes prior to stopping until 15 minutes after 
stopping PF-06947386 infusion, 2) anytime between 30 minutes and 90 minutes after 
stopping PF-06947386 infusion, and 3) anytime between 300 minutes (5 hours) and 360 
minutes (6 hours) after stopping PF-06947386 infusion but before the next dose. Blood 
samples for PK analyses are to be collected on Day 3 and Day 4. 
 
A listing of ceftazidime and avibactam plasma concentrations at the nominal sampling 
windows and actual times by patients will be provided. The plasma concentration will be 
summarized by nominal sampling time window using appropriate descriptive statistics [e.g., 
the number of patients, mean, CV, median, and ranges (minimum and maximum)]. 
 
Individual plasma concentration profiles will be presented graphically using actual sample 
collection time on both linear and semilogarithmic scales, showing all enrolled patients on a 
single plot for each analyte. 
 
An appropriate population PK model will be used for the purpose of estimating PK 
parameters and the time above MIC. Additional details of the methodology will be captured 
in a separate modeling plan and the results will also be reported separately. 
 
CCI  
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4. Subset Analyses 
Clinical cure rate at EOT, TOC, and LFU visits will be calculated by baseline patient 
characteristics and baseline demographics characteristic subgroup, by baseline disease 
characteristic subgroup, and by prior systemic antibiotic subgroup for the CE at TOC 
analysis set. Regarding these analyses, forest plots will be displayed graphically for the CE 
at TOC analysis set. 
 
Clinical cure rate at EOT, TOC, and LFU visits will be calculated by baseline pathogen and 
its MIC categories for the mMITT, ME at TOC, and eME at TOC analysis sets.  MIC 
categories will be grouped by susceptibility (Section 5.4) to CAZ-AVI for specific 
pathogens. 
 
Clinical cure rate at EOT, TOC, and LFU visits will be calculated by drug-resistance (AmpC, 
ESBL, and Carbapenemase) and genotype of baseline pathogen for the mMITT, ME at TOC, 
and eME at TOC analysis sets. 
 
Per-pathogen microbiological response at EOT, TOC, and LFU visits will be calculated by 
drug-resistance (AmpC, ESBL, and Carbapenemase) and genotype of baseline pathogen for 
the mMITT, ME at TOC, and eME at TOC analysis sets. 
 
Clinical cure rate at EOT, TOC, and LFU visits will be calculated for patients infected by 
ceftazidime-resistant Gram-negative pathogen (Intermediate or Resistant by CLSI criteria, 
Section 5.5) for the mMITT, ME at TOC, and eME at TOC analysis sets. 
 
Per-patient microbiological response at EOT, TOC, and LFU visits will be calculated in 
patients infected by ceftazidime-resistant aerobic Gram-negative pathogen (Intermediate or 
Resistant by CLSI criteria, Section 5.5) for the mMITT, ME at TOC, and eME at TOC 
analysis sets. 
 
Microbiological response per ceftazidime-resistant aerobic Gram-negative pathogen 
(Intermediate or Resistant by CLSI criteria, Section 5.5) at EOT, TOC, and LFU visits will 
be calculated for the mMITT, ME at TOC, and eME at TOC analysis set. 
CCI


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For sepsis patients subset and sepsis evaluable patients subset described in section 4, efficacy 
analyses of the primary endpoint described in section 6.1 and the secondary endpoints 
described in section 6.2 including PK analysis will be performed. However, analysis for 
emergent infections in section 6.2.2 will not be performed. Clinical cure rate at EOT, TOC, 
and LFU visits will also be calculated by baseline pathogen and its MIC categories. Safety 
summaries and analyses described in 6.6.1 will be performed without summaries of TEAEs 
up to the EOT, TEAEs leading to study discontinuation, SAEs and AEs of special interest, 
and listings. 
 
For sepsis patients subset and sepsis evaluable patients subset described in section 4, 
demographic characteristics, patient characteristics, and disease characteristics will be 
summarized. 
 
Criteria for sepsis patients subset and sepsis evaluable patients subset will be listed for all 
enrolled patients. 
 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
Demographic characteristics [age, age group (≥20 – 45, 46 – 64, 65 – 74, ≥75), sex, ethnicity, 
and race] will be summarized for the MITT and safety analysis sets, and will be listed for all 
enrolled patients. 
Patient characteristics [height, weight, BMI, BMI category (<18.5, 18.5 - <25, 25-<30, ≥30, 
Missing)] will be summarized for the MITT and safety analysis sets, and will be listed for all 
enrolled patients. 
Disease characteristics [APACHE II score, APACHE II (≤10, >10 - ≤30, >30, Missing), 
Heart rate, Prior systemic antibiotics use in the previous 3 days before enrollment including 
the day of enrollment, Estimated CrCl, Primary and secondary diagnosis, Infection type 
(monomicrobial or polymicrobial), Study qualifying procedure] will be summarized for the 
MITT and safety analysis sets, and will be listed for all enrolled patients. 
 
Imaging test will be listed for all enrolled patients. 
 
The number of patients/pathogens with monomicrobial and polymicrobial infections will be 
summarized for the mMITT and eME at TOC analysis sets. 
 
The number of pathogens identified at baseline will be summarized for the mMITT and eME 
at TOC analysis sets. 
 
CAZ-AVI minimum inhibitory concentration (MIC) by baseline pathogen will be 
summarized for the mMITT and eME at TOC analysis sets. 
 
Ceftazidime minimum inhibitory concentration (MIC) by baseline pathogen will be 
summarized for the mMITT and eME at TOC analysis sets. 


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The number of CAZ-AVI minimum inhibitory concentration (MIC) categories of baseline 
pathogens will be summarized for the mMITTand eME at TOC analysis sets. 
 
The number of Ceftazidime minimum inhibitory concentration (MIC) categories of baseline 
pathogens will be summarized for the mMITT and eME at TOC analysis sets. 
 
Minimum inhibitory concentration (MIC) for CAZ-AVI and other drugs will be summarized 
for pathogens isolated in this study, if available. 
 
Medical history, current medical conditions, surgical history will be summarized for the 
MITT analysis set, and listed for all enrolled patients. 
 
6.5.2. Study Conduct and Participant Disposition 
Patients who enrolled, who received treatment, who did not receive the treatment, who 
completed treatment, who discontinued the treatment including the reason for 
discontinuation, who completed the study up to the TOC visit, and up to the LFU visit, who 
did not complete the study with the reason for discontinuation from the study, will be 
summarized and listed. 
 
Important protocol deviations will be summarized and listed. 
 
Patients in each of the analysis sets will be summarized and listed for all enrolled patients. 
 
6.5.3. Study Treatment Exposure 
Duration of exposure will be summarized for the safety, MITT, and CE at TOC analysis sets. 
 
Study treatment compliance will be summarized for the safety, MITT, and CE at TOC 
analysis set and will be listed for the safety analysis set. Treatment compliance (%) over the 
entire treatment period is defined as the total number of infusions received divided by the 
total number of infusions expected, and then multiplied by 100.  The expected number of 
infusions are adjusted for renal function at baseline and investigator adjustment decision 
post-baseline. 
 
Administaration schedule will be listed for all enrolled patients. 
 
6.5.4. Concomitant Medications and Nondrug Treatments 
Prior systemic antibiotic medications will be summarized for the MITT analysis set, and will 
be listed for all enrolled patients. 
 
Prior medications other than prior systemic antibiotic medications will be summarized for the 
MITT analysis set, and will be listed for all enrolled patients.Concomitant antibiotic 
medications will be summarized for the MITT analysis set, and will be listed for all enrolled 
patients. 
 
Concomitant medications other than antibiotics will be summarized for the MITT analysis 
set, and will be listed for all enrolled patients. 


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6.6. Safety Summaries and Analyses 
6.6.1. Adverse Events 
Adverse events will be summarised in accordance with sponsor reporting standards using the 
safety analysis set.  Only treatment emergent adverse events (TEAEs) will be summarized. 
However, all AEs will be presented in data listings. 
 
All TEAEs during the study will be summarized by relationship to study drug (all causalities 
and treatment related) according to the MedDRA SOC and PT. TEAEs by severity and 
leading to study discontinuation will also be summarized, as well as SAEs. TEAEs 
summarized by overall and by SOC and PT will be aggregated by study period (up to the 
EOT visit and up to the LFU visit). 
 
Listings will be presented by subject for all AEs as well as for SAEs, AEs associated with 
death, and AEs leading to discontinuation of the study drug. 
 
Adverse events of special interest (Liver Disorders, Diarrhea, Hypersensitivity / 
Anaphylaxis, Hematological Disorders, Renal Disorders) will be summarized. The same 
definition as the global CTD will be used for adverse events of special interest (Appendix 
2.7.4.7.1, Table 4.1.1.7.6 Adverse events of special interest - preferred term search strategies 
by safety topic and subgroup).  However, the term will be used after the harmonization to the 
latest version of MedDRA. Event terms for adverse events of special interest will be listed. 
 
Medication errors will be listed. 
 
6.6.2. Laboratory Data 
Laboratory data will be summarized and listed in accordance with the sponsor reporting 
standards using the safety population. 
 
Hy's Law values will be listed for the safety population. 
 
6.6.3. Vital Signs 
Vital sign variables, weight, and BMI will be summarized by scheduled assessment 
including change from baseline for the safety analysis set.  Box and whisker plots will be 
produced for the parameters (vital sign variables) [y-axis] against visit [x-axis]. Vital sign 
variables, weight, and BMI will be listed for the safety population. 
 
6.6.4. Electrocardiograms 
See section 6.5.1 (Heart rate evaluated either in the 12-lead ECG or in the monitor ECG will 
be measured at Screening). 
 
Electrocardiogram data will be listed for the safety population. 
 
6.6.5. Physical Examination 
Not Applicable 


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7. INTERIM ANALYSES 
7.1. Introduction 
No formal interim analysis will be conducted for this study.  As this is an open label study, 
the sponsor may conduct reviews of the data during the course of the study for the purpose of 
safety assessment. 
 
7.2. Interim Analyses and Summaries 
Not Applicable. 
 
8. REFERENCES 
1. CLSI M100: Performance Standards for Antimicrobial Susceptibility Testing, 32nd 
Edition.  Clinical and Laboratory Standards Institute. February 2022. 
 
2. Guideline for Clinical Evaluation of Antibacterial Drugs. PSEHB/PED Notification No. 
1023-3. October 23, 2017. 


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9. APPENDICES 
Appendix 1. Summary of Efficacy Analyses 
 
Endpoint 
Visit 
Analysis Type 
Population 
Clinical response 
EOT, TOC, 
and LFU 
Summary 
MITT, mMITT, CE (CE at EOT, CE at TOC, 
and CE at LFU), ME (ME at EOT, ME at 
TOC, and ME at LFU), and eME (eME at 
EOT, eME at TOC, and eME at LFU) 
Per-patient microbiological response 
EOT, TOC, 
and LFU 
Summary 
mMITT, ME (ME at EOT, ME at TOC, and 
ME at LFU), and eME (eME at EOT, eME at 
TOC, and eME at LFU) 
Per-pathogen microbiological response 
EOT, TOC, 
and LFU 
Summary 
mMITT, ME (ME at EOT, ME at TOC, and 
ME at LFU), and eME (eME at EOT, eME at 
TOC, and eME at LFU) 
Per-pathogen microbiological response by MIC 
categories 
EOT, TOC, 
and LFU 
Summary 
mMITT, ME (ME at EOT, ME at TOC, and 
ME at LFU), and eME (eME at EOT, eME at 
TOC, and eME at LFU) 
Clinical response, 
Per-patient/Per-pathogen microbiological response, 
and 
Per-pathogen microbiological response by MIC 
categories 
EOT, TOC, 
and LFU 
Summary 
Sepsis patients subset, and Sepsis evaluable 
patients subset 
CCI 


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CCI


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Appendix 2. Data Derivation Details 
 
Appendix 2.1. Definitions of Clinical Response at the EOT, TOC, LFU, and Early 
Termination/Discontinuation Visits 
 
 
Clinical response 
Definition 
 
Cure 
Complete resolution or significant improvement of signs and symptoms of the 
index infection such that no further antimicrobial therapy, drainage, or surgical 
intervention is necessary. 
 
Note: Patients who receive coverage for MRSA or Enterococcus, as allowed per 
protocol, can still have a response definition of cure. 
Failure 
Patients who meet any 1 of the criteria below will be considered a treatment 
failure: 
• 
Death related to intra-abdominal infection 
• 
Persisting or recurrent infection within the abdomen documented by the 
findings at re-intervention either percutaneously or operatively 
• 
Postsurgical wound infections defined as an open wound with signs of local 
infection such as purulent exudates, erythema, or warmth that requires 
additional antibiotics and/or nonroutine wound care 
• 
Patient who receives treatment with additional antibiotics for ongoing 
symptoms of intra-abdominal infection (including patients prematurely 
discontinued from study drug due to an AE who require additional 
antibiotics for cIAI) 
• 
Patient previously met criteria for failure 
Indeterminate 
Study data are not available for evaluation of efficacy for any reason, including: 
• 
Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response cannot be made 
• 
Death where cIAI is clearly noncontributory 
• 
Circumstances that preclude classification as a cure or failure 
 
 
 
Appendix 2.2. Microbiological Response Categories at Day 1 (Baseline), EOT, TOC, 
LFU, and Early Termination/Discontinuation Visits 
 
 
Microbiological 
response 
Definition 
 
Eradication 
Absence of causative pathogen from appropriately obtained specimens at the site 
of infection. 
Presumed eradication 
Repeat cultures were not performed/clinically indicated in a patient who had a 
clinical response of cure. 
Colonization 
Obvious symptoms and signs of the infection have resolved in response to the 
treatment, but the initial causative bacteria are detected at the same site. 
Persistence 
Causative organism still present at or beyond the EOT visit from a culture of 
intra-abdominal abscess, peritonitis, or surgical wound infection. 
Persistence with 
increasing MIC 
Continued presence of the causative organism in a culture of the intra-abdominal 
abscess, peritonitis, or surgical wound infection obtained during or upon 
completion of treatment with IV study intervention, and the pathogen that was 
susceptible to IV study intervention pre-treatment displays a ≥4-fold higher MIC 
to IV study intervention after treatment with IV study intervention. 
Presumed persistence 
Patient was previously assessed as a clinical failure and repeat cultures were not 
  
performed/clinically indicated.  


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Microbiological 
response 
Indeterminate 
microbiological 
response 
Definition 
 
Study data are not available for evaluation of efficacy, for any reason including: 
• 
Patient lost to follow-up such that a determination of microbiological 
response cannot be made 
• 
Death where cIAI is clearly noncontributory 
• 
Circumstances that preclude classification as eradication, presumed 
eradication, colonization, persistence, persistence with increasing MIC, and 
presumed persistence 
• 
Patient with no pathogen isolated from a cIAI culture obtained at Baseline or 
for whom a culture was not obtained. 
 
 
 
Appendix 2.3. Emergent Infections 
 
 
Emergent Infection 
Definition 
 
Superinfection 
Emergence of new pathogen during treatment with IV study intervention, either 
at the site of infection or at a distant site with emergence or worsening of signs 
and symptoms of infection. 
New infection 
Emergence of new pathogen after completion of treatment with IV study 
intervention, either at the site of infection or at a distant site with emergence or 
  
worsening of signs and symptoms of infection.  
 
 
Appendix 3. List of Abbreviations 
 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
APACHE II 
acute physiology and chronic health evaluation II 
AST 
aspartate aminotransferase 
AVI 
avibactam 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAZ 
ceftazidime 
CE 
clinically evaluable 
CI 
confidence interval 
cIAI 
complicated intra-abdominal infection 
CLSI 
Clinical & Laboratory Standards Institute 
CrCL 
creatinine clearance 
CV 
coefficient of variation 
ECG 
electrocardiogram 
EOT 
end of treatment 
ESBL 
extended spectrum beta lactamase 
eME 
extended-microbiologically evaluable 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyltransferase 


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Abbreviation 
Term 
IV 
intravenous 
LFU 
late follow-up 
LLOQ 
lower limit of quantitation 
ME 
microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
MITT 
modified intent-to-treat 
mMITT 
microbiological modified intent-to-treat 
MTZ 
metronidazole 
PK 
pharmacokinetic(s) 
qSOFA 
quick Sequential Organ Failure Assessment 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOFA 
Sequential Organ Failure Assessment 
TBili 
total bilirubin 
TOC 
test of cure 
WBC 
white blood cell